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Re: Biomedical research

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  • aubrey.degrey
    Hi everyone, My attention was brought to this thread, by virtue of the fact that it was my work that gave rise to SENS Foundation, and I m looking forward to
    Message 1 of 18 , Oct 12, 2012
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      Hi everyone,

      My attention was brought to this thread, by virtue of the fact that it was my work that gave rise to SENS Foundation, and I'm looking forward to getting more involved here; I've held the Effective Altruism movement in high regard for some time. However, given my newbie status here I want to start by apologising in advance for any oversight of previously-discussed issues etc. I'm naturally delighted both at Holden's post and at Vipul's reply (which I should stress that I did not plant! - I do not know Vipul at all, though I look forward to changing that). I would like to mention just a few key points for discussion:

      - Holden, I want to compliment you on your appreciation of how academia really works. Everything you say about that is spot on. The aversion to "high risk high gain" work that has arisen and become so endemic in the system is the most important point here, in terms of why parallel funding routes are needed.

      - I'm slightly confused that a lot of Holden's remarks are focused on the private sector (i.e. startups), since my understanding was that GiveWell is about philanthropy; but I realise that there is not all that clear a boundary between the two (and I note the mention of Breakout Labs, with which I have close links and which sits astride that divide more than arguably anyone). The "valley of death" in pre-competitive translational research is a rather different one than that encountered by startups, but the principle is the same, and research to postpone aging certainly encounteres it.

      - Something that I presume factors highly among GiveWell's criteria is the extent to which a cause may be undervalued by the bulk of major philanthropists, such that an infusion of additional funds would make more of a difference than in an area that is already being well funded. To me this seems to mirror the logic of focusing on the shortcomings (gaps) in NIH's funding (and that of traditional-model foundations). Holden notes that "Anyone we consider for funding ought to be able to explain why they're better at allocating the funds than the NIH" and I agree wholeheartedly, but my inference is that he thinks that some orgs may indeed be able to explain that. I certainly think that SENS Foundation can.

      - Coming to aging: research to postpone aging has the unique problem of quite indescribeable irrationality on the part of most of the general public, policy-makers and even biologists with regard to its desirability. Biogerontologists have been talking to brick walls for decades in their effort to get the rest of the world to appreciate that aging is what causes age-related ill-health, and thus that treatments for aging are merely preventative geriatrics. The concept persists, despite biogerontologists' best efforts, that aging is "natural" and should be left alone, whereas the diseases that it brings about are awful and should be fought. This is made even more bizarre by the fact that the status of age-related diseases as aspects of the later stages of aging absolutely, unequivocally implies that efforts to attack those diseases directly are doomed to fail. As such, this is a (unique? certainly very rare) case where a philanthropic contribution can make a particularly big difference simply because most philanthropists don't see the case for it. It underpins why having an interest in treating aging, as opposed to cancer, absolutely has a major impact on which projects one funds. It's also a case for (if I understand the term correctly) meta-research.

      - A lot of the chatter about treating aging revolves around longevity, but it shouldn't. I'm all in favour of longevity, don't get me wrong, but it's not what gets me up in the morning: what does is health. I want people to be truly youthful, however long ago they were born: simple as that. The benefits of longevity per se to humanity may also be substantial, in the form of greater wisdom etc, but that would necessarily come about only very gradually (we won't have any 1000-year-old for at least 900 years whatever happens!), so it doesn't figure strongly in my calculations.

      - When forced to acknowledge that the idea of aging being a high-priority target for medicine is an inescapeable consequence of things they already believe (notably that health is good and ageism is bad), many people retreat to the standpoint that it's never going to be possible so it's OK to be irrational about whether it's desirable. The feasibility of postponing age-related ill-health by X years with medicine available Y years from now is, of course, a matter of speculation on which experts disagree, just as with any other pioneering technology. I know that Holden and others have expressed caution (at best) concerning the accuracy of any kind of calculation of probabilities of particular outcomes in the distant (or even not-so-distant) future, and I share that view. However, an approach that may appeal more is to estimate how much humanitarian benefit a given amount of progress would deliver, and then to ask how unlikely that scenario needs to be to make it not worth pursuing. My claim is that the benefits of hastening the defeat of aging by even a few years (which is the minimum that I claim SENS Foundation is in a position to do, given adequate funding) would be so astronomical that the required chance of success to make such an effort worthwhile would be tiny - too tiny for it to be reasonable to argue that such funding would be inadvisable. But of course that is precisely what I would want GiveWell to opine on.

      - In the event that GiveWell (or anyone else) were to decide and declare that the defeat of aging is indeed a cause that philanthropists should support, there then arises the question of which organisation(s) should be supported in the best interests of that mission. We at SENS Foundation have worked diligently to rise as quickly as possible in the legitimacy stakes by all standard measures, but we are still young and there remains more to do. If I were to offer an argument to fund us rather than any other entity, it would largely come down to the fact that no other organisation has even a serious plan for defeating aging, let alone a track record of implementing such a plan's early stages.

      - A significant chunk of what we do is of a kind that I think comes under "meta-research". A prominent example is a project we're funding at Denver University to extend the well-respected forecasting system "International Futures" so that it can analyse scenarios incorporating dramatically postponed aging.

      I greatly welcome any feedback.

      Cheers, Aubrey

      --- In givewell@yahoogroups.com, Holden Karnofsky <holden0@...> wrote:
      >
      > Hi Vipul,
      >
      > Thanks for the thoughts. I had a followup conversation with Dario about
      > this topic a few days ago. I think the question of "could one fund
      > translational research to treat/prevent aging?" provides an interesting
      > illustration of some of the tricky dynamics here for a funder:
      >
      > - It's possible that if there were a great deal more attention giving to
      > treating/preventing aging, we would have some promising treatments. So in a
      > broad sense it's possible that aging is underinvested in.
      > - A lot of the best basic biology research isn't clearly pointing toward
      > one treatment/condition or another; it's about understanding the
      > fundamentals of how organisms operate. So having an interest in treating
      > aging, as opposed to cancer, might not have a major impact on which
      > projects one funds, if one's main goal is to fund outstanding basic biology
      > research.
      > - Perhaps because of the lack of emphasis on treating aging (or perhaps
      > because it's simply too difficult of a problem), there don't seem to be
      > promising findings in the "Valley of Death" relevant to aging; the few
      > promising leads have been explored.
      > - So even if, in a broad sense, there is too little attention given to
      > this problem, knowing this doesn't necessarily yield a clear direction for
      > a relatively small-scale funder of biomedical research.
      >
      > Best,
      > Holden
      >
      > On Wed, Oct 10, 2012 at 11:55 PM, Vipul Naik <vipul@...>wrote:
      >
      > > **
      > >
      > >
      > > Holden,
      > >
      > > First, I think that this is an excellent document. I checked for a
      > > number of things that I had heard about (Breakout Labs, John
      > > Ioannidis, Cochrane Collaboration) and they're all there in your
      > > document.
      > >
      > > The one thing that's not explicitly mentioned: longevity and life
      > > extension research. At least prima facie, this seems like something
      > > that should be more important than individual disease research, and it
      > > seems like a classic "Valley of Death" case (pun unintended, but
      > > noted) -- T1 stage to use your terminology. I think the SENS website
      > > http://www.sens.org would be a good starting point for one of the (to
      > > me promising) approaches to life extension. I recall from past
      > > conversations that you were aware of SENS, so this is not new to you,
      > > but I think that longevity should be included as part of any
      > > discussion of biomedical research and given separate consideration
      > > given that it has a much lower status than research into specific
      > > conditions such as cancer, dementia, etc. You may ultimately conclude
      > > that not enough can be done in this area, but I think it should be
      > > part of your preliminary stuff. [btw, the United States has a National
      > > Institute of Aging, but it's much lower-status than most of the other
      > > grantmakers mentioned here].
      > >
      > > Vipul
      > >
      > > * Quoting Holden Karnofsky who at 2012-10-10 23:08:42+0000 (Wed) wrote
      > >
      > > > Note to the research list: we're now considering reopening our
      > > > investigation of the world of biomedical research. We've started and
      > > > stopped a couple of times in this area before; this time I decided to
      > > start
      > > > with a conversation with Dario Amodei, a longtime GiveWell follower and
      > > > personal friend who is currently a biology postdoc at Stanford. My goal
      > > > with the conversation was just to get some basic context and start
      > > putting
      > > > together a framework for thinking about the issue, not to use him as an
      > > > authoritative source, and the notes below should be read in that spirit.
      > > >
      > > >
      > > > This email has two sections:
      > > >
      > > >
      > > > 1. Notes that I emailed out internally after my conversation with Dario,
      > > > slightly edited
      > > >
      > > > 2. Some more context on the history of our work on biomedical research
      > > and
      > > > why we think it's appropriate to investigate this field (this was a
      > > > response to a question following my original email, along the lines of
      > > "Why
      > > > are you looking into biomedical research now, given that's an area with a
      > > > lot of buzz and funding from wealthy donors, and how does this work
      > > relate
      > > > to the 'meta-research' work?")
      > > >
      > > >
      > > >
      > > > *--*
      > > >
      > > > *
      > > > *
      > > >
      > > > *1. Notes that I emailed out internally after my conversation with Dario,
      > > > slightly edited*
      > > >
      > > > *
      > >
      > > > *
      > > >
      > > > I've done some preliminary work trying to figure out what it would look
      > > > like to explore biomedical sciences as funding area. This mostly
      > > consisted
      > > > of a 3-hour conversation with Dario (recording is available), reading two
      > > > papers he sent and a few I found while Googling, and prior knowledge. I'm
      > > > including Dario in all emails related to this stuff, as an informal
      > > advisor.
      > > >
      > > > * *
      > > >
      > > > *My picture of "what the biomedical research world roughly looks like"
      > > *(this
      > >
      > > > is mostly from talking with Dario + prior knowledge)
      > > >
      > > > · *Academic biology* studies how organisms work and develops tools to
      > >
      > > > observe and manipulate the building blocks of organisms.
      > > >
      > > > o The vast bulk of the funding - and the most prestigious funding - comes
      > > > from the NIH.
      > > >
      > > > o There is also funding from what I've heard called "foundations" -
      > > groups
      > > > like the American Cancer Society and American Heart Association - which
      > > > function very similarly to the NIH, in that they tend to hire people with
      > > > strong academic credentials and those people judge the merits of grant
      > > > proposals.
      > > >
      > > > o Both the NIH and "foundations" tend to be formally partitioned by
      > > > disease, but much of the work done by academic biologists is potentially
      > > > relevant to many diseases. A researcher seeking NIH funding may apply to
      > > > several different NIH "study sections," though only one at a time (a list
      > > > of "study sections" is at
      > > > http://public.csr.nih.gov/StudySections/Standing/Pages/default.aspx);
      > > > whether s/he gets funding is going to depend more on the academic merits
      > > of
      > > > the researcher & work than anything else.
      > > >
      > > > o There are basic definitions of "academic merit " that generally shape
      > > > the whole ecosystem: the people handing out money are selected by these
      > > > criteria and use these criteria, the people doing the research know that
      > > > these criteria shape their career prospects, etc.
      > > >
      > > > · *Private startups* investigate promising ideas for new
      > >
      > > > treatments/diagnostics/devices. They may often take the form of a biology
      > > > professor spinning off a biotech startup (run by former postdocs) that
      > > > raises venture capital, based on the research the professor did. They
      > > take
      > > > basic knowledge about how the body works (for example, protein X is
      > > crucial
      > > > for medical condition Y) and do the necessary testing to find a promising
      > > > treatment/diagnostic/device (for example, testing a lot of compounds on
      > > > animals until they find one that affects protein X).
      > > >
      > > > · *Big pharma/biotech companies *are best positioned to deal with the
      > >
      > > > extremely expensive process of conducting clinical trials and getting FDA
      > > > approval. Acquisition by one of these is the most common form of exit for
      > > > startups.
      > > >
      > > > · *Academic medicine, epidemiology and other fields* also do work
      > >
      > > > relevant to medicine, including studying questions whose main relevance
      > > is
      > > > to medical practice and public health programs: how effective is
      > > > treatment/practice X in situation Y, how cost-effective is it, etc.
      > > > Sometimes they will hit on commercializable insights (for example, a new
      > > > kind of device) as well.
      > > >
      > > > · *Translational research* is a broad term referring to a bridge between
      > >
      > > > academic research and treatments/practices. It can include (
      > > >
      > > http://medicalcenter.osu.edu/research/translational_research/pages/index.aspx
      > > > ):
      > > >
      > > > o T1 - going from basic science (usually academic biology, I presume) to
      > > a
      > > > new treatment/practice. This includes research that helps go from an
      > > > academic biology insight to a private startup.
      > > >
      > > > o T2 - I think this is basically what Cochrane does - going from academic
      > > > medicine/epidemiology (a bunch of studies on what treatments/practices
      > > are
      > > > effective) to the development of guidelines that actually affect
      > > practice.
      > > >
      > > > o T3, T4 - research on how to actually change practice (as opposed to
      > > > setting the guidelines that are a "target" for practice) and get better
      > > > real-world results.
      > > >
      > > > *
      > > > *
      > > >
      > > > *Potential "big opportunity to do good" #1: translational research and
      > > the
      > >
      > > > "Valley of Death" (this comes from prior knowledge, googling "Valley of
      > > > Death" and reading a bunch of the stuff I found, and checking out the
      > > > FasterCures website again)*
      > >
      > > >
      > > >
      > > >
      > > > The "Valley of Death" seems to mostly refer to a shortage of T1. The idea
      > > > is that there are a lot of cases where there's an academic insight that's
      > > > potentially valuable in coming up with a new treatment, but to get it to
      > > > the point where it's attractive from a for-profit perspective, you need
      > > to
      > > > do a lot of stuff that academics don't have a reason to do. "For example,
      > > > an upstream finding that a given protein is differentially expressed in
      > > > individuals with a particular disease may suggest that the protein merits
      > > > further investigation. However, much more work (especially medicinal
      > > > chemistry) is necessary to determine how good a target the protein really
      > > > is and whether a marketable drug candidate that affects the activity of
      > > the
      > > > protein is likely to be developed." (
      > > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf)
      > > >
      > > >
      > > >
      > > > There are claims that this sort of work is massively underfunded (by the
      > > > people we've spoken to who talked about the "Valley of Death"; also in
      > > >
      > > http://www.fastercures.org/documents/file/Valley%20of%20Death%20-%20Translational%20Research
      > > (1).pdf).
      > > > However, funding isn't the only issue. The other issue is that
      > > > "pharmaceutical firms that hold libraries of potentially useful small
      > > > molecules as trade secrets, making them largely off limits to ...
      > > academic
      > > > scientists" (
      > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf).
      > > > In other words, there is some room for new models of collaboration that
      > > > lead to better communication and information sharing between academia and
      > > > industry (or between industry and industry).
      > > >
      > > >
      > > > Both the Myelin Repair Foundation and Michael Milken's work on prostate
      > > > cancer have been pointed to as examples of innovative collaborations that
      > > > deal with some of the information sharing problems. Milken's model:
      > > > "drastically cutting the wait time for grant money, to flood the field
      > > with
      > > > fast cash, to fund therapy-driven ideas rather than basic science, to
      > > hold
      > > > researchers he funds accountable for results, and to demand collaboration
      > > > across disciplines and among institutions, private industry, and
      > > academia."
      > > > (
      > > >
      > > http://money.cnn.com/magazines/fortune/fortune_archive/2004/11/29/8192713/index.htm
      > > )
      > > > Myelin Repair Foundation sounds broadly similar (
      > > >
      > > http://opinionator.blogs.nytimes.com/2011/05/02/helping-new-drugs-out-of-academias-valley-of-death/
      > > ).
      > > >
      > > >
      > > >
      > > >
      > > > More broadly:
      > > >
      > > > · FasterCures (also a Michael Milken production) looks like it's focused
      > > > on the broad mission of "more research with a shorter timeline to
      > > > treatments," with a heavy sub-focus on the Valley of Death. In addition
      > > to
      > > > its conference and philanthropic advisory service, it advocates for FDA
      > > > improvements (presumably to speed the approval process), advocates for
      > > the
      > > > NIH to put more funding into translational research (there have
      > > definitely
      > > > been a lot of new initiatives at the NIH focused on this stuff in the
      > > past
      > > > few ~decade), promotes "innovative financing mechanisms" for bridging the
      > > > Valley of Death (these include Peter Thiel's Breakout Labs; I think they
      > > > occupy a conceptually similar space to "social enterprise investment"
      > > > though they tend to be structured more as grants and less as
      > > > double-bottom-line investments), and works on getting patient data opened
      > > > to researchers. The only program of theirs I haven't mentioned is TRAIN;
      > > I
      > > > can't (easily) figure out what this is.
      > > >
      > > > · John Ioannidis stated to us that all translational research is
      > > > underfunded, not just T1. (The context we talked to him in, of course,
      > > was
      > > > T2.)
      > > >
      > > >
      > > > These issues seem to have quite a bit of buzz. There are some really
      > > stark
      > > > #'s out there: even as R&D investment has gone way up over the past 50
      > > > years, the # of new drugs has stayed roughly constant at around 20 a
      > > year.
      > > >
      > > >
      > > > Dario sent a really interesting paper on this topic. It argues: (a) the #
      > > > of NMEs (new medical entities, i.e., drugs) per year has mostly remained
      > > > constant-with-noise (no trend); (b) all of the big companies seem to have
      > > > produced NMEs at a very steady pace, even as they've changed size, though
      > > > different companies do have different rates of NME creation; (c) when it
      > > > comes to mergers & acquisitions, "1+1=1": companies that acquire other
      > > > companies just keep up the same NME pace; (d) over time, the # of large
      > > > companies has shrunk (due to mergers) and the # of small companies has
      > > > risen, and the share of NMEs attributed to small companies has gone from
      > > > ~30% to ~70%; (e) the cost per NME has gone up over time and is now in
      > > the
      > > > neighborhood of $1 billion; (f) the % of NMEs that are "blockbusters"
      > > (huge
      > > > profits) has been steady around 20%, despite intensifying efforts on the
      > > > part of pharma to fund only potential blockbusters.
      > > >
      > > >
      > > >
      > > > There are also claims - such as by Derek Lowe, a blogger Dario pointed me
      > > > to - that the "Valley of Death" is an overrated concept: there is a high
      > > > ratio of academic discoveries to useful drugs, but this is just because a
      > > > lot of stuff turns out not to work, not because we have a shortage of
      > > > doable translational research. The paper above sort of takes this view,
      > > > essentially arguing that nothing seems to raise NME production; we'll
      > > need
      > > > something really radical to make any difference.
      > > >
      > > >
      > > >
      > > > The case studies in the FasterCures paper on this are interesting. They
      > > > imply that there were some pretty low-hanging fruit in the T1 domain. It
      > > > might be interesting to talk to Fastercures and see whether they can help
      > > > identify "Valley of Death" opportunities that are slam-dunkish.
      > > >
      > > >
      > > > *Potential "big opportunity to do good" #2: inefficiencies in academic
      > > > biology*
      > >
      > > >
      > > >
      > > >
      > > > All of the above seems pretty distinct from the question of how to make
      > > > academic biology better at doing its job of understanding the body. This
      > > is
      > > > the question that Dario and I focused on.
      > > >
      > > >
      > > >
      > > > Dario painted a picture in which most of academia plays by the same set
      > > of
      > > > rules, making it very hard for people to do things that break those rules
      > > > (for example, academics are expected to publish a lot; it's risky to work
      > > > on a "blue sky" or highly ambitious project). Thus, for anyone who wants
      > > a
      > > > career in academia, a couple of years working on a moonshot project are
      > > > risky; in addition, being on bad terms with a small number of people can
      > > > damage a career (since there is often a small set of people that makes a
      > > > large proportion of the career-impacting decisions for a given area, and
      > > it
      > > > can be hard to escape this set of people without changing research
      > > > interests significantly). The bad news is that this isn't particularly
      > > easy
      > > > to fix: you can offer funding for blue-sky projects, but (a) a lot of
      > > > academics basically train themselves to play by the rules, and won't
      > > > necessarily have thought about "what should be studied if these rules
      > > > didn't apply," and more importantly, (b) there are many incentives
      > > pushing
      > > > academics towards playing by certain rules; funding is only one of those
      > > > mechanisms (there's also tenure, peer review, etc) so changing that one
      > > > incentive won't always change behavior. Dario says that he might hesitate
      > > > to work on a particular blue-sky project that he thinks is interesting,
      > > > even if he got funding for it, for these reasons.
      > > >
      > > >
      > > > Despite this, there are some funders who push the boundaries. There are
      > > > medical centers that don't require teaching and do more ambitious work.
      > > > There's the McKnight foundation, which funded some of the pioneering work
      > > > on optical control of neurons for which funding might have been difficult
      > > > to obtain by traditional routes. There's the HHMI Janelia Farms campus,
      > > > which Dario thinks is the most promising thing out there in terms of a
      > > > model - academics who go there get guaranteed (and generous) funding for
      > > 6
      > > > years, which frees them up to take much bigger risks. (I saw a study
      > > > claiming that the work coming out of Janelia Farms has a much more skewed
      > > > citation count distribution, implying bigger risks - i.e., fewer papers
      > > > with decent #'s of citations but more "blockbuster" papers with lots of
      > > > citations). But Janelia Farms is only in one sub-field; comparable
      > > > institutions don't exist for other fields (as far as Dario knows)..
      > > >
      > > >
      > > >
      > > > Dario's gut is that one of the best things a funder could do would be to
      > > > work toward creating a large institute that largely "plays by its own
      > > > rules," encouraging more ambitious work and providing enough security and
      > > > sheer volume of dollars/researchers as to establish a sort of "parallel
      > > > system" to academia - thus becoming a place that could provide viable and
      > > > reliable career options for people interested in playing by different
      > > > rules. I'm also interested in the idea of trying to advocate for changes
      > > in
      > > > the rules, as we've discussed in the context of meta-research.
      > > >
      > > >
      > > >
      > > > There's also the other stuff like data/code sharing.
      > > >
      > > >
      > > >
      > > > *Another option: give $ to the NIH*
      > >
      > > >
      > > >
      > > >
      > > > The NIH is by far the largest, most prestigious, most respected funder in
      > > > academic biology, and most of academia runs on criteria that mirror the
      > > > NIH's. I would guess that an unrestricted check to the NIH would get
      > > > allocated in a pretty sector-agnostic way. It seems like this is a giving
      > > > option that is pretty nontrivial to beat. Anyone we consider for funding
      > > > ought to be able to explain why they're better at allocating the funds
      > > than
      > > > the NIH. We haven't talked to the NIH about whether it would accept these
      > > > sorts of donations.
      > > >
      > > >
      > > > With the context I now have, FasterCures strikes me as pretty
      > > > promising/interesting too, though their "room for more funding" situation
      > > > isn't clear (w/o talking to them). But they also seem sector-agnostic
      > > > within biomedical research, while pushing a very specific theory of
      > > change
      > > > that may or may not be valid.
      > > >
      > > >
      > > >
      > > > *Next steps*
      > >
      > > >
      > > >
      > > >
      > > > I think understanding this world would be a major undertaking. I think
      > > we'd
      > > > have to be ready to put in a lot of work and to be open to ways of
      > > bridging
      > > > "funder-expert gap" that we haven't tried before. For example:
      > > >
      > > > · Dario suggested that I read a freshman biology textbook. He said he
      > > > realizes that the time cost could be very large - something like 100
      > > hours
      > > > - but that without doing so, I'm going to be lacking too much context on
      > > > why biomedical research works the way it does. He thinks that reading a
      > > > basic textbook would get me to the point of strongly diminishing marginal
      > > > returns.
      > > >
      > > > · Also in the category of "personally picking up rudimentary subject
      > > > matter knowledge," I thought it might be worth trying to follow the
      > > > development of a particular drug from start to finish - Gleevec (the
      > > > "miracle drug") would be a good candidate. The goal would be to
      > > understand
      > > > each stage of insight leading to new investigation, and where the funding
      > > > came from at each stage.
      > > >
      > > > · I think hiring Dario or someone like him would make a lot of sense.
      > > > I've thought about whether we should be hiring "subject matter experts"
      > > in
      > > > other areas, such as global health, but in my view the need is clearer
      > > here
      > > > than in any other area. One of the things I don't love about hiring an
      > > > expert in a given field, at this stage of our research, is that we could
      > > > quickly decide that we're just not interested enough in the field in
      > > > question ... but someone with the right kind of technical knowledge &
      > > > experience would be so far ahead of us in evaluating *any* area of
      > > biology
      > > > research that it seems like a good idea. (JTBC, I'm also actively
      > > thinking
      > > > about whether it would make sense to hire experts in other fields ...)
      > > >
      > > > · Talking to major funders and potentially co-funding with them is
      > > > probably essential. Important groups to talk to would include NIH (by far
      > > > the most important; we've already talked to them a bit), the colloquium
      > > of
      > > > groups like the American Cancer Society (it has a name; I forget the
      > > name),
      > > > FasterCures, Wellcome, and potentially some funders with
      > > > unorthodox/buzzed-about approaches: Myelin Repair Foundation, McKnight
      > > > Foundation, and maybe another private foundation or two (I emailed Dario
      > > > all my notes on major foundations that do biomedical research so he could
      > > > send thoughts on whether any look interesting aside from McKnight).
      > > >
      > > >
      > > > My next plan had been to talk to academics (Dario had good suggestions
      > > > about how to approach them), but with all the potential work to be done
      > > on
      > > > gaining basic context, I'm not sure that's the right next step. But it's
      > > > also a possible step.
      > > >
      > > >
      > > >
      > > > *2. Some more context on the history of our work on biomedical research
      > > and
      > >
      > > > why we think it's appropriate to investigate this field (this was a
      > > > response to a question following my original email, along the lines of
      > > "Why
      > > > are you looking into biomedical research now, given that's an area with a
      > > > lot of buzz and funding from wealthy donors, and how does this work
      > > relate
      > > > to the 'meta-research' work?")*
      > > >
      > > >
      > > > - We've always had "disease research" as a cause we wanted to
      > >
      > > > investigate. We've never had a good reason for not investigating it other
      > > > than that investigating it seems difficult. We've tried more than once to
      > > > investigate it, and it's ended up falling by the wayside because of how
      > > big
      > > > an undertaking it is.
      > > > - It's true that there is a huge amount of funding and buzz in this
      > >
      > > > area. But it also seems quite possible that there isn't nearly enough; in
      > > > fact this seems like a possible point of consensus between all the people
      > > > concerned about the "Valley of Death." This potential good accomplished
      > > via
      > > > biomedical research appears unlimited. What I consider to be the mark of
      > > a
      > > > bad sector is "tons of buzz/$ and mediocre returns," but the latter part
      > > > doesn't apply to biomed; in fact biomedical research is arguably one of
      > > > philanthropy's and even humanity's top success stories.
      > > > - There are also indications that despite all the buzz and funding,
      > >
      > > > there are still opportunities to do things differently and shake things
      > > up.
      > > > There is more than one case where an outsider (Milken, MRF) basically
      > > came
      > > > in and did things very differently and now even experts in the field seem
      > > > to credit them with positive change. There's also a good explanation for
      > > > why this might be the case: while there are a ton of people and dollars,
      > > > they largely seem to play by one self-reinforcing/network-effect-prone
      > > set
      > > > of rules, implying high returns to disrupting that equilibrium.
      > > > - So, we've always wanted to get into this area. There was a period
      > >
      > > > where I was presenting meta-research as our best entry point into this
      > > > field: my vision was that we would talk to academics about what
      > > systematic
      > > > failings there were and what funding opportunities these implied, and
      > > that
      > > > would be as good a way as any to get acclimated in biomed. But this
      > > period
      > > > wasn't particularly long - the May blog post on Labs priority causes
      > > lists
      > > > scientific research as a promising area distinct from meta-research.
      > > > - I set up the call with Dario without having a clear idea of whether I
      > >
      > > > wanted to approach biomed from a "meta-research" angle or another angle.
      > > > After the call and other investigations described here, I got a clearer
      > > > idea of what I think is the best path forward.
      > > >
      > > > Bottom line - I think it's important to build an understanding of
      > > > biomedical research, and that we should take the best path to doing so
      > > > whether or not that dovetails with the meta-research work (likely it will
      > > > dovetail some but not 100%).
      > >
      > >
      > >
      >
    • Holden Karnofsky
      Hi Aubrey, Thanks for the thoughts. The NIH appears to have a division focused on research relevant to this topic: http://www.nia.nih.gov/research/dab . Its
      Message 2 of 18 , Oct 12, 2012
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        Hi Aubrey,

        Thanks for the thoughts.

        The NIH appears to have a division focused on research relevant to this topic: http://www.nia.nih.gov/research/dab . Its budget appears to be ~$175 million (per year). The National Institute on Aging, which houses this division, has a budget of about $1 billion per year, including a separate ~$400 million for neuroscience (which may also be relevant) as well as $115 million for intramural research. Figures are from http://www.nia.nih.gov/about/budget/2012/fiscal-year-2013-budget. The Institute states that its mandate includes translational research (http://www.nia.nih.gov/research/faq/does-nia-support-translational-research). How would you distinguish your work from this work?

        (For the moment I'm putting aside the question I raised in my previous response to Vipul on this topic, regarding whether it's best to approach biology funding from the perspective of "trying to treat/cure a particular condition" or "trying to understand  fundamental questions in biology whose applications are difficult to predict.")

        Best,
        Holden

        On Fri, Oct 12, 2012 at 7:32 AM, aubrey.degrey <aubrey@...> wrote:
         

        Hi everyone,

        My attention was brought to this thread, by virtue of the fact that it was my work that gave rise to SENS Foundation, and I'm looking forward to getting more involved here; I've held the Effective Altruism movement in high regard for some time. However, given my newbie status here I want to start by apologising in advance for any oversight of previously-discussed issues etc. I'm naturally delighted both at Holden's post and at Vipul's reply (which I should stress that I did not plant! - I do not know Vipul at all, though I look forward to changing that). I would like to mention just a few key points for discussion:

        - Holden, I want to compliment you on your appreciation of how academia really works. Everything you say about that is spot on. The aversion to "high risk high gain" work that has arisen and become so endemic in the system is the most important point here, in terms of why parallel funding routes are needed.

        - I'm slightly confused that a lot of Holden's remarks are focused on the private sector (i.e. startups), since my understanding was that GiveWell is about philanthropy; but I realise that there is not all that clear a boundary between the two (and I note the mention of Breakout Labs, with which I have close links and which sits astride that divide more than arguably anyone). The "valley of death" in pre-competitive translational research is a rather different one than that encountered by startups, but the principle is the same, and research to postpone aging certainly encounteres it.

        - Something that I presume factors highly among GiveWell's criteria is the extent to which a cause may be undervalued by the bulk of major philanthropists, such that an infusion of additional funds would make more of a difference than in an area that is already being well funded. To me this seems to mirror the logic of focusing on the shortcomings (gaps) in NIH's funding (and that of traditional-model foundations). Holden notes that "Anyone we consider for funding ought to be able to explain why they're better at allocating the funds than the NIH" and I agree wholeheartedly, but my inference is that he thinks that some orgs may indeed be able to explain that. I certainly think that SENS Foundation can.

        - Coming to aging: research to postpone aging has the unique problem of quite indescribeable irrationality on the part of most of the general public, policy-makers and even biologists with regard to its desirability. Biogerontologists have been talking to brick walls for decades in their effort to get the rest of the world to appreciate that aging is what causes age-related ill-health, and thus that treatments for aging are merely preventative geriatrics. The concept persists, despite biogerontologists' best efforts, that aging is "natural" and should be left alone, whereas the diseases that it brings about are awful and should be fought. This is made even more bizarre by the fact that the status of age-related diseases as aspects of the later stages of aging absolutely, unequivocally implies that efforts to attack those diseases directly are doomed to fail. As such, this is a (unique? certainly very rare) case where a philanthropic contribution can make a particularly big difference simply because most philanthropists don't see the case for it. It underpins why having an interest in treating aging, as opposed to cancer, absolutely has a major impact on which projects one funds. It's also a case for (if I understand the term correctly) meta-research.

        - A lot of the chatter about treating aging revolves around longevity, but it shouldn't. I'm all in favour of longevity, don't get me wrong, but it's not what gets me up in the morning: what does is health. I want people to be truly youthful, however long ago they were born: simple as that. The benefits of longevity per se to humanity may also be substantial, in the form of greater wisdom etc, but that would necessarily come about only very gradually (we won't have any 1000-year-old for at least 900 years whatever happens!), so it doesn't figure strongly in my calculations.

        - When forced to acknowledge that the idea of aging being a high-priority target for medicine is an inescapeable consequence of things they already believe (notably that health is good and ageism is bad), many people retreat to the standpoint that it's never going to be possible so it's OK to be irrational about whether it's desirable. The feasibility of postponing age-related ill-health by X years with medicine available Y years from now is, of course, a matter of speculation on which experts disagree, just as with any other pioneering technology. I know that Holden and others have expressed caution (at best) concerning the accuracy of any kind of calculation of probabilities of particular outcomes in the distant (or even not-so-distant) future, and I share that view. However, an approach that may appeal more is to estimate how much humanitarian benefit a given amount of progress would deliver, and then to ask how unlikely that scenario needs to be to make it not worth pursuing. My claim is that the benefits of hastening the defeat of aging by even a few years (which is the minimum that I claim SENS Foundation is in a position to do, given adequate funding) would be so astronomical that the required chance of success to make such an effort worthwhile would be tiny - too tiny for it to be reasonable to argue that such funding would be inadvisable. But of course that is precisely what I would want GiveWell to opine on.

