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COVER STORY

Assembly Required

Bioengineers are applying prefab principles to nature's construction materials. Their mission: a biological revolution.

Mirko Ilić

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By Kara Platoni

This morning the post delivered the last materials from Drew Endy's old lab: four brown glass bottles, each containing an inch of white powder that moves with the soft flakiness of confectioners' sugar. Each powder is one of the four nucleotides—A, C, G and T—that are the building blocks of DNA. With this four-letter alphabet, one can write the code for most living things. "We've got sixty times more material in these bottles than it would take to make a copy of every human's genome on the planet today," says Endy, hoisting one to eye level.

No one can yet assemble the entire human genome from scratch. But the potential hinted at by those four bottles—the capacity to design and build an entirely new wild kingdom—is one reason why Endy moved from MIT to Stanford in 2008. Now an assistant professor in the department of bioengineering, he hopes to take advantage of Silicon Valley's burgeoning interest in the new field of synthetic biology.

Synthetic biology seeks to take genetic engineering one step further by building biological components and systems—such as enzymes, cells or metabolic pathways—from the ground up, as an electrical engineer might design a circuit or processor. Endy and his fiancée, fellow Stanford bioengineer Christina Smolke, want to make the process of engineering biology faster, more reliable and more powerful—and therefore cheaper, easier and potentially more accessible. They want to establish a library of reliable, modular "BioBrick" parts—short sequences of DNA that code for specific functions—that engineers could freely exchange via a kind of BioBrick factory, or BioFab. BioBrick parts would range from the very simple, like the promoters that activate DNA transcription or the terminators that stop it, to more complicated devices like protein generators, counters or chemical sensors, to larger systems that can induce an engineered cell to carry out a specific function—for example, to produce a desired molecule.

The Bay Area's tech community has taken a warm interest in synthetic biology's most alluring premise: that hacking nature will yield novel solutions to some of the 21st century's most pressing problems. The discipline's supporters believe that engineering organisms to synthesize needed materials could birth a new generation of inexpensive, eco-friendly biofuels and medicines; or revolutionary treatments for diseases like cancer. Yet critics warn that synthetic biology could just as easily unleash new weapons and germs, and spur environmentally damaging behavior by pharmaceutical companies and agribusinesses that hope to profit by turning plants into fuels and drugs.

While synthetic biology has many bright lights, Endy is probably its most fervent evangelist. "Let's look at biology not as a science, but as a technology platform," he urges. "Biology is the most compelling technology platform anybody has ever seen. It's the stuff of life and it's a reproducing machine! It's a nanotechnology that actually works. You can program it with DNA—sort of. We're learning how to do that. It's the most overwhelmingly cool, impressive technology platform any engineer is ever going to encounter if they're alive today."

By nature, Endy and Smolke are both builders; they hope to equip the nascent synthetic biology community with better tools. Their work will greatly influence what bioengineers can create—and how easily.

Both Endy and Smolke came to synthetic biology through circuitous routes. Endy grew up in suburban Pennsylvania, a kid who loved exploring outdoors but also had a thing for proto-engineering toys like Legos and Lincoln Logs. "I come from the clan of the opposable thumbs," he says. "I like to make stuff." Endy emits a sense of barely contained energy; he'll speak in fluid, page-length arguments while absentmindedly picking up and twirling a small end table, or tapping his foot so animatedly that his sandal flies off.

His path to Stanford went roughly like this: civil engineering at Lehigh University, a fortuitous course in molecular genetics after a class in structural dynamics was cancelled, then a master's in environmental engineering, including a stint working on wastewater treatment. After receiving his PhD in biochemical engineering at Dartmouth, Endy spent a couple of years at Berkeley's Molecular Sciences Institute, growing increasingly frustrated with the difficulty of modeling the behavior of complex biological systems. He decided he'd rather build them from scratch.

At his next stop, MIT, Endy hit his groove, becoming a colleague of computer scientist-turned-synthetic biology pioneer Tom Knight, who had grokked the utility of modular bits of DNA and coined the term BioBrick. Endy ran with the idea; in 2003 he helped co-found the Registry of Standard Biological Parts and organized courses that led to iGEM, the International Genetically Engineered Machine competition, a sort of genetic engineering Olympics for students. Course and iGEM projects —making bacteria smell like bananas or arrange themselves into polka dots—seemed lighthearted but demonstrated an underlying power. In 2005, Wired noted Endy and Knight's aim to "do for biological molecules what electronics has done for electrons."

