Weird Science

The Promise and Peril of Synthetic Biology

In 1971, a microbiologist named Ananda Chakrabarty patented a bacteria genetically engineered to degrade and destroy crude oil. The next year scientists created the first synthesized gene, a bit of yeast RNA ushered into existence virtually from scratch. These discoveries, among others, raised the curtain on the science of biotechnology. Forty years later, in 2010, biologist Craig Venter, already known as a key figure behind the mapping of the human genome, announced his creation of a microbe that earned the name Synthia: “the first self-replicating species on the planet whose parent was a computer.” Between Chakrabarty’s oil-eating microbe and the birth of Venter’s Synthia, a wave of gene therapies, pharmaceuticals, genetically engineered crops, and manufactured biofuels have transformed science, medicine, industry, and quite possibly, global ecology.

In the second decade of the twenty-first century, genetically engineered crops account for 88 percent of the corn, 93 percent of the soy, and 94 percent of the cotton, grown in the US (by acreage). In 2011, the first commercial flight powered by algae took off from Chicago’s O’Hare Airport. During the recent United Nations Earth Summit in Brazil, Amyris Inc., one of the leading companies in the emergent field of synthetic biology, flew a sugarcane-powered airplane over Rio de Janeiro. The same company, with a healthy infusion of cash from the Gates Foundation, is on the verge of releasing a malaria drug that, the company says, will be cheaper and more effective than any on the market today. The drug mimics the action of artemisia, an ancient Chinese herb. But rather than being extracted from a plant, Amyris’ drug will be manufactured within the cellular membranes of a fully synthetic strain of yeast.

The eminent evolutionary biologist Stephen Jay Gould once said: “Our planet has always been in the Age of Bacteria.” But scientists’ rapidly accelerating ability to harness microbes and turn them into what the field of synthetic biology calls “platforms for industrial production” is entirely without precedent. We are witnessing a revolution in the biological sciences of a speed and scale that is dazzling to some, and more than a little frightening to others.

“If you want to change the world in some big way that’s where you should start – biological molecules,” Bill Gates told Wired magazine in 2010. The microchip revolution has transformed the globe, and men like Gates made a fortune in the process. Unlike microchips, however, microbes are alive, and the implications of tinkering with them are almost entirely unknown.

In April, the Obama administration published a report called the “National Bioeconomy Blueprint” to assess and promote “economic activity fueled by research and innovation in the biological sciences.” Annual revenues from the bioeconomy in 2010, the report announces, totaled $176 billion.

“The growth of today’s US bioeconomy,” the report says, “is due in large part to three foundational technologies: Genetic engineering, DNA sequencing, and automated high-throughput manipulations of biomolecules.” In a certain kind of translation, that means writing genetic code, printing it in vitro, and employing robotic assembly lines to insert it into living microbes. Translated further into simple English, it means inventing and breeding living things that have never before existed in nature.

“Whereas standard biology treats the structure and chemistry of living things as natural phenomena to be understood and explained,” one definition of the technology states, “synthetic biology treats biochemical processes, molecules, and structures as raw materials and tools to be used in novel and potentially useful ways, quite independent of their natural roles. It joins the knowledge and techniques of biology with the practical principles and techniques of engineering.”

Where genetic engineering inserts genes from one species into another in what many biotechnologists now call a crude, clumsy, and outdated process, the goal of synthetic biology is to create novel life forms by inserting computer-generated DNA sequences into living cells, and then propagating them. As an applied technology, synthetic biology seeks to squeeze diesel out of algae or pharmaceuticals out of yeast by changing the cellular makeup of the yeast used in the fermentation process, or the lipid excreted by the algae. A decade ago, such applications were a mere fever dream. Today, given the exponential speed at which DNA sequencing, nanotechnology, and computational biology are developing, the technology has sparked a billion-dollar industry.

A report for investors produced in 2009 by the insurance giant Lloyd’s of London notes that the speed of DNA sequencing has increased 500-fold over the past 10 years and is now doubling every 24 months. “If this rate of development were to continue,” the report notes, “it would be possible to have a personalized genome map for under $1,000 by 2020, leading to some interesting questions for life insurers.”