        - In the event that GiveWell (or anyone else) were to decide and declare that the defeat of aging is indeed a cause that philanthropists should support, there then arises the question of which organisation(s) should be supported in the best interests of that mission. We at SENS Foundation have worked diligently to rise as quickly as possible in the legitimacy stakes by all standard measures, but we are still young and there remains more to do. If I were to offer an argument to fund us rather than any other entity, it would largely come down to the fact that no other organisation has even a serious plan for defeating aging, let alone a track record of implementing such a plan's early stages.

        - A significant chunk of what we do is of a kind that I think comes under "meta-research". A prominent example is a project we're funding at Denver University to extend the well-respected forecasting system "International Futures" so that it can analyse scenarios incorporating dramatically postponed aging.

        I greatly welcome any feedback.

        Cheers, Aubrey



        --- In givewell@yahoogroups.com, Holden Karnofsky <holden0@...> wrote:
        >
        > Hi Vipul,
        >
        > Thanks for the thoughts. I had a followup conversation with Dario about
        > this topic a few days ago. I think the question of "could one fund
        > translational research to treat/prevent aging?" provides an interesting
        > illustration of some of the tricky dynamics here for a funder:
        >
        > - It's possible that if there were a great deal more attention giving to

        > treating/preventing aging, we would have some promising treatments. So in a
        > broad sense it's possible that aging is underinvested in.
        > - A lot of the best basic biology research isn't clearly pointing toward

        > one treatment/condition or another; it's about understanding the
        > fundamentals of how organisms operate. So having an interest in treating
        > aging, as opposed to cancer, might not have a major impact on which
        > projects one funds, if one's main goal is to fund outstanding basic biology
        > research.
        > - Perhaps because of the lack of emphasis on treating aging (or perhaps

        > because it's simply too difficult of a problem), there don't seem to be
        > promising findings in the "Valley of Death" relevant to aging; the few
        > promising leads have been explored.
        > - So even if, in a broad sense, there is too little attention given to

        > this problem, knowing this doesn't necessarily yield a clear direction for
        > a relatively small-scale funder of biomedical research.
        >
        > Best,
        > Holden
        >
        > On Wed, Oct 10, 2012 at 11:55 PM, Vipul Naik <vipul@...>wrote:
        >
        > > **

        > >
        > >
        > > Holden,
        > >
        > > First, I think that this is an excellent document. I checked for a
        > > number of things that I had heard about (Breakout Labs, John
        > > Ioannidis, Cochrane Collaboration) and they're all there in your
        > > document.
        > >
        > > The one thing that's not explicitly mentioned: longevity and life
        > > extension research. At least prima facie, this seems like something
        > > that should be more important than individual disease research, and it
        > > seems like a classic "Valley of Death" case (pun unintended, but
        > > noted) -- T1 stage to use your terminology. I think the SENS website
        > > http://www.sens.org would be a good starting point for one of the (to
        > > me promising) approaches to life extension. I recall from past
        > > conversations that you were aware of SENS, so this is not new to you,
        > > but I think that longevity should be included as part of any
        > > discussion of biomedical research and given separate consideration
        > > given that it has a much lower status than research into specific
        > > conditions such as cancer, dementia, etc. You may ultimately conclude
        > > that not enough can be done in this area, but I think it should be
        > > part of your preliminary stuff. [btw, the United States has a National
        > > Institute of Aging, but it's much lower-status than most of the other
        > > grantmakers mentioned here].
        > >
        > > Vipul
        > >
        > > * Quoting Holden Karnofsky who at 2012-10-10 23:08:42+0000 (Wed) wrote
        > >
        > > > Note to the research list: we're now considering reopening our
        > > > investigation of the world of biomedical research. We've started and
        > > > stopped a couple of times in this area before; this time I decided to
        > > start
        > > > with a conversation with Dario Amodei, a longtime GiveWell follower and
        > > > personal friend who is currently a biology postdoc at Stanford. My goal
        > > > with the conversation was just to get some basic context and start
        > > putting
        > > > together a framework for thinking about the issue, not to use him as an
        > > > authoritative source, and the notes below should be read in that spirit.
        > > >
        > > >
        > > > This email has two sections:
        > > >
        > > >
        > > > 1. Notes that I emailed out internally after my conversation with Dario,
        > > > slightly edited
        > > >
        > > > 2. Some more context on the history of our work on biomedical research
        > > and
        > > > why we think it's appropriate to investigate this field (this was a
        > > > response to a question following my original email, along the lines of
        > > "Why
        > > > are you looking into biomedical research now, given that's an area with a
        > > > lot of buzz and funding from wealthy donors, and how does this work
        > > relate
        > > > to the 'meta-research' work?")
        > > >
        > > >
        > > >
        > > > *--*
        > > >
        > > > *
        > > > *
        > > >
        > > > *1. Notes that I emailed out internally after my conversation with Dario,
        > > > slightly edited*
        > > >
        > > > *
        > >
        > > > *
        > > >
        > > > I've done some preliminary work trying to figure out what it would look
        > > > like to explore biomedical sciences as funding area. This mostly
        > > consisted
        > > > of a 3-hour conversation with Dario (recording is available), reading two
        > > > papers he sent and a few I found while Googling, and prior knowledge. I'm
        > > > including Dario in all emails related to this stuff, as an informal
        > > advisor.
        > > >
        > > > * *
        > > >
        > > > *My picture of "what the biomedical research world roughly looks like"
        > > *(this
        > >
        > > > is mostly from talking with Dario + prior knowledge)
        > > >
        > > > · *Academic biology* studies how organisms work and develops tools to
        > >
        > > > observe and manipulate the building blocks of organisms.
        > > >
        > > > o The vast bulk of the funding - and the most prestigious funding - comes
        > > > from the NIH.
        > > >
        > > > o There is also funding from what I've heard called "foundations" -
        > > groups
        > > > like the American Cancer Society and American Heart Association - which
        > > > function very similarly to the NIH, in that they tend to hire people with
        > > > strong academic credentials and those people judge the merits of grant
        > > > proposals.
        > > >
        > > > o Both the NIH and "foundations" tend to be formally partitioned by
        > > > disease, but much of the work done by academic biologists is potentially
        > > > relevant to many diseases. A researcher seeking NIH funding may apply to
        > > > several different NIH "study sections," though only one at a time (a list
        > > > of "study sections" is at
        > > > http://public.csr.nih.gov/StudySections/Standing/Pages/default.aspx);
        > > > whether s/he gets funding is going to depend more on the academic merits
        > > of
        > > > the researcher & work than anything else.
        > > >
        > > > o There are basic definitions of "academic merit " that generally shape
        > > > the whole ecosystem: the people handing out money are selected by these
        > > > criteria and use these criteria, the people doing the research know that
        > > > these criteria shape their career prospects, etc.
        > > >
        > > > · *Private startups* investigate promising ideas for new
        > >
        > > > treatments/diagnostics/devices. They may often take the form of a biology
        > > > professor spinning off a biotech startup (run by former postdocs) that
        > > > raises venture capital, based on the research the professor did. They
        > > take
        > > > basic knowledge about how the body works (for example, protein X is
        > > crucial
        > > > for medical condition Y) and do the necessary testing to find a promising
        > > > treatment/diagnostic/device (for example, testing a lot of compounds on
        > > > animals until they find one that affects protein X).
        > > >
        > > > · *Big pharma/biotech companies *are best positioned to deal with the
        > >
        > > > extremely expensive process of conducting clinical trials and getting FDA
        > > > approval. Acquisition by one of these is the most common form of exit for
        > > > startups.
        > > >
        > > > · *Academic medicine, epidemiology and other fields* also do work
        > >
        > > > relevant to medicine, including studying questions whose main relevance
        > > is
        > > > to medical practice and public health programs: how effective is
        > > > treatment/practice X in situation Y, how cost-effective is it, etc.
        > > > Sometimes they will hit on commercializable insights (for example, a new
        > > > kind of device) as well.
        > > >
        > > > · *Translational research* is a broad term referring to a bridge between
        > >
        > > > academic research and treatments/practices. It can include (
        > > >
        > > http://medicalcenter.osu.edu/research/translational_research/pages/index.aspx
        > > > ):
        > > >
        > > > o T1 - going from basic science (usually academic biology, I presume) to
        > > a
        > > > new treatment/practice. This includes research that helps go from an
        > > > academic biology insight to a private startup.
        > > >
        > > > o T2 - I think this is basically what Cochrane does - going from academic
        > > > medicine/epidemiology (a bunch of studies on what treatments/practices
        > > are
        > > > effective) to the development of guidelines that actually affect
        > > practice.
        > > >
        > > > o T3, T4 - research on how to actually change practice (as opposed to
        > > > setting the guidelines that are a "target" for practice) and get better
        > > > real-world results.
        > > >
        > > > *
        > > > *
        > > >
        > > > *Potential "big opportunity to do good" #1: translational research and
        > > the
        > >
        > > > "Valley of Death" (this comes from prior knowledge, googling "Valley of
        > > > Death" and reading a bunch of the stuff I found, and checking out the
        > > > FasterCures website again)*
        > >
        > > >
        > > >
        > > >
        > > > The "Valley of Death" seems to mostly refer to a shortage of T1. The idea
        > > > is that there are a lot of cases where there's an academic insight that's
        > > > potentially valuable in coming up with a new treatment, but to get it to
        > > > the point where it's attractive from a for-profit perspective, you need
        > > to
        > > > do a lot of stuff that academics don't have a reason to do. "For example,
        > > > an upstream finding that a given protein is differentially expressed in
        > > > individuals with a particular disease may suggest that the protein merits
        > > > further investigation. However, much more work (especially medicinal
        > > > chemistry) is necessary to determine how good a target the protein really
        > > > is and whether a marketable drug candidate that affects the activity of
        > > the
        > > > protein is likely to be developed." (
        > > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf)
        > > >
        > > >
        > > >
        > > > There are claims that this sort of work is massively underfunded (by the
        > > > people we've spoken to who talked about the "Valley of Death"; also in
        > > >
        > > http://www.fastercures.org/documents/file/Valley%20of%20Death%20-%20Translational%20Research
        > > (1).pdf).
        > > > However, funding isn't the only issue. The other issue is that
        > > > "pharmaceutical firms that hold libraries of potentially useful small
        > > > molecules as trade secrets, making them largely off limits to ...
        > > academic
        > > > scientists" (
        > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf).
        > > > In other words, there is some room for new models of collaboration that
        > > > lead to better communication and information sharing between academia and
        > > > industry (or between industry and industry).
        > > >
        > > >
        > > > Both the Myelin Repair Foundation and Michael Milken's work on prostate
        > > > cancer have been pointed to as examples of innovative collaborations that
        > > > deal with some of the information sharing problems. Milken's model:
        > > > "drastically cutting the wait time for grant money, to flood the field
        > > with
        > > > fast cash, to fund therapy-driven ideas rather than basic science, to
        > > hold
        > > > researchers he funds accountable for results, and to demand collaboration
        > > > across disciplines and among institutions, private industry, and
        > > academia."
        > > > (
        > > >
        > > http://money.cnn.com/magazines/fortune/fortune_archive/2004/11/29/8192713/index.htm
        > > )
        > > > Myelin Repair Foundation sounds broadly similar (
        > > >
        > > http://opinionator.blogs.nytimes.com/2011/05/02/helping-new-drugs-out-of-academias-valley-of-death/
        > > ).
        > > >
        > > >
        > > >
        > > >
        > > > More broadly:
        > > >
        > > > · FasterCures (also a Michael Milken production) looks like it's focused
        > > > on the broad mission of "more research with a shorter timeline to
        > > > treatments," with a heavy sub-focus on the Valley of Death. In addition
        > > to
        > > > its conference and philanthropic advisory service, it advocates for FDA
        > > > improvements (presumably to speed the approval process), advocates for
        > > the
        > > > NIH to put more funding into translational research (there have
        > > definitely
        > > > been a lot of new initiatives at the NIH focused on this stuff in the
        > > past
        > > > few ~decade), promotes "innovative financing mechanisms" for bridging the
        > > > Valley of Death (these include Peter Thiel's Breakout Labs; I think they
        > > > occupy a conceptually similar space to "social enterprise investment"
        > > > though they tend to be structured more as grants and less as
        > > > double-bottom-line investments), and works on getting patient data opened
        > > > to researchers. The only program of theirs I haven't mentioned is TRAIN;
        > > I
        > > > can't (easily) figure out what this is.
        > > >
        > > > · John Ioannidis stated to us that all translational research is
        > > > underfunded, not just T1. (The context we talked to him in, of course,
        > > was
        > > > T2.)
        > > >
        > > >
        > > > These issues seem to have quite a bit of buzz. There are some really
        > > stark
        > > > #'s out there: even as R&D investment has gone way up over the past 50
        > > > years, the # of new drugs has stayed roughly constant at around 20 a
        > > year.
        > > >
        > > >
        > > > Dario sent a really interesting paper on this topic. It argues: (a) the #
        > > > of NMEs (new medical entities, i.e., drugs) per year has mostly remained
        > > > constant-with-noise (no trend); (b) all of the big companies seem to have
        > > > produced NMEs at a very steady pace, even as they've changed size, though
        > > > different companies do have different rates of NME creation; (c) when it
        > > > comes to mergers & acquisitions, "1+1=1": companies that acquire other
        > > > companies just keep up the same NME pace; (d) over time, the # of large
        > > > companies has shrunk (due to mergers) and the # of small companies has
        > > > risen, and the share of NMEs attributed to small companies has gone from
        > > > ~30% to ~70%; (e) the cost per NME has gone up over time and is now in
        > > the
        > > > neighborhood of $1 billion; (f) the % of NMEs that are "blockbusters"
        > > (huge
        > > > profits) has been steady around 20%, despite intensifying efforts on the
        > > > part of pharma to fund only potential blockbusters.
        > > >
        > > >
        > > >
        > > > There are also claims - such as by Derek Lowe, a blogger Dario pointed me
        > > > to - that the "Valley of Death" is an overrated concept: there is a high
        > > > ratio of academic discoveries to useful drugs, but this is just because a
        > > > lot of stuff turns out not to work, not because we have a shortage of
        > > > doable translational research. The paper above sort of takes this view,
        > > > essentially arguing that nothing seems to raise NME production; we'll
        > > need
        > > > something really radical to make any difference.
        > > >
        > > >
        > > >
        > > > The case studies in the FasterCures paper on this are interesting. They
        > > > imply that there were some pretty low-hanging fruit in the T1 domain. It
        > > > might be interesting to talk to Fastercures and see whether they can help
        > > > identify "Valley of Death" opportunities that are slam-dunkish.
        > > >
        > > >
        > > > *Potential "big opportunity to do good" #2: inefficiencies in academic
        > > > biology*
        > >
        > > >
        > > >
        > > >
        > > > All of the above seems pretty distinct from the question of how to make
        > > > academic biology better at doing its job of understanding the body. This
        > > is
        > > > the question that Dario and I focused on.
        > > >
        > > >
        > > >
        > > > Dario painted a picture in which most of academia plays by the same set
        > > of
        > > > rules, making it very hard for people to do things that break those rules
        > > > (for example, academics are expected to publish a lot; it's risky to work
        > > > on a "blue sky" or highly ambitious project). Thus, for anyone who wants
        > > a
        > > > career in academia, a couple of years working on a moonshot project are
        > > > risky; in addition, being on bad terms with a small number of people can
        > > > damage a career (since there is often a small set of people that makes a
        > > > large proportion of the career-impacting decisions for a given area, and
        > > it
        > > > can be hard to escape this set of people without changing research
        > > > interests significantly). The bad news is that this isn't particularly
        > > easy
        > > > to fix: you can offer funding for blue-sky projects, but (a) a lot of
        > > > academics basically train themselves to play by the rules, and won't
        > > > necessarily have thought about "what should be studied if these rules
        > > > didn't apply," and more importantly, (b) there are many incentives
        > > pushing
        > > > academics towards playing by certain rules; funding is only one of those
        > > > mechanisms (there's also tenure, peer review, etc) so changing that one
        > > > incentive won't always change behavior. Dario says that he might hesitate
        > > > to work on a particular blue-sky project that he thinks is interesting,
        > > > even if he got funding for it, for these reasons.
        > > >
        > > >
        > > > Despite this, there are some funders who push the boundaries. There are
        > > > medical centers that don't require teaching and do more ambitious work.
        > > > There's the McKnight foundation, which funded some of the pioneering work
        > > > on optical control of neurons for which funding might have been difficult
        > > > to obtain by traditional routes. There's the HHMI Janelia Farms campus,
        > > > which Dario thinks is the most promising thing out there in terms of a
        > > > model - academics who go there get guaranteed (and generous) funding for
        > > 6
        > > > years, which frees them up to take much bigger risks. (I saw a study
        > > > claiming that the work coming out of Janelia Farms has a much more skewed
        > > > citation count distribution, implying bigger risks - i.e., fewer papers
        > > > with decent #'s of citations but more "blockbuster" papers with lots of
        > > > citations). But Janelia Farms is only in one sub-field; comparable
        > > > institutions don't exist for other fields (as far as Dario knows)..
        > > >
        > > >
        > > >
        > > > Dario's gut is that one of the best things a funder could do would be to
        > > > work toward creating a large institute that largely "plays by its own
        > > > rules," encouraging more ambitious work and providing enough security and
        > > > sheer volume of dollars/researchers as to establish a sort of "parallel
        > > > system" to academia - thus becoming a place that could provide viable and
        > > > reliable career options for people interested in playing by different
        > > > rules. I'm also interested in the idea of trying to advocate for changes
        > > in
        > > > the rules, as we've discussed in the context of meta-research.
        > > >
        > > >
        > > >
        > > > There's also the other stuff like data/code sharing.
        > > >
        > > >
        > > >
        > > > *Another option: give $ to the NIH*
        > >
        > > >
        > > >
        > > >
        > > > The NIH is by far the largest, most prestigious, most respected funder in
        > > > academic biology, and most of academia runs on criteria that mirror the
        > > > NIH's. I would guess that an unrestricted check to the NIH would get
        > > > allocated in a pretty sector-agnostic way. It seems like this is a giving
        > > > option that is pretty nontrivial to beat. Anyone we consider for funding
        > > > ought to be able to explain why they're better at allocating the funds
        > > than
        > > > the NIH. We haven't talked to the NIH about whether it would accept these
        > > > sorts of donations.
        > > >
        > > >
        > > > With the context I now have, FasterCures strikes me as pretty
        > > > promising/interesting too, though their "room for more funding" situation
        > > > isn't clear (w/o talking to them). But they also seem sector-agnostic
        > > > within biomedical research, while pushing a very specific theory of
        > > change
        > > > that may or may not be valid.
        > > >
        > > >
        > > >
        > > > *Next steps*
        > >
        > > >
        > > >
        > > >
        > > > I think understanding this world would be a major undertaking. I think
        > > we'd
        > > > have to be ready to put in a lot of work and to be open to ways of
        > > bridging
        > > > "funder-expert gap" that we haven't tried before. For example:
        > > >
        > > > · Dario suggested that I read a freshman biology textbook. He said he
        > > > realizes that the time cost could be very large - something like 100
        > > hours
        > > > - but that without doing so, I'm going to be lacking too much context on
        > > > why biomedical research works the way it does. He thinks that reading a
        > > > basic textbook would get me to the point of strongly diminishing marginal
        > > > returns.
        > > >
        > > > · Also in the category of "personally picking up rudimentary subject
        > > > matter knowledge," I thought it might be worth trying to follow the
        > > > development of a particular drug from start to finish - Gleevec (the
        > > > "miracle drug") would be a good candidate. The goal would be to
        > > understand
        > > > each stage of insight leading to new investigation, and where the funding
        > > > came from at each stage.
        > > >
        > > > · I think hiring Dario or someone like him would make a lot of sense.
        > > > I've thought about whether we should be hiring "subject matter experts"
        > > in
        > > > other areas, such as global health, but in my view the need is clearer
        > > here
        > > > than in any other area. One of the things I don't love about hiring an
        > > > expert in a given field, at this stage of our research, is that we could
        > > > quickly decide that we're just not interested enough in the field in
        > > > question ... but someone with the right kind of technical knowledge &
        > > > experience would be so far ahead of us in evaluating *any* area of
        > > biology
        > > > research that it seems like a good idea. (JTBC, I'm also actively
        > > thinking
        > > > about whether it would make sense to hire experts in other fields ...)
        > > >
        > > > · Talking to major funders and potentially co-funding with them is
        > > > probably essential. Important groups to talk to would include NIH (by far
        > > > the most important; we've already talked to them a bit), the colloquium
        > > of
        > > > groups like the American Cancer Society (it has a name; I forget the
        > > name),
        > > > FasterCures, Wellcome, and potentially some funders with
        > > > unorthodox/buzzed-about approaches: Myelin Repair Foundation, McKnight
        > > > Foundation, and maybe another private foundation or two (I emailed Dario
        > > > all my notes on major foundations that do biomedical research so he could
        > > > send thoughts on whether any look interesting aside from McKnight).
        > > >
        > > >
        > > > My next plan had been to talk to academics (Dario had good suggestions
        > > > about how to approach them), but with all the potential work to be done
        > > on
        > > > gaining basic context, I'm not sure that's the right next step. But it's
        > > > also a possible step.
        > > >
        > > >
        > > >
        > > > *2. Some more context on the history of our work on biomedical research
        > > and
        > >
        > > > why we think it's appropriate to investigate this field (this was a
        > > > response to a question following my original email, along the lines of
        > > "Why
        > > > are you looking into biomedical research now, given that's an area with a
        > > > lot of buzz and funding from wealthy donors, and how does this work
        > > relate
        > > > to the 'meta-research' work?")*
        > > >
        > > >
        > > > - We've always had "disease research" as a cause we wanted to
        > >
        > > > investigate. We've never had a good reason for not investigating it other
        > > > than that investigating it seems difficult. We've tried more than once to
        > > > investigate it, and it's ended up falling by the wayside because of how
        > > big
        > > > an undertaking it is.
        > > > - It's true that there is a huge amount of funding and buzz in this
        > >
        > > > area. But it also seems quite possible that there isn't nearly enough; in
        > > > fact this seems like a possible point of consensus between all the people
        > > > concerned about the "Valley of Death." This potential good accomplished
        > > via
        > > > biomedical research appears unlimited. What I consider to be the mark of
        > > a
        > > > bad sector is "tons of buzz/$ and mediocre returns," but the latter part
        > > > doesn't apply to biomed; in fact biomedical research is arguably one of
        > > > philanthropy's and even humanity's top success stories.
        > > > - There are also indications that despite all the buzz and funding,
        > >
        > > > there are still opportunities to do things differently and shake things
        > > up.
        > > > There is more than one case where an outsider (Milken, MRF) basically
        > > came
        > > > in and did things very differently and now even experts in the field seem
        > > > to credit them with positive change. There's also a good explanation for
        > > > why this might be the case: while there are a ton of people and dollars,
        > > > they largely seem to play by one self-reinforcing/network-effect-prone
        > > set
        > > > of rules, implying high returns to disrupting that equilibrium.
        > > > - So, we've always wanted to get into this area. There was a period
        > >
        > > > where I was presenting meta-research as our best entry point into this
        > > > field: my vision was that we would talk to academics about what
        > > systematic
        > > > failings there were and what funding opportunities these implied, and
        > > that
        > > > would be as good a way as any to get acclimated in biomed. But this
        > > period
        > > > wasn't particularly long - the May blog post on Labs priority causes
        > > lists
        > > > scientific research as a promising area distinct from meta-research.
        > > > - I set up the call with Dario without having a clear idea of whether I
        > >
        > > > wanted to approach biomed from a "meta-research" angle or another angle.
        > > > After the call and other investigations described here, I got a clearer
        > > > idea of what I think is the best path forward.
        > > >
        > > > Bottom line - I think it's important to build an understanding of
        > > > biomedical research, and that we should take the best path to doing so
        > > > whether or not that dovetails with the meta-research work (likely it will
        > > > dovetail some but not 100%).
        > >
        > >
        > >
        >


      • Aubrey de Grey
        Hi Holden - many thanks. First: yes, there are really three somewhat separate questions for someone trying to evaluate whether to support SENS Foundation: 1)
        Message 3 of 18 , Oct 13, 2012
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          Hi Holden - many thanks.

          First: yes, there are really three somewhat separate questions for someone trying to evaluate whether to support SENS Foundation:

          1) Is the medical control of aging a hugely valuable mission?

          2) Assuming "yes" to (1), is it best achieved by basic research or translational research?

          3) Assuming translational, is SENS Foundation the organisation that uses money most effectively in pursuit of that mission?

          I had rather expected that you would take some convincing on item (1), and much of what I wrote last time was focused on that. Since it isn't the focus of your question to me, I'm now going to assume until further notice that there is no dissent on that.

          So, to answer your question: actually you're not putting aside the basic-vs-translational question as much as you may think you are. The word "translational" is flavour of the month in government funding circles these days (not only in the USA), so it's not surprising that the NIA has a public statement of the kind you pointed to. However, notice that the link they give "for more information" is to a page listing ALL "Funding Opportunity Announcements". There is no page specifically for translational ones, and the reason there isn't is that the amount of work that the NIA actually funds that could really be called translational is tiny. In other words, the page you found is actually just blatant spin. The neuroscience slice you mention is an anomaly arising from the way NIA was founded (the natural place for that money is clearly NINDS): the fact that it's NIA money does not, in practice, translate into its being spent on work to prevent neurodegeneration by treating its cause (aging). Instead, just like NINDS money, it's spent on attacking neurodegeneration directly, as if such diseases could be eliminated from the body just like an infection: the same old mistake that afflicts, and dooms, the whole of geriatric medicine.

          So, the first answer to your question is that SENS Foundation really DOES focus on translational research, with an explicit goal of postponing age-related ill-health. But there's also another big difference: we can attack this problem relatively free of the other priorities that afflict mainstream funding (whether from NIH or from trasitional foundations). Most importantly, though we do and will continue to publish our interim results in the peer-reviewed literature, we are much less constrained by "publish or perish" tyranny than typical academics are. This allows us to proceed by constructing and implementing a rational "project plan" (namely SENS) to get to the intended goal (the defeat of aging), whereas what little translational work is funded by NIA or others is guided overwhelmingly by the imperative to get some kind of positive result as quickly as possible, even when it's understood that those results are not remotely likely to "scale", i.e. to translate into eventual medical treatments that significantly delay aging. A great example of this is the NIA's Interventions Testing Program (ITP) to test the mouse longevity effects of various small molecules. The ITP only exists at all (and in a far smaller form than originally intended) as a result of several years of persistence by the then head of the NIA's biology division (Huber Warner), and it focuses entirely on delivery of simple drugs starting rather early in life, with the result that no information emerges that's relevant to treating people who are already in middle age or older. (This is despite the fact that by far the most high-profile result that the ITP has delivered so far, the benefits of rapamycin, actually WAS a late-onset study: it wasn't meant to be, but technical issues delayed the experiment.) In a nutshell, there is a huge bias against high-risk high-gain work.

          The third thing that distinguishes SENS Foundation's approach is that we can transcend the "balkanisation" (silo mentality) that dominates mainstream academic funding. When one submits a grant application to NIA, it is evaluated by gerontologists, just as when one submits to NCI it is evaluated by oncologists, etc. What's wrong with this is that it biases the system immensely against cross-disciplinary proposals. SENS is a plan that brings together a large body of knowledge from gerontology but also a huge amount of expertise that was developed for other reasons entirely - to treat acute disease/injury, or in some cases for purposes that were not biomedical at all (notably environmental decontamination). It doesn't matter how robust the objective scientific and technological argument is for work of that sort: it will never compete (especially in today's very tight funding environment) with more single-topic proposals all of whose details can be understood by reviewers from a particular single field.

          The final thing to mention, and this actually also answers your question to Vipul about basic versus translational research, is that SENS is a plan that has stood the test of time. I've been propounding it since 2000, well before SENS Foundation existed, and it used to come in for a lot of criticism (initially more in the form of off-the-record ridicule, and latterly, at my behest, in print), but in every single case that criticism was found to stem from ignorance on the part of the detractor, either of what I proposed or of published experimental work on which the proposal was based. That's why I'm now regularly asked to organise entire sessions at mainstream gerontology conferences, whereas as little as five years ago I would never even be invited to speak. It's also why the Research Advisory Board of SENS Foundation consists of such prestigious scientists. This is a very strong argument, in my view, for believing that now is the time to sink a proper amount of money into translational gerontology (though certainly not to cease doin basic biogerontology too). It's well known that basic scientists are often not the most far-sighted when it comes to seeing how to apply their discoveries (attitudes in 1900 to the feasibility of powered flight being the canonical example). It is therefore a source of concern that almost all the experts who have the ear of funders in this field are basic scientists, whose instinct is to carry on finding things out and to deprioritise the tedious business of applying that knowledge. SENS has achieved a gratisfying level of legitimacy in gerontology, but it is still foreign to most card-carrying gerontologists, and as such it remains essentially unfundable via mainstream mechanisms. Hence the need to create a philanthropy-driven entity, SENS Foundation, to get this work done.

          Let me know if this helps, or if you have further questions.

