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What is life? Can we make it?

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  • Michael Korns
    What is life? Can we make it? August 2004 Is synthetic biology on the point of making life? Unlike genetic engineering or biotechnology, the new discipline
    Message 1 of 1 , Aug 2, 2004
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      What is life? Can we make it?

      August 2004

      Is "synthetic biology" on the point of making life? Unlike genetic
      engineering or biotechnology, the new discipline is not about
      tinkering with biology but about remaking it. Risks and rewards will
      be greater than anything yet encountered

      Philip Ball


      Two years ago American scientists created life. Or did they? It all
      depends on what you mean by life. More specifically, it depends on
      whether you are prepared to regard viruses as living entities.
      Viruses have genes, and they replicate, mutate and evolve, all of
      which sounds lifelike enough. And in August 2002, a team at the State
      University of New York (SUNY) announced that it had made a virus from
      scratch, by chemistry alone.

      What this meant was that, for the first time since life began over
      3.5bn years ago, a living organism had been created with genetic
      material that was not inherited from a progenitor.

      To what did the SUNY researchers choose to award the honour of being
      the first synthetic organism? They selected a virus that scientists
      have spent decades trying to eradicate, a cause of human disability
      and death: polio. If you think that sounds unwise, so did some
      biologists. Craig Venter, former head of the privately-funded US
      human genome project conducted by Celera Genomics, called the
      work "irresponsible" and claimed that it could hurt the scientific
      community.

      To Eckard Wimmer, who led the SUNY team, this alarming choice of
      target was the whole point. If they could do it, so could
      bioterrorists. Wimmer's group did not apply any great technical
      wizardry: they simply looked up the chemical structure of the polio
      virus genome on the internet, ordered segments of the genetic
      material from companies that synthesise DNA, and then strung them
      together to make a complete genome. When mixed with the appropriate
      enzymes, this synthetic DNA provided the seed from which the
      infectious polio virus particles grew. It was so simple that some
      researchers claimed it could be done by undergraduates.

      Making viruses from scratch is just one of the potentially
      devastating capabilities of a new field of science called synthetic
      biology. Most biologists cling to the belief that theirs is a pure
      science, an exploration of the world "out there" - far removed from
      the moral dilemmas of applied science and technology. But synthetic
      biology tells us that biology is no longer an immutable aspect of the
      world.

      In a sense, that is nothing new: several of the most contentious
      moral issues which science has generated in the past decades have
      hinged on the question of whether, or how much, we should tamper with
      biology. Every genetically modified organism (GMO) is in some degree
      synthetic, a product of the human manipulation of genetic material.
      The same can be argued of genetic clones, and perhaps even of embryos
      made by in vitro fertilisation. But synthetic biology aims for much
      deeper levels of intervention than, say, simply adding a herbicide-
      resistance gene to a plant's genome. Synthetic biology regards living
      organisms - at the most basic level, single cells - as assemblies of
      parts that can be reassembled in new ways, or redesigned, or indeed
      built from scratch, perhaps with completely different materials. It
      is not about tinkering with biology, but about what exactly biology
      is, whether alternative biologies are possible, and whether we can
      remake life just as we can redesign cars or houses.



      Bigger benefits, bigger risks

      There are some powerful arguments for why we might want such new
      forms of biology. Some researchers believe that synthetic biology
      could solve the energy crisis, transform manufacturing into a green
      technology or rid the world of infectious diseases. It could allow us
      to combat lethal viruses and tumour cells on their own terms, using
      their own tricks and weapons. It could deliver new drugs and provide
      cheaper means of making existing ones.

      Yet if ever there were a science guaranteed to cause public alarm and
      outrage, this is it. Compared with conventional biotechnology and
      genetic engineering, the risks involved in synthetic biology are far
      scarier. Whether you approve of them or not, GMOs are more like
      patients with an organ transplant than Frankenstein's monster. There
      is no sense in which genetic engineers are "making life" - but that
      is what synthetic biologists propose to do, if indeed they have not
      already done so.