Nor is synthetic biology merely a science. It could be interpreted more as a worldview – a kind of techno-utopian vision that purports to “support Darwinian evolution,” as the boosterish website syntheticbiology.org puts it. Or, as Craig Venter says of one of his strains of synthetic algae, the idea is “to force nature to produce things for us.” Drew Endy, a Stanford-based synthetic biologist whom The Wall Street Journal has called “the next Steve Jobs,” dreams of designing in a few years what it took nature millennia to create, and “liberating ourselves from the tyranny of evolution by being able to design our own offspring.”

Endy is best known outside the lab for fostering the field of synthetic biology writ large. As an assistant professor at MIT he founded the international Genetically Engineered Machine competition (iGEM), an annual contest that has engaged thousands of students in inventing artificial organisms and helped make syn-bio (as insiders abbreviate it) an avid hobbyists’ art. Endy has also established an open-source “Registry of Standard Biological Parts” to give lab researchers a collection of “artificial genetic constructions” to work with. The constructions, called BioBricks, are standardized DNA sequences that, when inserted into living cells, act like switches or signals, performing pre-coded functions. The operative analogy is to Lego blocks, or to transistors or semiconductor chips in a computer.

Another method, one that may help to elucidate the exotic inner workings of synthetic biology, is the re-creation of what are called “metabolic pathways” in plants in order to synthesize high-value chemical compounds. A metabolic pathway is a series of reactions that take place within a cell resulting in the creation of a chemical compound. That compound is then altered by the production of different enzymes, in specific sequences, leading to the creation of another compound which is what we recognize as the product of the plant: rubber, say, or nicotine or vanilla. Synthetic biologists engineer these pathways in order to change the compound that is created. By building a metabolic pathway from scratch using synthetic DNA and then inserting it into a microbial host – say, a yeast cell – scientists change the way the cell metabolizes sugars in order to create marketable compounds on demand.

As few as eight key pathways may be responsible for most of the 200,000 natural plant compounds known to science, and synthetic biologists are rapidly and systematically decoding, reconstructing, and patenting these pathways. As they create microbes that act as production platforms for their high-value chemicals, they establish start-up companies to patent, produce, and commercialize the end product.

One such company is Amyris. Founded by Dr. Jay Keasling, another of syn-bio’s leading figures, Amyris develops “renewable compounds” such as its proprietary molecule, farnesene – a petroleum alternative that can be turned into diesel, surfactants, creams, emollients, lubricants, and other chemicals. Spawned at UC Berkeley, where Keasling is a professor, the California company has been fed on venture capital, built up with support from the US Department of Energy ($25 million to construct pilot biofuel facilities), and bolstered by philanthropic funding ($42.5 million from the Gates Foundation for its malaria drug). At its plant in Emeryville, a few miles from the UC Berkeley campus, the company genetically modifies microorganisms, uses them as living factories to convert plant-sourced sugars, and employs robotics to create and test thousands of synthetic microbes a day in order to find those that are “most efficient and scalable.”

Amyris is a flagship company of the synthetic biology industry. It also demonstrates the challenges inherent to the industry. In 2010, Keasling confidently declared to shareholders that the company’s microbes could be scaled from the test tube to the refinery, “ensuring commercial quantities of fuel to stave off the peak oil crisis.” But two years later, Amyris’s diesel was running $29 a gallon – too costly to market – leading it to farm out its biofuels business to a subsidiary in order to focus on high-value products like face creams. Its malaria medication, the focus of extensive PR, has yet to yield a single vaccination. The company’s stock has fluctuated wildly, bottoming out at $1.57 a share, leading Biofuels Digest to call such fluctuations “the Amyris effect.”

Synthetic biology is in its infancy, and, despite such setbacks, is still an exploding market. Synthetic-bio based fuels and chemicals brought in $80.6 million in 2008, and the biotech watchdog ETC Group, citing industry reports, says that figure is expected to grow to $1.6 billion in 2013.

Syn-bio is the epitome of a “team science” – the kind pioneered by government labs going back to the Manhattan Project – that requires huge investment and a broad multidisciplinary approach. As such, the bulk of the firms at the bleeding edge of the industry are fueled largely either by public money or by investors from the top-tier companies in the fossil fuel, agribusiness, chemical, and big pharma sectors, or, like Amyris, by both.