          Cheers, Aubrey

          On 12 Oct 2012, at 15:28, Holden Karnofsky wrote:

          >
          > Hi Aubrey,
          >
          > Thanks for the thoughts.
          >
          > The NIH appears to have a division focused on research relevant to this topic: http://www.nia.nih.gov/research/dab . Its budget appears to be ~$175 million (per year). The National Institute on Aging, which houses this division, has a budget of about $1 billion per year, including a separate ~$400 million for neuroscience (which may also be relevant) as well as $115 million for intramural research. Figures are from http://www.nia.nih.gov/about/budget/2012/fiscal-year-2013-budget. The Institute states that its mandate includes translational research (http://www.nia.nih.gov/research/faq/does-nia-support-translational-research). How would you distinguish your work from this work?
          >
          > (For the moment I'm putting aside the question I raised in my previous response to Vipul on this topic, regarding whether it's best to approach biology funding from the perspective of "trying to treat/cure a particular condition" or "trying to understand fundamental questions in biology whose applications are difficult to predict.")
          >
          > Best,
          > Holden
          >
          > On Fri, Oct 12, 2012 at 7:32 AM, aubrey.degrey <aubrey@...> wrote:
          >
          > Hi everyone,
          >
          > My attention was brought to this thread, by virtue of the fact that it was my work that gave rise to SENS Foundation, and I'm looking forward to getting more involved here; I've held the Effective Altruism movement in high regard for some time. However, given my newbie status here I want to start by apologising in advance for any oversight of previously-discussed issues etc. I'm naturally delighted both at Holden's post and at Vipul's reply (which I should stress that I did not plant! - I do not know Vipul at all, though I look forward to changing that). I would like to mention just a few key points for discussion:
          >
          > - Holden, I want to compliment you on your appreciation of how academia really works. Everything you say about that is spot on. The aversion to "high risk high gain" work that has arisen and become so endemic in the system is the most important point here, in terms of why parallel funding routes are needed.
          >
          > - I'm slightly confused that a lot of Holden's remarks are focused on the private sector (i.e. startups), since my understanding was that GiveWell is about philanthropy; but I realise that there is not all that clear a boundary between the two (and I note the mention of Breakout Labs, with which I have close links and which sits astride that divide more than arguably anyone). The "valley of death" in pre-competitive translational research is a rather different one than that encountered by startups, but the principle is the same, and research to postpone aging certainly encounteres it.
          >
          > - Something that I presume factors highly among GiveWell's criteria is the extent to which a cause may be undervalued by the bulk of major philanthropists, such that an infusion of additional funds would make more of a difference than in an area that is already being well funded. To me this seems to mirror the logic of focusing on the shortcomings (gaps) in NIH's funding (and that of traditional-model foundations). Holden notes that "Anyone we consider for funding ought to be able to explain why they're better at allocating the funds than the NIH" and I agree wholeheartedly, but my inference is that he thinks that some orgs may indeed be able to explain that. I certainly think that SENS Foundation can.
          >
          > - Coming to aging: research to postpone aging has the unique problem of quite indescribeable irrationality on the part of most of the general public, policy-makers and even biologists with regard to its desirability. Biogerontologists have been talking to brick walls for decades in their effort to get the rest of the world to appreciate that aging is what causes age-related ill-health, and thus that treatments for aging are merely preventative geriatrics. The concept persists, despite biogerontologists' best efforts, that aging is "natural" and should be left alone, whereas the diseases that it brings about are awful and should be fought. This is made even more bizarre by the fact that the status of age-related diseases as aspects of the later stages of aging absolutely, unequivocally implies that efforts to attack those diseases directly are doomed to fail. As such, this is a (unique? certainly very rare) case where a philanthropic contribution can make a particularly big difference simply because most philanthropists don't see the case for it. It underpins why having an interest in treating aging, as opposed to cancer, absolutely has a major impact on which projects one funds. It's also a case for (if I understand the term correctly) meta-research.
          >
          > - A lot of the chatter about treating aging revolves around longevity, but it shouldn't. I'm all in favour of longevity, don't get me wrong, but it's not what gets me up in the morning: what does is health. I want people to be truly youthful, however long ago they were born: simple as that. The benefits of longevity per se to humanity may also be substantial, in the form of greater wisdom etc, but that would necessarily come about only very gradually (we won't have any 1000-year-old for at least 900 years whatever happens!), so it doesn't figure strongly in my calculations.
          >
          > - When forced to acknowledge that the idea of aging being a high-priority target for medicine is an inescapeable consequence of things they already believe (notably that health is good and ageism is bad), many people retreat to the standpoint that it's never going to be possible so it's OK to be irrational about whether it's desirable. The feasibility of postponing age-related ill-health by X years with medicine available Y years from now is, of course, a matter of speculation on which experts disagree, just as with any other pioneering technology. I know that Holden and others have expressed caution (at best) concerning the accuracy of any kind of calculation of probabilities of particular outcomes in the distant (or even not-so-distant) future, and I share that view. However, an approach that may appeal more is to estimate how much humanitarian benefit a given amount of progress would deliver, and then to ask how unlikely that scenario needs to be to make it not worth pursuing. My claim is that the benefits of hastening the defeat of aging by even a few years (which is the minimum that I claim SENS Foundation is in a position to do, given adequate funding) would be so astronomical that the required chance of success to make such an effort worthwhile would be tiny - too tiny for it to be reasonable to argue that such funding would be inadvisable. But of course that is precisely what I would want GiveWell to opine on.
          >
          > - In the event that GiveWell (or anyone else) were to decide and declare that the defeat of aging is indeed a cause that philanthropists should support, there then arises the question of which organisation(s) should be supported in the best interests of that mission. We at SENS Foundation have worked diligently to rise as quickly as possible in the legitimacy stakes by all standard measures, but we are still young and there remains more to do. If I were to offer an argument to fund us rather than any other entity, it would largely come down to the fact that no other organisation has even a serious plan for defeating aging, let alone a track record of implementing such a plan's early stages.
          >
          > - A significant chunk of what we do is of a kind that I think comes under "meta-research". A prominent example is a project we're funding at Denver University to extend the well-respected forecasting system "International Futures" so that it can analyse scenarios incorporating dramatically postponed aging.
          >
          > I greatly welcome any feedback.
          >
          > Cheers, Aubrey
          >
          >
          >
          > --- In givewell@yahoogroups.com, Holden Karnofsky <holden0@...> wrote:
          > >
          > > Hi Vipul,
          > >
          > > Thanks for the thoughts. I had a followup conversation with Dario about
          > > this topic a few days ago. I think the question of "could one fund
          > > translational research to treat/prevent aging?" provides an interesting
          > > illustration of some of the tricky dynamics here for a funder:
          > >
          > > - It's possible that if there were a great deal more attention giving to
          >
          > > treating/preventing aging, we would have some promising treatments. So in a
          > > broad sense it's possible that aging is underinvested in.
          > > - A lot of the best basic biology research isn't clearly pointing toward
          >
          > > one treatment/condition or another; it's about understanding the
          > > fundamentals of how organisms operate. So having an interest in treating
          > > aging, as opposed to cancer, might not have a major impact on which
          > > projects one funds, if one's main goal is to fund outstanding basic biology
          > > research.
          > > - Perhaps because of the lack of emphasis on treating aging (or perhaps
          >
          > > because it's simply too difficult of a problem), there don't seem to be
          > > promising findings in the "Valley of Death" relevant to aging; the few
          > > promising leads have been explored.
          > > - So even if, in a broad sense, there is too little attention given to
          >
          > > this problem, knowing this doesn't necessarily yield a clear direction for
          > > a relatively small-scale funder of biomedical research.
          > >
          > > Best,
          > > Holden
          > >
          > > On Wed, Oct 10, 2012 at 11:55 PM, Vipul Naik <vipul@...>wrote:
          > >
          > > > **
          >
          > > >
          > > >
          > > > Holden,
          > > >
          > > > First, I think that this is an excellent document. I checked for a
          > > > number of things that I had heard about (Breakout Labs, John
          > > > Ioannidis, Cochrane Collaboration) and they're all there in your
          > > > document.
          > > >
          > > > The one thing that's not explicitly mentioned: longevity and life
          > > > extension research. At least prima facie, this seems like something
          > > > that should be more important than individual disease research, and it
          > > > seems like a classic "Valley of Death" case (pun unintended, but
          > > > noted) -- T1 stage to use your terminology. I think the SENS website
          > > > http://www.sens.org would be a good starting point for one of the (to
          > > > me promising) approaches to life extension. I recall from past
          > > > conversations that you were aware of SENS, so this is not new to you,
          > > > but I think that longevity should be included as part of any
          > > > discussion of biomedical research and given separate consideration
          > > > given that it has a much lower status than research into specific
          > > > conditions such as cancer, dementia, etc. You may ultimately conclude
          > > > that not enough can be done in this area, but I think it should be
          > > > part of your preliminary stuff. [btw, the United States has a National
          > > > Institute of Aging, but it's much lower-status than most of the other
          > > > grantmakers mentioned here].
          > > >
          > > > Vipul
          > > >
          > > > * Quoting Holden Karnofsky who at 2012-10-10 23:08:42+0000 (Wed) wrote
          > > >
          > > > > Note to the research list: we're now considering reopening our
          > > > > investigation of the world of biomedical research. We've started and
          > > > > stopped a couple of times in this area before; this time I decided to
          > > > start
          > > > > with a conversation with Dario Amodei, a longtime GiveWell follower and
          > > > > personal friend who is currently a biology postdoc at Stanford. My goal
          > > > > with the conversation was just to get some basic context and start
          > > > putting
          > > > > together a framework for thinking about the issue, not to use him as an
          > > > > authoritative source, and the notes below should be read in that spirit.
          > > > >
          > > > >
          > > > > This email has two sections:
          > > > >
          > > > >
          > > > > 1. Notes that I emailed out internally after my conversation with Dario,
          > > > > slightly edited
          > > > >
          > > > > 2. Some more context on the history of our work on biomedical research
          > > > and
          > > > > why we think it's appropriate to investigate this field (this was a
          > > > > response to a question following my original email, along the lines of
          > > > "Why
          > > > > are you looking into biomedical research now, given that's an area with a
          > > > > lot of buzz and funding from wealthy donors, and how does this work
          > > > relate
          > > > > to the 'meta-research' work?")
          > > > >
          > > > >
          > > > >
          > > > > *--*
          > > > >
          > > > > *
          > > > > *
          > > > >
          > > > > *1. Notes that I emailed out internally after my conversation with Dario,
          > > > > slightly edited*
          > > > >
          > > > > *
          > > >
          > > > > *
          > > > >
          > > > > I've done some preliminary work trying to figure out what it would look
          > > > > like to explore biomedical sciences as funding area. This mostly
          > > > consisted
          > > > > of a 3-hour conversation with Dario (recording is available), reading two
          > > > > papers he sent and a few I found while Googling, and prior knowledge. I'm
          > > > > including Dario in all emails related to this stuff, as an informal
          > > > advisor.
          > > > >
          > > > > * *
          > > > >
          > > > > *My picture of "what the biomedical research world roughly looks like"
          > > > *(this
          > > >
          > > > > is mostly from talking with Dario + prior knowledge)
          > > > >
          > > > > · *Academic biology* studies how organisms work and develops tools to
          > > >
          > > > > observe and manipulate the building blocks of organisms.
          > > > >
          > > > > o The vast bulk of the funding - and the most prestigious funding - comes
          > > > > from the NIH.
          > > > >
          > > > > o There is also funding from what I've heard called "foundations" -
          > > > groups
          > > > > like the American Cancer Society and American Heart Association - which
          > > > > function very similarly to the NIH, in that they tend to hire people with
          > > > > strong academic credentials and those people judge the merits of grant
          > > > > proposals.
          > > > >
          > > > > o Both the NIH and "foundations" tend to be formally partitioned by
          > > > > disease, but much of the work done by academic biologists is potentially
          > > > > relevant to many diseases. A researcher seeking NIH funding may apply to
          > > > > several different NIH "study sections," though only one at a time (a list
          > > > > of "study sections" is at
          > > > > http://public.csr.nih.gov/StudySections/Standing/Pages/default.aspx);
          > > > > whether s/he gets funding is going to depend more on the academic merits
          > > > of
          > > > > the researcher & work than anything else.
          > > > >
          > > > > o There are basic definitions of "academic merit " that generally shape
          > > > > the whole ecosystem: the people handing out money are selected by these
          > > > > criteria and use these criteria, the people doing the research know that
          > > > > these criteria shape their career prospects, etc.
          > > > >
          > > > > · *Private startups* investigate promising ideas for new
          > > >
          > > > > treatments/diagnostics/devices. They may often take the form of a biology
          > > > > professor spinning off a biotech startup (run by former postdocs) that
          > > > > raises venture capital, based on the research the professor did. They
          > > > take
          > > > > basic knowledge about how the body works (for example, protein X is
          > > > crucial
          > > > > for medical condition Y) and do the necessary testing to find a promising
          > > > > treatment/diagnostic/device (for example, testing a lot of compounds on
          > > > > animals until they find one that affects protein X).
          > > > >
          > > > > · *Big pharma/biotech companies *are best positioned to deal with the
          > > >
          > > > > extremely expensive process of conducting clinical trials and getting FDA
          > > > > approval. Acquisition by one of these is the most common form of exit for
          > > > > startups.
          > > > >
          > > > > · *Academic medicine, epidemiology and other fields* also do work
          > > >
          > > > > relevant to medicine, including studying questions whose main relevance
          > > > is
          > > > > to medical practice and public health programs: how effective is
          > > > > treatment/practice X in situation Y, how cost-effective is it, etc.
          > > > > Sometimes they will hit on commercializable insights (for example, a new
          > > > > kind of device) as well.
          > > > >
          > > > > · *Translational research* is a broad term referring to a bridge between
          > > >
          > > > > academic research and treatments/practices. It can include (
          > > > >
          > > > http://medicalcenter.osu.edu/research/translational_research/pages/index.aspx
          > > > > ):
          > > > >
          > > > > o T1 - going from basic science (usually academic biology, I presume) to
          > > > a
          > > > > new treatment/practice. This includes research that helps go from an
          > > > > academic biology insight to a private startup.
          > > > >
          > > > > o T2 - I think this is basically what Cochrane does - going from academic
          > > > > medicine/epidemiology (a bunch of studies on what treatments/practices
          > > > are
          > > > > effective) to the development of guidelines that actually affect
          > > > practice.
          > > > >
          > > > > o T3, T4 - research on how to actually change practice (as opposed to
          > > > > setting the guidelines that are a "target" for practice) and get better
          > > > > real-world results.
          > > > >
          > > > > *
          > > > > *
          > > > >
          > > > > *Potential "big opportunity to do good" #1: translational research and
          > > > the
          > > >
          > > > > "Valley of Death" (this comes from prior knowledge, googling "Valley of
          > > > > Death" and reading a bunch of the stuff I found, and checking out the
          > > > > FasterCures website again)*
          > > >
          > > > >
          > > > >
          > > > >
          > > > > The "Valley of Death" seems to mostly refer to a shortage of T1. The idea
          > > > > is that there are a lot of cases where there's an academic insight that's
          > > > > potentially valuable in coming up with a new treatment, but to get it to
          > > > > the point where it's attractive from a for-profit perspective, you need
          > > > to
          > > > > do a lot of stuff that academics don't have a reason to do. "For example,
          > > > > an upstream finding that a given protein is differentially expressed in
          > > > > individuals with a particular disease may suggest that the protein merits
          > > > > further investigation. However, much more work (especially medicinal
          > > > > chemistry) is necessary to determine how good a target the protein really
          > > > > is and whether a marketable drug candidate that affects the activity of
          > > > the
          > > > > protein is likely to be developed." (
          > > > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf)
          > > > >
          > > > >
          > > > >
          > > > > There are claims that this sort of work is massively underfunded (by the
          > > > > people we've spoken to who talked about the "Valley of Death"; also in
          > > > >
          > > > http://www.fastercures.org/documents/file/Valley%20of%20Death%20-%20Translational%20Research
          > > > (1).pdf).
          > > > > However, funding isn't the only issue. The other issue is that
          > > > > "pharmaceutical firms that hold libraries of potentially useful small
          > > > > molecules as trade secrets, making them largely off limits to ...
          > > > academic
          > > > > scientists" (
          > > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf).
          > > > > In other words, there is some room for new models of collaboration that
          > > > > lead to better communication and information sharing between academia and
          > > > > industry (or between industry and industry).
          > > > >
          > > > >
          > > > > Both the Myelin Repair Foundation and Michael Milken's work on prostate
          > > > > cancer have been pointed to as examples of innovative collaborations that
          > > > > deal with some of the information sharing problems. Milken's model:
          > > > > "drastically cutting the wait time for grant money, to flood the field
          > > > with
          > > > > fast cash, to fund therapy-driven ideas rather than basic science, to
          > > > hold
          > > > > researchers he funds accountable for results, and to demand collaboration
          > > > > across disciplines and among institutions, private industry, and
          > > > academia."
          > > > > (
          > > > >
          > > > http://money.cnn.com/magazines/fortune/fortune_archive/2004/11/29/8192713/index.htm
          > > > )
          > > > > Myelin Repair Foundation sounds broadly similar (
          > > > >
          > > > http://opinionator.blogs.nytimes.com/2011/05/02/helping-new-drugs-out-of-academias-valley-of-death/
          > > > ).
          > > > >
          > > > >
          > > > >
          > > > >
          > > > > More broadly:
          > > > >
          > > > > · FasterCures (also a Michael Milken production) looks like it's focused
          > > > > on the broad mission of "more research with a shorter timeline to
          > > > > treatments," with a heavy sub-focus on the Valley of Death. In addition
          > > > to
          > > > > its conference and philanthropic advisory service, it advocates for FDA
          > > > > improvements (presumably to speed the approval process), advocates for
          > > > the
          > > > > NIH to put more funding into translational research (there have
          > > > definitely
          > > > > been a lot of new initiatives at the NIH focused on this stuff in the
          > > > past
          > > > > few ~decade), promotes "innovative financing mechanisms" for bridging the
          > > > > Valley of Death (these include Peter Thiel's Breakout Labs; I think they
          > > > > occupy a conceptually similar space to "social enterprise investment"
          > > > > though they tend to be structured more as grants and less as
          > > > > double-bottom-line investments), and works on getting patient data opened
          > > > > to researchers. The only program of theirs I haven't mentioned is TRAIN;
          > > > I
          > > > > can't (easily) figure out what this is.
          > > > >
          > > > > · John Ioannidis stated to us that all translational research is
          > > > > underfunded, not just T1. (The context we talked to him in, of course,
          > > > was
          > > > > T2.)
          > > > >
          > > > >
          > > > > These issues seem to have quite a bit of buzz. There are some really
          > > > stark
          > > > > #'s out there: even as R&D investment has gone way up over the past 50
          > > > > years, the # of new drugs has stayed roughly constant at around 20 a
          > > > year.
          > > > >
          > > > >
          > > > > Dario sent a really interesting paper on this topic. It argues: (a) the #
          > > > > of NMEs (new medical entities, i.e., drugs) per year has mostly remained
          > > > > constant-with-noise (no trend); (b) all of the big companies seem to have
          > > > > produced NMEs at a very steady pace, even as they've changed size, though
          > > > > different companies do have different rates of NME creation; (c) when it
          > > > > comes to mergers & acquisitions, "1+1=1": companies that acquire other
          > > > > companies just keep up the same NME pace; (d) over time, the # of large
          > > > > companies has shrunk (due to mergers) and the # of small companies has
          > > > > risen, and the share of NMEs attributed to small companies has gone from
          > > > > ~30% to ~70%; (e) the cost per NME has gone up over time and is now in
          > > > the
          > > > > neighborhood of $1 billion; (f) the % of NMEs that are "blockbusters"
          > > > (huge
          > > > > profits) has been steady around 20%, despite intensifying efforts on the
          > > > > part of pharma to fund only potential blockbusters.
          > > > >
          > > > >
          > > > >
          > > > > There are also claims - such as by Derek Lowe, a blogger Dario pointed me
          > > > > to - that the "Valley of Death" is an overrated concept: there is a high
          > > > > ratio of academic discoveries to useful drugs, but this is just because a
          > > > > lot of stuff turns out not to work, not because we have a shortage of
          > > > > doable translational research. The paper above sort of takes this view,
          > > > > essentially arguing that nothing seems to raise NME production; we'll
          > > > need
          > > > > something really radical to make any difference.
          > > > >
          > > > >
          > > > >
          > > > > The case studies in the FasterCures paper on this are interesting. They
          > > > > imply that there were some pretty low-hanging fruit in the T1 domain. It
          > > > > might be interesting to talk to Fastercures and see whether they can help
          > > > > identify "Valley of Death" opportunities that are slam-dunkish.
          > > > >
          > > > >
          > > > > *Potential "big opportunity to do good" #2: inefficiencies in academic
          > > > > biology*
          > > >
          > > > >
          > > > >
          > > > >
          > > > > All of the above seems pretty distinct from the question of how to make
          > > > > academic biology better at doing its job of understanding the body. This
          > > > is
          > > > > the question that Dario and I focused on.
          > > > >
          > > > >
          > > > >
          > > > > Dario painted a picture in which most of academia plays by the same set
          > > > of
          > > > > rules, making it very hard for people to do things that break those rules
          > > > > (for example, academics are expected to publish a lot; it's risky to work
          > > > > on a "blue sky" or highly ambitious project). Thus, for anyone who wants
          > > > a
          > > > > career in academia, a couple of years working on a moonshot project are
          > > > > risky; in addition, being on bad terms with a small number of people can
          > > > > damage a career (since there is often a small set of people that makes a
          > > > > large proportion of the career-impacting decisions for a given area, and
          > > > it
          > > > > can be hard to escape this set of people without changing research
          > > > > interests significantly). The bad news is that this isn't particularly
          > > > easy
          > > > > to fix: you can offer funding for blue-sky projects, but (a) a lot of
          > > > > academics basically train themselves to play by the rules, and won't
          > > > > necessarily have thought about "what should be studied if these rules
          > > > > didn't apply," and more importantly, (b) there are many incentives
          > > > pushing
          > > > > academics towards playing by certain rules; funding is only one of those
          > > > > mechanisms (there's also tenure, peer review, etc) so changing that one
          > > > > incentive won't always change behavior. Dario says that he might hesitate
          > > > > to work on a particular blue-sky project that he thinks is interesting,
          > > > > even if he got funding for it, for these reasons.
          > > > >
          > > > >
          > > > > Despite this, there are some funders who push the boundaries. There are
          > > > > medical centers that don't require teaching and do more ambitious work.
          > > > > There's the McKnight foundation, which funded some of the pioneering work
          > > > > on optical control of neurons for which funding might have been difficult
          > > > > to obtain by traditional routes. There's the HHMI Janelia Farms campus,
          > > > > which Dario thinks is the most promising thing out there in terms of a
          > > > > model - academics who go there get guaranteed (and generous) funding for
          > > > 6
          > > > > years, which frees them up to take much bigger risks. (I saw a study
          > > > > claiming that the work coming out of Janelia Farms has a much more skewed
          > > > > citation count distribution, implying bigger risks - i.e., fewer papers
          > > > > with decent #'s of citations but more "blockbuster" papers with lots of
          > > > > citations). But Janelia Farms is only in one sub-field; comparable
          > > > > institutions don't exist for other fields (as far as Dario knows)..
          > > > >
          > > > >
          > > > >
          > > > > Dario's gut is that one of the best things a funder could do would be to
          > > > > work toward creating a large institute that largely "plays by its own
          > > > > rules," encouraging more ambitious work and providing enough security and
          > > > > sheer volume of dollars/researchers as to establish a sort of "parallel
          > > > > system" to academia - thus becoming a place that could provide viable and
          > > > > reliable career options for people interested in playing by different
          > > > > rules. I'm also interested in the idea of trying to advocate for changes
          > > > in
          > > > > the rules, as we've discussed in the context of meta-research.
          > > > >
          > > > >
          > > > >
          > > > > There's also the other stuff like data/code sharing.
          > > > >
          > > > >
          > > > >
          > > > > *Another option: give $ to the NIH*
          > > >
          > > > >
          > > > >
          > > > >
          > > > > The NIH is by far the largest, most prestigious, most respected funder in
          > > > > academic biology, and most of academia runs on criteria that mirror the
          > > > > NIH's. I would guess that an unrestricted check to the NIH would get
          > > > > allocated in a pretty sector-agnostic way. It seems like this is a giving
          > > > > option that is pretty nontrivial to beat. Anyone we consider for funding
          > > > > ought to be able to explain why they're better at allocating the funds
          > > > than
          > > > > the NIH. We haven't talked to the NIH about whether it would accept these
          > > > > sorts of donations.
          > > > >
          > > > >
          > > > > With the context I now have, FasterCures strikes me as pretty
          > > > > promising/interesting too, though their "room for more funding" situation
          > > > > isn't clear (w/o talking to them). But they also seem sector-agnostic
          > > > > within biomedical research, while pushing a very specific theory of
          > > > change
          > > > > that may or may not be valid.
          > > > >
          > > > >
          > > > >
          > > > > *Next steps*
          > > >
          > > > >
          > > > >
          > > > >
          > > > > I think understanding this world would be a major undertaking. I think
          > > > we'd
          > > > > have to be ready to put in a lot of work and to be open to ways of
          > > > bridging
          > > > > "funder-expert gap" that we haven't tried before. For example:
          > > > >
          > > > > · Dario suggested that I read a freshman biology textbook. He said he
          > > > > realizes that the time cost could be very large - something like 100
          > > > hours
          > > > > - but that without doing so, I'm going to be lacking too much context on
          > > > > why biomedical research works the way it does. He thinks that reading a
          > > > > basic textbook would get me to the point of strongly diminishing marginal
          > > > > returns.
          > > > >
          > > > > · Also in the category of "personally picking up rudimentary subject
          > > > > matter knowledge," I thought it might be worth trying to follow the
          > > > > development of a particular drug from start to finish - Gleevec (the
          > > > > "miracle drug") would be a good candidate. The goal would be to
          > > > understand
          > > > > each stage of insight leading to new investigation, and where the funding
          > > > > came from at each stage.
          > > > >
          > > > > · I think hiring Dario or someone like him would make a lot of sense.
          > > > > I've thought about whether we should be hiring "subject matter experts"
          > > > in
          > > > > other areas, such as global health, but in my view the need is clearer
          > > > here
          > > > > than in any other area. One of the things I don't love about hiring an
          > > > > expert in a given field, at this stage of our research, is that we could
          > > > > quickly decide that we're just not interested enough in the field in
          > > > > question ... but someone with the right kind of technical knowledge &
          > > > > experience would be so far ahead of us in evaluating *any* area of
          > > > biology
          > > > > research that it seems like a good idea. (JTBC, I'm also actively
          > > > thinking
          > > > > about whether it would make sense to hire experts in other fields ...)
          > > > >
          > > > > · Talking to major funders and potentially co-funding with them is
          > > > > probably essential. Important groups to talk to would include NIH (by far
          > > > > the most important; we've already talked to them a bit), the colloquium
          > > > of
          > > > > groups like the American Cancer Society (it has a name; I forget the
          > > > name),
          > > > > FasterCures, Wellcome, and potentially some funders with
          > > > > unorthodox/buzzed-about approaches: Myelin Repair Foundation, McKnight
          > > > > Foundation, and maybe another private foundation or two (I emailed Dario
          > > > > all my notes on major foundations that do biomedical research so he could
          > > > > send thoughts on whether any look interesting aside from McKnight).
          > > > >
          > > > >
          > > > > My next plan had been to talk to academics (Dario had good suggestions
          > > > > about how to approach them), but with all the potential work to be done
          > > > on
          > > > > gaining basic context, I'm not sure that's the right next step. But it's
          > > > > also a possible step.
          > > > >
          > > > >
          > > > >
          > > > > *2. Some more context on the history of our work on biomedical research
          > > > and
          > > >
          > > > > why we think it's appropriate to investigate this field (this was a
          > > > > response to a question following my original email, along the lines of
          > > > "Why
          > > > > are you looking into biomedical research now, given that's an area with a
          > > > > lot of buzz and funding from wealthy donors, and how does this work
          > > > relate
          > > > > to the 'meta-research' work?")*
          > > > >
          > > > >
          > > > > - We've always had "disease research" as a cause we wanted to
          > > >
          > > > > investigate. We've never had a good reason for not investigating it other
          > > > > than that investigating it seems difficult. We've tried more than once to
          > > > > investigate it, and it's ended up falling by the wayside because of how
          > > > big
          > > > > an undertaking it is.
          > > > > - It's true that there is a huge amount of funding and buzz in this
          > > >
          > > > > area. But it also seems quite possible that there isn't nearly enough; in
          > > > > fact this seems like a possible point of consensus between all the people
          > > > > concerned about the "Valley of Death." This potential good accomplished
          > > > via
          > > > > biomedical research appears unlimited. What I consider to be the mark of
          > > > a
          > > > > bad sector is "tons of buzz/$ and mediocre returns," but the latter part
          > > > > doesn't apply to biomed; in fact biomedical research is arguably one of
          > > > > philanthropy's and even humanity's top success stories.
          > > > > - There are also indications that despite all the buzz and funding,
          > > >
          > > > > there are still opportunities to do things differently and shake things
          > > > up.
          > > > > There is more than one case where an outsider (Milken, MRF) basically
          > > > came
          > > > > in and did things very differently and now even experts in the field seem
          > > > > to credit them with positive change. There's also a good explanation for
          > > > > why this might be the case: while there are a ton of people and dollars,
          > > > > they largely seem to play by one self-reinforcing/network-effect-prone
          > > > set
          > > > > of rules, implying high returns to disrupting that equilibrium.
          > > > > - So, we've always wanted to get into this area. There was a period
          > > >
          > > > > where I was presenting meta-research as our best entry point into this
          > > > > field: my vision was that we would talk to academics about what
          > > > systematic
          > > > > failings there were and what funding opportunities these implied, and
          > > > that
          > > > > would be as good a way as any to get acclimated in biomed. But this
          > > > period
          > > > > wasn't particularly long - the May blog post on Labs priority causes
          > > > lists
          > > > > scientific research as a promising area distinct from meta-research.
          > > > > - I set up the call with Dario without having a clear idea of whether I
          > > >
          > > > > wanted to approach biomed from a "meta-research" angle or another angle.
          > > > > After the call and other investigations described here, I got a clearer
          > > > > idea of what I think is the best path forward.
          > > > >
          > > > > Bottom line - I think it's important to build an understanding of
          > > > > biomedical research, and that we should take the best path to doing so
          > > > > whether or not that dovetails with the meta-research work (likely it will
          > > > > dovetail some but not 100%).
          > > >
          > > >
          > > >
          > >
          >
          >
          >
          >
          >
        • Holden Karnofsky
          Hi Aubrey, Thanks again for engaging so thoughtfully. I agree that a new technology/treatment that could delay or reverse aging (or aspects of it) would be
          Message 4 of 18 , Oct 13, 2012
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            Hi Aubrey,

            Thanks again for engaging so thoughtfully.

            I agree that a new technology/treatment that could delay or reverse aging (or aspects of it) would be enormously valuable. Regarding the rest of your argument, this is a good example of the challenges I've been discussing in understanding biomedical research.

            You state that you have a high-expected-value plan that the academic world can't recognize the value of because of shortcomings such as "balkanisation" and risk aversion. I believe it may be true that the academic world has such problems to a degree; however, I also believe that there are a lot of extremely talented people in academia and that they often (though not necessarily always) find ways to move forward on promising work. Without more subject-matter expertise (or the advice of someone with such expertise), I can't easily assess the technical merits of your argument or potential counterarguments. Hopefully we'll have a better system for doing so at some point in the future.

            I'll be very interested to see Dario's thoughts on the matter if he responds. I'd cite Dario as an example of an academic who ultimately wants to do work of the greatest humanitarian value possible, regardless of whether it is prestigious work. And as my summary of our conversation shows, he acknowledges that the world of biomedical research may have certain suboptimal incentives, but didn't seem to think that these issues are leaving specific, visible outstanding research programs on the table the way that your email implies.

            Best,
            Holden

            On Sat, Oct 13, 2012 at 6:24 AM, Aubrey de Grey <aubrey@...> wrote:
            Hi Holden - many thanks.

            First: yes, there are really three somewhat separate questions for someone trying to evaluate whether to support SENS Foundation:

            1) Is the medical control of aging a hugely valuable mission?

            2) Assuming "yes" to (1), is it best achieved by basic research or translational research?

            3) Assuming translational, is SENS Foundation the organisation that uses money most effectively in pursuit of that mission?

            I had rather expected that you would take some convincing on item (1), and much of what I wrote last time was focused on that. Since it isn't the focus of your question to me, I'm now going to assume until further notice that there is no dissent on that.

            So, to answer your question: actually you're not putting aside the basic-vs-translational question as much as you may think you are. The word "translational" is flavour of the month in government funding circles these days (not only in the USA), so it's not surprising that the NIA has a public statement of the kind you pointed to. However, notice that the link they give "for more information" is to a page listing ALL "Funding Opportunity Announcements". There is no page specifically for translational ones, and the reason there isn't is that the amount of work that the NIA actually funds that could really be called translational is tiny. In other words, the page you found is actually just blatant spin. The neuroscience slice you mention is an anomaly arising from the way NIA was founded (the natural place for that money is clearly NINDS): the fact that it's NIA money does not, in practice, translate into its being spent on work to prevent neurodegeneration by treating its cause (aging). Instead, just like NINDS money, it's spent on attacking neurodegeneration directly, as if such diseases could be eliminated from the body just like an infection: the same old mistake that afflicts, and dooms, the whole of geriatric medicine.

            So, the first answer to your question is that SENS Foundation really DOES focus on translational research, with an explicit goal of postponing age-related ill-health. But there's also another big difference: we can attack this problem relatively free of the other priorities that afflict mainstream funding (whether from NIH or from trasitional foundations). Most importantly, though we do and will continue to publish our interim results in the peer-reviewed literature, we are much less constrained by "publish or perish" tyranny than typical academics are. This allows us to proceed by constructing and implementing a rational "project plan" (namely SENS) to get to the intended goal (the defeat of aging), whereas what little translational work is funded by NIA or others is guided overwhelmingly by the imperative to get some kind of positive result as quickly as possible, even when it's understood that those results are not remotely likely to "scale", i.e. to translate into eventual medical treatments that significantly delay aging. A great example of this is the NIA's Interventions Testing Program (ITP) to test the mouse longevity effects of various small molecules. The ITP only exists at all (and in a far smaller form than originally intended) as a result of several years of persistence by the then head of the NIA's biology division (Huber Warner), and it focuses entirely on delivery of simple drugs starting rather early in life, with the result that no information emerges that's relevant to treating people who are already in middle age or older. (This is despite the fact that by far the most high-profile result that the ITP has delivered so far, the benefits of rapamycin, actually WAS a late-onset study: it wasn't meant to be, but technical issues delayed the experiment.) In a nutshell, there is a huge bias against high-risk high-gain work.

            The third thing that distinguishes SENS Foundation's approach is that we can transcend the "balkanisation" (silo mentality) that dominates mainstream academic funding. When one submits a grant application to NIA, it is evaluated by gerontologists, just as when one submits to NCI it is evaluated by oncologists, etc. What's wrong with this is that it biases the system immensely against cross-disciplinary proposals. SENS is a plan that brings together a large body of knowledge from gerontology but also a huge amount of expertise that was developed for other reasons entirely - to treat acute disease/injury, or in some cases for purposes that were not biomedical at all (notably environmental decontamination). It doesn't matter how robust the objective scientific and technological argument is for work of that sort: it will never compete (especially in today's very tight funding environment) with more single-topic proposals all of whose details can be understood by reviewers from a particular single field.

            The final thing to mention, and this actually also answers your question to Vipul about basic versus translational research, is that SENS is a plan that has stood the test of time. I've been propounding it since 2000, well before SENS Foundation existed, and it used to come in for a lot of criticism (initially more in the form of off-the-record ridicule, and latterly, at my behest, in print), but in every single case that criticism was found to stem from ignorance on the part of the detractor, either of what I proposed or of published experimental work on which the proposal was based. That's why I'm now regularly asked to organise entire sessions at mainstream gerontology conferences, whereas as little as five years ago I would never even be invited to speak. It's also why the Research Advisory Board of SENS Foundation consists of such prestigious scientists. This is a very strong argument, in my view, for believing that now is the time to sink a proper amount of money into translational gerontology (though certainly not to cease doin basic biogerontology too). It's well known that basic scientists are often not the most far-sighted when it comes to seeing how to apply their discoveries (attitudes in 1900 to the feasibility of powered flight being the canonical example). It is therefore a source of concern that almost all the experts who have the ear of funders in this field are basic scientists, whose instinct is to carry on finding things out and to deprioritise the tedious business of applying that knowledge. SENS has achieved a gratisfying level of legitimacy in gerontology, but it is still foreign to most card-carrying gerontologists, and as such it remains essentially unfundable via mainstream mechanisms. Hence the need to create a philanthropy-driven entity, SENS Foundation, to get this work done.