      Building known viruses from the genome up is one thing, but some
      researchers are redesigning DNA itself. "I suspect that in five years
      or so, the artificial genetic systems that we have developed will be
      supporting an artificial lifeform that can reproduce, evolve, learn
      and respond to environmental change," says Steven Benner, a chemical
      biologist at the University of Florida. Benner is no stranger to the
      controversy that this is likely to excite. Sixteen years ago he
      organised a conference in Switzerland that pre-empted the new field
      of synthetic biology. It was to have been called "Redesigning
      life." "The conference title raised such a furore that it had to be
      changed to 'Redesigning the molecules of life,'" says Benner. "People
      were convinced that the original title would incite riots."

      The idea of "playing God" is beside the point here - the notion that
      God cobbled organisms together from nucleic acids and proteins like a
      chemist experimenting in the lab should be offensive to any theistic
      faith. In fact, one of the brightest prospects of synthetic biology
      is that it might allow us to begin exploring how life began, which in
      turn could force us to take a less sentimental view of what we mean
      by life in the first place.

      There is nothing very spiritual about DNA and proteins, the "stuff of
      life." To chemists they are just beautifully ingenious molecules. If
      there does turn out to be anything special about these chemical
      building blocks which makes them uniquely suitable for sustaining
      life (and this is by no means clear), it will be for prosaic reasons
      such as their chemical stability, not because of any vitalistic magic.



      What is life, anyway?

      Life is not embodied in its molecular building blocks, but it is a
      characteristic of the way in which they interact. It may be that you
      could create life from a completely different pool of constituents,
      just as a computer can be made from ping-pong balls running down
      tubes, instead of silicon chips. Despite the hype of the human genome
      project, life's grandeur does not reside in a filament of DNA.

      The truth is that life does not have an objective, scientific
      meaning. Even scientists sometimes fail to recognise this, wasting
      much ink in trying to come up with an airtight set of criteria that a
      living organism must meet. They typically invoke such characteristics
      as the ability to reproduce, grow, metabolise, evolve and respond to
      the environment. They will fret about whether a living entity must
      have boundaries, or whether a computer program or a planet can
      be "alive."

      The futility of all this was recognised 70 years ago by the British
      virologist Norman Pirie, who wrote: "'Life' and 'living' are words
      that the scientist has borrowed from the plain man. The loan has
      worked satisfactorily until comparatively recently, for the scientist
      seldom cared and certainly never knew just what he meant by these
      words, nor for that matter did the plain man. Now, however, systems
      are being discovered and studied which are neither obviously living
      nor obviously dead, and it is necessary to define these words or else
      give up using them and coin others."

      It is natural that a virologist like Pirie should understand this,
      because viruses are nature's reminder that there are no boundaries
      between the animate and inanimate realms. No one knows whether to
      call viruses living or not. Their genes are sometimes, as in the case
      of polio, encoded not in DNA but in its sister molecule RNA, and they
      cannot reproduce autonomously: they must infect a host organism and
      borrow its cellular enzyme machinery to make copies of themselves.

      So it remains a moot point whether by creating viruses synthetic
      biologists have made life. But that ambiguity is likely to disappear
      in the next few years. Viruses inhabit a grey area, but bacteria are
      clearly alive: they are single-cell organisms that sequester raw
      materials and energy from their environment and replicate on their
      own. No one has synthesised a bacterial cell chemically yet, but it
      is not far off. The technology for synthesising strands of DNA
      chemically - by stringing together their four distinct molecular
      building blocks, or nucleotides, one by one in specified sequences,
      like combining words to make sentences - is on the verge of being
      able to generate sequences of 1m or so nucleotides. That is long
      enough to construct the genome of some bacteria - the smallest known
      bacterial genome, that of the Mycoplasma genitalium, contains just
      517 genes, encoded in a genome of 580,000 nucleotides.