Smolke took an equally roundabout path. Growing up in Southern California, she thought she might study English or drama; she loved theater, and designing and sewing her own clothes. But, worried about the unpredictability of an acting career, she opted for engineering. For a crafter, engineering had a pull that a pure science like biology or chemistry didn't, she says. In those disciplines, "You weren't making things, you weren't building things—you were sort of studying what existed."

Her path, then, went like this: chemical engineering at USC, punctuated by summers working on an oil lease and a refinery, learning how design mapped onto real factories. While scoping grad schools, she had a pivotal meeting with UC-Berkeley chemical engineer Jay Keasling, whose lab was investigating how to use microorganisms to cheaply produce useful chemicals. (His lab would become famous for engineering E. coli and yeast to synthesize the antimalarial drug artemisinin, traditionally extracted from wormwood.)

"That's when it clicked," recalls Smolke. "This idea of these mini chemical factories, of going in there and engineering and thinking about what I had been trained to do at a macroscopic level in these large plants, but thinking about that at the molecular level inside of cells." She earned her chemical engineering doctorate, then spent two more years at Berkeley as a postdoc in cell biology before becoming an assistant professor of chemical engineering at Caltech.

Both Endy and Smolke were frustrated by the many unknowns involved in using life as a building block. "We don't fully have a physical model for how a cell works yet," say Smolke. As she points out, an engineer working with steel or electronics can reasonably estimate a project's timeframe, cost and reliability. "We don't have that in biology," she says. Lacking the tools they wanted to use, Smolke and Endy set out to make them.

During the 1970s and '80s, scientists developed the basic technologies behind genetic engineering: sequencing, or reading out the letters of DNA; recombinant DNA technologies that enable cutting and pasting bits of genetic code; and polymerase chain reaction (PCR), which enables those bits to be copied quickly. But writing code this way largely means manipulating what already exists. What if you could build from scratch?

Although the time it takes to do DNA sequencing (or reading) is decreasing and the cost dropping, DNA synthesis (or writing) is still laborious. Endy estimates there's a five- to seven-year lag between the two technologies. Because researchers must manually assemble so many of the biological components they use, instead of ordering them premade, Endy likens today's bioengineering to monks copying manuscripts in the Middle Ages. What if the biotech tool base had an Industrial Revolution?

This revolution, as Endy sees it, starts with three prongs. First: "Separation of design and fabrication can allow people to specialize, becoming experts in each area," he says. "We've seen this with microprocessors. Someone designs the chip and somebody else builds it." As a result, more complicated systems can be built.

The next step, standardization, would mean engineering parts that could be easier to exchange and reuse—that's where the BioFab comes in. Finally, there's abstraction: Endy would like to get away from engineering DNA by ordering its bases—A, C, T and G. Instead, he envisions a stack of higher-level engineering languages, just as computer programmers developed Fortran or Java to control machines without having to strip every command down to binary code. "They've invented a language hierarchy that abstracts up from these basic details the functions one wants to be able to deploy. Could we do the same?" Endy asks. If so, he says, it would greatly simplify bioengineering.

Endy's not the only one pushing for a tools revolution or a BioFab. "It's just that Drew, being a good evangelist, is able to communicate many of these ideas better than almost anyone I've ever seen," Keasling says. Endy makes a half-dozen pitches a week to garner support for a BioFab, which he thinks could produce 20,000 standardized parts a year while serving as a library for DNA code. Letting researchers freely swap genetic information would sidestep many of the financial and intellectual property constraints on bioengineering. For example, Endy estimates that patenting the 1,500 parts iGEM students developed in 2008 would cost $30 million in legal fees—10 times the cost of the competition itself.

Keasling, whose antimalarial drug took years and $42 million to develop, agrees. "If we'd had these standard components, I have no doubt it would have definitely gone much faster."

But Endy still takes some pointed questioning from fellow scientists. What if this engineering approach is wrong? You can't just break cells down into modular parts and then reassemble them, because part of what makes them function are complex interactions between parts that we don't yet understand. What if we don't know enough about DNA to program it as exactly as we would a computer? What if most researchers need specific parts nobody else wants, or ones more complicated than simple BioBrick parts? And ultimately, what should we try to build?

On a rainy spring afternoon at Berkeley's Faculty Club, some of the top names in synthetic biology have gathered at a meeting of the Synthetic Biology Engineering Research Center, or SynBERC, a multi-university/industry partnership Endy helped start in 2006. The researchers have split up into groups to brainstorm projects that could showcase synthetic biology's utility.