            Let me know if this helps, or if you have further questions.

            Cheers, Aubrey

            On 12 Oct 2012, at 15:28, Holden Karnofsky wrote:

            >
            > Hi Aubrey,
            >
            > Thanks for the thoughts.
            >
            > The NIH appears to have a division focused on research relevant to this topic: http://www.nia.nih.gov/research/dab . Its budget appears to be ~$175 million (per year). The National Institute on Aging, which houses this division, has a budget of about $1 billion per year, including a separate ~$400 million for neuroscience (which may also be relevant) as well as $115 million for intramural research. Figures are from http://www.nia.nih.gov/about/budget/2012/fiscal-year-2013-budget. The Institute states that its mandate includes translational research (http://www.nia.nih.gov/research/faq/does-nia-support-translational-research). How would you distinguish your work from this work?
            >
            > (For the moment I'm putting aside the question I raised in my previous response to Vipul on this topic, regarding whether it's best to approach biology funding from the perspective of "trying to treat/cure a particular condition" or "trying to understand  fundamental questions in biology whose applications are difficult to predict.")
            >
            > Best,
            > Holden
            >
            > On Fri, Oct 12, 2012 at 7:32 AM, aubrey.degrey <aubrey@...> wrote:
            >
            > Hi everyone,
            >
            > My attention was brought to this thread, by virtue of the fact that it was my work that gave rise to SENS Foundation, and I'm looking forward to getting more involved here; I've held the Effective Altruism movement in high regard for some time. However, given my newbie status here I want to start by apologising in advance for any oversight of previously-discussed issues etc. I'm naturally delighted both at Holden's post and at Vipul's reply (which I should stress that I did not plant! - I do not know Vipul at all, though I look forward to changing that). I would like to mention just a few key points for discussion:
            >
            > - Holden, I want to compliment you on your appreciation of how academia really works. Everything you say about that is spot on. The aversion to "high risk high gain" work that has arisen and become so endemic in the system is the most important point here, in terms of why parallel funding routes are needed.
            >
            > - I'm slightly confused that a lot of Holden's remarks are focused on the private sector (i.e. startups), since my understanding was that GiveWell is about philanthropy; but I realise that there is not all that clear a boundary between the two (and I note the mention of Breakout Labs, with which I have close links and which sits astride that divide more than arguably anyone). The "valley of death" in pre-competitive translational research is a rather different one than that encountered by startups, but the principle is the same, and research to postpone aging certainly encounteres it.
            >
            > - Something that I presume factors highly among GiveWell's criteria is the extent to which a cause may be undervalued by the bulk of major philanthropists, such that an infusion of additional funds would make more of a difference than in an area that is already being well funded. To me this seems to mirror the logic of focusing on the shortcomings (gaps) in NIH's funding (and that of traditional-model foundations). Holden notes that "Anyone we consider for funding ought to be able to explain why they're better at allocating the funds than the NIH" and I agree wholeheartedly, but my inference is that he thinks that some orgs may indeed be able to explain that. I certainly think that SENS Foundation can.
            >
            > - Coming to aging: research to postpone aging has the unique problem of quite indescribeable irrationality on the part of most of the general public, policy-makers and even biologists with regard to its desirability. Biogerontologists have been talking to brick walls for decades in their effort to get the rest of the world to appreciate that aging is what causes age-related ill-health, and thus that treatments for aging are merely preventative geriatrics. The concept persists, despite biogerontologists' best efforts, that aging is "natural" and should be left alone, whereas the diseases that it brings about are awful and should be fought. This is made even more bizarre by the fact that the status of age-related diseases as aspects of the later stages of aging absolutely, unequivocally implies that efforts to attack those diseases directly are doomed to fail. As such, this is a (unique? certainly very rare) case where a philanthropic contribution can make a particularly big difference simply because most philanthropists don't see the case for it. It underpins why having an interest in treating aging, as opposed to cancer, absolutely has a major impact on which projects one funds. It's also a case for (if I understand the term correctly) meta-research.
            >
            > - A lot of the chatter about treating aging revolves around longevity, but it shouldn't. I'm all in favour of longevity, don't get me wrong, but it's not what gets me up in the morning: what does is health. I want people to be truly youthful, however long ago they were born: simple as that. The benefits of longevity per se to humanity may also be substantial, in the form of greater wisdom etc, but that would necessarily come about only very gradually (we won't have any 1000-year-old for at least 900 years whatever happens!), so it doesn't figure strongly in my calculations.
            >
            > - When forced to acknowledge that the idea of aging being a high-priority target for medicine is an inescapeable consequence of things they already believe (notably that health is good and ageism is bad), many people retreat to the standpoint that it's never going to be possible so it's OK to be irrational about whether it's desirable. The feasibility of postponing age-related ill-health by X years with medicine available Y years from now is, of course, a matter of speculation on which experts disagree, just as with any other pioneering technology. I know that Holden and others have expressed caution (at best) concerning the accuracy of any kind of calculation of probabilities of particular outcomes in the distant (or even not-so-distant) future, and I share that view. However, an approach that may appeal more is to estimate how much humanitarian benefit a given amount of progress would deliver, and then to ask how unlikely that scenario needs to be to make it not worth pursuing. My claim is that the benefits of hastening the defeat of aging by even a few years (which is the minimum that I claim SENS Foundation is in a position to do, given adequate funding) would be so astronomical that the required chance of success to make such an effort worthwhile would be tiny - too tiny for it to be reasonable to argue that such funding would be inadvisable. But of course that is precisely what I would want GiveWell to opine on.
            >
            > - In the event that GiveWell (or anyone else) were to decide and declare that the defeat of aging is indeed a cause that philanthropists should support, there then arises the question of which organisation(s) should be supported in the best interests of that mission. We at SENS Foundation have worked diligently to rise as quickly as possible in the legitimacy stakes by all standard measures, but we are still young and there remains more to do. If I were to offer an argument to fund us rather than any other entity, it would largely come down to the fact that no other organisation has even a serious plan for defeating aging, let alone a track record of implementing such a plan's early stages.
            >
            > - A significant chunk of what we do is of a kind that I think comes under "meta-research". A prominent example is a project we're funding at Denver University to extend the well-respected forecasting system "International Futures" so that it can analyse scenarios incorporating dramatically postponed aging.
            >
            > I greatly welcome any feedback.
            >
            > Cheers, Aubrey
            >
            >
            >
            > --- In givewell@yahoogroups.com, Holden Karnofsky <holden0@...> wrote:
            > >
            > > Hi Vipul,
            > >
            > > Thanks for the thoughts. I had a followup conversation with Dario about
            > > this topic a few days ago. I think the question of "could one fund
            > > translational research to treat/prevent aging?" provides an interesting
            > > illustration of some of the tricky dynamics here for a funder:
            > >
            > > - It's possible that if there were a great deal more attention giving to
            >
            > > treating/preventing aging, we would have some promising treatments. So in a
            > > broad sense it's possible that aging is underinvested in.
            > > - A lot of the best basic biology research isn't clearly pointing toward
            >
            > > one treatment/condition or another; it's about understanding the
            > > fundamentals of how organisms operate. So having an interest in treating
            > > aging, as opposed to cancer, might not have a major impact on which
            > > projects one funds, if one's main goal is to fund outstanding basic biology
            > > research.
            > > - Perhaps because of the lack of emphasis on treating aging (or perhaps
            >
            > > because it's simply too difficult of a problem), there don't seem to be
            > > promising findings in the "Valley of Death" relevant to aging; the few
            > > promising leads have been explored.
            > > - So even if, in a broad sense, there is too little attention given to
            >
            > > this problem, knowing this doesn't necessarily yield a clear direction for
            > > a relatively small-scale funder of biomedical research.
            > >
            > > Best,
            > > Holden
            > >
            > > On Wed, Oct 10, 2012 at 11:55 PM, Vipul Naik <vipul@...>wrote:
            > >
            > > > **
            >
            > > >
            > > >
            > > > Holden,
            > > >
            > > > First, I think that this is an excellent document. I checked for a
            > > > number of things that I had heard about (Breakout Labs, John
            > > > Ioannidis, Cochrane Collaboration) and they're all there in your
            > > > document.
            > > >
            > > > The one thing that's not explicitly mentioned: longevity and life
            > > > extension research. At least prima facie, this seems like something
            > > > that should be more important than individual disease research, and it
            > > > seems like a classic "Valley of Death" case (pun unintended, but
            > > > noted) -- T1 stage to use your terminology. I think the SENS website
            > > > http://www.sens.org would be a good starting point for one of the (to
            > > > me promising) approaches to life extension. I recall from past
            > > > conversations that you were aware of SENS, so this is not new to you,
            > > > but I think that longevity should be included as part of any
            > > > discussion of biomedical research and given separate consideration
            > > > given that it has a much lower status than research into specific
            > > > conditions such as cancer, dementia, etc. You may ultimately conclude
            > > > that not enough can be done in this area, but I think it should be
            > > > part of your preliminary stuff. [btw, the United States has a National
            > > > Institute of Aging, but it's much lower-status than most of the other
            > > > grantmakers mentioned here].
            > > >
            > > > Vipul
            > > >
            > > > * Quoting Holden Karnofsky who at 2012-10-10 23:08:42+0000 (Wed) wrote
            > > >
            > > > > Note to the research list: we're now considering reopening our
            > > > > investigation of the world of biomedical research. We've started and
            > > > > stopped a couple of times in this area before; this time I decided to
            > > > start
            > > > > with a conversation with Dario Amodei, a longtime GiveWell follower and
            > > > > personal friend who is currently a biology postdoc at Stanford. My goal
            > > > > with the conversation was just to get some basic context and start
            > > > putting
            > > > > together a framework for thinking about the issue, not to use him as an
            > > > > authoritative source, and the notes below should be read in that spirit.
            > > > >
            > > > >
            > > > > This email has two sections:
            > > > >
            > > > >
            > > > > 1. Notes that I emailed out internally after my conversation with Dario,
            > > > > slightly edited
            > > > >
            > > > > 2. Some more context on the history of our work on biomedical research
            > > > and
            > > > > why we think it's appropriate to investigate this field (this was a
            > > > > response to a question following my original email, along the lines of
            > > > "Why
            > > > > are you looking into biomedical research now, given that's an area with a
            > > > > lot of buzz and funding from wealthy donors, and how does this work
            > > > relate
            > > > > to the 'meta-research' work?")
            > > > >
            > > > >
            > > > >
            > > > > *--*
            > > > >
            > > > > *
            > > > > *
            > > > >
            > > > > *1. Notes that I emailed out internally after my conversation with Dario,
            > > > > slightly edited*
            > > > >
            > > > > *
            > > >
            > > > > *
            > > > >
            > > > > I've done some preliminary work trying to figure out what it would look
            > > > > like to explore biomedical sciences as funding area. This mostly
            > > > consisted
            > > > > of a 3-hour conversation with Dario (recording is available), reading two
            > > > > papers he sent and a few I found while Googling, and prior knowledge. I'm
            > > > > including Dario in all emails related to this stuff, as an informal
            > > > advisor.
            > > > >
            > > > > * *
            > > > >
            > > > > *My picture of "what the biomedical research world roughly looks like"
            > > > *(this
            > > >
            > > > > is mostly from talking with Dario + prior knowledge)
            > > > >
            > > > > · *Academic biology* studies how organisms work and develops tools to
            > > >
            > > > > observe and manipulate the building blocks of organisms.
            > > > >
            > > > > o The vast bulk of the funding - and the most prestigious funding - comes
            > > > > from the NIH.
            > > > >
            > > > > o There is also funding from what I've heard called "foundations" -
            > > > groups
            > > > > like the American Cancer Society and American Heart Association - which
            > > > > function very similarly to the NIH, in that they tend to hire people with
            > > > > strong academic credentials and those people judge the merits of grant
            > > > > proposals.
            > > > >
            > > > > o Both the NIH and "foundations" tend to be formally partitioned by
            > > > > disease, but much of the work done by academic biologists is potentially
            > > > > relevant to many diseases. A researcher seeking NIH funding may apply to
            > > > > several different NIH "study sections," though only one at a time (a list
            > > > > of "study sections" is at
            > > > > http://public.csr.nih.gov/StudySections/Standing/Pages/default.aspx);
            > > > > whether s/he gets funding is going to depend more on the academic merits
            > > > of
            > > > > the researcher & work than anything else.
            > > > >
            > > > > o There are basic definitions of "academic merit " that generally shape
            > > > > the whole ecosystem: the people handing out money are selected by these
            > > > > criteria and use these criteria, the people doing the research know that
            > > > > these criteria shape their career prospects, etc.
            > > > >
            > > > > · *Private startups* investigate promising ideas for new
            > > >
            > > > > treatments/diagnostics/devices. They may often take the form of a biology
            > > > > professor spinning off a biotech startup (run by former postdocs) that
            > > > > raises venture capital, based on the research the professor did. They
            > > > take
            > > > > basic knowledge about how the body works (for example, protein X is
            > > > crucial
            > > > > for medical condition Y) and do the necessary testing to find a promising
            > > > > treatment/diagnostic/device (for example, testing a lot of compounds on
            > > > > animals until they find one that affects protein X).
            > > > >
            > > > > · *Big pharma/biotech companies *are best positioned to deal with the
            > > >
            > > > > extremely expensive process of conducting clinical trials and getting FDA
            > > > > approval. Acquisition by one of these is the most common form of exit for
            > > > > startups.
            > > > >
            > > > > · *Academic medicine, epidemiology and other fields* also do work
            > > >
            > > > > relevant to medicine, including studying questions whose main relevance
            > > > is
            > > > > to medical practice and public health programs: how effective is
            > > > > treatment/practice X in situation Y, how cost-effective is it, etc.
            > > > > Sometimes they will hit on commercializable insights (for example, a new
            > > > > kind of device) as well.
            > > > >
            > > > > · *Translational research* is a broad term referring to a bridge between
            > > >
            > > > > academic research and treatments/practices. It can include (
            > > > >
            > > > http://medicalcenter.osu.edu/research/translational_research/pages/index.aspx
            > > > > ):
            > > > >
            > > > > o T1 - going from basic science (usually academic biology, I presume) to
            > > > a
            > > > > new treatment/practice. This includes research that helps go from an
            > > > > academic biology insight to a private startup.
            > > > >
            > > > > o T2 - I think this is basically what Cochrane does - going from academic
            > > > > medicine/epidemiology (a bunch of studies on what treatments/practices
            > > > are
            > > > > effective) to the development of guidelines that actually affect
            > > > practice.
            > > > >
            > > > > o T3, T4 - research on how to actually change practice (as opposed to
            > > > > setting the guidelines that are a "target" for practice) and get better
            > > > > real-world results.
            > > > >
            > > > > *
            > > > > *
            > > > >
            > > > > *Potential "big opportunity to do good" #1: translational research and
            > > > the
            > > >
            > > > > "Valley of Death" (this comes from prior knowledge, googling "Valley of
            > > > > Death" and reading a bunch of the stuff I found, and checking out the
            > > > > FasterCures website again)*
            > > >
            > > > >
            > > > >
            > > > >
            > > > > The "Valley of Death" seems to mostly refer to a shortage of T1. The idea
            > > > > is that there are a lot of cases where there's an academic insight that's
            > > > > potentially valuable in coming up with a new treatment, but to get it to
            > > > > the point where it's attractive from a for-profit perspective, you need
            > > > to
            > > > > do a lot of stuff that academics don't have a reason to do. "For example,
            > > > > an upstream finding that a given protein is differentially expressed in
            > > > > individuals with a particular disease may suggest that the protein merits
            > > > > further investigation. However, much more work (especially medicinal
            > > > > chemistry) is necessary to determine how good a target the protein really
            > > > > is and whether a marketable drug candidate that affects the activity of
            > > > the
            > > > > protein is likely to be developed." (
            > > > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf)
            > > > >
            > > > >
            > > > >
            > > > > There are claims that this sort of work is massively underfunded (by the
            > > > > people we've spoken to who talked about the "Valley of Death"; also in
            > > > >
            > > > http://www.fastercures.org/documents/file/Valley%20of%20Death%20-%20Translational%20Research
            > > > (1).pdf).
            > > > > However, funding isn't the only issue. The other issue is that
            > > > > "pharmaceutical firms that hold libraries of potentially useful small
            > > > > molecules as trade secrets, making them largely off limits to ...
            > > > academic
            > > > > scientists" (
            > > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf).
            > > > > In other words, there is some room for new models of collaboration that
            > > > > lead to better communication and information sharing between academia and
            > > > > industry (or between industry and industry).
            > > > >
            > > > >
            > > > > Both the Myelin Repair Foundation and Michael Milken's work on prostate
            > > > > cancer have been pointed to as examples of innovative collaborations that
            > > > > deal with some of the information sharing problems. Milken's model:
            > > > > "drastically cutting the wait time for grant money, to flood the field
            > > > with
            > > > > fast cash, to fund therapy-driven ideas rather than basic science, to
            > > > hold
            > > > > researchers he funds accountable for results, and to demand collaboration
            > > > > across disciplines and among institutions, private industry, and
            > > > academia."
            > > > > (
            > > > >
            > > > http://money.cnn.com/magazines/fortune/fortune_archive/2004/11/29/8192713/index.htm
            > > > )
            > > > > Myelin Repair Foundation sounds broadly similar (
            > > > >
            > > > http://opinionator.blogs.nytimes.com/2011/05/02/helping-new-drugs-out-of-academias-valley-of-death/
            > > > ).
            > > > >
            > > > >
            > > > >
            > > > >
            > > > > More broadly:
            > > > >
            > > > > · FasterCures (also a Michael Milken production) looks like it's focused
            > > > > on the broad mission of "more research with a shorter timeline to
            > > > > treatments," with a heavy sub-focus on the Valley of Death. In addition
            > > > to
            > > > > its conference and philanthropic advisory service, it advocates for FDA
            > > > > improvements (presumably to speed the approval process), advocates for
            > > > the
            > > > > NIH to put more funding into translational research (there have
            > > > definitely
            > > > > been a lot of new initiatives at the NIH focused on this stuff in the
            > > > past
            > > > > few ~decade), promotes "innovative financing mechanisms" for bridging the
            > > > > Valley of Death (these include Peter Thiel's Breakout Labs; I think they
            > > > > occupy a conceptually similar space to "social enterprise investment"
            > > > > though they tend to be structured more as grants and less as
            > > > > double-bottom-line investments), and works on getting patient data opened
            > > > > to researchers. The only program of theirs I haven't mentioned is TRAIN;
            > > > I
            > > > > can't (easily) figure out what this is.
            > > > >
            > > > > · John Ioannidis stated to us that all translational research is
            > > > > underfunded, not just T1. (The context we talked to him in, of course,
            > > > was
            > > > > T2.)
            > > > >
            > > > >
            > > > > These issues seem to have quite a bit of buzz. There are some really
            > > > stark
            > > > > #'s out there: even as R&D investment has gone way up over the past 50
            > > > > years, the # of new drugs has stayed roughly constant at around 20 a
            > > > year.
            > > > >
            > > > >
            > > > > Dario sent a really interesting paper on this topic. It argues: (a) the #
            > > > > of NMEs (new medical entities, i.e., drugs) per year has mostly remained
            > > > > constant-with-noise (no trend); (b) all of the big companies seem to have
            > > > > produced NMEs at a very steady pace, even as they've changed size, though
            > > > > different companies do have different rates of NME creation; (c) when it
            > > > > comes to mergers & acquisitions, "1+1=1": companies that acquire other
            > > > > companies just keep up the same NME pace; (d) over time, the # of large
            > > > > companies has shrunk (due to mergers) and the # of small companies has
            > > > > risen, and the share of NMEs attributed to small companies has gone from
            > > > > ~30% to ~70%; (e) the cost per NME has gone up over time and is now in
            > > > the
            > > > > neighborhood of $1 billion; (f) the % of NMEs that are "blockbusters"
            > > > (huge
            > > > > profits) has been steady around 20%, despite intensifying efforts on the
            > > > > part of pharma to fund only potential blockbusters.
            > > > >
            > > > >
            > > > >
            > > > > There are also claims - such as by Derek Lowe, a blogger Dario pointed me
            > > > > to - that the "Valley of Death" is an overrated concept: there is a high
            > > > > ratio of academic discoveries to useful drugs, but this is just because a
            > > > > lot of stuff turns out not to work, not because we have a shortage of
            > > > > doable translational research. The paper above sort of takes this view,
            > > > > essentially arguing that nothing seems to raise NME production; we'll
            > > > need
            > > > > something really radical to make any difference.
            > > > >
            > > > >
            > > > >
            > > > > The case studies in the FasterCures paper on this are interesting. They
            > > > > imply that there were some pretty low-hanging fruit in the T1 domain. It
            > > > > might be interesting to talk to Fastercures and see whether they can help
            > > > > identify "Valley of Death" opportunities that are slam-dunkish.
            > > > >
            > > > >
            > > > > *Potential "big opportunity to do good" #2: inefficiencies in academic
            > > > > biology*
            > > >
            > > > >
            > > > >
            > > > >
            > > > > All of the above seems pretty distinct from the question of how to make
            > > > > academic biology better at doing its job of understanding the body. This
            > > > is
            > > > > the question that Dario and I focused on.
            > > > >
            > > > >
            > > > >
            > > > > Dario painted a picture in which most of academia plays by the same set
            > > > of
            > > > > rules, making it very hard for people to do things that break those rules
            > > > > (for example, academics are expected to publish a lot; it's risky to work
            > > > > on a "blue sky" or highly ambitious project). Thus, for anyone who wants
            > > > a
            > > > > career in academia, a couple of years working on a moonshot project are
            > > > > risky; in addition, being on bad terms with a small number of people can
            > > > > damage a career (since there is often a small set of people that makes a
            > > > > large proportion of the career-impacting decisions for a given area, and
            > > > it
            > > > > can be hard to escape this set of people without changing research
            > > > > interests significantly). The bad news is that this isn't particularly
            > > > easy
            > > > > to fix: you can offer funding for blue-sky projects, but (a) a lot of
            > > > > academics basically train themselves to play by the rules, and won't
            > > > > necessarily have thought about "what should be studied if these rules
            > > > > didn't apply," and more importantly, (b) there are many incentives
            > > > pushing
            > > > > academics towards playing by certain rules; funding is only one of those
            > > > > mechanisms (there's also tenure, peer review, etc) so changing that one
            > > > > incentive won't always change behavior. Dario says that he might hesitate
            > > > > to work on a particular blue-sky project that he thinks is interesting,
            > > > > even if he got funding for it, for these reasons.
            > > > >
            > > > >
            > > > > Despite this, there are some funders who push the boundaries. There are
            > > > > medical centers that don't require teaching and do more ambitious work.
            > > > > There's the McKnight foundation, which funded some of the pioneering work
            > > > > on optical control of neurons for which funding might have been difficult
            > > > > to obtain by traditional routes. There's the HHMI Janelia Farms campus,
            > > > > which Dario thinks is the most promising thing out there in terms of a
            > > > > model - academics who go there get guaranteed (and generous) funding for
            > > > 6
            > > > > years, which frees them up to take much bigger risks. (I saw a study
            > > > > claiming that the work coming out of Janelia Farms has a much more skewed
            > > > > citation count distribution, implying bigger risks - i.e., fewer papers
            > > > > with decent #'s of citations but more "blockbuster" papers with lots of
            > > > > citations). But Janelia Farms is only in one sub-field; comparable
            > > > > institutions don't exist for other fields (as far as Dario knows)..
            > > > >
            > > > >
            > > > >
            > > > > Dario's gut is that one of the best things a funder could do would be to
            > > > > work toward creating a large institute that largely "plays by its own
            > > > > rules," encouraging more ambitious work and providing enough security and
            > > > > sheer volume of dollars/researchers as to establish a sort of "parallel
            > > > > system" to academia - thus becoming a place that could provide viable and
            > > > > reliable career options for people interested in playing by different
            > > > > rules. I'm also interested in the idea of trying to advocate for changes
            > > > in
            > > > > the rules, as we've discussed in the context of meta-research.
            > > > >
            > > > >
            > > > >
            > > > > There's also the other stuff like data/code sharing.
            > > > >
            > > > >
            > > > >
            > > > > *Another option: give $ to the NIH*
            > > >
            > > > >
            > > > >
            > > > >
            > > > > The NIH is by far the largest, most prestigious, most respected funder in
            > > > > academic biology, and most of academia runs on criteria that mirror the
            > > > > NIH's. I would guess that an unrestricted check to the NIH would get
            > > > > allocated in a pretty sector-agnostic way. It seems like this is a giving
            > > > > option that is pretty nontrivial to beat. Anyone we consider for funding
            > > > > ought to be able to explain why they're better at allocating the funds
            > > > than
            > > > > the NIH. We haven't talked to the NIH about whether it would accept these
            > > > > sorts of donations.
            > > > >
            > > > >
            > > > > With the context I now have, FasterCures strikes me as pretty
            > > > > promising/interesting too, though their "room for more funding" situation
            > > > > isn't clear (w/o talking to them). But they also seem sector-agnostic
            > > > > within biomedical research, while pushing a very specific theory of
            > > > change
            > > > > that may or may not be valid.
            > > > >
            > > > >
            > > > >
            > > > > *Next steps*
            > > >
            > > > >
            > > > >
            > > > >
            > > > > I think understanding this world would be a major undertaking. I think
            > > > we'd
            > > > > have to be ready to put in a lot of work and to be open to ways of
            > > > bridging
            > > > > "funder-expert gap" that we haven't tried before. For example:
            > > > >
            > > > > · Dario suggested that I read a freshman biology textbook. He said he
            > > > > realizes that the time cost could be very large - something like 100
            > > > hours
            > > > > - but that without doing so, I'm going to be lacking too much context on
            > > > > why biomedical research works the way it does. He thinks that reading a
            > > > > basic textbook would get me to the point of strongly diminishing marginal
            > > > > returns.
            > > > >
            > > > > · Also in the category of "personally picking up rudimentary subject
            > > > > matter knowledge," I thought it might be worth trying to follow the
            > > > > development of a particular drug from start to finish - Gleevec (the
            > > > > "miracle drug") would be a good candidate. The goal would be to
            > > > understand
            > > > > each stage of insight leading to new investigation, and where the funding
            > > > > came from at each stage.
            > > > >
            > > > > · I think hiring Dario or someone like him would make a lot of sense.
            > > > > I've thought about whether we should be hiring "subject matter experts"
            > > > in
            > > > > other areas, such as global health, but in my view the need is clearer
            > > > here
            > > > > than in any other area. One of the things I don't love about hiring an
            > > > > expert in a given field, at this stage of our research, is that we could
            > > > > quickly decide that we're just not interested enough in the field in
            > > > > question ... but someone with the right kind of technical knowledge &
            > > > > experience would be so far ahead of us in evaluating *any* area of
            > > > biology
            > > > > research that it seems like a good idea. (JTBC, I'm also actively
            > > > thinking
            > > > > about whether it would make sense to hire experts in other fields ...)
            > > > >
            > > > > · Talking to major funders and potentially co-funding with them is
            > > > > probably essential. Important groups to talk to would include NIH (by far
            > > > > the most important; we've already talked to them a bit), the colloquium
            > > > of
            > > > > groups like the American Cancer Society (it has a name; I forget the
            > > > name),
            > > > > FasterCures, Wellcome, and potentially some funders with
            > > > > unorthodox/buzzed-about approaches: Myelin Repair Foundation, McKnight
            > > > > Foundation, and maybe another private foundation or two (I emailed Dario
            > > > > all my notes on major foundations that do biomedical research so he could
            > > > > send thoughts on whether any look interesting aside from McKnight).
            > > > >
            > > > >
            > > > > My next plan had been to talk to academics (Dario had good suggestions
            > > > > about how to approach them), but with all the potential work to be done
            > > > on
            > > > > gaining basic context, I'm not sure that's the right next step. But it's
            > > > > also a possible step.
            > > > >
            > > > >
            > > > >
            > > > > *2. Some more context on the history of our work on biomedical research
            > > > and
            > > >
            > > > > why we think it's appropriate to investigate this field (this was a
            > > > > response to a question following my original email, along the lines of
            > > > "Why
            > > > > are you looking into biomedical research now, given that's an area with a
            > > > > lot of buzz and funding from wealthy donors, and how does this work
            > > > relate
            > > > > to the 'meta-research' work?")*
            > > > >
            > > > >
            > > > > - We've always had "disease research" as a cause we wanted to
            > > >
            > > > > investigate. We've never had a good reason for not investigating it other
            > > > > than that investigating it seems difficult. We've tried more than once to
            > > > > investigate it, and it's ended up falling by the wayside because of how
            > > > big
            > > > > an undertaking it is.
            > > > > - It's true that there is a huge amount of funding and buzz in this
            > > >
            > > > > area. But it also seems quite possible that there isn't nearly enough; in
            > > > > fact this seems like a possible point of consensus between all the people
            > > > > concerned about the "Valley of Death." This potential good accomplished
            > > > via
            > > > > biomedical research appears unlimited. What I consider to be the mark of
            > > > a
            > > > > bad sector is "tons of buzz/$ and mediocre returns," but the latter part
            > > > > doesn't apply to biomed; in fact biomedical research is arguably one of
            > > > > philanthropy's and even humanity's top success stories.
            > > > > - There are also indications that despite all the buzz and funding,
            > > >
            > > > > there are still opportunities to do things differently and shake things
            > > > up.
            > > > > There is more than one case where an outsider (Milken, MRF) basically
            > > > came
            > > > > in and did things very differently and now even experts in the field seem
            > > > > to credit them with positive change. There's also a good explanation for
            > > > > why this might be the case: while there are a ton of people and dollars,
            > > > > they largely seem to play by one self-reinforcing/network-effect-prone
            > > > set
            > > > > of rules, implying high returns to disrupting that equilibrium.
            > > > > - So, we've always wanted to get into this area. There was a period
            > > >
            > > > > where I was presenting meta-research as our best entry point into this
            > > > > field: my vision was that we would talk to academics about what
            > > > systematic
            > > > > failings there were and what funding opportunities these implied, and
            > > > that
            > > > > would be as good a way as any to get acclimated in biomed. But this
            > > > period
            > > > > wasn't particularly long - the May blog post on Labs priority causes
            > > > lists
            > > > > scientific research as a promising area distinct from meta-research.
            > > > > - I set up the call with Dario without having a clear idea of whether I
            > > >
            > > > > wanted to approach biomed from a "meta-research" angle or another angle.
            > > > > After the call and other investigations described here, I got a clearer
            > > > > idea of what I think is the best path forward.
            > > > >
            > > > > Bottom line - I think it's important to build an understanding of
            > > > > biomedical research, and that we should take the best path to doing so
            > > > > whether or not that dovetails with the meta-research work (likely it will
            > > > > dovetail some but not 100%).
            > > >
            > > >
            > > >
            > >
            >
            >
            >
            >
            >


          • Aubrey de Grey
            Excellent. I too am keen to see Dario s comments. Dario also has the advantage of being based just a few miles from SENS Foundation s research centre, so we
            Message 5 of 18 , Oct 13, 2012
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              Excellent. I too am keen to see Dario's comments. Dario also has the advantage of being based just a few miles from SENS Foundation's research centre, so we can definitely get together f2f soon if he wants.