      Craig Venter, who now heads the Institute for Biological Energy
      Alternatives in Rockville, Maryland, believes that Mycoplasma
      genitalium could point the way to a "minimal genome": the smallest
      complement of genes that can support a viable organism. One way of
      finding out what is essential and what is an evolutionary luxury is
      to strip out genes from the bacteria one by one and see if the cells
      survive. Another option is to make the pared-down genome from the
      bottom up, by chemical synthesis of DNA, and see if it can be brought
      to life - that is, used as the blueprint for making an organism. Last
      November, Venter reported the synthesis of the complete genome of
      another virus, a bacterial pathogen called phi X. In contrast to the
      polio virus genome, which was patched together over many months,
      Venter's team made the phi X genome in just a few days, demonstrating
      how quick this DNA technology has become.



      Redesigning cells

      The odd name of Venter's institute testifies to his desire to use a
      bacteria-building technology to solve important practical problems.
      He is being funded by the US department of energy to explore the
      redesign of bacteria as hydrogen-generating organisms. Some natural
      bacteria produce hydrogen, but they are neither robust nor efficient
      enough to provide an abundant natural source of this clean fuel.
      Venter hopes that, either by transforming existing microbes or by
      creating entirely new, synthetic species, he can design microbes that
      make hydrogen for power generation.

      Such practical applications are not the only reason for wanting to
      identify a minimal organism. One of the prime motivations behind
      synthetic biology is to understand how natural cells work. While this
      has arguably been the objective of molecular biologists for over 100
      years, only recently have they been forced to accept that decoding
      genomes - reading out the sequences of nucleotides in an organism's
      DNA - is not going to supply the answer. For all the talk of "reading
      the book of life," the sequencing of the human genome (completed in
      draft form in 2000) tells biologists as much about the way human
      cells function as a pile of engine parts tells the mechanic how a car
      works. The question is how the parts fit together, and how they
      interact with one another. This is now being addressed in the
      discipline known as systems biology.

      Systems biologists think of cells as circuits, rather like the
      electronic circuits of silicon chips. The individual components are
      genes and proteins, and they are "wired" into networks in which
      specific elements regulate the behaviour of other components, for
      example by switching them on or off. Most genes encode the
      instructions for making particular protein molecules, each with a
      definite role in cell function. One gene might regulate another gene
      by generating a protein that binds to the other gene and prevents it
      from producing its own protein. Biologists are now mapping out this
      network of interactions, providing them with circuit diagrams of
      cells. They are finding that many of the motifs familiar from
      electronic engineering, such as feedback loops, switches and
      amplifiers, appear in gene circuits too. That is why systems
      biologists are as likely to be computer scientists or electrical
      engineers as molecular biologists.

      It was inevitable that, once this engineer's view of the cell began
      to emerge from systems biology, the engineers would start asking what
      they always ask: what can we make? If cell circuits can be broken
      down into gene modules that perform well defined functions, what
      happens if the modules are rewired? Can one design new modules from
      scratch?

      The first demonstration of this thinking came four years ago, when
      Princeton researchers Stanislas Leibler and Michael Elowitz designed
      an oscillator gene circuit and plugged it into the genome of E coli,
      the bacteria that live in our guts. The experimental techniques
      involved in such a manipulation are tried and tested:
      biotechnologists have been splicing foreign DNA into genomes for over
      two decades, using a method called recombinant DNA technology. But
      until then, no one had thought of making a module that did something
      as physics-like as oscillate.

      What does it mean for a genome to oscillate? In Elowitz and Leibler's
      module, which they called a repressilator, three genes switched each
      other off in cyclic succession, so that the cycle of gene repression
      repeated with a steady rhythm like a game of pass the parcel. The
      researchers designed one of the genes so that it also triggered the
      cells to produce a protein that glowed green when light was shone on
      it. They found that E coli cells fitted with the repressilator module
      blinked on and off periodically, like tiny living beacons.

