What is life? Can we make it?
- What is life? Can we make it?
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
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
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
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
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.
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
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
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
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)