              Cheers, Aubrey

              On 13 Oct 2012, at 17:50, Holden Karnofsky wrote:

              > Hi Aubrey,
              >
              > Thanks again for engaging so thoughtfully.
              >
              > I agree that a new technology/treatment that could delay or reverse aging (or aspects of it) would be enormously valuable. Regarding the rest of your argument, this is a good example of the challenges I've been discussing in understanding biomedical research.
              >
              > You state that you have a high-expected-value plan that the academic world can't recognize the value of because of shortcomings such as "balkanisation" and risk aversion. I believe it may be true that the academic world has such problems to a degree; however, I also believe that there are a lot of extremely talented people in academia and that they often (though not necessarily always) find ways to move forward on promising work. Without more subject-matter expertise (or the advice of someone with such expertise), I can't easily assess the technical merits of your argument or potential counterarguments. Hopefully we'll have a better system for doing so at some point in the future.
              >
              > I'll be very interested to see Dario's thoughts on the matter if he responds. I'd cite Dario as an example of an academic who ultimately wants to do work of the greatest humanitarian value possible, regardless of whether it is prestigious work. And as my summary of our conversation shows, he acknowledges that the world of biomedical research may have certain suboptimal incentives, but didn't seem to think that these issues are leaving specific, visible outstanding research programs on the table the way that your email implies.
              >
              > Best,
              > Holden
              >
              > On Sat, Oct 13, 2012 at 6:24 AM, Aubrey de Grey <aubrey@...> wrote:
              > Hi Holden - many thanks.
              >
              > First: yes, there are really three somewhat separate questions for someone trying to evaluate whether to support SENS Foundation:
              >
              > 1) Is the medical control of aging a hugely valuable mission?
              >
              > 2) Assuming "yes" to (1), is it best achieved by basic research or translational research?
              >
              > 3) Assuming translational, is SENS Foundation the organisation that uses money most effectively in pursuit of that mission?
              >
              > I had rather expected that you would take some convincing on item (1), and much of what I wrote last time was focused on that. Since it isn't the focus of your question to me, I'm now going to assume until further notice that there is no dissent on that.
              >
              > So, to answer your question: actually you're not putting aside the basic-vs-translational question as much as you may think you are. The word "translational" is flavour of the month in government funding circles these days (not only in the USA), so it's not surprising that the NIA has a public statement of the kind you pointed to. However, notice that the link they give "for more information" is to a page listing ALL "Funding Opportunity Announcements". There is no page specifically for translational ones, and the reason there isn't is that the amount of work that the NIA actually funds that could really be called translational is tiny. In other words, the page you found is actually just blatant spin. The neuroscience slice you mention is an anomaly arising from the way NIA was founded (the natural place for that money is clearly NINDS): the fact that it's NIA money does not, in practice, translate into its being spent on work to prevent neurodegeneration by treating its cause (aging). Instead, just like NINDS money, it's spent on attacking neurodegeneration directly, as if such diseases could be eliminated from the body just like an infection: the same old mistake that afflicts, and dooms, the whole of geriatric medicine.
              >
              > So, the first answer to your question is that SENS Foundation really DOES focus on translational research, with an explicit goal of postponing age-related ill-health. But there's also another big difference: we can attack this problem relatively free of the other priorities that afflict mainstream funding (whether from NIH or from trasitional foundations). Most importantly, though we do and will continue to publish our interim results in the peer-reviewed literature, we are much less constrained by "publish or perish" tyranny than typical academics are. This allows us to proceed by constructing and implementing a rational "project plan" (namely SENS) to get to the intended goal (the defeat of aging), whereas what little translational work is funded by NIA or others is guided overwhelmingly by the imperative to get some kind of positive result as quickly as possible, even when it's understood that those results are not remotely likely to "scale", i.e. to translate into eventual medical treatments that significantly delay aging. A great example of this is the NIA's Interventions Testing Program (ITP) to test the mouse longevity effects of various small molecules. The ITP only exists at all (and in a far smaller form than originally intended) as a result of several years of persistence by the then head of the NIA's biology division (Huber Warner), and it focuses entirely on delivery of simple drugs starting rather early in life, with the result that no information emerges that's relevant to treating people who are already in middle age or older. (This is despite the fact that by far the most high-profile result that the ITP has delivered so far, the benefits of rapamycin, actually WAS a late-onset study: it wasn't meant to be, but technical issues delayed the experiment.) In a nutshell, there is a huge bias against high-risk high-gain work.
              >
              > The third thing that distinguishes SENS Foundation's approach is that we can transcend the "balkanisation" (silo mentality) that dominates mainstream academic funding. When one submits a grant application to NIA, it is evaluated by gerontologists, just as when one submits to NCI it is evaluated by oncologists, etc. What's wrong with this is that it biases the system immensely against cross-disciplinary proposals. SENS is a plan that brings together a large body of knowledge from gerontology but also a huge amount of expertise that was developed for other reasons entirely - to treat acute disease/injury, or in some cases for purposes that were not biomedical at all (notably environmental decontamination). It doesn't matter how robust the objective scientific and technological argument is for work of that sort: it will never compete (especially in today's very tight funding environment) with more single-topic proposals all of whose details can be understood by reviewers from a particular single field.
              >
              > The final thing to mention, and this actually also answers your question to Vipul about basic versus translational research, is that SENS is a plan that has stood the test of time. I've been propounding it since 2000, well before SENS Foundation existed, and it used to come in for a lot of criticism (initially more in the form of off-the-record ridicule, and latterly, at my behest, in print), but in every single case that criticism was found to stem from ignorance on the part of the detractor, either of what I proposed or of published experimental work on which the proposal was based. That's why I'm now regularly asked to organise entire sessions at mainstream gerontology conferences, whereas as little as five years ago I would never even be invited to speak. It's also why the Research Advisory Board of SENS Foundation consists of such prestigious scientists. This is a very strong argument, in my view, for believing that now is the time to sink a proper amount of money into translational gerontology (though certainly not to cease doin basic biogerontology too). It's well known that basic scientists are often not the most far-sighted when it comes to seeing how to apply their discoveries (attitudes in 1900 to the feasibility of powered flight being the canonical example). It is therefore a source of concern that almost all the experts who have the ear of funders in this field are basic scientists, whose instinct is to carry on finding things out and to deprioritise the tedious business of applying that knowledge. SENS has achieved a gratisfying level of legitimacy in gerontology, but it is still foreign to most card-carrying gerontologists, and as such it remains essentially unfundable via mainstream mechanisms. Hence the need to create a philanthropy-driven entity, SENS Foundation, to get this work done.
              >
              > Let me know if this helps, or if you have further questions.
              >
              > Cheers, Aubrey
              >
              > On 12 Oct 2012, at 15:28, Holden Karnofsky wrote:
              >
              > >
              > > Hi Aubrey,
              > >
              > > Thanks for the thoughts.
              > >
              > > The NIH appears to have a division focused on research relevant to this topic: http://www.nia.nih.gov/research/dab . Its budget appears to be ~$175 million (per year). The National Institute on Aging, which houses this division, has a budget of about $1 billion per year, including a separate ~$400 million for neuroscience (which may also be relevant) as well as $115 million for intramural research. Figures are from http://www.nia.nih.gov/about/budget/2012/fiscal-year-2013-budget. The Institute states that its mandate includes translational research (http://www.nia.nih.gov/research/faq/does-nia-support-translational-research). How would you distinguish your work from this work?
              > >
              > > (For the moment I'm putting aside the question I raised in my previous response to Vipul on this topic, regarding whether it's best to approach biology funding from the perspective of "trying to treat/cure a particular condition" or "trying to understand fundamental questions in biology whose applications are difficult to predict.")
              > >
              > > Best,
              > > Holden
              > >
              > > On Fri, Oct 12, 2012 at 7:32 AM, aubrey.degrey <aubrey@...> wrote:
              > >
              > > Hi everyone,
              > >
              > > My attention was brought to this thread, by virtue of the fact that it was my work that gave rise to SENS Foundation, and I'm looking forward to getting more involved here; I've held the Effective Altruism movement in high regard for some time. However, given my newbie status here I want to start by apologising in advance for any oversight of previously-discussed issues etc. I'm naturally delighted both at Holden's post and at Vipul's reply (which I should stress that I did not plant! - I do not know Vipul at all, though I look forward to changing that). I would like to mention just a few key points for discussion:
              > >
              > > - Holden, I want to compliment you on your appreciation of how academia really works. Everything you say about that is spot on. The aversion to "high risk high gain" work that has arisen and become so endemic in the system is the most important point here, in terms of why parallel funding routes are needed.
              > >
              > > - I'm slightly confused that a lot of Holden's remarks are focused on the private sector (i.e. startups), since my understanding was that GiveWell is about philanthropy; but I realise that there is not all that clear a boundary between the two (and I note the mention of Breakout Labs, with which I have close links and which sits astride that divide more than arguably anyone). The "valley of death" in pre-competitive translational research is a rather different one than that encountered by startups, but the principle is the same, and research to postpone aging certainly encounteres it.
              > >
              > > - Something that I presume factors highly among GiveWell's criteria is the extent to which a cause may be undervalued by the bulk of major philanthropists, such that an infusion of additional funds would make more of a difference than in an area that is already being well funded. To me this seems to mirror the logic of focusing on the shortcomings (gaps) in NIH's funding (and that of traditional-model foundations). Holden notes that "Anyone we consider for funding ought to be able to explain why they're better at allocating the funds than the NIH" and I agree wholeheartedly, but my inference is that he thinks that some orgs may indeed be able to explain that. I certainly think that SENS Foundation can.
              > >
              > > - Coming to aging: research to postpone aging has the unique problem of quite indescribeable irrationality on the part of most of the general public, policy-makers and even biologists with regard to its desirability. Biogerontologists have been talking to brick walls for decades in their effort to get the rest of the world to appreciate that aging is what causes age-related ill-health, and thus that treatments for aging are merely preventative geriatrics. The concept persists, despite biogerontologists' best efforts, that aging is "natural" and should be left alone, whereas the diseases that it brings about are awful and should be fought. This is made even more bizarre by the fact that the status of age-related diseases as aspects of the later stages of aging absolutely, unequivocally implies that efforts to attack those diseases directly are doomed to fail. As such, this is a (unique? certainly very rare) case where a philanthropic contribution can make a particularly big difference simply because most philanthropists don't see the case for it. It underpins why having an interest in treating aging, as opposed to cancer, absolutely has a major impact on which projects one funds. It's also a case for (if I understand the term correctly) meta-research.
              > >
              > > - A lot of the chatter about treating aging revolves around longevity, but it shouldn't. I'm all in favour of longevity, don't get me wrong, but it's not what gets me up in the morning: what does is health. I want people to be truly youthful, however long ago they were born: simple as that. The benefits of longevity per se to humanity may also be substantial, in the form of greater wisdom etc, but that would necessarily come about only very gradually (we won't have any 1000-year-old for at least 900 years whatever happens!), so it doesn't figure strongly in my calculations.
              > >
              > > - When forced to acknowledge that the idea of aging being a high-priority target for medicine is an inescapeable consequence of things they already believe (notably that health is good and ageism is bad), many people retreat to the standpoint that it's never going to be possible so it's OK to be irrational about whether it's desirable. The feasibility of postponing age-related ill-health by X years with medicine available Y years from now is, of course, a matter of speculation on which experts disagree, just as with any other pioneering technology. I know that Holden and others have expressed caution (at best) concerning the accuracy of any kind of calculation of probabilities of particular outcomes in the distant (or even not-so-distant) future, and I share that view. However, an approach that may appeal more is to estimate how much humanitarian benefit a given amount of progress would deliver, and then to ask how unlikely that scenario needs to be to make it not worth pursuing. My claim is that the benefits of hastening the defeat of aging by even a few years (which is the minimum that I claim SENS Foundation is in a position to do, given adequate funding) would be so astronomical that the required chance of success to make such an effort worthwhile would be tiny - too tiny for it to be reasonable to argue that such funding would be inadvisable. But of course that is precisely what I would want GiveWell to opine on.
              > >
              > > - In the event that GiveWell (or anyone else) were to decide and declare that the defeat of aging is indeed a cause that philanthropists should support, there then arises the question of which organisation(s) should be supported in the best interests of that mission. We at SENS Foundation have worked diligently to rise as quickly as possible in the legitimacy stakes by all standard measures, but we are still young and there remains more to do. If I were to offer an argument to fund us rather than any other entity, it would largely come down to the fact that no other organisation has even a serious plan for defeating aging, let alone a track record of implementing such a plan's early stages.
              > >
              > > - A significant chunk of what we do is of a kind that I think comes under "meta-research". A prominent example is a project we're funding at Denver University to extend the well-respected forecasting system "International Futures" so that it can analyse scenarios incorporating dramatically postponed aging.
              > >
              > > I greatly welcome any feedback.
              > >
              > > Cheers, Aubrey
              > >
              > >
              > >
              > > --- In givewell@yahoogroups.com, Holden Karnofsky <holden0@...> wrote:
              > > >
              > > > Hi Vipul,
              > > >
              > > > Thanks for the thoughts. I had a followup conversation with Dario about
              > > > this topic a few days ago. I think the question of "could one fund
              > > > translational research to treat/prevent aging?" provides an interesting
              > > > illustration of some of the tricky dynamics here for a funder:
              > > >
              > > > - It's possible that if there were a great deal more attention giving to
              > >
              > > > treating/preventing aging, we would have some promising treatments. So in a
              > > > broad sense it's possible that aging is underinvested in.
              > > > - A lot of the best basic biology research isn't clearly pointing toward
              > >
              > > > one treatment/condition or another; it's about understanding the
              > > > fundamentals of how organisms operate. So having an interest in treating
              > > > aging, as opposed to cancer, might not have a major impact on which
              > > > projects one funds, if one's main goal is to fund outstanding basic biology
              > > > research.
              > > > - Perhaps because of the lack of emphasis on treating aging (or perhaps
              > >
              > > > because it's simply too difficult of a problem), there don't seem to be
              > > > promising findings in the "Valley of Death" relevant to aging; the few
              > > > promising leads have been explored.
              > > > - So even if, in a broad sense, there is too little attention given to
              > >
              > > > this problem, knowing this doesn't necessarily yield a clear direction for
              > > > a relatively small-scale funder of biomedical research.
              > > >
              > > > Best,
              > > > Holden
              > > >
              > > > On Wed, Oct 10, 2012 at 11:55 PM, Vipul Naik <vipul@...>wrote:
              > > >
              > > > > **
              > >
              > > > >
              > > > >
              > > > > Holden,
              > > > >
              > > > > First, I think that this is an excellent document. I checked for a
              > > > > number of things that I had heard about (Breakout Labs, John
              > > > > Ioannidis, Cochrane Collaboration) and they're all there in your
              > > > > document.
              > > > >
              > > > > The one thing that's not explicitly mentioned: longevity and life
              > > > > extension research. At least prima facie, this seems like something
              > > > > that should be more important than individual disease research, and it
              > > > > seems like a classic "Valley of Death" case (pun unintended, but
              > > > > noted) -- T1 stage to use your terminology. I think the SENS website
              > > > > http://www.sens.org would be a good starting point for one of the (to
              > > > > me promising) approaches to life extension. I recall from past
              > > > > conversations that you were aware of SENS, so this is not new to you,
              > > > > but I think that longevity should be included as part of any
              > > > > discussion of biomedical research and given separate consideration
              > > > > given that it has a much lower status than research into specific
              > > > > conditions such as cancer, dementia, etc. You may ultimately conclude
              > > > > that not enough can be done in this area, but I think it should be
              > > > > part of your preliminary stuff. [btw, the United States has a National
              > > > > Institute of Aging, but it's much lower-status than most of the other
              > > > > grantmakers mentioned here].
              > > > >
              > > > > Vipul
              > > > >
              > > > > * Quoting Holden Karnofsky who at 2012-10-10 23:08:42+0000 (Wed) wrote
              > > > >
              > > > > > Note to the research list: we're now considering reopening our
              > > > > > investigation of the world of biomedical research. We've started and
              > > > > > stopped a couple of times in this area before; this time I decided to
              > > > > start
              > > > > > with a conversation with Dario Amodei, a longtime GiveWell follower and
              > > > > > personal friend who is currently a biology postdoc at Stanford. My goal
              > > > > > with the conversation was just to get some basic context and start
              > > > > putting
              > > > > > together a framework for thinking about the issue, not to use him as an
              > > > > > authoritative source, and the notes below should be read in that spirit.
              > > > > >
              > > > > >
              > > > > > This email has two sections:
              > > > > >
              > > > > >
              > > > > > 1. Notes that I emailed out internally after my conversation with Dario,
              > > > > > slightly edited
              > > > > >
              > > > > > 2. Some more context on the history of our work on biomedical research
              > > > > and
              > > > > > why we think it's appropriate to investigate this field (this was a
              > > > > > response to a question following my original email, along the lines of
              > > > > "Why
              > > > > > are you looking into biomedical research now, given that's an area with a
              > > > > > lot of buzz and funding from wealthy donors, and how does this work
              > > > > relate
              > > > > > to the 'meta-research' work?")
              > > > > >
              > > > > >
              > > > > >
              > > > > > *--*
              > > > > >
              > > > > > *
              > > > > > *
              > > > > >
              > > > > > *1. Notes that I emailed out internally after my conversation with Dario,
              > > > > > slightly edited*
              > > > > >
              > > > > > *
              > > > >
              > > > > > *
              > > > > >
              > > > > > I've done some preliminary work trying to figure out what it would look
              > > > > > like to explore biomedical sciences as funding area. This mostly
              > > > > consisted
              > > > > > of a 3-hour conversation with Dario (recording is available), reading two
              > > > > > papers he sent and a few I found while Googling, and prior knowledge. I'm
              > > > > > including Dario in all emails related to this stuff, as an informal
              > > > > advisor.
              > > > > >
              > > > > > * *
              > > > > >
              > > > > > *My picture of "what the biomedical research world roughly looks like"
              > > > > *(this
              > > > >
              > > > > > is mostly from talking with Dario + prior knowledge)
              > > > > >
              > > > > > · *Academic biology* studies how organisms work and develops tools to
              > > > >
              > > > > > observe and manipulate the building blocks of organisms.
              > > > > >
              > > > > > o The vast bulk of the funding - and the most prestigious funding - comes
              > > > > > from the NIH.
              > > > > >
              > > > > > o There is also funding from what I've heard called "foundations" -
              > > > > groups
              > > > > > like the American Cancer Society and American Heart Association - which
              > > > > > function very similarly to the NIH, in that they tend to hire people with
              > > > > > strong academic credentials and those people judge the merits of grant
              > > > > > proposals.
              > > > > >
              > > > > > o Both the NIH and "foundations" tend to be formally partitioned by
              > > > > > disease, but much of the work done by academic biologists is potentially
              > > > > > relevant to many diseases. A researcher seeking NIH funding may apply to
              > > > > > several different NIH "study sections," though only one at a time (a list
              > > > > > of "study sections" is at
              > > > > > http://public.csr.nih.gov/StudySections/Standing/Pages/default.aspx);
              > > > > > whether s/he gets funding is going to depend more on the academic merits
              > > > > of
              > > > > > the researcher & work than anything else.
              > > > > >
              > > > > > o There are basic definitions of "academic merit " that generally shape
              > > > > > the whole ecosystem: the people handing out money are selected by these
              > > > > > criteria and use these criteria, the people doing the research know that
              > > > > > these criteria shape their career prospects, etc.
              > > > > >
              > > > > > · *Private startups* investigate promising ideas for new
              > > > >
              > > > > > treatments/diagnostics/devices. They may often take the form of a biology
              > > > > > professor spinning off a biotech startup (run by former postdocs) that
              > > > > > raises venture capital, based on the research the professor did. They
              > > > > take
              > > > > > basic knowledge about how the body works (for example, protein X is
              > > > > crucial
              > > > > > for medical condition Y) and do the necessary testing to find a promising
              > > > > > treatment/diagnostic/device (for example, testing a lot of compounds on
              > > > > > animals until they find one that affects protein X).
              > > > > >
              > > > > > · *Big pharma/biotech companies *are best positioned to deal with the
              > > > >
              > > > > > extremely expensive process of conducting clinical trials and getting FDA
              > > > > > approval. Acquisition by one of these is the most common form of exit for
              > > > > > startups.
              > > > > >
              > > > > > · *Academic medicine, epidemiology and other fields* also do work
              > > > >
              > > > > > relevant to medicine, including studying questions whose main relevance
              > > > > is
              > > > > > to medical practice and public health programs: how effective is
              > > > > > treatment/practice X in situation Y, how cost-effective is it, etc.
              > > > > > Sometimes they will hit on commercializable insights (for example, a new
              > > > > > kind of device) as well.
              > > > > >
              > > > > > · *Translational research* is a broad term referring to a bridge between
              > > > >
              > > > > > academic research and treatments/practices. It can include (
              > > > > >
              > > > > http://medicalcenter.osu.edu/research/translational_research/pages/index.aspx
              > > > > > ):
              > > > > >
              > > > > > o T1 - going from basic science (usually academic biology, I presume) to
              > > > > a
              > > > > > new treatment/practice. This includes research that helps go from an
              > > > > > academic biology insight to a private startup.
              > > > > >
              > > > > > o T2 - I think this is basically what Cochrane does - going from academic
              > > > > > medicine/epidemiology (a bunch of studies on what treatments/practices
              > > > > are
              > > > > > effective) to the development of guidelines that actually affect
              > > > > practice.
              > > > > >
              > > > > > o T3, T4 - research on how to actually change practice (as opposed to
              > > > > > setting the guidelines that are a "target" for practice) and get better
              > > > > > real-world results.
              > > > > >
              > > > > > *
              > > > > > *
              > > > > >
              > > > > > *Potential "big opportunity to do good" #1: translational research and
              > > > > the
              > > > >
              > > > > > "Valley of Death" (this comes from prior knowledge, googling "Valley of
              > > > > > Death" and reading a bunch of the stuff I found, and checking out the
              > > > > > FasterCures website again)*
              > > > >
              > > > > >
              > > > > >
              > > > > >
              > > > > > The "Valley of Death" seems to mostly refer to a shortage of T1. The idea
              > > > > > is that there are a lot of cases where there's an academic insight that's
              > > > > > potentially valuable in coming up with a new treatment, but to get it to
              > > > > > the point where it's attractive from a for-profit perspective, you need
              > > > > to
              > > > > > do a lot of stuff that academics don't have a reason to do. "For example,
              > > > > > an upstream finding that a given protein is differentially expressed in
              > > > > > individuals with a particular disease may suggest that the protein merits
              > > > > > further investigation. However, much more work (especially medicinal
              > > > > > chemistry) is necessary to determine how good a target the protein really
              > > > > > is and whether a marketable drug candidate that affects the activity of
              > > > > the
              > > > > > protein is likely to be developed." (
              > > > > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf)
              > > > > >
              > > > > >
              > > > > >
              > > > > > There are claims that this sort of work is massively underfunded (by the
              > > > > > people we've spoken to who talked about the "Valley of Death"; also in
              > > > > >
              > > > > http://www.fastercures.org/documents/file/Valley%20of%20Death%20-%20Translational%20Research
              > > > > (1).pdf).
              > > > > > However, funding isn't the only issue. The other issue is that
              > > > > > "pharmaceutical firms that hold libraries of potentially useful small
              > > > > > molecules as trade secrets, making them largely off limits to ...
              > > > > academic
              > > > > > scientists" (
              > > > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf).
              > > > > > In other words, there is some room for new models of collaboration that
              > > > > > lead to better communication and information sharing between academia and
              > > > > > industry (or between industry and industry).
              > > > > >
              > > > > >
              > > > > > Both the Myelin Repair Foundation and Michael Milken's work on prostate
              > > > > > cancer have been pointed to as examples of innovative collaborations that
              > > > > > deal with some of the information sharing problems. Milken's model:
              > > > > > "drastically cutting the wait time for grant money, to flood the field
              > > > > with
              > > > > > fast cash, to fund therapy-driven ideas rather than basic science, to
              > > > > hold
              > > > > > researchers he funds accountable for results, and to demand collaboration
              > > > > > across disciplines and among institutions, private industry, and
              > > > > academia."
              > > > > > (
              > > > > >
              > > > > http://money.cnn.com/magazines/fortune/fortune_archive/2004/11/29/8192713/index.htm
              > > > > )
              > > > > > Myelin Repair Foundation sounds broadly similar (
              > > > > >
              > > > > http://opinionator.blogs.nytimes.com/2011/05/02/helping-new-drugs-out-of-academias-valley-of-death/
              > > > > ).
              > > > > >
              > > > > >
              > > > > >
              > > > > >
              > > > > > More broadly:
              > > > > >
              > > > > > · FasterCures (also a Michael Milken production) looks like it's focused
              > > > > > on the broad mission of "more research with a shorter timeline to
              > > > > > treatments," with a heavy sub-focus on the Valley of Death. In addition
              > > > > to
              > > > > > its conference and philanthropic advisory service, it advocates for FDA
              > > > > > improvements (presumably to speed the approval process), advocates for
              > > > > the
              > > > > > NIH to put more funding into translational research (there have
              > > > > definitely
              > > > > > been a lot of new initiatives at the NIH focused on this stuff in the
              > > > > past
              > > > > > few ~decade), promotes "innovative financing mechanisms" for bridging the
              > > > > > Valley of Death (these include Peter Thiel's Breakout Labs; I think they
              > > > > > occupy a conceptually similar space to "social enterprise investment"
              > > > > > though they tend to be structured more as grants and less as
              > > > > > double-bottom-line investments), and works on getting patient data opened
              > > > > > to researchers. The only program of theirs I haven't mentioned is TRAIN;
              > > > > I
              > > > > > can't (easily) figure out what this is.
              > > > > >
              > > > > > · John Ioannidis stated to us that all translational research is
              > > > > > underfunded, not just T1. (The context we talked to him in, of course,
              > > > > was
              > > > > > T2.)
              > > > > >
              > > > > >
              > > > > > These issues seem to have quite a bit of buzz. There are some really
              > > > > stark
              > > > > > #'s out there: even as R&D investment has gone way up over the past 50
              > > > > > years, the # of new drugs has stayed roughly constant at around 20 a
              > > > > year.
              > > > > >
              > > > > >
              > > > > > Dario sent a really interesting paper on this topic. It argues: (a) the #
              > > > > > of NMEs (new medical entities, i.e., drugs) per year has mostly remained
              > > > > > constant-with-noise (no trend); (b) all of the big companies seem to have
              > > > > > produced NMEs at a very steady pace, even as they've changed size, though
              > > > > > different companies do have different rates of NME creation; (c) when it
              > > > > > comes to mergers & acquisitions, "1+1=1": companies that acquire other
              > > > > > companies just keep up the same NME pace; (d) over time, the # of large
              > > > > > companies has shrunk (due to mergers) and the # of small companies has
              > > > > > risen, and the share of NMEs attributed to small companies has gone from
              > > > > > ~30% to ~70%; (e) the cost per NME has gone up over time and is now in
              > > > > the
              > > > > > neighborhood of $1 billion; (f) the % of NMEs that are "blockbusters"
              > > > > (huge
              > > > > > profits) has been steady around 20%, despite intensifying efforts on the
              > > > > > part of pharma to fund only potential blockbusters.
              > > > > >
              > > > > >
              > > > > >
              > > > > > There are also claims - such as by Derek Lowe, a blogger Dario pointed me
              > > > > > to - that the "Valley of Death" is an overrated concept: there is a high
              > > > > > ratio of academic discoveries to useful drugs, but this is just because a
              > > > > > lot of stuff turns out not to work, not because we have a shortage of
              > > > > > doable translational research. The paper above sort of takes this view,
              > > > > > essentially arguing that nothing seems to raise NME production; we'll
              > > > > need
              > > > > > something really radical to make any difference.
              > > > > >
              > > > > >
              > > > > >
              > > > > > The case studies in the FasterCures paper on this are interesting. They
              > > > > > imply that there were some pretty low-hanging fruit in the T1 domain. It
              > > > > > might be interesting to talk to Fastercures and see whether they can help
              > > > > > identify "Valley of Death" opportunities that are slam-dunkish.
              > > > > >
              > > > > >
              > > > > > *Potential "big opportunity to do good" #2: inefficiencies in academic
              > > > > > biology*
              > > > >
              > > > > >
              > > > > >
              > > > > >
              > > > > > All of the above seems pretty distinct from the question of how to make
              > > > > > academic biology better at doing its job of understanding the body. This
              > > > > is
              > > > > > the question that Dario and I focused on.
              > > > > >
              > > > > >
              > > > > >
              > > > > > Dario painted a picture in which most of academia plays by the same set
              > > > > of
              > > > > > rules, making it very hard for people to do things that break those rules
              > > > > > (for example, academics are expected to publish a lot; it's risky to work
              > > > > > on a "blue sky" or highly ambitious project). Thus, for anyone who wants
              > > > > a
              > > > > > career in academia, a couple of years working on a moonshot project are
              > > > > > risky; in addition, being on bad terms with a small number of people can
              > > > > > damage a career (since there is often a small set of people that makes a
              > > > > > large proportion of the career-impacting decisions for a given area, and
              > > > > it
              > > > > > can be hard to escape this set of people without changing research
              > > > > > interests significantly). The bad news is that this isn't particularly
              > > > > easy
              > > > > > to fix: you can offer funding for blue-sky projects, but (a) a lot of
              > > > > > academics basically train themselves to play by the rules, and won't
              > > > > > necessarily have thought about "what should be studied if these rules
              > > > > > didn't apply," and more importantly, (b) there are many incentives
              > > > > pushing
              > > > > > academics towards playing by certain rules; funding is only one of those
              > > > > > mechanisms (there's also tenure, peer review, etc) so changing that one
              > > > > > incentive won't always change behavior. Dario says that he might hesitate
              > > > > > to work on a particular blue-sky project that he thinks is interesting,
              > > > > > even if he got funding for it, for these reasons.
              > > > > >
              > > > > >
              > > > > > Despite this, there are some funders who push the boundaries. There are
              > > > > > medical centers that don't require teaching and do more ambitious work.
              > > > > > There's the McKnight foundation, which funded some of the pioneering work
              > > > > > on optical control of neurons for which funding might have been difficult
              > > > > > to obtain by traditional routes. There's the HHMI Janelia Farms campus,
              > > > > > which Dario thinks is the most promising thing out there in terms of a
              > > > > > model - academics who go there get guaranteed (and generous) funding for
              > > > > 6
              > > > > > years, which frees them up to take much bigger risks. (I saw a study
              > > > > > claiming that the work coming out of Janelia Farms has a much more skewed
              > > > > > citation count distribution, implying bigger risks - i.e., fewer papers
              > > > > > with decent #'s of citations but more "blockbuster" papers with lots of
              > > > > > citations). But Janelia Farms is only in one sub-field; comparable
              > > > > > institutions don't exist for other fields (as far as Dario knows)..
              > > > > >
              > > > > >
              > > > > >
              > > > > > Dario's gut is that one of the best things a funder could do would be to
              > > > > > work toward creating a large institute that largely "plays by its own
              > > > > > rules," encouraging more ambitious work and providing enough security and
              > > > > > sheer volume of dollars/researchers as to establish a sort of "parallel
              > > > > > system" to academia - thus becoming a place that could provide viable and
              > > > > > reliable career options for people interested in playing by different
              > > > > > rules. I'm also interested in the idea of trying to advocate for changes
              > > > > in
              > > > > > the rules, as we've discussed in the context of meta-research.
              > > > > >
              > > > > >
              > > > > >
              > > > > > There's also the other stuff like data/code sharing.
              > > > > >
              > > > > >
              > > > > >
              > > > > > *Another option: give $ to the NIH*
              > > > >
              > > > > >
              > > > > >
              > > > > >
              > > > > > The NIH is by far the largest, most prestigious, most respected funder in
              > > > > > academic biology, and most of academia runs on criteria that mirror the
              > > > > > NIH's. I would guess that an unrestricted check to the NIH would get
              > > > > > allocated in a pretty sector-agnostic way. It seems like this is a giving
              > > > > > option that is pretty nontrivial to beat. Anyone we consider for funding
              > > > > > ought to be able to explain why they're better at allocating the funds
              > > > > than
              > > > > > the NIH. We haven't talked to the NIH about whether it would accept these
              > > > > > sorts of donations.
              > > > > >
              > > > > >
              > > > > > With the context I now have, FasterCures strikes me as pretty
              > > > > > promising/interesting too, though their "room for more funding" situation
              > > > > > isn't clear (w/o talking to them). But they also seem sector-agnostic
              > > > > > within biomedical research, while pushing a very specific theory of
              > > > > change
              > > > > > that may or may not be valid.
              > > > > >
              > > > > >
              > > > > >
              > > > > > *Next steps*
              > > > >
              > > > > >
              > > > > >
              > > > > >
              > > > > > I think understanding this world would be a major undertaking. I think
              > > > > we'd
              > > > > > have to be ready to put in a lot of work and to be open to ways of
              > > > > bridging
              > > > > > "funder-expert gap" that we haven't tried before. For example:
              > > > > >
              > > > > > · Dario suggested that I read a freshman biology textbook. He said he
              > > > > > realizes that the time cost could be very large - something like 100
              > > > > hours
              > > > > > - but that without doing so, I'm going to be lacking too much context on
              > > > > > why biomedical research works the way it does. He thinks that reading a
              > > > > > basic textbook would get me to the point of strongly diminishing marginal
              > > > > > returns.
              > > > > >
              > > > > > · Also in the category of "personally picking up rudimentary subject
              > > > > > matter knowledge," I thought it might be worth trying to follow the
              > > > > > development of a particular drug from start to finish - Gleevec (the
              > > > > > "miracle drug") would be a good candidate. The goal would be to
              > > > > understand
              > > > > > each stage of insight leading to new investigation, and where the funding
              > > > > > came from at each stage.
              > > > > >
              > > > > > · I think hiring Dario or someone like him would make a lot of sense.
              > > > > > I've thought about whether we should be hiring "subject matter experts"
              > > > > in
              > > > > > other areas, such as global health, but in my view the need is clearer
              > > > > here
              > > > > > than in any other area. One of the things I don't love about hiring an
              > > > > > expert in a given field, at this stage of our research, is that we could
              > > > > > quickly decide that we're just not interested enough in the field in
              > > > > > question ... but someone with the right kind of technical knowledge &
              > > > > > experience would be so far ahead of us in evaluating *any* area of
              > > > > biology
              > > > > > research that it seems like a good idea. (JTBC, I'm also actively
              > > > > thinking
              > > > > > about whether it would make sense to hire experts in other fields ...)
              > > > > >
              > > > > > · Talking to major funders and potentially co-funding with them is
              > > > > > probably essential. Important groups to talk to would include NIH (by far
              > > > > > the most important; we've already talked to them a bit), the colloquium
              > > > > of
              > > > > > groups like the American Cancer Society (it has a name; I forget the
              > > > > name),
              > > > > > FasterCures, Wellcome, and potentially some funders with
              > > > > > unorthodox/buzzed-about approaches: Myelin Repair Foundation, McKnight
              > > > > > Foundation, and maybe another private foundation or two (I emailed Dario
              > > > > > all my notes on major foundations that do biomedical research so he could
              > > > > > send thoughts on whether any look interesting aside from McKnight).
              > > > > >
              > > > > >
              > > > > > My next plan had been to talk to academics (Dario had good suggestions
              > > > > > about how to approach them), but with all the potential work to be done
              > > > > on
              > > > > > gaining basic context, I'm not sure that's the right next step. But it's
              > > > > > also a possible step.
              > > > > >
              > > > > >
              > > > > >
              > > > > > *2. Some more context on the history of our work on biomedical research
              > > > > and
              > > > >
              > > > > > why we think it's appropriate to investigate this field (this was a
              > > > > > response to a question following my original email, along the lines of
              > > > > "Why
              > > > > > are you looking into biomedical research now, given that's an area with a
              > > > > > lot of buzz and funding from wealthy donors, and how does this work
              > > > > relate
              > > > > > to the 'meta-research' work?")*
              > > > > >
              > > > > >
              > > > > > - We've always had "disease research" as a cause we wanted to
              > > > >
              > > > > > investigate. We've never had a good reason for not investigating it other
              > > > > > than that investigating it seems difficult. We've tried more than once to
              > > > > > investigate it, and it's ended up falling by the wayside because of how
              > > > > big
              > > > > > an undertaking it is.
              > > > > > - It's true that there is a huge amount of funding and buzz in this
              > > > >
              > > > > > area. But it also seems quite possible that there isn't nearly enough; in
              > > > > > fact this seems like a possible point of consensus between all the people
              > > > > > concerned about the "Valley of Death." This potential good accomplished
              > > > > via
              > > > > > biomedical research appears unlimited. What I consider to be the mark of
              > > > > a
              > > > > > bad sector is "tons of buzz/$ and mediocre returns," but the latter part
              > > > > > doesn't apply to biomed; in fact biomedical research is arguably one of
              > > > > > philanthropy's and even humanity's top success stories.
              > > > > > - There are also indications that despite all the buzz and funding,
              > > > >
              > > > > > there are still opportunities to do things differently and shake things
              > > > > up.
              > > > > > There is more than one case where an outsider (Milken, MRF) basically
              > > > > came
              > > > > > in and did things very differently and now even experts in the field seem
              > > > > > to credit them with positive change. There's also a good explanation for
              > > > > > why this might be the case: while there are a ton of people and dollars,
              > > > > > they largely seem to play by one self-reinforcing/network-effect-prone
              > > > > set
              > > > > > of rules, implying high returns to disrupting that equilibrium.
              > > > > > - So, we've always wanted to get into this area. There was a period
              > > > >
              > > > > > where I was presenting meta-research as our best entry point into this
              > > > > > field: my vision was that we would talk to academics about what
              > > > > systematic
              > > > > > failings there were and what funding opportunities these implied, and
              > > > > that
              > > > > > would be as good a way as any to get acclimated in biomed. But this
              > > > > period
              > > > > > wasn't particularly long - the May blog post on Labs priority causes
              > > > > lists
              > > > > > scientific research as a promising area distinct from meta-research.
              > > > > > - I set up the call with Dario without having a clear idea of whether I
              > > > >
              > > > > > wanted to approach biomed from a "meta-research" angle or another angle.
              > > > > > After the call and other investigations described here, I got a clearer
              > > > > > idea of what I think is the best path forward.
              > > > > >
              > > > > > Bottom line - I think it's important to build an understanding of
              > > > > > biomedical research, and that we should take the best path to doing so
              > > > > > whether or not that dovetails with the meta-research work (likely it will
              > > > > > dovetail some but not 100%).
              > > > >
              > > > >
              > > > >
              > > >
              > >
              > >
              > >
              > >
              > >
              >
              >
            • Susheela Peres da Costa
              Aubrey, I would love to hear more about two things you raise as worthwhile questions. 1) The distinction between longevity on the one hand and the postponement
              Message 6 of 18 , Oct 14, 2012
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                Aubrey, I would love to hear more about two things you raise as worthwhile questions.
                 