Endy's group, focusing on the environment, begins to spitball: What about a macadam road that could grow in the desert? Plants that change color in response to contaminants? Glowing grass that could gently light nighttime streets without electricity? Or a plant that sequesters dirty water by collecting it in a balloon? This idea generates a good deal of enthusiasm until someone sheepishly points out that nature has already engineered the watermelon.

Endy, tilted back in one chair, feet up on another, rapidly pages through websites on his laptop, although he breaks off long enough to gaze into the middle distance and muses, "I have this impractical fantasy that the Golden Gate Bridge is this living bridge with hugely hacked redwoods —that's the towers—and then it has programmable spiders laying down cables and it gets the nutrients from photosynthesis and from sucking in fish underneath."

"I don't see why not," shrugs a tablemate. When it's time to reconvene, the other groups present five concepts. Endy's group has 27.

Part of synthetic biology's allure for its practitioners is this seemingly bottomless well of ideas for addressing modern problems. Clean energy is one holy grail; Keasling's lab, with artemisinin now slated for production, is investigating using microbes to produce biofuels. "We're going to be able to engineer microbes to produce any chemical we want, and this could change us from being a petroleum-based economy to a sugar-based economy," he says. "This could transform world politics."

Health applications are another goal. One of Smolke's projects, now in the animal model stage, investigates using the body's natural immune system to fight cancer by controlling the activation and proliferation of T cells, perhaps programming them to sense when they are near cancer cells so they can "crank up" their activation. If doctors can accurately target therapies to diseased cells, says Smolke, "that allows you to build things that are more effective and also safer."

Still, there's some public unease with the idea of "extreme" genetic engineering, especially because the first wave of the science largely failed to deliver on promises of life-saving gene therapies and inspired worries about monocrops and Frankenfoods. Jim Thomas, research program manager for the Montreal-based human and environmental rights organization ETC Group, is one of synthetic biology's most outspoken critics. Last November he faced off against Endy at a debate sponsored by The Long Now Foundation. "Synthetic biology may be a useful tool for learning about the natural world," he argues, but "it's a terrible and unjust tool to found an industry on."

Thomas worries about a "massive commercial grab on plant life" by companies and governments interested in biofuels and bio-based chemicals that could "destroy ecosystems, displace people from their lands and worsen climate change." Endy maintains that synthetic biology could actually conserve wildlife if drugs once harvested from plants could be synthesized in the lab "without destroying an environment somewhere to plant hundreds of millions of trees to get a little bit of a chemical from the bark of each one."

There are concerns that transnational corporations will develop wide-reaching patent monopolies allowing them to dominate markets and disregard the public interest. "This technology will largely benefit the already powerful—energy, chemical and biotech companies who are climbing on the SynBio bandwagon, as well as military interests," Thomas argues. In turn, that could undermine the welfare of small farmers and native peoples. After all, he points out, the natural versions of many of the medical compounds one might wish to synthesize—including artemisinin—were traditionally cultivated by indigenous farmers. "Making them in a microbe using synthetic biology amounts to biopiracy and will undercut the livelihoods of already vulnerable communities."

Critics also worry that engineered organisms could escape the lab and wreak havoc, or worse, that bioterrorists could release them deliberately. The DNA sequences for lethal viruses like smallpox are already available online, and some fear that making bioengineering easier will put dangerous knowledge in the hands of rogues and crackpots. Smolke points out that there are still a number of complex steps required before creating a working, infectious virus. But given how fast the field is developing, today's insurmountable obstacles might be overcome tomorrow.

There already is a move toward "DIY Bio" for amateurs. Endy observes that while that morning he'd been putting in an order for $27,000 worth of freezers to keep his lab's stocks at -80 Celsius, there'd been a thread on the Google DIY Bio group about hacking the controller on an ordinary freezer to make it colder. As he looks around his pristine Stanford lab, he muses, "The difference between this environment and my garage is quite dramatic—many steps in between. But the number of steps between the biology in this lab and the biology you can do in a garage—well, there are hardly any now."

