He went to a whiteboard in the office. “This is a little bit of math I did a number of years ago which freaked me out,” he said, and then went on to multiply the molecular weight of the nucleotides in those four bottles by the number of base pairs in a human genome. He used ten billion people instead of the current world population of six and a half billion and also rounded up the number of bases to ten billion, just to be conservative. “What we come out with in these bottles,” he said, placing one on the palm of his left hand, “is sixty times more material than is necessary to reconstruct a copy of every human’s genome on this planet.”
Endy shrugged. Of course, we don’t have machines that can turn those sugars into genetic parts yet—“but I don’t see any physical reason why we won’t,” he said. “It’s a question of money. If somebody wants to pay for it then it will get done.” He looked at his watch, apologized, and said, “I’m sorry we will have to continue this discussion another day because I have an appointment with some people from the Department of Homeland Security.”
I was a little surprised. Why? I asked.
“They are asking the same questions as you,” he said. “They want to know how far is this really going to go.”
The next time I saw Endy, a few months later, was in his new office at Stanford. The Bay Area is rapidly becoming as central to synthetic biology as it has always been to the computer industry. Endy looked rattled. “I just drove across the Golden Gate Bridge,” he said. “The whole way I kept thinking, ‘How does this thing stay up?’ ” I was confused. Drew Endy is a structural engineer. If crossing a bridge—particularly that bridge—worries him, who wouldn’t it worry? “Look,” he said, “there is uncertainty in the world. When it comes to engineering biology we don’t, for the most part, know enough to do useful things. But we also don’t know enough about physics. Gravity has not worked out perfectly—and yet we have the Golden Gate Bridge. And that’s okay because I am comfortable with learning by doing. Biology is a really impressive manufacturing platform. And we suck at it. But if we wait until we accumulate all the knowledge, we will accomplish nothing.”
Endy made his first mark on the world of biology by nearly failing the course in high school. “I got a D,” he said. “And I was lucky to get it.” While pursuing his engineering degree at Lehigh University, not far from Valley Forge, Pennsylvania, where he was raised, Endy took a course in molecular genetics. Because he saw the world through the eyes of an engineer he looked at the parts of cells and decided it would be interesting to try and build one. He spent his years in graduate school modeling bacterial viruses, but they are complex and Endy craved simplicity. That’s when he began to think about putting cellular components together.
In 2005, never forgetting the secret of Legos—they work because you can take any single part and attach it to any other—Endy and colleagues on both coasts started the BioBricks Foundation, a nonprofit organization formed to register and develop standard parts for assembling DNA. (Endy is not the only biologist, nor even the only synthetic biologist, to translate a youth spent with blocks into a useful scientific vocabulary. “The notion of pieces fitting together—whether those pieces are integrated circuits, microfluidic components, or molecules—guides much of what I do in the laboratory,” the physicist and synthetic biologist Rob Carlson wrote in his 2009 book Biology Is Technology: The Promise, Peril, and Business of Engineering Life, “and some of my best work has come together in my mind’s eye accompanied by what I swear was an audible click.”)
BioBricks, then, have become the thinking man’s Lego system. The registry is a physical repository, but also an online catalog. If you want to construct an organism, or engineer it in new ways, you can go to the site in much the same way you would buy lumber or industrial pipes online. The constituent parts of DNA—promoters, ribosomes, plasmid backbones, and thousands of other components—are cataloged, explained, and discussed. It is a kind of Wikipedia of future life forms—with the added benefit of actually providing the parts necessary to build them.
Endy argues that scientists skipped a step, at the birth of biotechnology thirty-five years ago, moving immediately to products without first focusing on the tools necessary to make them. Using standard biological parts, a synthetic biologist or biological engineer can already to some extent program living organisms in the same way a computer scientist can program a computer. The analogy doesn’t work perfectly, though, because genetic code is not as linear as computer code. Genes work together in ways that are staggeringly complex and therefore difficult to predict; proteins produced by one gene will counteract or enhance those made by another. We are far from the point where we can yank a few genes off the shelf, mix them together, and produce a variety of products. But the registry is growing rapidly—and so is the knowledge needed to drive the field forward.