                1) The distinction between longevity on the one hand and the postponement of age-related ill health on the other (I understand the different definitions, but am interested in thoughts on the likely implications of each for the other, in a real-world population-wide context - for instance, would better health result simply delay the in one's 70s-80s result in viewing the demise of health in 90s-100s .)
                 
                2) In the context of any implications for longevity, whether / why "the medical control of aging [is] a hugely valuable mission?" relative to other uses of philanthropic funds for medical research. 
                 

                On 13 October 2012 21:24, Aubrey de Grey <aubrey@...> wrote:
                Hi Holden - many thanks.

                First: yes, there are really three somewhat separate questions for someone trying to evaluate whether to support SENS Foundation:

                1) Is the medical control of aging a hugely valuable mission?

                2) Assuming "yes" to (1), is it best achieved by basic research or translational research?

                3) Assuming translational, is SENS Foundation the organisation that uses money most effectively in pursuit of that mission?

                I had rather expected that you would take some convincing on item (1), and much of what I wrote last time was focused on that. Since it isn't the focus of your question to me, I'm now going to assume until further notice that there is no dissent on that.

                So, to answer your question: actually you're not putting aside the basic-vs-translational question as much as you may think you are. The word "translational" is flavour of the month in government funding circles these days (not only in the USA), so it's not surprising that the NIA has a public statement of the kind you pointed to. However, notice that the link they give "for more information" is to a page listing ALL "Funding Opportunity Announcements". There is no page specifically for translational ones, and the reason there isn't is that the amount of work that the NIA actually funds that could really be called translational is tiny. In other words, the page you found is actually just blatant spin. The neuroscience slice you mention is an anomaly arising from the way NIA was founded (the natural place for that money is clearly NINDS): the fact that it's NIA money does not, in practice, translate into its being spent on work to prevent neurodegeneration by treating its cause (aging). Instead, just like NINDS money, it's spent on attacking neurodegeneration directly, as if such diseases could be eliminated from the body just like an infection: the same old mistake that afflicts, and dooms, the whole of geriatric medicine.

                So, the first answer to your question is that SENS Foundation really DOES focus on translational research, with an explicit goal of postponing age-related ill-health. But there's also another big difference: we can attack this problem relatively free of the other priorities that afflict mainstream funding (whether from NIH or from trasitional foundations). Most importantly, though we do and will continue to publish our interim results in the peer-reviewed literature, we are much less constrained by "publish or perish" tyranny than typical academics are. This allows us to proceed by constructing and implementing a rational "project plan" (namely SENS) to get to the intended goal (the defeat of aging), whereas what little translational work is funded by NIA or others is guided overwhelmingly by the imperative to get some kind of positive result as quickly as possible, even when it's understood that those results are not remotely likely to "scale", i.e. to translate into eventual medical treatments that significantly delay aging. A great example of this is the NIA's Interventions Testing Program (ITP) to test the mouse longevity effects of various small molecules. The ITP only exists at all (and in a far smaller form than originally intended) as a result of several years of persistence by the then head of the NIA's biology division (Huber Warner), and it focuses entirely on delivery of simple drugs starting rather early in life, with the result that no information emerges that's relevant to treating people who are already in middle age or older. (This is despite the fact that by far the most high-profile result that the ITP has delivered so far, the benefits of rapamycin, actually WAS a late-onset study: it wasn't meant to be, but technical issues delayed the experiment.) In a nutshell, there is a huge bias against high-risk high-gain work.

                The third thing that distinguishes SENS Foundation's approach is that we can transcend the "balkanisation" (silo mentality) that dominates mainstream academic funding. When one submits a grant application to NIA, it is evaluated by gerontologists, just as when one submits to NCI it is evaluated by oncologists, etc. What's wrong with this is that it biases the system immensely against cross-disciplinary proposals. SENS is a plan that brings together a large body of knowledge from gerontology but also a huge amount of expertise that was developed for other reasons entirely - to treat acute disease/injury, or in some cases for purposes that were not biomedical at all (notably environmental decontamination). It doesn't matter how robust the objective scientific and technological argument is for work of that sort: it will never compete (especially in today's very tight funding environment) with more single-topic proposals all of whose details can be understood by reviewers from a particular single field.

                The final thing to mention, and this actually also answers your question to Vipul about basic versus translational research, is that SENS is a plan that has stood the test of time. I've been propounding it since 2000, well before SENS Foundation existed, and it used to come in for a lot of criticism (initially more in the form of off-the-record ridicule, and latterly, at my behest, in print), but in every single case that criticism was found to stem from ignorance on the part of the detractor, either of what I proposed or of published experimental work on which the proposal was based. That's why I'm now regularly asked to organise entire sessions at mainstream gerontology conferences, whereas as little as five years ago I would never even be invited to speak. It's also why the Research Advisory Board of SENS Foundation consists of such prestigious scientists. This is a very strong argument, in my view, for believing that now is the time to sink a proper amount of money into translational gerontology (though certainly not to cease doin basic biogerontology too). It's well known that basic scientists are often not the most far-sighted when it comes to seeing how to apply their discoveries (attitudes in 1900 to the feasibility of powered flight being the canonical example). It is therefore a source of concern that almost all the experts who have the ear of funders in this field are basic scientists, whose instinct is to carry on finding things out and to deprioritise the tedious business of applying that knowledge. SENS has achieved a gratisfying level of legitimacy in gerontology, but it is still foreign to most card-carrying gerontologists, and as such it remains essentially unfundable via mainstream mechanisms. Hence the need to create a philanthropy-driven entity, SENS Foundation, to get this work done.

                Let me know if this helps, or if you have further questions.

                Cheers, Aubrey

                On 12 Oct 2012, at 15:28, Holden Karnofsky wrote:

                >
                > Hi Aubrey,
                >
                > Thanks for the thoughts.
                >
                > The NIH appears to have a division focused on research relevant to this topic: http://www.nia.nih.gov/research/dab . Its budget appears to be ~$175 million (per year). The National Institute on Aging, which houses this division, has a budget of about $1 billion per year, including a separate ~$400 million for neuroscience (which may also be relevant) as well as $115 million for intramural research. Figures are from http://www.nia.nih.gov/about/budget/2012/fiscal-year-2013-budget. The Institute states that its mandate includes translational research (http://www.nia.nih.gov/research/faq/does-nia-support-translational-research). How would you distinguish your work from this work?
                >
                > (For the moment I'm putting aside the question I raised in my previous response to Vipul on this topic, regarding whether it's best to approach biology funding from the perspective of "trying to treat/cure a particular condition" or "trying to understand  fundamental questions in biology whose applications are difficult to predict.")
                >
                > Best,
                > Holden
                >
                > On Fri, Oct 12, 2012 at 7:32 AM, aubrey.degrey <aubrey@...> wrote:
                >
                > Hi everyone,
                >
                > My attention was brought to this thread, by virtue of the fact that it was my work that gave rise to SENS Foundation, and I'm looking forward to getting more involved here; I've held the Effective Altruism movement in high regard for some time. However, given my newbie status here I want to start by apologising in advance for any oversight of previously-discussed issues etc. I'm naturally delighted both at Holden's post and at Vipul's reply (which I should stress that I did not plant! - I do not know Vipul at all, though I look forward to changing that). I would like to mention just a few key points for discussion:
                >
                > - Holden, I want to compliment you on your appreciation of how academia really works. Everything you say about that is spot on. The aversion to "high risk high gain" work that has arisen and become so endemic in the system is the most important point here, in terms of why parallel funding routes are needed.
                >
                > - I'm slightly confused that a lot of Holden's remarks are focused on the private sector (i.e. startups), since my understanding was that GiveWell is about philanthropy; but I realise that there is not all that clear a boundary between the two (and I note the mention of Breakout Labs, with which I have close links and which sits astride that divide more than arguably anyone). The "valley of death" in pre-competitive translational research is a rather different one than that encountered by startups, but the principle is the same, and research to postpone aging certainly encounteres it.
                >
                > - Something that I presume factors highly among GiveWell's criteria is the extent to which a cause may be undervalued by the bulk of major philanthropists, such that an infusion of additional funds would make more of a difference than in an area that is already being well funded. To me this seems to mirror the logic of focusing on the shortcomings (gaps) in NIH's funding (and that of traditional-model foundations). Holden notes that "Anyone we consider for funding ought to be able to explain why they're better at allocating the funds than the NIH" and I agree wholeheartedly, but my inference is that he thinks that some orgs may indeed be able to explain that. I certainly think that SENS Foundation can.
                >
                > - Coming to aging: research to postpone aging has the unique problem of quite indescribeable irrationality on the part of most of the general public, policy-makers and even biologists with regard to its desirability. Biogerontologists have been talking to brick walls for decades in their effort to get the rest of the world to appreciate that aging is what causes age-related ill-health, and thus that treatments for aging are merely preventative geriatrics. The concept persists, despite biogerontologists' best efforts, that aging is "natural" and should be left alone, whereas the diseases that it brings about are awful and should be fought. This is made even more bizarre by the fact that the status of age-related diseases as aspects of the later stages of aging absolutely, unequivocally implies that efforts to attack those diseases directly are doomed to fail. As such, this is a (unique? certainly very rare) case where a philanthropic contribution can make a particularly big difference simply because most philanthropists don't see the case for it. It underpins why having an interest in treating aging, as opposed to cancer, absolutely has a major impact on which projects one funds. It's also a case for (if I understand the term correctly) meta-research.
                >
                > - A lot of the chatter about treating aging revolves around longevity, but it shouldn't. I'm all in favour of longevity, don't get me wrong, but it's not what gets me up in the morning: what does is health. I want people to be truly youthful, however long ago they were born: simple as that. The benefits of longevity per se to humanity may also be substantial, in the form of greater wisdom etc, but that would necessarily come about only very gradually (we won't have any 1000-year-old for at least 900 years whatever happens!), so it doesn't figure strongly in my calculations.
                >
                > - When forced to acknowledge that the idea of aging being a high-priority target for medicine is an inescapeable consequence of things they already believe (notably that health is good and ageism is bad), many people retreat to the standpoint that it's never going to be possible so it's OK to be irrational about whether it's desirable. The feasibility of postponing age-related ill-health by X years with medicine available Y years from now is, of course, a matter of speculation on which experts disagree, just as with any other pioneering technology. I know that Holden and others have expressed caution (at best) concerning the accuracy of any kind of calculation of probabilities of particular outcomes in the distant (or even not-so-distant) future, and I share that view. However, an approach that may appeal more is to estimate how much humanitarian benefit a given amount of progress would deliver, and then to ask how unlikely that scenario needs to be to make it not worth pursuing. My claim is that the benefits of hastening the defeat of aging by even a few years (which is the minimum that I claim SENS Foundation is in a position to do, given adequate funding) would be so astronomical that the required chance of success to make such an effort worthwhile would be tiny - too tiny for it to be reasonable to argue that such funding would be inadvisable. But of course that is precisely what I would want GiveWell to opine on.
                >
                > - In the event that GiveWell (or anyone else) were to decide and declare that the defeat of aging is indeed a cause that philanthropists should support, there then arises the question of which organisation(s) should be supported in the best interests of that mission. We at SENS Foundation have worked diligently to rise as quickly as possible in the legitimacy stakes by all standard measures, but we are still young and there remains more to do. If I were to offer an argument to fund us rather than any other entity, it would largely come down to the fact that no other organisation has even a serious plan for defeating aging, let alone a track record of implementing such a plan's early stages.
                >
                > - A significant chunk of what we do is of a kind that I think comes under "meta-research". A prominent example is a project we're funding at Denver University to extend the well-respected forecasting system "International Futures" so that it can analyse scenarios incorporating dramatically postponed aging.
                >
                > I greatly welcome any feedback.
                >
                > Cheers, Aubrey
                >
                >
                >
                > --- In givewell@yahoogroups.com, Holden Karnofsky <holden0@...> wrote:
                > >
                > > Hi Vipul,
                > >
                > > Thanks for the thoughts. I had a followup conversation with Dario about
                > > this topic a few days ago. I think the question of "could one fund
                > > translational research to treat/prevent aging?" provides an interesting
                > > illustration of some of the tricky dynamics here for a funder:
                > >
                > > - It's possible that if there were a great deal more attention giving to
                >
                > > treating/preventing aging, we would have some promising treatments. So in a
                > > broad sense it's possible that aging is underinvested in.
                > > - A lot of the best basic biology research isn't clearly pointing toward
                >
                > > one treatment/condition or another; it's about understanding the
                > > fundamentals of how organisms operate. So having an interest in treating
                > > aging, as opposed to cancer, might not have a major impact on which
                > > projects one funds, if one's main goal is to fund outstanding basic biology
                > > research.
                > > - Perhaps because of the lack of emphasis on treating aging (or perhaps
                >
                > > because it's simply too difficult of a problem), there don't seem to be
                > > promising findings in the "Valley of Death" relevant to aging; the few
                > > promising leads have been explored.
                > > - So even if, in a broad sense, there is too little attention given to
                >
                > > this problem, knowing this doesn't necessarily yield a clear direction for
                > > a relatively small-scale funder of biomedical research.
                > >
                > > Best,
                > > Holden
                > >
                > > On Wed, Oct 10, 2012 at 11:55 PM, Vipul Naik <vipul@...>wrote:
                > >
                > > > **
                >
                > > >
                > > >
                > > > Holden,
                > > >
                > > > First, I think that this is an excellent document. I checked for a
                > > > number of things that I had heard about (Breakout Labs, John
                > > > Ioannidis, Cochrane Collaboration) and they're all there in your
                > > > document.
                > > >
                > > > The one thing that's not explicitly mentioned: longevity and life
                > > > extension research. At least prima facie, this seems like something
                > > > that should be more important than individual disease research, and it
                > > > seems like a classic "Valley of Death" case (pun unintended, but
                > > > noted) -- T1 stage to use your terminology. I think the SENS website
                > > > http://www.sens.org would be a good starting point for one of the (to
                > > > me promising) approaches to life extension. I recall from past
                > > > conversations that you were aware of SENS, so this is not new to you,
                > > > but I think that longevity should be included as part of any
                > > > discussion of biomedical research and given separate consideration
                > > > given that it has a much lower status than research into specific
                > > > conditions such as cancer, dementia, etc. You may ultimately conclude
                > > > that not enough can be done in this area, but I think it should be
                > > > part of your preliminary stuff. [btw, the United States has a National
                > > > Institute of Aging, but it's much lower-status than most of the other
                > > > grantmakers mentioned here].
                > > >
                > > > Vipul
                > > >
                > > > * Quoting Holden Karnofsky who at 2012-10-10 23:08:42+0000 (Wed) wrote
                > > >
                > > > > Note to the research list: we're now considering reopening our
                > > > > investigation of the world of biomedical research. We've started and
                > > > > stopped a couple of times in this area before; this time I decided to
                > > > start
                > > > > with a conversation with Dario Amodei, a longtime GiveWell follower and
                > > > > personal friend who is currently a biology postdoc at Stanford. My goal
                > > > > with the conversation was just to get some basic context and start
                > > > putting
                > > > > together a framework for thinking about the issue, not to use him as an
                > > > > authoritative source, and the notes below should be read in that spirit.
                > > > >
                > > > >
                > > > > This email has two sections:
                > > > >
                > > > >
                > > > > 1. Notes that I emailed out internally after my conversation with Dario,
                > > > > slightly edited
                > > > >
                > > > > 2. Some more context on the history of our work on biomedical research
                > > > and
                > > > > why we think it's appropriate to investigate this field (this was a
                > > > > response to a question following my original email, along the lines of
                > > > "Why
                > > > > are you looking into biomedical research now, given that's an area with a
                > > > > lot of buzz and funding from wealthy donors, and how does this work
                > > > relate
                > > > > to the 'meta-research' work?")
                > > > >
                > > > >
                > > > >
                > > > > *--*
                > > > >
                > > > > *
                > > > > *
                > > > >
                > > > > *1. Notes that I emailed out internally after my conversation with Dario,
                > > > > slightly edited*
                > > > >
                > > > > *
                > > >
                > > > > *
                > > > >
                > > > > I've done some preliminary work trying to figure out what it would look
                > > > > like to explore biomedical sciences as funding area. This mostly
                > > > consisted
                > > > > of a 3-hour conversation with Dario (recording is available), reading two
                > > > > papers he sent and a few I found while Googling, and prior knowledge. I'm
                > > > > including Dario in all emails related to this stuff, as an informal
                > > > advisor.
                > > > >
                > > > > * *
                > > > >
                > > > > *My picture of "what the biomedical research world roughly looks like"
                > > > *(this
                > > >
                > > > > is mostly from talking with Dario + prior knowledge)
                > > > >
                > > > > · *Academic biology* studies how organisms work and develops tools to
                > > >
                > > > > observe and manipulate the building blocks of organisms.
                > > > >
                > > > > o The vast bulk of the funding - and the most prestigious funding - comes
                > > > > from the NIH.
                > > > >
                > > > > o There is also funding from what I've heard called "foundations" -
                > > > groups
                > > > > like the American Cancer Society and American Heart Association - which
                > > > > function very similarly to the NIH, in that they tend to hire people with
                > > > > strong academic credentials and those people judge the merits of grant
                > > > > proposals.
                > > > >
                > > > > o Both the NIH and "foundations" tend to be formally partitioned by
                > > > > disease, but much of the work done by academic biologists is potentially
                > > > > relevant to many diseases. A researcher seeking NIH funding may apply to
                > > > > several different NIH "study sections," though only one at a time (a list
                > > > > of "study sections" is at
                > > > > http://public.csr.nih.gov/StudySections/Standing/Pages/default.aspx);
                > > > > whether s/he gets funding is going to depend more on the academic merits
                > > > of
                > > > > the researcher & work than anything else.
                > > > >
                > > > > o There are basic definitions of "academic merit " that generally shape
                > > > > the whole ecosystem: the people handing out money are selected by these
                > > > > criteria and use these criteria, the people doing the research know that
                > > > > these criteria shape their career prospects, etc.
                > > > >
                > > > > · *Private startups* investigate promising ideas for new
                > > >
                > > > > treatments/diagnostics/devices. They may often take the form of a biology
                > > > > professor spinning off a biotech startup (run by former postdocs) that
                > > > > raises venture capital, based on the research the professor did. They
                > > > take
                > > > > basic knowledge about how the body works (for example, protein X is
                > > > crucial
                > > > > for medical condition Y) and do the necessary testing to find a promising
                > > > > treatment/diagnostic/device (for example, testing a lot of compounds on
                > > > > animals until they find one that affects protein X).
                > > > >
                > > > > · *Big pharma/biotech companies *are best positioned to deal with the
                > > >
                > > > > extremely expensive process of conducting clinical trials and getting FDA
                > > > > approval. Acquisition by one of these is the most common form of exit for
                > > > > startups.
                > > > >
                > > > > · *Academic medicine, epidemiology and other fields* also do work
                > > >
                > > > > relevant to medicine, including studying questions whose main relevance
                > > > is
                > > > > to medical practice and public health programs: how effective is
                > > > > treatment/practice X in situation Y, how cost-effective is it, etc.
                > > > > Sometimes they will hit on commercializable insights (for example, a new
                > > > > kind of device) as well.
                > > > >
                > > > > · *Translational research* is a broad term referring to a bridge between
                > > >
                > > > > academic research and treatments/practices. It can include (
                > > > >
                > > > http://medicalcenter.osu.edu/research/translational_research/pages/index.aspx
                > > > > ):
                > > > >
                > > > > o T1 - going from basic science (usually academic biology, I presume) to
                > > > a
                > > > > new treatment/practice. This includes research that helps go from an
                > > > > academic biology insight to a private startup.
                > > > >
                > > > > o T2 - I think this is basically what Cochrane does - going from academic
                > > > > medicine/epidemiology (a bunch of studies on what treatments/practices
                > > > are
                > > > > effective) to the development of guidelines that actually affect
                > > > practice.
                > > > >
                > > > > o T3, T4 - research on how to actually change practice (as opposed to
                > > > > setting the guidelines that are a "target" for practice) and get better
                > > > > real-world results.
                > > > >
                > > > > *
                > > > > *
                > > > >
                > > > > *Potential "big opportunity to do good" #1: translational research and
                > > > the
                > > >
                > > > > "Valley of Death" (this comes from prior knowledge, googling "Valley of
                > > > > Death" and reading a bunch of the stuff I found, and checking out the
                > > > > FasterCures website again)*
                > > >
                > > > >
                > > > >
                > > > >
                > > > > The "Valley of Death" seems to mostly refer to a shortage of T1. The idea
                > > > > is that there are a lot of cases where there's an academic insight that's
                > > > > potentially valuable in coming up with a new treatment, but to get it to
                > > > > the point where it's attractive from a for-profit perspective, you need
                > > > to
                > > > > do a lot of stuff that academics don't have a reason to do. "For example,
                > > > > an upstream finding that a given protein is differentially expressed in
                > > > > individuals with a particular disease may suggest that the protein merits
                > > > > further investigation. However, much more work (especially medicinal
                > > > > chemistry) is necessary to determine how good a target the protein really
                > > > > is and whether a marketable drug candidate that affects the activity of
                > > > the
                > > > > protein is likely to be developed." (
                > > > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf)
                > > > >
                > > > >
                > > > >
                > > > > There are claims that this sort of work is massively underfunded (by the
                > > > > people we've spoken to who talked about the "Valley of Death"; also in
                > > > >
                > > > http://www.fastercures.org/documents/file/Valley%20of%20Death%20-%20Translational%20Research
                > > > (1).pdf).
                > > > > However, funding isn't the only issue. The other issue is that
                > > > > "pharmaceutical firms that hold libraries of potentially useful small
                > > > > molecules as trade secrets, making them largely off limits to ...
                > > > academic
                > > > > scientists" (
                > > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf).
                > > > > In other words, there is some room for new models of collaboration that
                > > > > lead to better communication and information sharing between academia and
                > > > > industry (or between industry and industry).
                > > > >
                > > > >
                > > > > Both the Myelin Repair Foundation and Michael Milken's work on prostate
                > > > > cancer have been pointed to as examples of innovative collaborations that
                > > > > deal with some of the information sharing problems. Milken's model:
                > > > > "drastically cutting the wait time for grant money, to flood the field
                > > > with
                > > > > fast cash, to fund therapy-driven ideas rather than basic science, to
                > > > hold
                > > > > researchers he funds accountable for results, and to demand collaboration
                > > > > across disciplines and among institutions, private industry, and
                > > > academia."
                > > > > (
                > > > >
                > > > http://money.cnn.com/magazines/fortune/fortune_archive/2004/11/29/8192713/index.htm
                > > > )
                > > > > Myelin Repair Foundation sounds broadly similar (
                > > > >
                > > > http://opinionator.blogs.nytimes.com/2011/05/02/helping-new-drugs-out-of-academias-valley-of-death/
                > > > ).
                > > > >
                > > > >
                > > > >
                > > > >
                > > > > More broadly:
                > > > >
                > > > > · FasterCures (also a Michael Milken production) looks like it's focused
                > > > > on the broad mission of "more research with a shorter timeline to
                > > > > treatments," with a heavy sub-focus on the Valley of Death. In addition
                > > > to
                > > > > its conference and philanthropic advisory service, it advocates for FDA
                > > > > improvements (presumably to speed the approval process), advocates for
                > > > the
                > > > > NIH to put more funding into translational research (there have
                > > > definitely
                > > > > been a lot of new initiatives at the NIH focused on this stuff in the
                > > > past
                > > > > few ~decade), promotes "innovative financing mechanisms" for bridging the
                > > > > Valley of Death (these include Peter Thiel's Breakout Labs; I think they
                > > > > occupy a conceptually similar space to "social enterprise investment"
                > > > > though they tend to be structured more as grants and less as
                > > > > double-bottom-line investments), and works on getting patient data opened
                > > > > to researchers. The only program of theirs I haven't mentioned is TRAIN;
                > > > I
                > > > > can't (easily) figure out what this is.
                > > > >
                > > > > · John Ioannidis stated to us that all translational research is
                > > > > underfunded, not just T1. (The context we talked to him in, of course,
                > > > was
                > > > > T2.)
                > > > >
                > > > >
                > > > > These issues seem to have quite a bit of buzz. There are some really
                > > > stark
                > > > > #'s out there: even as R&D investment has gone way up over the past 50
                > > > > years, the # of new drugs has stayed roughly constant at around 20 a
                > > > year.
                > > > >
                > > > >
                > > > > Dario sent a really interesting paper on this topic. It argues: (a) the #
                > > > > of NMEs (new medical entities, i.e., drugs) per year has mostly remained
                > > > > constant-with-noise (no trend); (b) all of the big companies seem to have
                > > > > produced NMEs at a very steady pace, even as they've changed size, though
                > > > > different companies do have different rates of NME creation; (c) when it
                > > > > comes to mergers & acquisitions, "1+1=1": companies that acquire other
                > > > > companies just keep up the same NME pace; (d) over time, the # of large
                > > > > companies has shrunk (due to mergers) and the # of small companies has
                > > > > risen, and the share of NMEs attributed to small companies has gone from
                > > > > ~30% to ~70%; (e) the cost per NME has gone up over time and is now in
                > > > the
                > > > > neighborhood of $1 billion; (f) the % of NMEs that are "blockbusters"
                > > > (huge
                > > > > profits) has been steady around 20%, despite intensifying efforts on the
                > > > > part of pharma to fund only potential blockbusters.
                > > > >
                > > > >
                > > > >
                > > > > There are also claims - such as by Derek Lowe, a blogger Dario pointed me
                > > > > to - that the "Valley of Death" is an overrated concept: there is a high
                > > > > ratio of academic discoveries to useful drugs, but this is just because a
                > > > > lot of stuff turns out not to work, not because we have a shortage of
                > > > > doable translational research. The paper above sort of takes this view,
                > > > > essentially arguing that nothing seems to raise NME production; we'll
                > > > need
                > > > > something really radical to make any difference.
                > > > >
                > > > >
                > > > >
                > > > > The case studies in the FasterCures paper on this are interesting. They
                > > > > imply that there were some pretty low-hanging fruit in the T1 domain. It
                > > > > might be interesting to talk to Fastercures and see whether they can help
                > > > > identify "Valley of Death" opportunities that are slam-dunkish.
                > > > >
                > > > >
                > > > > *Potential "big opportunity to do good" #2: inefficiencies in academic
                > > > > biology*
                > > >
                > > > >
                > > > >
                > > > >
                > > > > All of the above seems pretty distinct from the question of how to make
                > > > > academic biology better at doing its job of understanding the body. This
                > > > is
                > > > > the question that Dario and I focused on.
                > > > >
                > > > >
                > > > >
                > > > > Dario painted a picture in which most of academia plays by the same set
                > > > of
                > > > > rules, making it very hard for people to do things that break those rules
                > > > > (for example, academics are expected to publish a lot; it's risky to work
                > > > > on a "blue sky" or highly ambitious project). Thus, for anyone who wants
                > > > a
                > > > > career in academia, a couple of years working on a moonshot project are
                > > > > risky; in addition, being on bad terms with a small number of people can
                > > > > damage a career (since there is often a small set of people that makes a
                > > > > large proportion of the career-impacting decisions for a given area, and
                > > > it
                > > > > can be hard to escape this set of people without changing research
                > > > > interests significantly). The bad news is that this isn't particularly
                > > > easy
                > > > > to fix: you can offer funding for blue-sky projects, but (a) a lot of
                > > > > academics basically train themselves to play by the rules, and won't
                > > > > necessarily have thought about "what should be studied if these rules
                > > > > didn't apply," and more importantly, (b) there are many incentives
                > > > pushing
                > > > > academics towards playing by certain rules; funding is only one of those
                > > > > mechanisms (there's also tenure, peer review, etc) so changing that one
                > > > > incentive won't always change behavior. Dario says that he might hesitate
                > > > > to work on a particular blue-sky project that he thinks is interesting,
                > > > > even if he got funding for it, for these reasons.
                > > > >
                > > > >
                > > > > Despite this, there are some funders who push the boundaries. There are
                > > > > medical centers that don't require teaching and do more ambitious work.
                > > > > There's the McKnight foundation, which funded some of the pioneering work
                > > > > on optical control of neurons for which funding might have been difficult
                > > > > to obtain by traditional routes. There's the HHMI Janelia Farms campus,
                > > > > which Dario thinks is the most promising thing out there in terms of a
                > > > > model - academics who go there get guaranteed (and generous) funding for
                > > > 6
                > > > > years, which frees them up to take much bigger risks. (I saw a study
                > > > > claiming that the work coming out of Janelia Farms has a much more skewed
                > > > > citation count distribution, implying bigger risks - i.e., fewer papers
                > > > > with decent #'s of citations but more "blockbuster" papers with lots of
                > > > > citations). But Janelia Farms is only in one sub-field; comparable
                > > > > institutions don't exist for other fields (as far as Dario knows)..
                > > > >
                > > > >
                > > > >
                > > > > Dario's gut is that one of the best things a funder could do would be to
                > > > > work toward creating a large institute that largely "plays by its own
                > > > > rules," encouraging more ambitious work and providing enough security and
                > > > > sheer volume of dollars/researchers as to establish a sort of "parallel
                > > > > system" to academia - thus becoming a place that could provide viable and
                > > > > reliable career options for people interested in playing by different
                > > > > rules. I'm also interested in the idea of trying to advocate for changes
                > > > in
                > > > > the rules, as we've discussed in the context of meta-research.
                > > > >
                > > > >
                > > > >
                > > > > There's also the other stuff like data/code sharing.
                > > > >
                > > > >
                > > > >
                > > > > *Another option: give $ to the NIH*
                > > >
                > > > >
                > > > >
                > > > >
                > > > > The NIH is by far the largest, most prestigious, most respected funder in
                > > > > academic biology, and most of academia runs on criteria that mirror the
                > > > > NIH's. I would guess that an unrestricted check to the NIH would get
                > > > > allocated in a pretty sector-agnostic way. It seems like this is a giving
                > > > > option that is pretty nontrivial to beat. Anyone we consider for funding
                > > > > ought to be able to explain why they're better at allocating the funds
                > > > than
                > > > > the NIH. We haven't talked to the NIH about whether it would accept these
                > > > > sorts of donations.
                > > > >
                > > > >
                > > > > With the context I now have, FasterCures strikes me as pretty
                > > > > promising/interesting too, though their "room for more funding" situation
                > > > > isn't clear (w/o talking to them). But they also seem sector-agnostic
                > > > > within biomedical research, while pushing a very specific theory of
                > > > change
                > > > > that may or may not be valid.
                > > > >
                > > > >
                > > > >
                > > > > *Next steps*
                > > >
                > > > >
                > > > >
                > > > >
                > > > > I think understanding this world would be a major undertaking. I think
                > > > we'd
                > > > > have to be ready to put in a lot of work and to be open to ways of
                > > > bridging
                > > > > "funder-expert gap" that we haven't tried before. For example:
                > > > >
                > > > > · Dario suggested that I read a freshman biology textbook. He said he
                > > > > realizes that the time cost could be very large - something like 100
                > > > hours
                > > > > - but that without doing so, I'm going to be lacking too much context on
                > > > > why biomedical research works the way it does. He thinks that reading a
                > > > > basic textbook would get me to the point of strongly diminishing marginal
                > > > > returns.
                > > > >
                > > > > · Also in the category of "personally picking up rudimentary subject
                > > > > matter knowledge," I thought it might be worth trying to follow the
                > > > > development of a particular drug from start to finish - Gleevec (the
                > > > > "miracle drug") would be a good candidate. The goal would be to
                > > > understand
                > > > > each stage of insight leading to new investigation, and where the funding
                > > > > came from at each stage.
                > > > >
                > > > > · I think hiring Dario or someone like him would make a lot of sense.
                > > > > I've thought about whether we should be hiring "subject matter experts"
                > > > in
                > > > > other areas, such as global health, but in my view the need is clearer
                > > > here
                > > > > than in any other area. One of the things I don't love about hiring an
                > > > > expert in a given field, at this stage of our research, is that we could
                > > > > quickly decide that we're just not interested enough in the field in
                > > > > question ... but someone with the right kind of technical knowledge &
                > > > > experience would be so far ahead of us in evaluating *any* area of
                > > > biology
                > > > > research that it seems like a good idea. (JTBC, I'm also actively
                > > > thinking
                > > > > about whether it would make sense to hire experts in other fields ...)
                > > > >
                > > > > · Talking to major funders and potentially co-funding with them is
                > > > > probably essential. Important groups to talk to would include NIH (by far
                > > > > the most important; we've already talked to them a bit), the colloquium
                > > > of
                > > > > groups like the American Cancer Society (it has a name; I forget the
                > > > name),
                > > > > FasterCures, Wellcome, and potentially some funders with
                > > > > unorthodox/buzzed-about approaches: Myelin Repair Foundation, McKnight
                > > > > Foundation, and maybe another private foundation or two (I emailed Dario
                > > > > all my notes on major foundations that do biomedical research so he could
                > > > > send thoughts on whether any look interesting aside from McKnight).
                > > > >
                > > > >
                > > > > My next plan had been to talk to academics (Dario had good suggestions
                > > > > about how to approach them), but with all the potential work to be done
                > > > on
                > > > > gaining basic context, I'm not sure that's the right next step. But it's
                > > > > also a possible step.
                > > > >
                > > > >
                > > > >
                > > > > *2. Some more context on the history of our work on biomedical research
                > > > and
                > > >
                > > > > why we think it's appropriate to investigate this field (this was a
                > > > > response to a question following my original email, along the lines of
                > > > "Why
                > > > > are you looking into biomedical research now, given that's an area with a
                > > > > lot of buzz and funding from wealthy donors, and how does this work
                > > > relate
                > > > > to the 'meta-research' work?")*
                > > > >
                > > > >
                > > > > - We've always had "disease research" as a cause we wanted to
                > > >
                > > > > investigate. We've never had a good reason for not investigating it other
                > > > > than that investigating it seems difficult. We've tried more than once to
                > > > > investigate it, and it's ended up falling by the wayside because of how
                > > > big
                > > > > an undertaking it is.
                > > > > - It's true that there is a huge amount of funding and buzz in this
                > > >
                > > > > area. But it also seems quite possible that there isn't nearly enough; in
                > > > > fact this seems like a possible point of consensus between all the people
                > > > > concerned about the "Valley of Death." This potential good accomplished
                > > > via
                > > > > biomedical research appears unlimited. What I consider to be the mark of
                > > > a
                > > > > bad sector is "tons of buzz/$ and mediocre returns," but the latter part
                > > > > doesn't apply to biomed; in fact biomedical research is arguably one of
                > > > > philanthropy's and even humanity's top success stories.
                > > > > - There are also indications that despite all the buzz and funding,
                > > >
                > > > > there are still opportunities to do things differently and shake things
                > > > up.
                > > > > There is more than one case where an outsider (Milken, MRF) basically
                > > > came
                > > > > in and did things very differently and now even experts in the field seem
                > > > > to credit them with positive change. There's also a good explanation for
                > > > > why this might be the case: while there are a ton of people and dollars,
                > > > > they largely seem to play by one self-reinforcing/network-effect-prone
                > > > set
                > > > > of rules, implying high returns to disrupting that equilibrium.
                > > > > - So, we've always wanted to get into this area. There was a period
                > > >
                > > > > where I was presenting meta-research as our best entry point into this
                > > > > field: my vision was that we would talk to academics about what
                > > > systematic
                > > > > failings there were and what funding opportunities these implied, and
                > > > that
                > > > > would be as good a way as any to get acclimated in biomed. But this
                > > > period
                > > > > wasn't particularly long - the May blog post on Labs priority causes
                > > > lists
                > > > > scientific research as a promising area distinct from meta-research.
                > > > > - I set up the call with Dario without having a clear idea of whether I
                > > >
                > > > > wanted to approach biomed from a "meta-research" angle or another angle.
                > > > > After the call and other investigations described here, I got a clearer
                > > > > idea of what I think is the best path forward.
                > > > >
                > > > > Bottom line - I think it's important to build an understanding of
                > > > > biomedical research, and that we should take the best path to doing so
                > > > > whether or not that dovetails with the meta-research work (likely it will
                > > > > dovetail some but not 100%).
                > > >
                > > >
                > > >
                > >
                >
                >
                >
                >
                >