Earlier this year, at a three-day confab in Berkeley, US Energy Secretary Steven Chu held forth to top corporate executives and researchers and administrators from UC Berkeley and Lawrence Berkeley National Labs about the need to develop closer partnerships between industry and government. Chu, who directed the Lawrence Berkeley Labs before joining Obama’s cabinet, is a major booster of synthetic biology. In his first year as the head of DOE, the department spent over $305 million on synthetic biology research. During his tenure at Lawrence Berkeley, Chu was instrumental in stepping up the lab’s leadership in the field. He’s now doing everything he can to bolster public-private partnerships and support protégés like Jay Keasling.

In many ways, Dr. Keasling is emblematic of the public-private approach driving the syn-bio industry. The multimillionaire founder of numerous biotech start-ups, Keasling is also a lead investigator at the UC Berkeley-based Synthetic Biology Engineering Research Center (SynBERC), and is heading efforts to launch a second Lawrence Berkeley Lab campus in Richmond, CA that will be the largest synthetic biology lab in the world.

If this spate of government support, private investment, and academic enthusiasm reveals a biotech revolution that’s poised to underwrite a new wave of green economic development, its detractors fear the opposite: a commodity bubble, a bio-ethical quagmire, and, potentially, an ecological and public health catastrophe. Some observers believe the entire project to be, to some degree, a hoax.

“Most of what they are selling are ideas. Promises. Hopes for applications that really haven’t happened,” says Ignacio Chapela, a UC Berkeley microbiologist best known for his team’s discovery of GMO contamination in Mexican corn crops, and the controversy that followed. “We continue to hear that we’re five and ten years away from the next big breakthrough, but the reality is that biotechnology has always promised a never-ending frontier of innovation and technological application that will drive the world,” he says. “But they continue to draw a blank. They continue to sell stuff, and they sometimes can produce some things, but they continue to run at a loss. If you look at the markets, you’ll see that even though we have invested over 40 or 50 years, and hundreds of billions of dollars, we are still yet to make a profit, and we’re still yet to make a predictable, controllable living organism.”

Paul Rabinow, an anthropologist at UC Berkeley whose work focuses on synthetic biology labs, agrees. Referring to Chakrabarty’s oil-eating microbe, Rabinow says: “Here we are 40 years later, and they still claim to be on the cutting edge. But there are big questions about what they are actually achieving.”

Detractors fear a commodity bubble, an ethical quagmire, a public health catastrophe.

As the statements of Drew Endy, Craig Venter, Jay Keasling, and other leading scientists make clear, the science of synthetic biology thrives on speculation. What it promises is a future in which biomachines manufacture our products, eliminate our ailments, clean up our messes, and extend our lives. The venture capitalists financing the science also thrive on speculation. But as we know from the Great Recession, speculation is like a microbial broth – it breeds best in the dark. Speculation makes dreams as real as bricks, as long as it lasts. But how well does it hold up to the light of scrutiny? How well does its promise of rapid innovation and “automated high-throughput manipulations of biomolecules” hold up to oversight or regulation?

And if the promises of synthetic biology are still a ways off, what of the perils?

Civil society groups like Friends of the Earth and the Center for Genetics and Society, and technology activists like ETC Group and the International Center for Technology Assessment, raise concerns about the risks synthetic biology poses to public health and the environment. They worry about the potential uses of synthetic biology for bio-warfare, citing the long and obscure history of bio-weapons research in government labs, including Lawrence Berkeley and the nearby Lawrence Livermore Lab. President Obama’s 2010 budget provided $20 million to the Defense Advanced Research Projects Agency, a research arm of the Pentagon, for synthetic biology research. At the same time, a Congressionally mandated panel and numerous independent experts cite poor government response to the 2009 swine flu epidemic – a relatively benign threat – to point out that the US is unprepared to deal with a contagion.

It is not only bio-terror that concerns public interest groups. They’re also concerned about “bio-error.” Just as genetically engineered crops have cross-pollinated with non-GMO plants, there is no guarantee that synthetic organisms won’t escape into the environment. As Isaac Berzin, founder of GreenFuel Technologies Corp., the first algae-to-biofuels company, says of his algal product: A leak is inevitable because “people make mistakes.”

