NOTE: Back in 2004, we were not following synthetic biology, and have just come upon one of the most comprehensive and critical notes on the emerging industry that we know of, which was wriiten back then, and which we post below. The article was written by former Nature editor Phillip Ball. After reading a current article of his which poses the question, ‘Is the scientific endeavour always a bold and noble quest for truth?’ and offers the answer, ‘Not when it is writing its own history’ — a real concern when science becomes technology and technology is controlled and regulated by private industry — we did a little search and discovered his seminal essay on synthetic biology, Biology Poised to Lose its Innocence? — Synbiowatch

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.

By Philip Ball, August 2004

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)