Endy and Smolke admit that new bioengineering technologies could be used destructively, and both are active in scientific discussions about safety practices and regulations. Smolke would like to see synthetic biology develop an accreditation process, culminating in a professional bioengineering exam, as other engineering majors require. Now that DNA is essentially a commodity, Endy thinks it's important for synthesis facilities to screen orders so they're not unwittingly constructing dangerous materials. Both believe that making bioengineering easier and faster could actually make the world safer. After all, time is on the side of those developing a harmful biological agent; diagnosing and neutralizing a biological threat requires a speedy response.

Even critics like Thomas give Endy props for pushing to make synthetic biology's building blocks public through a BioFab. "Drew's concerns about the monopolization of synthetic biology have had a big impact on the character of the field," says Thomas, adding that Endy "deserves credit for also starting a discussion about appropriate oversight, reaching out to civil society and being willing to take controversial stands." But Thomas calls Endy "a bit blinded by optimism that this powerful and potentially dangerous technology can be 'made good' even without any real democratic oversight in place and despite powerful interests now taking control of the field." He points out that making a technology more transparent doesn't necessarily make it safe or ethical.

Endy does, however, spend a good deal of time thinking about safety and ethics, and how to convey these ideals to his students. They're now as likely to be entering the field from engineering, physics or computer science as from microbiology, and to have missed out on conversations with their predecessors about safety and ethics. "So how do you build the next community of would-be biological engineers?" he asks.

His answer, at least in part, is iGEM. Stanford's first team of 10 undergraduates will head this fall to the iGEM "MIT Jamboree," which attracts participants from 21 countries. Their challenge is to use BioBrick parts to design a novel biological system that could improve the world. The event is designed to give students hands-on experience with creating their own project, doing lab work and interacting with more senior researchers who can guide them on safety issues.

Endy and Smolke advise Stanford's team; tonight students present a project idea: increasing photosynthetic efficiency in blue-green algae by engineering them to absorb a wider range of sunlight, an idea that might be useful in making biofuels.

Two students begin a PowerPoint presentation spelling out a possible approach. A few minutes into it, Endy cuts them off, then grills them on the details. "You have really important, profound ideas," he tells them, but "you don't have an idea that sings."

Nobody seems to mind; they expect Endy to throw the occasional bomb. After some discussion, the students decide to do more research then reformulate. "He's always blunt and very objective, but it's good, it keeps us from getting too complacent," says materials science and engineering student Ariane Tom, '11, the team's co-director, as she packs up afterward. She says she's less focused on winning than on getting the team to mature as researchers and collaborators. After all, she points out, it's rare for undergraduates to develop an entire project with people their own age, rather than being the youngest apprentices in someone else's lab.

But even beyond that, says Tom, the broader vision for iGEM is to get students thinking about a paradigm shift. "Drew is extremely visionary," she says. "It's not just about learning bioengineering and learning how to do PCR and all that. It's about the big picture, that biology wants to transform. If we want to innovate and do great things, we need to change the way we think about it—simplify it and make it easier for everyone to do biology and accelerate this process."

Here is something that was not accelerated: the Endy/Smolke Life Collaboration Project.

Despite both living in Berkeley in the late '90s, Smolke and Endy didn't cross paths until 2003 when they met at a workshop, and they didn't start dating until a few years later. For three years, they conducted a commuter romance between MIT and Caltech. "It is 2,611 miles by United Airlines, Boston to LAX," Endy recalls flatly. Then Stanford came calling. "Problem solved," Endy says. (They will be married in September.)

At Stanford, says Smolke, their discipline will need the expertise of the medical, business and law schools to tackle the complex issues it faces. Ronald Davis, director of the Stanford Genome Technology Center at the Medical School, welcomes the pair bringing "the discipline and thinking of engineering" to genetics. "They're coming from a different point of view, and that's very commonly where you get the big breakthroughs," Davis says.

Today the two work in next-door offices; Smolke's has neat stacks of Post-Its, Endy's has conga drums. They hope one day to collaborate scientifically, but right now they are partnering more on projects that build synthetic biology's community and infrastructure. Smolke is continuing her work on information processing and control within cells, and Endy's lab has a new project: genetic memory. For example, he says, creating a biological "clicker" inside a cell could tell you how many times it has divided. Endy isn't set on how this memory could be used. As usual, he's more interested in tools, in raw potential, than in any one application.

He collects his bottles of A, C, G and T and heads back into the lab, pausing for a second to marvel at what they contain. "It's unbelievable—sixty times all the human genomes on the planet." He shakes his head, and then says, more to himself than to anybody else, "Go build it!"

Read a March 2010 update on this story.


KARA PLATONI is a journalist in Oakland.

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