While some of the industry’s key figures choose to play down concerns, no one doubts that synthetic biology is a high-risk, high-reward industry. The Lloyd’s of London report considers “What could go wrong,” and concludes that the more significant risks include “hackers producing viruses just for the kudos of having disrupted global trade,” the creation of monopolies, unexpected gene transfer, unexpected release, evolution (“GM organisms may behave as we expect in the short term, but organisms evolve”), and “unintended and unimagined consequences.”

“It is hard enough to predict how a single strand of DNA will behave when a new gene is inserted,” the report notes. “Even harder to consider how it will affect a cell or whole multicellular organism. But the difficulties in predicting how an ecosystem will behave are staggering.”

An article published in March in Nature titled “Four Steps to Stop a Synthetic-Biology Disaster,” warns: “No one yet understands the risks that synthetic organisms pose to the environment, what kinds of information are needed to support rigorous assessments, or who should collect such data.” The authors argues that at least $20 million to $30 million in government research is needed over the next decade to identify and address the ecological risks of synthetic biology. The amount currently spent on these assessments is closer to zero.

In 2010, following the birth of Synthia, President Obama established a Presidential Commission for the Study of Bioethical Issues to examine such questions. The commission ultimately expressed faith that synthetic biology could “be developed in an ethically responsible manner.” It established no new principles of government oversight and recommended no funding for risk-assessment, preferring to allow the industry to essentially self-regulate.

Synthia’s progenitor, Craig Venter, provides one of the strongest cases for independent oversight. A recent profile in The New York Times Magazine describes Venter “riding his German motorcycle through the California mountains, cutting the inside corners so close that his kneepads skim the pavement” and “snorkeling naked in the Sargasso Sea surrounded by Portuguese men-of-war.” Undoubtedly it takes a man of such outsize will to break the bounds of science and invention. But, without being prudish, it is reasonable to ask whether an industry driven by the likes of Venter can be trusted to conduct appropriate risk assessment.

The scientist-entrepreneurs at the forefront of syn-bio argue persuasively that the technologies are safe. But in an area of science that is moving so rapidly, there is no way to completely ensure safety. The New York Times, in a 2010 article titled “Safety Rules Can’t Keep Up With Biotech Industry,” cited numerous workers injured and killed in biolabs, including Becky McClain, a former molecular biologist at Pfizer who suffered bouts of paralysis after being infected by a genetically engineered virus. “The cutting edge can be a risky place to work,” The Times wrote.

The Center for Genetics and Society, a watchdog group, says no comprehensive framework for assessment and oversight of synthetic biology exists nationally or internationally. The main US federal agencies overseeing safety in biological laboratories are the Occupational Safety and Health Administration (OSHA) and National Institutes of Health (NIH). A 2010 report produced by the Council for Responsible Genetics points out that “the NIH guidelines are largely advisory” and “largely unenforced.” OSHA regulations, “while mandatory, do not address a broad range of potential safety issues encountered in biological laboratories.”

In the words of syn-bio critic Jim Thomas of ETC Group: “Saying that synthetic biology is regulated is tantamount to saying that the rules of the road for horse and buggy driving are adequate for car driving.”

“Even with the best intentions,” Thomas points out, “there will be escapes of synthetic organisms through clothing, waste streams and human error.”

ETC Group, Friends of the Earth, and 111 other civil society groups find the lack of oversight so worrisome that in March they called for a moratorium on the release of any synthetic organisms, “to make sure the technology does not keep developing as our laws and regulations keep getting more outdated.”

The biologists, however, take the risks in stride. “We’ve always bred plants for meeting an industrial goal,” Adam Arkin, another leading synthetic biologist at Lawrence Berkeley and UC Berkeley, told me. “Synthetic biology is trying to meet industrial goals in a way that is more efficient. And honestly, that’s a good thing.”

I asked Arkin about the risk of “horizontal gene transfer” – the poorly understood passage of genes from one microbe to another, which is one of the primary concerns that scientists raise when looking at engineered microbes.