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              • Susheela Peres da Costa
                sorry, realise a sentence wasn t finished, amended below On 15 October 2012 12:43, Susheela Peres da Costa
                Message 7 of 18 , Oct 14, 2012
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                  sorry, realise a sentence wasn't finished, amended below

                  On 15 October 2012 12:43, Susheela Peres da Costa <susheela.peresdacosta@...> wrote:
                  Aubrey, I would love to hear more about two things you raise as worthwhile questions.
                   
                  1) The distinction between longevity on the one hand and the postponement of age-related ill health on the other (I understand the different definitions, but am interested in thoughts on the likely implications of each for the other, in a real-world population-wide context - for instance, would better health in one's 70s-80s result in viewing the demise of health in 90s-100s as the next frontier, essentially buying a net longevity gain rather than a net health-costs gain?)
                   
                  2) In the context of any implications for longevity, whether / why "the medical control of aging [is] a hugely valuable mission?" relative to other uses of philanthropic funds for medical research. 
                   

                  On 13 October 2012 21:24, Aubrey de Grey <aubrey@...> wrote:
                  Hi Holden - many thanks.

                  First: yes, there are really three somewhat separate questions for someone trying to evaluate whether to support SENS Foundation:

                  1) Is the medical control of aging a hugely valuable mission?

                  2) Assuming "yes" to (1), is it best achieved by basic research or translational research?

                  3) Assuming translational, is SENS Foundation the organisation that uses money most effectively in pursuit of that mission?

                  I had rather expected that you would take some convincing on item (1), and much of what I wrote last time was focused on that. Since it isn't the focus of your question to me, I'm now going to assume until further notice that there is no dissent on that.

                  So, to answer your question: actually you're not putting aside the basic-vs-translational question as much as you may think you are. The word "translational" is flavour of the month in government funding circles these days (not only in the USA), so it's not surprising that the NIA has a public statement of the kind you pointed to. However, notice that the link they give "for more information" is to a page listing ALL "Funding Opportunity Announcements". There is no page specifically for translational ones, and the reason there isn't is that the amount of work that the NIA actually funds that could really be called translational is tiny. In other words, the page you found is actually just blatant spin. The neuroscience slice you mention is an anomaly arising from the way NIA was founded (the natural place for that money is clearly NINDS): the fact that it's NIA money does not, in practice, translate into its being spent on work to prevent neurodegeneration by treating its cause (aging). Instead, just like NINDS money, it's spent on attacking neurodegeneration directly, as if such diseases could be eliminated from the body just like an infection: the same old mistake that afflicts, and dooms, the whole of geriatric medicine.

                  So, the first answer to your question is that SENS Foundation really DOES focus on translational research, with an explicit goal of postponing age-related ill-health. But there's also another big difference: we can attack this problem relatively free of the other priorities that afflict mainstream funding (whether from NIH or from trasitional foundations). Most importantly, though we do and will continue to publish our interim results in the peer-reviewed literature, we are much less constrained by "publish or perish" tyranny than typical academics are. This allows us to proceed by constructing and implementing a rational "project plan" (namely SENS) to get to the intended goal (the defeat of aging), whereas what little translational work is funded by NIA or others is guided overwhelmingly by the imperative to get some kind of positive result as quickly as possible, even when it's understood that those results are not remotely likely to "scale", i.e. to translate into eventual medical treatments that significantly delay aging. A great example of this is the NIA's Interventions Testing Program (ITP) to test the mouse longevity effects of various small molecules. The ITP only exists at all (and in a far smaller form than originally intended) as a result of several years of persistence by the then head of the NIA's biology division (Huber Warner), and it focuses entirely on delivery of simple drugs starting rather early in life, with the result that no information emerges that's relevant to treating people who are already in middle age or older. (This is despite the fact that by far the most high-profile result that the ITP has delivered so far, the benefits of rapamycin, actually WAS a late-onset study: it wasn't meant to be, but technical issues delayed the experiment.) In a nutshell, there is a huge bias against high-risk high-gain work.

                  The third thing that distinguishes SENS Foundation's approach is that we can transcend the "balkanisation" (silo mentality) that dominates mainstream academic funding. When one submits a grant application to NIA, it is evaluated by gerontologists, just as when one submits to NCI it is evaluated by oncologists, etc. What's wrong with this is that it biases the system immensely against cross-disciplinary proposals. SENS is a plan that brings together a large body of knowledge from gerontology but also a huge amount of expertise that was developed for other reasons entirely - to treat acute disease/injury, or in some cases for purposes that were not biomedical at all (notably environmental decontamination). It doesn't matter how robust the objective scientific and technological argument is for work of that sort: it will never compete (especially in today's very tight funding environment) with more single-topic proposals all of whose details can be understood by reviewers from a particular single field.

                  The final thing to mention, and this actually also answers your question to Vipul about basic versus translational research, is that SENS is a plan that has stood the test of time. I've been propounding it since 2000, well before SENS Foundation existed, and it used to come in for a lot of criticism (initially more in the form of off-the-record ridicule, and latterly, at my behest, in print), but in every single case that criticism was found to stem from ignorance on the part of the detractor, either of what I proposed or of published experimental work on which the proposal was based. That's why I'm now regularly asked to organise entire sessions at mainstream gerontology conferences, whereas as little as five years ago I would never even be invited to speak. It's also why the Research Advisory Board of SENS Foundation consists of such prestigious scientists. This is a very strong argument, in my view, for believing that now is the time to sink a proper amount of money into translational gerontology (though certainly not to cease doin basic biogerontology too). It's well known that basic scientists are often not the most far-sighted when it comes to seeing how to apply their discoveries (attitudes in 1900 to the feasibility of powered flight being the canonical example). It is therefore a source of concern that almost all the experts who have the ear of funders in this field are basic scientists, whose instinct is to carry on finding things out and to deprioritise the tedious business of applying that knowledge. SENS has achieved a gratisfying level of legitimacy in gerontology, but it is still foreign to most card-carrying gerontologists, and as such it remains essentially unfundable via mainstream mechanisms. Hence the need to create a philanthropy-driven entity, SENS Foundation, to get this work done.

                  Let me know if this helps, or if you have further questions.

                  Cheers, Aubrey

                  On 12 Oct 2012, at 15:28, Holden Karnofsky wrote:

                  >
                  > Hi Aubrey,
                  >
                  > Thanks for the thoughts.
                  >
                  > The NIH appears to have a division focused on research relevant to this topic: http://www.nia.nih.gov/research/dab . Its budget appears to be ~$175 million (per year). The National Institute on Aging, which houses this division, has a budget of about $1 billion per year, including a separate ~$400 million for neuroscience (which may also be relevant) as well as $115 million for intramural research. Figures are from http://www.nia.nih.gov/about/budget/2012/fiscal-year-2013-budget. The Institute states that its mandate includes translational research (http://www.nia.nih.gov/research/faq/does-nia-support-translational-research). How would you distinguish your work from this work?
                  >
                  > (For the moment I'm putting aside the question I raised in my previous response to Vipul on this topic, regarding whether it's best to approach biology funding from the perspective of "trying to treat/cure a particular condition" or "trying to understand  fundamental questions in biology whose applications are difficult to predict.")
                  >
                  > Best,
                  > Holden
                  >
                  > On Fri, Oct 12, 2012 at 7:32 AM, aubrey.degrey <aubrey@...> wrote:
                  >
                  > Hi everyone,
                  >
                  > My attention was brought to this thread, by virtue of the fact that it was my work that gave rise to SENS Foundation, and I'm looking forward to getting more involved here; I've held the Effective Altruism movement in high regard for some time. However, given my newbie status here I want to start by apologising in advance for any oversight of previously-discussed issues etc. I'm naturally delighted both at Holden's post and at Vipul's reply (which I should stress that I did not plant! - I do not know Vipul at all, though I look forward to changing that). I would like to mention just a few key points for discussion:
                  >
                  > - Holden, I want to compliment you on your appreciation of how academia really works. Everything you say about that is spot on. The aversion to "high risk high gain" work that has arisen and become so endemic in the system is the most important point here, in terms of why parallel funding routes are needed.
                  >
                  > - I'm slightly confused that a lot of Holden's remarks are focused on the private sector (i.e. startups), since my understanding was that GiveWell is about philanthropy; but I realise that there is not all that clear a boundary between the two (and I note the mention of Breakout Labs, with which I have close links and which sits astride that divide more than arguably anyone). The "valley of death" in pre-competitive translational research is a rather different one than that encountered by startups, but the principle is the same, and research to postpone aging certainly encounteres it.
                  >
                  > - Something that I presume factors highly among GiveWell's criteria is the extent to which a cause may be undervalued by the bulk of major philanthropists, such that an infusion of additional funds would make more of a difference than in an area that is already being well funded. To me this seems to mirror the logic of focusing on the shortcomings (gaps) in NIH's funding (and that of traditional-model foundations). Holden notes that "Anyone we consider for funding ought to be able to explain why they're better at allocating the funds than the NIH" and I agree wholeheartedly, but my inference is that he thinks that some orgs may indeed be able to explain that. I certainly think that SENS Foundation can.
                  >
                  > - Coming to aging: research to postpone aging has the unique problem of quite indescribeable irrationality on the part of most of the general public, policy-makers and even biologists with regard to its desirability. Biogerontologists have been talking to brick walls for decades in their effort to get the rest of the world to appreciate that aging is what causes age-related ill-health, and thus that treatments for aging are merely preventative geriatrics. The concept persists, despite biogerontologists' best efforts, that aging is "natural" and should be left alone, whereas the diseases that it brings about are awful and should be fought. This is made even more bizarre by the fact that the status of age-related diseases as aspects of the later stages of aging absolutely, unequivocally implies that efforts to attack those diseases directly are doomed to fail. As such, this is a (unique? certainly very rare) case where a philanthropic contribution can make a particularly big difference simply because most philanthropists don't see the case for it. It underpins why having an interest in treating aging, as opposed to cancer, absolutely has a major impact on which projects one funds. It's also a case for (if I understand the term correctly) meta-research.
                  >
                  > - A lot of the chatter about treating aging revolves around longevity, but it shouldn't. I'm all in favour of longevity, don't get me wrong, but it's not what gets me up in the morning: what does is health. I want people to be truly youthful, however long ago they were born: simple as that. The benefits of longevity per se to humanity may also be substantial, in the form of greater wisdom etc, but that would necessarily come about only very gradually (we won't have any 1000-year-old for at least 900 years whatever happens!), so it doesn't figure strongly in my calculations.
                  >
                  > - When forced to acknowledge that the idea of aging being a high-priority target for medicine is an inescapeable consequence of things they already believe (notably that health is good and ageism is bad), many people retreat to the standpoint that it's never going to be possible so it's OK to be irrational about whether it's desirable. The feasibility of postponing age-related ill-health by X years with medicine available Y years from now is, of course, a matter of speculation on which experts disagree, just as with any other pioneering technology. I know that Holden and others have expressed caution (at best) concerning the accuracy of any kind of calculation of probabilities of particular outcomes in the distant (or even not-so-distant) future, and I share that view. However, an approach that may appeal more is to estimate how much humanitarian benefit a given amount of progress would deliver, and then to ask how unlikely that scenario needs to be to make it not worth pursuing. My claim is that the benefits of hastening the defeat of aging by even a few years (which is the minimum that I claim SENS Foundation is in a position to do, given adequate funding) would be so astronomical that the required chance of success to make such an effort worthwhile would be tiny - too tiny for it to be reasonable to argue that such funding would be inadvisable. But of course that is precisely what I would want GiveWell to opine on.
                  >
                  > - In the event that GiveWell (or anyone else) were to decide and declare that the defeat of aging is indeed a cause that philanthropists should support, there then arises the question of which organisation(s) should be supported in the best interests of that mission. We at SENS Foundation have worked diligently to rise as quickly as possible in the legitimacy stakes by all standard measures, but we are still young and there remains more to do. If I were to offer an argument to fund us rather than any other entity, it would largely come down to the fact that no other organisation has even a serious plan for defeating aging, let alone a track record of implementing such a plan's early stages.
                  >
                  > - A significant chunk of what we do is of a kind that I think comes under "meta-research". A prominent example is a project we're funding at Denver University to extend the well-respected forecasting system "International Futures" so that it can analyse scenarios incorporating dramatically postponed aging.
                  >
                  > I greatly welcome any feedback.
                  >
                  > Cheers, Aubrey
                  >
                  >
                  >
                  > --- In givewell@yahoogroups.com, Holden Karnofsky <holden0@...> wrote:
                  > >
                  > > Hi Vipul,
                  > >
                  > > Thanks for the thoughts. I had a followup conversation with Dario about
                  > > this topic a few days ago. I think the question of "could one fund
                  > > translational research to treat/prevent aging?" provides an interesting
                  > > illustration of some of the tricky dynamics here for a funder:
                  > >
                  > > - It's possible that if there were a great deal more attention giving to
                  >
                  > > treating/preventing aging, we would have some promising treatments. So in a
                  > > broad sense it's possible that aging is underinvested in.
                  > > - A lot of the best basic biology research isn't clearly pointing toward
                  >
                  > > one treatment/condition or another; it's about understanding the
                  > > fundamentals of how organisms operate. So having an interest in treating
                  > > aging, as opposed to cancer, might not have a major impact on which
                  > > projects one funds, if one's main goal is to fund outstanding basic biology
                  > > research.
                  > > - Perhaps because of the lack of emphasis on treating aging (or perhaps
                  >
                  > > because it's simply too difficult of a problem), there don't seem to be
                  > > promising findings in the "Valley of Death" relevant to aging; the few
                  > > promising leads have been explored.
                  > > - So even if, in a broad sense, there is too little attention given to
                  >
                  > > this problem, knowing this doesn't necessarily yield a clear direction for
                  > > a relatively small-scale funder of biomedical research.
                  > >
                  > > Best,
                  > > Holden
                  > >
                  > > On Wed, Oct 10, 2012 at 11:55 PM, Vipul Naik <vipul@...>wrote:
                  > >
                  > > > **
                  >
                  > > >
                  > > >
                  > > > Holden,
                  > > >
                  > > > First, I think that this is an excellent document. I checked for a
                  > > > number of things that I had heard about (Breakout Labs, John
                  > > > Ioannidis, Cochrane Collaboration) and they're all there in your
                  > > > document.
                  > > >
                  > > > The one thing that's not explicitly mentioned: longevity and life
                  > > > extension research. At least prima facie, this seems like something
                  > > > that should be more important than individual disease research, and it
                  > > > seems like a classic "Valley of Death" case (pun unintended, but
                  > > > noted) -- T1 stage to use your terminology. I think the SENS website
                  > > > http://www.sens.org would be a good starting point for one of the (to
                  > > > me promising) approaches to life extension. I recall from past
                  > > > conversations that you were aware of SENS, so this is not new to you,
                  > > > but I think that longevity should be included as part of any
                  > > > discussion of biomedical research and given separate consideration
                  > > > given that it has a much lower status than research into specific
                  > > > conditions such as cancer, dementia, etc. You may ultimately conclude
                  > > > that not enough can be done in this area, but I think it should be
                  > > > part of your preliminary stuff. [btw, the United States has a National
                  > > > Institute of Aging, but it's much lower-status than most of the other
                  > > > grantmakers mentioned here].
                  > > >
                  > > > Vipul
                  > > >
                  > > > * Quoting Holden Karnofsky who at 2012-10-10 23:08:42+0000 (Wed) wrote
                  > > >
                  > > > > Note to the research list: we're now considering reopening our
                  > > > > investigation of the world of biomedical research. We've started and
                  > > > > stopped a couple of times in this area before; this time I decided to
                  > > > start
                  > > > > with a conversation with Dario Amodei, a longtime GiveWell follower and
                  > > > > personal friend who is currently a biology postdoc at Stanford. My goal
                  > > > > with the conversation was just to get some basic context and start
                  > > > putting
                  > > > > together a framework for thinking about the issue, not to use him as an
                  > > > > authoritative source, and the notes below should be read in that spirit.
                  > > > >
                  > > > >
                  > > > > This email has two sections:
                  > > > >
                  > > > >
                  > > > > 1. Notes that I emailed out internally after my conversation with Dario,
                  > > > > slightly edited
                  > > > >
                  > > > > 2. Some more context on the history of our work on biomedical research
                  > > > and
                  > > > > why we think it's appropriate to investigate this field (this was a
                  > > > > response to a question following my original email, along the lines of
                  > > > "Why
                  > > > > are you looking into biomedical research now, given that's an area with a
                  > > > > lot of buzz and funding from wealthy donors, and how does this work
                  > > > relate
                  > > > > to the 'meta-research' work?")
                  > > > >
                  > > > >
                  > > > >
                  > > > > *--*
                  > > > >
                  > > > > *
                  > > > > *
                  > > > >
                  > > > > *1. Notes that I emailed out internally after my conversation with Dario,
                  > > > > slightly edited*
                  > > > >
                  > > > > *
                  > > >
                  > > > > *
                  > > > >
                  > > > > I've done some preliminary work trying to figure out what it would look
                  > > > > like to explore biomedical sciences as funding area. This mostly
                  > > > consisted
                  > > > > of a 3-hour conversation with Dario (recording is available), reading two
                  > > > > papers he sent and a few I found while Googling, and prior knowledge. I'm
                  > > > > including Dario in all emails related to this stuff, as an informal
                  > > > advisor.
                  > > > >
                  > > > > * *
                  > > > >
                  > > > > *My picture of "what the biomedical research world roughly looks like"
                  > > > *(this
                  > > >
                  > > > > is mostly from talking with Dario + prior knowledge)
                  > > > >
                  > > > > · *Academic biology* studies how organisms work and develops tools to
                  > > >
                  > > > > observe and manipulate the building blocks of organisms.
                  > > > >
                  > > > > o The vast bulk of the funding - and the most prestigious funding - comes
                  > > > > from the NIH.
                  > > > >
                  > > > > o There is also funding from what I've heard called "foundations" -
                  > > > groups
                  > > > > like the American Cancer Society and American Heart Association - which
                  > > > > function very similarly to the NIH, in that they tend to hire people with
                  > > > > strong academic credentials and those people judge the merits of grant
                  > > > > proposals.
                  > > > >
                  > > > > o Both the NIH and "foundations" tend to be formally partitioned by
                  > > > > disease, but much of the work done by academic biologists is potentially
                  > > > > relevant to many diseases. A researcher seeking NIH funding may apply to
                  > > > > several different NIH "study sections," though only one at a time (a list
                  > > > > of "study sections" is at
                  > > > > http://public.csr.nih.gov/StudySections/Standing/Pages/default.aspx);
                  > > > > whether s/he gets funding is going to depend more on the academic merits
                  > > > of
                  > > > > the researcher & work than anything else.
                  > > > >
                  > > > > o There are basic definitions of "academic merit " that generally shape
                  > > > > the whole ecosystem: the people handing out money are selected by these
                  > > > > criteria and use these criteria, the people doing the research know that
                  > > > > these criteria shape their career prospects, etc.
                  > > > >
                  > > > > · *Private startups* investigate promising ideas for new
                  > > >
                  > > > > treatments/diagnostics/devices. They may often take the form of a biology
                  > > > > professor spinning off a biotech startup (run by former postdocs) that
                  > > > > raises venture capital, based on the research the professor did. They
                  > > > take
                  > > > > basic knowledge about how the body works (for example, protein X is
                  > > > crucial
                  > > > > for medical condition Y) and do the necessary testing to find a promising
                  > > > > treatment/diagnostic/device (for example, testing a lot of compounds on
                  > > > > animals until they find one that affects protein X).
                  > > > >
                  > > > > · *Big pharma/biotech companies *are best positioned to deal with the
                  > > >
                  > > > > extremely expensive process of conducting clinical trials and getting FDA
                  > > > > approval. Acquisition by one of these is the most common form of exit for
                  > > > > startups.
                  > > > >
                  > > > > · *Academic medicine, epidemiology and other fields* also do work
                  > > >
                  > > > > relevant to medicine, including studying questions whose main relevance
                  > > > is
                  > > > > to medical practice and public health programs: how effective is
                  > > > > treatment/practice X in situation Y, how cost-effective is it, etc.
                  > > > > Sometimes they will hit on commercializable insights (for example, a new
                  > > > > kind of device) as well.
                  > > > >
                  > > > > · *Translational research* is a broad term referring to a bridge between
                  > > >
                  > > > > academic research and treatments/practices. It can include (
                  > > > >
                  > > > http://medicalcenter.osu.edu/research/translational_research/pages/index.aspx
                  > > > > ):
                  > > > >
                  > > > > o T1 - going from basic science (usually academic biology, I presume) to
                  > > > a
                  > > > > new treatment/practice. This includes research that helps go from an
                  > > > > academic biology insight to a private startup.
                  > > > >
                  > > > > o T2 - I think this is basically what Cochrane does - going from academic
                  > > > > medicine/epidemiology (a bunch of studies on what treatments/practices
                  > > > are
                  > > > > effective) to the development of guidelines that actually affect
                  > > > practice.
                  > > > >
                  > > > > o T3, T4 - research on how to actually change practice (as opposed to
                  > > > > setting the guidelines that are a "target" for practice) and get better
                  > > > > real-world results.
                  > > > >
                  > > > > *
                  > > > > *
                  > > > >
                  > > > > *Potential "big opportunity to do good" #1: translational research and
                  > > > the
                  > > >
                  > > > > "Valley of Death" (this comes from prior knowledge, googling "Valley of
                  > > > > Death" and reading a bunch of the stuff I found, and checking out the
                  > > > > FasterCures website again)*
                  > > >
                  > > > >
                  > > > >
                  > > > >
                  > > > > The "Valley of Death" seems to mostly refer to a shortage of T1. The idea
                  > > > > is that there are a lot of cases where there's an academic insight that's
                  > > > > potentially valuable in coming up with a new treatment, but to get it to
                  > > > > the point where it's attractive from a for-profit perspective, you need
                  > > > to
                  > > > > do a lot of stuff that academics don't have a reason to do. "For example,
                  > > > > an upstream finding that a given protein is differentially expressed in
                  > > > > individuals with a particular disease may suggest that the protein merits
                  > > > > further investigation. However, much more work (especially medicinal
                  > > > > chemistry) is necessary to determine how good a target the protein really
                  > > > > is and whether a marketable drug candidate that affects the activity of
                  > > > the
                  > > > > protein is likely to be developed." (
                  > > > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf)
                  > > > >
                  > > > >
                  > > > >
                  > > > > There are claims that this sort of work is massively underfunded (by the
                  > > > > people we've spoken to who talked about the "Valley of Death"; also in
                  > > > >
                  > > > http://www.fastercures.org/documents/file/Valley%20of%20Death%20-%20Translational%20Research
                  > > > (1).pdf).
                  > > > > However, funding isn't the only issue. The other issue is that
                  > > > > "pharmaceutical firms that hold libraries of potentially useful small
                  > > > > molecules as trade secrets, making them largely off limits to ...
                  > > > academic
                  > > > > scientists" (
                  > > > https://www.law.upenn.edu/institutes/ctic/papers/200708/Rai.pdf).
                  > > > > In other words, there is some room for new models of collaboration that
                  > > > > lead to better communication and information sharing between academia and
                  > > > > industry (or between industry and industry).
                  > > > >
                  > > > >
                  > > > > Both the Myelin Repair Foundation and Michael Milken's work on prostate
                  > > > > cancer have been pointed to as examples of innovative collaborations that
                  > > > > deal with some of the information sharing problems. Milken's model:
                  > > > > "drastically cutting the wait time for grant money, to flood the field
                  > > > with
                  > > > > fast cash, to fund therapy-driven ideas rather than basic science, to
                  > > > hold
                  > > > > researchers he funds accountable for results, and to demand collaboration
                  > > > > across disciplines and among institutions, private industry, and
                  > > > academia."
                  > > > > (
                  > > > >
                  > > > http://money.cnn.com/magazines/fortune/fortune_archive/2004/11/29/8192713/index.htm
                  > > > )
                  > > > > Myelin Repair Foundation sounds broadly similar (
                  > > > >
                  > > > http://opinionator.blogs.nytimes.com/2011/05/02/helping-new-drugs-out-of-academias-valley-of-death/
                  > > > ).
                  > > > >
                  > > > >
                  > > > >
                  > > > >
                  > > > > More broadly:
                  > > > >
                  > > > > · FasterCures (also a Michael Milken production) looks like it's focused
                  > > > > on the broad mission of "more research with a shorter timeline to
                  > > > > treatments," with a heavy sub-focus on the Valley of Death. In addition
                  > > > to
                  > > > > its conference and philanthropic advisory service, it advocates for FDA
                  > > > > improvements (presumably to speed the approval process), advocates for
                  > > > the
                  > > > > NIH to put more funding into translational research (there have
                  > > > definitely
                  > > > > been a lot of new initiatives at the NIH focused on this stuff in the
                  > > > past
                  > > > > few ~decade), promotes "innovative financing mechanisms" for bridging the
                  > > > > Valley of Death (these include Peter Thiel's Breakout Labs; I think they
                  > > > > occupy a conceptually similar space to "social enterprise investment"
                  > > > > though they tend to be structured more as grants and less as
                  > > > > double-bottom-line investments), and works on getting patient data opened
                  > > > > to researchers. The only program of theirs I haven't mentioned is TRAIN;
                  > > > I
                  > > > > can't (easily) figure out what this is.
                  > > > >
                  > > > > · John Ioannidis stated to us that all translational research is
                  > > > > underfunded, not just T1. (The context we talked to him in, of course,
                  > > > was
                  > > > > T2.)
                  > > > >
                  > > > >
                  > > > > These issues seem to have quite a bit of buzz. There are some really
                  > > > stark
                  > > > > #'s out there: even as R&D investment has gone way up over the past 50
                  > > > > years, the # of new drugs has stayed roughly constant at around 20 a
                  > > > year.
                  > > > >
                  > > > >
                  > > > > Dario sent a really interesting paper on this topic. It argues: (a) the #
                  > > > > of NMEs (new medical entities, i.e., drugs) per year has mostly remained
                  > > > > constant-with-noise (no trend); (b) all of the big companies seem to have
                  > > > > produced NMEs at a very steady pace, even as they've changed size, though
                  > > > > different companies do have different rates of NME creation; (c) when it
                  > > > > comes to mergers & acquisitions, "1+1=1": companies that acquire other
                  > > > > companies just keep up the same NME pace; (d) over time, the # of large
                  > > > > companies has shrunk (due to mergers) and the # of small companies has
                  > > > > risen, and the share of NMEs attributed to small companies has gone from
                  > > > > ~30% to ~70%; (e) the cost per NME has gone up over time and is now in
                  > > > the
                  > > > > neighborhood of $1 billion; (f) the % of NMEs that are "blockbusters"
                  > > > (huge
                  > > > > profits) has been steady around 20%, despite intensifying efforts on the
                  > > > > part of pharma to fund only potential blockbusters.
                  > > > >
                  > > > >
                  > > > >
                  > > > > There are also claims - such as by Derek Lowe, a blogger Dario pointed me
                  > > > > to - that the "Valley of Death" is an overrated concept: there is a high
                  > > > > ratio of academic discoveries to useful drugs, but this is just because a
                  > > > > lot of stuff turns out not to work, not because we have a shortage of
                  > > > > doable translational research. The paper above sort of takes this view,
                  > > > > essentially arguing that nothing seems to raise NME production; we'll
                  > > > need
                  > > > > something really radical to make any difference.
                  > > > >
                  > > > >
                  > > > >
                  > > > > The case studies in the FasterCures paper on this are interesting. They
                  > > > > imply that there were some pretty low-hanging fruit in the T1 domain. It
                  > > > > might be interesting to talk to Fastercures and see whether they can help
                  > > > > identify "Valley of Death" opportunities that are slam-dunkish.
                  > > > >
                  > > > >
                  > > > > *Potential "big opportunity to do good" #2: inefficiencies in academic
                  > > > > biology*
                  > > >
                  > > > >
                  > > > >
                  > > > >
                  > > > > All of the above seems pretty distinct from the question of how to make
                  > > > > academic biology better at doing its job of understanding the body. This
                  > > > is
                  > > > > the question that Dario and I focused on.
                  > > > >
                  > > > >
                  > > > >
                  > > > > Dario painted a picture in which most of academia plays by the same set
                  > > > of
                  > > > > rules, making it very hard for people to do things that break those rules
                  > > > > (for example, academics are expected to publish a lot; it's risky to work
                  > > > > on a "blue sky" or highly ambitious project). Thus, for anyone who wants
                  > > > a
                  > > > > career in academia, a couple of years working on a moonshot project are
                  > > > > risky; in addition, being on bad terms with a small number of people can
                  > > > > damage a career (since there is often a small set of people that makes a
                  > > > > large proportion of the career-impacting decisions for a given area, and
                  > > > it
                  > > > > can be hard to escape this set of people without changing research
                  > > > > interests significantly). The bad news is that this isn't particularly
                  > > > easy
                  > > > > to fix: you can offer funding for blue-sky projects, but (a) a lot of
                  > > > > academics basically train themselves to play by the rules, and won't
                  > > > > necessarily have thought about "what should be studied if these rules
                  > > > > didn't apply," and more importantly, (b) there are many incentives
                  > > > pushing
                  > > > > academics towards playing by certain rules; funding is only one of those
                  > > > > mechanisms (there's also tenure, peer review, etc) so changing that one
                  > > > > incentive won't always change behavior. Dario says that he might hesitate
                  > > > > to work on a particular blue-sky project that he thinks is interesting,
                  > > > > even if he got funding for it, for these reasons.
                  > > > >
                  > > > >
                  > > > > Despite this, there are some funders who push the boundaries. There are
                  > > > > medical centers that don't require teaching and do more ambitious work.
                  > > > > There's the McKnight foundation, which funded some of the pioneering work
                  > > > > on optical control of neurons for which funding might have been difficult
                  > > > > to obtain by traditional routes. There's the HHMI Janelia Farms campus,
                  > > > > which Dario thinks is the most promising thing out there in terms of a
                  > > > > model - academics who go there get guaranteed (and generous) funding for
                  > > > 6
                  > > > > years, which frees them up to take much bigger risks. (I saw a study
                  > > > > claiming that the work coming out of Janelia Farms has a much more skewed
                  > > > > citation count distribution, implying bigger risks - i.e., fewer papers
                  > > > > with decent #'s of citations but more "blockbuster" papers with lots of
                  > > > > citations). But Janelia Farms is only in one sub-field; comparable
                  > > > > institutions don't exist for other fields (as far as Dario knows)..
                  > > > >
                  > > > >
                  > > > >
                  > > > > Dario's gut is that one of the best things a funder could do would be to
                  > > > > work toward creating a large institute that largely "plays by its own
                  > > > > rules," encouraging more ambitious work and providing enough security and
                  > > > > sheer volume of dollars/researchers as to establish a sort of "parallel
                  > > > > system" to academia - thus becoming a place that could provide viable and
                  > > > > reliable career options for people interested in playing by different
                  > > > > rules. I'm also interested in the idea of trying to advocate for changes
                  > > > in
                  > > > > the rules, as we've discussed in the context of meta-research.
                  > > > >
                  > > > >
                  > > > >
                  > > > > There's also the other stuff like data/code sharing.
                  > > > >
                  > > > >
                  > > > >
                  > > > > *Another option: give $ to the NIH*
                  > > >
                  > > > >
                  > > > >
                  > > > >
                  > > > > The NIH is by far the largest, most prestigious, most respected funder in
                  > > > > academic biology, and most of academia runs on criteria that mirror the
                  > > > > NIH's. I would guess that an unrestricted check to the NIH would get
                  > > > > allocated in a pretty sector-agnostic way. It seems like this is a giving
                  > > > > option that is pretty nontrivial to beat. Anyone we consider for funding
                  > > > > ought to be able to explain why they're better at allocating the funds
                  > > > than
                  > > > > the NIH. We haven't talked to the NIH about whether it would accept these
                  > > > > sorts of donations.
                  > > > >
                  > > > >
                  > > > > With the context I now have, FasterCures strikes me as pretty
                  > > > > promising/interesting too, though their "room for more funding" situation
                  > > > > isn't clear (w/o talking to them). But they also seem sector-agnostic
                  > > > > within biomedical research, while pushing a very specific theory of
                  > > > change
                  > > > > that may or may not be valid.
                  > > > >
                  > > > >
                  > > > >
                  > > > > *Next steps*
                  > > >
                  > > > >
                  > > > >
                  > > > >
                  > > > > I think understanding this world would be a major undertaking. I think
                  > > > we'd
                  > > > > have to be ready to put in a lot of work and to be open to ways of
                  > > > bridging
                  > > > > "funder-expert gap" that we haven't tried before. For example:
                  > > > >
                  > > > > · Dario suggested that I read a freshman biology textbook. He said he
                  > > > > realizes that the time cost could be very large - something like 100
                  > > > hours
                  > > > > - but that without doing so, I'm going to be lacking too much context on
                  > > > > why biomedical research works the way it does. He thinks that reading a
                  > > > > basic textbook would get me to the point of strongly diminishing marginal
                  > > > > returns.
                  > > > >
                  > > > > · Also in the category of "personally picking up rudimentary subject
                  > > > > matter knowledge," I thought it might be worth trying to follow the
                  > > > > development of a particular drug from start to finish - Gleevec (the
                  > > > > "miracle drug") would be a good candidate. The goal would be to
                  > > > understand
                  > > > > each stage of insight leading to new investigation, and where the funding
                  > > > > came from at each stage.
                  > > > >
                  > > > > · I think hiring Dario or someone like him would make a lot of sense.
                  > > > > I've thought about whether we should be hiring "subject matter experts"
                  > > > in
                  > > > > other areas, such as global health, but in my view the need is clearer
                  > > > here
                  > > > > than in any other area. One of the things I don't love about hiring an
                  > > > > expert in a given field, at this stage of our research, is that we could
                  > > > > quickly decide that we're just not interested enough in the field in
                  > > > > question ... but someone with the right kind of technical knowledge &
                  > > > > experience would be so far ahead of us in evaluating *any* area of
                  > > > biology
                  > > > > research that it seems like a good idea. (JTBC, I'm also actively
                  > > > thinking
                  > > > > about whether it would make sense to hire experts in other fields ...)
                  > > > >
                  > > > > · Talking to major funders and potentially co-funding with them is
                  > > > > probably essential. Important groups to talk to would include NIH (by far
                  > > > > the most important; we've already talked to them a bit), the colloquium
                  > > > of
                  > > > > groups like the American Cancer Society (it has a name; I forget the
                  > > > name),
                  > > > > FasterCures, Wellcome, and potentially some funders with
                  > > > > unorthodox/buzzed-about approaches: Myelin Repair Foundation, McKnight
                  > > > > Foundation, and maybe another private foundation or two (I emailed Dario
                  > > > > all my notes on major foundations that do biomedical research so he could
                  > > > > send thoughts on whether any look interesting aside from McKnight).
                  > > > >
                  > > > >
                  > > > > My next plan had been to talk to academics (Dario had good suggestions
                  > > > > about how to approach them), but with all the potential work to be done
                  > > > on
                  > > > > gaining basic context, I'm not sure that's the right next step. But it's
                  > > > > also a possible step.
                  > > > >
                  > > > >
                  > > > >
                  > > > > *2. Some more context on the history of our work on biomedical research
                  > > > and
                  > > >
                  > > > > why we think it's appropriate to investigate this field (this was a
                  > > > > response to a question following my original email, along the lines of
                  > > > "Why
                  > > > > are you looking into biomedical research now, given that's an area with a
                  > > > > lot of buzz and funding from wealthy donors, and how does this work
                  > > > relate
                  > > > > to the 'meta-research' work?")*
                  > > > >
                  > > > >
                  > > > > - We've always had "disease research" as a cause we wanted to
                  > > >
                  > > > > investigate. We've never had a good reason for not investigating it other
                  > > > > than that investigating it seems difficult. We've tried more than once to
                  > > > > investigate it, and it's ended up falling by the wayside because of how
                  > > > big
                  > > > > an undertaking it is.
                  > > > > - It's true that there is a huge amount of funding and buzz in this
                  > > >
                  > > > > area. But it also seems quite possible that there isn't nearly enough; in
                  > > > > fact this seems like a possible point of consensus between all the people
                  > > > > concerned about the "Valley of Death." This potential good accomplished
                  > > > via
                  > > > > biomedical research appears unlimited. What I consider to be the mark of
                  > > > a
                  > > > > bad sector is "tons of buzz/$ and mediocre returns," but the latter part
                  > > > > doesn't apply to biomed; in fact biomedical research is arguably one of
                  > > > > philanthropy's and even humanity's top success stories.
                  > > > > - There are also indications that despite all the buzz and funding,
                  > > >
                  > > > > there are still opportunities to do things differently and shake things
                  > > > up.
                  > > > > There is more than one case where an outsider (Milken, MRF) basically
                  > > > came
                  > > > > in and did things very differently and now even experts in the field seem
                  > > > > to credit them with positive change. There's also a good explanation for
                  > > > > why this might be the case: while there are a ton of people and dollars,
                  > > > > they largely seem to play by one self-reinforcing/network-effect-prone
                  > > > set
                  > > > > of rules, implying high returns to disrupting that equilibrium.
                  > > > > - So, we've always wanted to get into this area. There was a period
                  > > >
                  > > > > where I was presenting meta-research as our best entry point into this
                  > > > > field: my vision was that we would talk to academics about what
                  > > > systematic
                  > > > > failings there were and what funding opportunities these implied, and
                  > > > that
                  > > > > would be as good a way as any to get acclimated in biomed. But this
                  > > > period
                  > > > > wasn't particularly long - the May blog post on Labs priority causes
                  > > > lists
                  > > > > scientific research as a promising area distinct from meta-research.
                  > > > > - I set up the call with Dario without having a clear idea of whether I
                  > > >
                  > > > > wanted to approach biomed from a "meta-research" angle or another angle.
                  > > > > After the call and other investigations described here, I got a clearer
                  > > > > idea of what I think is the best path forward.
                  > > > >
                  > > > > Bottom line - I think it's important to build an understanding of
                  > > > > biomedical research, and that we should take the best path to doing so
                  > > > > whether or not that dovetails with the meta-research work (likely it will
                  > > > > dovetail some but not 100%).
                  > > >
                  > > >
                  > > >
                  > >
                  >
                  >
                  >
                  >
                  >