      As researchers heard at the first conference on synthetic biology at
      MIT in June, there is now an expanding toolbox of gene modules that
      can be wired into cells to alter and control their behaviour. In
      April, Ron Weiss and collaborators at Princeton described E coli
      cells equipped with population-control modules, so that the cells
      committed suicide if their population density rose above a certain
      level. The synthetic module includes genes that make the bacteria
      emit a chemical, so that they can "smell" how many other cells are in
      their vicinity. If this "smell" gets too strong, a killer gene is
      activated that causes the cell to die. Programmed behaviour like this
      could be exploited to turn bacteria into environmental sensors that
      spot and signal the presence of toxic chemicals.

      Some researchers consider these reprogrammed cells to be like wet
      micro-robots that can be directed towards useful tasks by downloading
      genetic instructions into their genomes. It may be possible to fit
      such cells with safety circuits to prevent their unwanted
      proliferation in the wild - they could be programmed to die if they
      were to escape from some highly controlled environment, or could even
      be fitted with genetic "counters" so that they would become incapable
      of dividing after a specified number of generations. But it is not
      clear yet how secure such measures would be. Because of the random
      mutations that occur during any process of cell division, some of
      Weiss's cells evolved to escape the population-control mechanism.

      As well as rearranging and redesigning the molecular components of
      life, synthetic biologists are introducing completely new materials
      into biology. When it comes to making organisms, nature is endlessly
      inventive, but it is remarkably conservative with its basic building
      blocks. Just about all proteins are constructed from only 20
      different types of amino acid: each protein molecule is a distinct
      permutation of these ingredients, strung together in a chain and then
      usually folded up into a compact shape. Similarly, the genome of
      every organism in existence contains just the four nucleotides of DNA
      (except for RNA-based viruses, which are a minor variation) arranged
      in different sequences. There seems to be no fundamental reason why
      biology has to use this limited palette - it is simply that, just as
      with some industrial processes, changing the set of components is too
      costly to be worthwhile. But scientists have now made bacteria that
      can use new, non-natural amino acids in their proteins, and non-
      natural nucleotides in their DNA.

      Similarly, the genetic code - the correspondence between nucleotides
      and amino acids, which enables protein structures to be encoded in
      genes - is essentially identical across all of biology. But it is now
      possible to change the code: to make cells that perform the DNA-
      protein translation in another language from the one employed
      throughout the course of evolution. The book of life, in other words,
      is written not in stone but in soft clay, and we can wipe it clean
      and start again. How would a bacterium fare if its genetic code was
      entirely different? Would it evolve more quickly, or in unexpected
      directions? Could it breed with natural bacteria? We may soon find
      out.



      How worried should we be?

      New ethical questions raised by science tend to fall back fairly
      quickly on old templates. And the notion of creating life is an
      ancient template indeed: Mary Shelley was fully conscious of the
      legends she evoked, since her father William Godwin was the author of
      Lives of the Necromancers, with chapters on Paracelsus and Faust.
      Paracelsus's instructions for making the homunculus, an "artificial
      man," were drawn from the same mythic well that produced the Golem of
      Jewish cabbalistic fable. When science intersects with cultural myths
      as profound as this, the ensuing debates tend to get shaped by
      undercurrents of which the participants are often unaware.

      There is greater continuity between Mary Shelley's tale and modern
      biochemistry than is often appreciated. The dream of a chemical
      creation of life was very much alive at the turn of the 20th century,
      and was announced more than once in the newspapers. In 1899,
      biologist Jacques Loeb discovered that sea urchin eggs could be made
      to produce larvae by treating them with inorganic salts, without the
      need for fertilisation by sperm - "artificial parthenogenesis," as
      Loeb called it. The Boston Herald hailed this as the "Creation of
      life: Lower animals produced by chemical means."