“What if the genes you put in organism one, get into organism two? Yeah that could be an issue,” Arkin said. “But the first thing to recognize is that most of the genes that we transplant are already out there in the world, in exceptionally high numbers. Horizontal gene transfer happens all the damn time. The second thing is whether what we’re introducing into the environment is actually harmful.”

If anyone should understand the promises and perils of the field, it is Paul Rabinow. He was hired by the National Science Foundation to evaluate the security and ethical ramifications of the work being done by SynBERC and to report his findings to federal administrators. But, Rabinow says, “these are very high-powered scientists in a very competitive environment, both professionally and academically, and they simply had no time to talk to us seriously.”

From his office on the UC campus, Rabinow told me that the scientists at SynBERC, among them Jay Keasling and Drew Endy, “were negligent and indifferent” regarding ethical concerns, unconvinced of the need for stricter security measures, and “wholly tone deaf” to environmental arguments.

Rabinow made a set of recommendations to improve security and preparedness at SynBERC, but his assignment came to an abrupt and contentious end when his recommendations were ignored. Despite his protestations that the role of an ethicist is to be “outside of and downstream from” the science, he was replaced by Drew Endy, one of the field’s leading evangelists.

”They are promising technological miracles, but what are they delivering?”

“I wouldn’t say I was muzzled,” Rabinow says with a measure of rancor in his voice. “But I certainly wasn’t taken seriously. Jay Keasling’s basic response to me was, ‘If you want more money, don’t complain.’” And Rabinow says he was shut out of the presidential bioethics committee. “The only person in the US who is officially funded by the government to consider bioethics, and I’ve been consulted by absolutely no one.”

Rabinow is not in principle against the science of synthetic biology. “I hold the position that we’ve been manipulating nature for so long that there is no longer any such thing as ‘nature,’” he says. “But they wanted simple assurance that everything they were doing was fine. And we wouldn’t give them that.” He pointed out that the technology might be safe, but whether it is secure is another matter. “Safety is a lab issue,” he says. “Security is a political issue.”

In “The Deadliest Virus,” a recent article in The New Yorker, author Michael Specter cites a 2002 incident during which a researcher at Stony Brook University acquired hundreds of DNA fragments via the Internet and stitched together a functioning polio virus. Lab escapes or acts of terror based on published genomic information, Specter concludes, are a matter of if, not when.

Beyond issues of bio-terror, which Rabinow holds front and center, another concern is the ultimate purpose of synthetic biology. “They are promising technological miracles, but what are they delivering?” he asks. “Not a single person has been vaccinated with synthetic artemisinin. The BioBricks don’t work. Not a single disease has been cured by this research. They’ve been able to produce fuels from waste, but the case of Amyris shows that they haven’t been able to scale up.”

He continues: “So what are they doing? The same people have said this is genetic engineering, and this is not genetic engineering. There’s some amount of continually trying to recast what they’re doing in order to get the grants. The whole thing is a bit of a ruse.”

When I asked Arkin about the ethical issues at SynBERC, he reduced them to a problem of perception. “We speak glibly about these things, much like cattlemen speak about cattle, and maybe we shouldn’t. We harness oxen. The fact is we are harnessing these things to work for us. If the ecological sorts are upset about this, then perhaps we should find a new language to talk about it in.”

Arkin, like other syn-bio boosters, appears not to understand that the criticisms of synthetic biology aren’t just about the ethics of lab workers or the public perception of the science, but rather, the thrust of the technology. The major innovation of synthetic biology is not simply the insertion of an artificial strand of DNA into a microbe to produce a novel product. It is the convergence of multiple industrial and academic fields in the service of a single goal – the production of artificial life. And it is the assumptions behind it – that “playing God” is not only okay, but is necessary and lucrative – that are the Achilles heel of synthetic biology.

Wherever the science may go, the multi-billion dollar drive to solve the problem of artificial life has already ensured that the forces behind it – BP and Chevron, Dupont and Dow, the Pentagon and the DOE – will effectively undermine any ethical oversight or democratic governance. With the ethical concerns and regulatory roadblocks swept aside, the future looks promising for the growth of the artificial life industry. The question is whether this growth is benign or malignant.

Jeff Conant is author of A Community Guide to Environmental Health and editor of Synbiowatch.org, a clearinghouse for critical perspectives on synthetic biology.