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                • Aubrey de Grey
                  Hello Susheela, Yes, I expected that some people here would be interested in discussing these topics, even if Holden t focus is currently more on whom best to
                  Message 8 of 18 , Oct 15, 2012
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                    Hello Susheela,

                    Yes, I expected that some people here would be interested in discussing these topics, even if Holden't focus is currently more on whom best to fund to get the job done.

                    Your first question is one that gives rise to a big outreach dilemma, as it happens. A major reason why the SENS approach (turning back the aging clock with regenerative medicine, rather than slowing the clock down) is so attractive is that it buys so much time to figure out what to do next, i.e. how to make the therapies a notch better so that they can address what you term the next frontier. If we can rejuvenate 60-year-olds well enough that they won't be biologically 60 again until they're chronologically 90 - which is what I believe the "first-generation" SENS therapies will deliver - then we have all those 30 years to develop second-generation therapies that deliver a further 30 years of postponement, and so on. From what we know about the nature of the molecular and cellular damage that these therapies will repair, we can say with great confidence (or so I claim!) that these further improvements will overwhelmingly be in the form of relatively minor extensions of/variations on the initial therapies, which implies that it is vanishingly unlikely that progress will be so slow that we fail to stay one step ahead of the problem. (I have termed the necessary rate of improvement of the therapies "longevity escape velocity".) So, what this means is that for practical purposes we can regard the initial SENS therapies as delivering, with high probability, an indefinite postponement of age-related ill-health. The outreach dilemma is that objectively this is great, since the gain would absolutely be in terms of health costs as well as healthy longevity, but emotionally it ignites all kinds of knee-jerk reactions concerning the nature of a post-aging world, such as overpopulation risks, pensions crises, dictators living forever etc etc, which in my experience are powerful disincentives to supporting this work despite the acknowledgement that (a) health is good and (b) old people are people too, which in my view is pretty much all one needs to acknowledge in order to want aging to be eliminated.

                    On your second question, for sure there are issues here that cause some people to hesitate. Ultimately the question breaks down (I believe) into the following categories:

                    Positive:
                    1 how valuable is the anticipated health gain over the period when someone would otherwise be in impaired health?
                    2 how valuable is the anticipated additional [all healthy] healthy longevity gain?
                    3 how valuable are the anticipated gains in quality of life resulting indirectly from expecting to live a lot longer?

                    Negative:
                    4 how valuable are the lives that might not exist if we curtailed the birth rate more than we otherwise might?
                    5 how valuable are the aspects of today's life that might be compromised by the expectation of much longer lives?

                    My own view is that (1) and 2) are definitely as big as any other humanitarian mission, that (3) could be huge too (for example we might try a lot harder to combat climate change, end war etc), that (4) is unclear even if we regard future people as important, because we're curtailing the birth rate so fast anyway, and that (5) is a figment of Luddite imagination. But others may disagree! In particular, there seems to be a fairly widespread notion that (chronologically) old people really are less deserving of medical care than the young - and I refer here to intrinsic merits, independent of today's problem that it's in practice harder to give the elderly as much additional healthy life as the young. Whether this is a legitimate view or one that we must work against in the same way that people worked against the acceptance of slavery is a matter for debate.

                    Cheers, Aubrey

                    On 15 Oct 2012, at 04:05, Susheela Peres da Costa wrote:

                    > sorry, realise a sentence wasn't finished, amended below
                    >
                    > On 15 October 2012 12:43, Susheela Peres da Costa <susheela.peresdacosta@...> wrote:
                    > Aubrey, I would love to hear more about two things you raise as worthwhile questions.
                    >
                    > 1) The distinction between longevity on the one hand and the postponement of age-related ill health on the other (I understand the different definitions, but am interested in thoughts on the likely implications of each for the other, in a real-world population-wide context - for instance, would better health in one's 70s-80s result in viewing the demise of health in 90s-100s as the next frontier, essentially buying a net longevity gain rather than a net health-costs gain?)
                    >
                    > 2) In the context of any implications for longevity, whether / why "the medical control of aging [is] a hugely valuable mission?" relative to other uses of philanthropic funds for medical research.
                  • Brian Douglas Skinner
                    Hi Aubrey, Thanks for the detailed answer to Holden s question about the differences between what the NIA is doing and what the SENS Foundation is doing. If
                    Message 9 of 18 , Oct 29, 2012
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                      Hi Aubrey,

                      Thanks for the detailed answer to Holden's question about the differences between what the NIA is doing and what the SENS Foundation is doing. 

                      If you have a moment, I have a follow-up question: can you give a quick summary of the main differences between what the SENS Foundation is doing and what the Buck Institute is doing, and the difference between funding one of those vs. the other?

                      Thanks,
                         Brian Skinner



                      On Mon, Oct 15, 2012 at 11:39 AM, Aubrey de Grey <aubrey@...> wrote:
                       

                      Hello Susheela,

                      Yes, I expected that some people here would be interested in discussing these topics, even if Holden't focus is currently more on whom best to fund to get the job done.

                      Your first question is one that gives rise to a big outreach dilemma, as it happens. A major reason why the SENS approach (turning back the aging clock with regenerative medicine, rather than slowing the clock down) is so attractive is that it buys so much time to figure out what to do next, i.e. how to make the therapies a notch better so that they can address what you term the next frontier. If we can rejuvenate 60-year-olds well enough that they won't be biologically 60 again until they're chronologically 90 - which is what I believe the "first-generation" SENS therapies will deliver - then we have all those 30 years to develop second-generation therapies that deliver a further 30 years of postponement, and so on. From what we know about the nature of the molecular and cellular damage that these therapies will repair, we can say with great confidence (or so I claim!) that these further improvements will overwhelmingly be in the form of relatively minor extensions of/variations on the initial therapies, which implies that it is vanishingly unlikely that progress will be so slow that we fail to stay one step ahead of the problem. (I have termed the necessary rate of improvement of the therapies "longevity escape velocity".) So, what this means is that for practical purposes we can regard the initial SENS therapies as delivering, with high probability, an indefinite postponement of age-related ill-health. The outreach dilemma is that objectively this is great, since the gain would absolutely be in terms of health costs as well as healthy longevity, but emotionally it ignites all kinds of knee-jerk reactions concerning the nature of a post-aging world, such as overpopulation risks, pensions crises, dictators living forever etc etc, which in my experience are powerful disincentives to supporting this work despite the acknowledgement that (a) health is good and (b) old people are people too, which in my view is pretty much all o ne needs to acknowledge in order to want aging to be eliminated.

                      On your second question, for sure there are issues here that cause some people to hesitate. Ultimately the question breaks down (I believe) into the following categories:

                      Positive:
                      1 how valuable is the anticipated health gain over the period when someone would otherwise be in impaired health?
                      2 how valuable is the anticipated additional [all healthy] healthy longevity gain?
                      3 how valuable are the anticipated gains in quality of life resulting indirectly from expecting to live a lot longer?

                      Negative:
                      4 how valuable are the lives that might not exist if we curtailed the birth rate more than we otherwise might?
                      5 how valuable are the aspects of today's life that might be compromised by the expectation of much longer lives?

                      My own view is that (1) and 2) are definitely as big as any other humanitarian mission, that (3) could be huge too (for example we might try a lot harder to combat climate change, end war etc), that (4) is unclear even if we regard future people as important, because we're curtailing the birth rate so fast anyway, and that (5) is a figment of Luddite imagination. But others may disagree! In particular, there seems to be a fairly widespread notion that (chronologically) old people really are less deserving of medical care than the young - and I refer here to intrinsic merits, independent of today's problem that it's in practice harder to give the elderly as much additional healthy life as the young. Whether this is a legitimate view or one that we must work against in the same way that people worked against the acceptance of slavery is a matter for debate.

                      Cheers, Aubrey



                      On 15 Oct 2012, at 04:05, Susheela Peres da Costa wrote:

                      > sorry, realise a sentence wasn't finished, amended below
                      >
                      > On 15 October 2012 12:43, Susheela Peres da Costa <susheela.peresdacosta@...> wrote:
                      > Aubrey, I would love to hear more about two things you raise as worthwhile questions.
                      >
                      > 1) The distinction between longevity on the one hand and the postponement of age-related ill health on the other (I understand the different definitions, but am interested in thoughts on the likely implications of each for the other, in a real-world population-wide context - for instance, would better health in one's 70s-80s result in viewing the demise of health in 90s-100s as the next frontier, essentially buying a net longevity gain rather than a net health-costs gain?)
                      >
                      > 2) In the context of any implications for longevity, whether / why "the medical control of aging [is] a hugely valuable mission?" relative to other uses of philanthropic funds for medical research.


                    • Aubrey de Grey
                      Hello Brian, Thanks for this question. In brief, the main differences between SENS Foundation and the Buck are quite similar to those between SENS Foundation
                      Message 10 of 18 , Oct 30, 2012
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                        Hello Brian,

                        Thanks for this question. In brief, the main differences between SENS Foundation and the Buck are quite similar to those between SENS Foundation and the NIA, because their funding sources and mechanisms are largely the same. The Buck was founded with a substantial endowment, but that is only a minor source of its scientists' research funds: most of it is from the same sources that university labs use, namely the NIA and other public or philanthropic sources (such as the California Institute of Regenerative Medicine or the Ellison Medical Foundation) that evaluate grant applications by methods that have the various shortcomings I described earlier. The Buck scientists produce excellent work, no question, but ultimately their research priorities are constrained to be no different than other conventionally-funded scientists in universities. In particular, they can only pay lip service to the idea of truly translational research that takes us closer to bringing human aging under genuine medical control.

                        Cheers, Aubrey

                        On 30 Oct 2012, at 00:45, Brian Douglas Skinner wrote:

                        > Hi Aubrey,
                        >
                        >
                        > Thanks for the detailed answer to Holden's question about the differences between what the NIA is doing and what the SENS Foundation is doing.
                        >
                        > If you have a moment, I have a follow-up question: can you give a quick summary of the main differences between what the SENS Foundation is doing and what the Buck Institute is doing, and the difference between funding one of those vs. the other?
                        >
                        > Thanks,
                        > Brian Skinner
                        >
                        >
                        >
                        > On Mon, Oct 15, 2012 at 11:39 AM, Aubrey de Grey <aubrey@...> wrote:
                        >
                        > Hello Susheela,
                        >
                        > Yes, I expected that some people here would be interested in discussing these topics, even if Holden't focus is currently more on whom best to fund to get the job done.
                        >
                        > Your first question is one that gives rise to a big outreach dilemma, as it happens. A major reason why the SENS approach (turning back the aging clock with regenerative medicine, rather than slowing the clock down) is so attractive is that it buys so much time to figure out what to do next, i.e. how to make the therapies a notch better so that they can address what you term the next frontier. If we can rejuvenate 60-year-olds well enough that they won't be biologically 60 again until they're chronologically 90 - which is what I believe the "first-generation" SENS therapies will deliver - then we have all those 30 years to develop second-generation therapies that deliver a further 30 years of postponement, and so on. From what we know about the nature of the molecular and cellular damage that these therapies will repair, we can say with great confidence (or so I claim!) that these further improvements will overwhelmingly be in the form of relatively minor extensions of/variations on the initial therapies, which implies that it is vanishingly unlikely that progress will be so slow that we fail to stay one step ahead of the problem. (I have termed the necessary rate of improvement of the therapies "longevity escape velocity".) So, what this means is that for practical purposes we can regard the initial SENS therapies as delivering, with high probability, an indefinite postponement of age-related ill-health. The outreach dilemma is that objectively this is great, since the gain would absolutely be in terms of health costs as well as healthy longevity, but emotionally it ignites all kinds of knee-jerk reactions concerning the nature of a post-aging world, such as overpopulation risks, pensions crises, dictators living forever etc etc, which in my experience are powerful disincentives to supporting this work despite the acknowledgement that (a) health is good and (b) old people are people too, which in my view is pretty much all o ne needs to acknowledge in order to want aging to be eliminated.
                        >
                        > On your second question, for sure there are issues here that cause some people to hesitate. Ultimately the question breaks down (I believe) into the following categories:
                        >
                        > Positive:
                        > 1 how valuable is the anticipated health gain over the period when someone would otherwise be in impaired health?
                        > 2 how valuable is the anticipated additional [all healthy] healthy longevity gain?
                        > 3 how valuable are the anticipated gains in quality of life resulting indirectly from expecting to live a lot longer?
                        >
                        > Negative:
                        > 4 how valuable are the lives that might not exist if we curtailed the birth rate more than we otherwise might?
                        > 5 how valuable are the aspects of today's life that might be compromised by the expectation of much longer lives?
                        >
                        > My own view is that (1) and 2) are definitely as big as any other humanitarian mission, that (3) could be huge too (for example we might try a lot harder to combat climate change, end war etc), that (4) is unclear even if we regard future people as important, because we're curtailing the birth rate so fast anyway, and that (5) is a figment of Luddite imagination. But others may disagree! In particular, there seems to be a fairly widespread notion that (chronologically) old people really are less deserving of medical care than the young - and I refer here to intrinsic merits, independent of today's problem that it's in practice harder to give the elderly as much additional healthy life as the young. Whether this is a legitimate view or one that we must work against in the same way that people worked against the acceptance of slavery is a matter for debate.
                        >
                        > Cheers, Aubrey
                        >
                        >
                        >
                        > On 15 Oct 2012, at 04:05, Susheela Peres da Costa wrote:
                        >
                        > > sorry, realise a sentence wasn't finished, amended below
                        > >
                        > > On 15 October 2012 12:43, Susheela Peres da Costa <susheela.peresdacosta@...> wrote:
                        > > Aubrey, I would love to hear more about two things you raise as worthwhile questions.
                        > >
                        > > 1) The distinction between longevity on the one hand and the postponement of age-related ill health on the other (I understand the different definitions, but am interested in thoughts on the likely implications of each for the other, in a real-world population-wide context - for instance, would better health in one's 70s-80s result in viewing the demise of health in 90s-100s as the next frontier, essentially buying a net longevity gain rather than a net health-costs gain?)
                        > >
                        > > 2) In the context of any implications for longevity, whether / why "the medical control of aging [is] a hugely valuable mission?" relative to other uses of philanthropic funds for medical research.
                        >
                        >
                        >
                        >
                        >
                      • Brian Douglas Skinner
                        Hi Aubrey, Thanks for the quick response. That gives me a better understanding for where the Buck Institute fits in the landscape of organizations. Best, Brian
                        Message 11 of 18 , Oct 30, 2012
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                          Hi Aubrey, 

                          Thanks for the quick response. That gives me a better understanding for where the Buck Institute fits in the landscape of organizations.

                          Best,
                             Brian


                          On Tue, Oct 30, 2012 at 2:20 AM, Aubrey de Grey <aubrey@...> wrote:
                          Hello Brian,

                          Thanks for this question. In brief, the main differences between SENS Foundation and the Buck are quite similar to those between SENS Foundation and the NIA, because their funding sources and mechanisms are largely the same. The Buck was founded with a substantial endowment, but that is only a minor source of its scientists' research funds: most of it is from the same sources that university labs use, namely the NIA and other public or philanthropic sources (such as the California Institute of Regenerative Medicine or the Ellison Medical Foundation) that evaluate grant applications by methods that have the various shortcomings I described earlier. The Buck scientists produce excellent work, no question, but ultimately their research priorities are constrained to be no different than other conventionally-funded scientists in universities. In particular, they can only pay lip service to the idea of truly translational research that takes us closer to bringing human aging under genuine medical control.

                          Cheers, Aubrey

                          On 30 Oct 2012, at 00:45, Brian Douglas Skinner wrote:

                          > Hi Aubrey,
                          >
                          >
                          > Thanks for the detailed answer to Holden's question about the differences between what the NIA is doing and what the SENS Foundation is doing.
                          >
                          > If you have a moment, I have a follow-up question: can you give a quick summary of the main differences between what the SENS Foundation is doing and what the Buck Institute is doing, and the difference between funding one of those vs. the other?
                          >
                          > Thanks,
                          >    Brian Skinner
                          >
                          >
                          >
                          > On Mon, Oct 15, 2012 at 11:39 AM, Aubrey de Grey <aubrey@...> wrote:
                          >
                          > Hello Susheela,
                          >
                          > Yes, I expected that some people here would be interested in discussing these topics, even if Holden't focus is currently more on whom best to fund to get the job done.
                          >
                          > Your first question is one that gives rise to a big outreach dilemma, as it happens. A major reason why the SENS approach (turning back the aging clock with regenerative medicine, rather than slowing the clock down) is so attractive is that it buys so much time to figure out what to do next, i.e. how to make the therapies a notch better so that they can address what you term the next frontier. If we can rejuvenate 60-year-olds well enough that they won't be biologically 60 again until they're chronologically 90 - which is what I believe the "first-generation" SENS therapies will deliver - then we have all those 30 years to develop second-generation therapies that deliver a further 30 years of postponement, and so on. From what we know about the nature of the molecular and cellular damage that these therapies will repair, we can say with great confidence (or so I claim!) that these further improvements will overwhelmingly be in the form of relatively minor extensions of/variations on the initial therapies, which implies that it is vanishingly unlikely that progress will be so slow that we fail to stay one step ahead of the problem. (I have termed the necessary rate of improvement of the therapies "longevity escape velocity".) So, what this means is that for practical purposes we can regard the initial SENS therapies as delivering, with high probability, an indefinite postponement of age-related ill-health. The outreach dilemma is that objectively this is great, since the gain would absolutely be in terms of health costs as well as healthy longevity, but emotionally it ignites all kinds of knee-jerk reactions concerning the nature of a post-aging world, such as overpopulation risks, pensions crises, dictators living forever etc etc, which in my experience are powerful disincentives to supporting this work despite the acknowledgement that (a) health is good and (b) old people are people too, which in my view is pretty much all o ne needs to acknowledge in order to want aging to be eliminated.
                          >
                          > On your second question, for sure there are issues here that cause some people to hesitate. Ultimately the question breaks down (I believe) into the following categories:
                          >
                          > Positive:
                          > 1 how valuable is the anticipated health gain over the period when someone would otherwise be in impaired health?
                          > 2 how valuable is the anticipated additional [all healthy] healthy longevity gain?
                          > 3 how valuable are the anticipated gains in quality of life resulting indirectly from expecting to live a lot longer?
                          >
                          > Negative:
                          > 4 how valuable are the lives that might not exist if we curtailed the birth rate more than we otherwise might?
                          > 5 how valuable are the aspects of today's life that might be compromised by the expectation of much longer lives?
                          >
                          > My own view is that (1) and 2) are definitely as big as any other humanitarian mission, that (3) could be huge too (for example we might try a lot harder to combat climate change, end war etc), that (4) is unclear even if we regard future people as important, because we're curtailing the birth rate so fast anyway, and that (5) is a figment of Luddite imagination. But others may disagree! In particular, there seems to be a fairly widespread notion that (chronologically) old people really are less deserving of medical care than the young - and I refer here to intrinsic merits, independent of today's problem that it's in practice harder to give the elderly as much additional healthy life as the young. Whether this is a legitimate view or one that we must work against in the same way that people worked against the acceptance of slavery is a matter for debate.
                          >
                          > Cheers, Aubrey
                          >
                          >
                          >
                          > On 15 Oct 2012, at 04:05, Susheela Peres da Costa wrote:
                          >
                          > > sorry, realise a sentence wasn't finished, amended below
                          > >
                          > > On 15 October 2012 12:43, Susheela Peres da Costa <susheela.peresdacosta@...> wrote:
                          > > Aubrey, I would love to hear more about two things you raise as worthwhile questions.
                          > >
                          > > 1) The distinction between longevity on the one hand and the postponement of age-related ill health on the other (I understand the different definitions, but am interested in thoughts on the likely implications of each for the other, in a real-world population-wide context - for instance, would better health in one's 70s-80s result in viewing the demise of health in 90s-100s as the next frontier, essentially buying a net longevity gain rather than a net health-costs gain?)
                          > >
                          > > 2) In the context of any implications for longevity, whether / why "the medical control of aging [is] a hugely valuable mission?" relative to other uses of philanthropic funds for medical research.
                          >
                          >
                          >
                          >
                          >


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