      Three years later, Loeb was being compared to Frankenstein. He did
      little to dispel such notions, claiming that "We may already see
      ahead of us the day when a scientist, experimenting with chemicals in
      a test tube, may see them unite and form a substance which will live
      and move and reproduce itself." Nor was this an idiosyncratic
      position: Darwin's champion Thomas Huxley maintained that the
      biological goo known as "protoplasm" was sure to be put together some
      day by chemists. "I can find no intelligible ground for refusing to
      say that the properties of protoplasm result from the nature and
      disposition of its molecules," he insisted. By 1912, the president of
      the British Association for the Advance-ment of Science confirmed
      that scientists were on the threshold of "bringing about in the
      laboratory the gradual passage of chemical combinations into the
      condition which we call living." The dream has always been too
      seductive to relinquish.

      The image of the Promethean scientist whose quest for knowledge
      unleashes destructive forces beyond his control might be a romantic
      distortion of the way in which science works, but synthetic biology
      surely provides more cause than biotechnology or nanotechnology ever
      have to worry about a runaway catastrophe. And synthetic biologists
      themselves admit as much - they are already showing deep concern
      about the directions their nascent discipline could take.

      The most immediate fear is that catastrophe could be engineered. Last
      November, the CIA issued a report, "The Darker Bioweapons Future,"
      which cited the SUNY work on the polio virus and cautioned that the
      advances that are driving synthetic biology could also lead to
      biological agents with effects "worse than any disease known to man."
      The report hinted at the need for "a qualitatively different working
      relationship between the intelligence and biological sciences
      communities."

      Scientists would, of course, prefer self-regulation. Already,
      scientific journal editors have taken it upon themselves to delete
      from papers details that could be judged as posing security risks.
      The American Society for Microbiology asked an author to remove a
      description of how a lethal natural toxin could be modified to boost
      its potency one hundredfold.

      Some feel that such measures do not go far enough; others fear that
      they are already a threat to academic freedom. Certain precautions
      ought to be routine: for example, some companies that synthesise DNA
      sequences now check their orders against the genome sequences of
      known pathogens. But the industry remains barely regulated; biologist
      Roger Brent of the Molecular Sciences Institute in California has
      suggested that DNA synthesis might in future require a licence. The
      nightmare scenario, however, is that synthetic biology could generate
      a "hacker" culture analogous to the internet - except that the
      viruses which hackers designed would be real, not virtual.

      George Poste of Arizona State University, who weathered several
      scientific controversies as chief science and technology officer of
      the pharmaceuticals giant SmithKline Beecham in the 1990s, fears that
      synthetic biology is poised to fall foul of the fantasy of a zero-
      risk culture. While the problems this new science might address, such
      as the spread of diseases ranging from Aids to Sars to malaria, have
      come to be regarded by society as business as usual, public concern
      focuses on the extreme, rare disasters that new technologies could
      precipitate. According to Poste, a powerful technology like synthetic
      biology whose implications are extremely hard to predict requires "a
      framework for navigation, not prescriptive controls."

      But Poste acknowledges that some of the risks of this field are real.
      He has suggested how a "risk factor" for new scientific developments
      might be estimated on the basis of their possible benefits, dangers
      and unknowns. When the risk factor exceeds a given threshold, this
      would act as an alarm signal.

      Whichever path is taken, Poste believes that "biology is poised to
      lose its innocence" - the price that is always paid when science
      becomes technology. Some might argue that this innocence was
      forfeited years ago with the development of the recombinant DNA
      techniques that enable genetic engineering. But we would be wrong to
      regard synthetic biology as "the same thing, only more so." The field
      should bring real benefits, and it poses real dangers. It will also
      signal a new relationship with nature, one that will uproot some
      treasured, if confused, notions about what "nature" and "life" mean.



      The author is a science writer and a consultant editor for "Nature."
      His latest book is "Critical Mass" (Heinemann)
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