Research in Endy’s lab has largely been animated by his fascination with switches that turn genes on and off. He and his students are attempting to create genetically encoded memory systems. His current goal is to construct a cell that can count to about 256—a number based on basic computer code. Solving the practical challenges will not be easy, since cells that count will need to send reliable signals when they divide and remember that they did.
“If the cells in our bodies had a little memory, think what we could do,” Endy said. I wasn’t quite sure what he meant. “You have memory in your phone,” he explained. “Think of all the information it allows you to store. The phone and the technology on which it is based do not function inside cells. But if we could count to two hundred, using a system that was based on proteins and DNA and RNA, well now, all of a sudden we would have a tool that gives us access to computing and memory that we just don’t have.
“Do you know how we study aging?” he continued. “The tools we use today are almost akin to cutting a tree in half and counting the rings. But if the cells had a memory we could count properly. Every time a cell divides just move the counter by one. Maybe that will let me see them changing with a precision nobody can have today. Then I could give people controllers to start retooling those cells. Or we could say, ‘Wow, this cell has divided two hundred times, it’s obviously lost control of itself and become cancer. Kill it.’ That lets us think about new therapies for all kinds of diseases.”
Synthetic biology is changing so rapidly that predictions seem pointless. Even that fact presents people like Endy with a new kind of problem. “Wayne Gretzky once famously said, ‘I skate to where the puck is going, not to where the puck is.’ That’s what you do to become a great hockey player,” Endy said. “But where do you skate when the puck is accelerating at something that seems like the speed of light, when the trajectory is impossible to follow? Who do you hire and what do we ask them to do? Because what preoccupies our finest minds today will be a seventh-grade science project in five years. Or three years.
“That is where we are with this technology. The thrill is real—but so are the fears. We are surfing an exponential now, and even for people who pay attention, surfing an exponential is a really tricky thing to do. And when the exponential you are surfing has the capacity to impact the world in such a fundamental way, in ways we have never before considered, what do you do then? How do you even talk about that?”
IN AUGUST 2002, Science magazine published a report titled “Chemical Synthesis of Poliovirus cDNA.” It began with an assertion few virologists would dispute: “Research on viruses is driven not only by an urgent need to understand, prevent, and cure viral disease. It is also fueled by a strong curiosity about the minute particles that we can view both as chemicals and as ‘living’ entities.” That curiosity led a team directed by Eckard Wimmer at Stony Brook University to stitch together hundreds of DNA fragments, most of which were purchased on the Internet, and then use them to build a fully functioning polio virus. The scientists then injected the virus into mice, which promptly became paralyzed and died.
The experiment, the first in which a virus was created in a
laboratory solely from chemicals, caused outrage “This is a blueprint that could conceivably enable terrorists to inexpensively create human pathogens,” Representative Dave Weldon said at the time; he and five other members of Congress introduced a resolution criticizing the American Association for the Advancement of Science, which publishes Science magazine, for publishing the study. Many scientists considered the research an irresponsible stunt. Then, in 2005, federal scientists deciphered the genetic code of the 1918 flu virus, which killed at least fifty million people, and reconstructed that virus too.
A renowned virologist once described Wimmer’s polio research to me as nothing more than “proof of principle for bioterrorism,” a comment I used in an article about scientists who were bringing ancient viruses back to life. He said the report would serve only to remind people how easily they could obtain the various components required to make a virus. After all, anyone can order strands of DNA over the Internet from scores of companies, nearly all of which will deliver via Federal Express. Soon after the article was published, I received a polite e-mail from Wimmer, who said I had completely misunderstood the purpose of his work, and he invited me to his laboratory to discuss it.
Wimmer met me at the door to his office, a thin, elegant man in a maroon turtleneck, gray flannel pants, and a blue cashmere sweater. He had chalked out various viral particles on the whiteboard. “I want to say before anything else that we didn’t do this work to show we were good at chemistry,” he told me. “First—and I think this is important—people need to know what is possible. It’s not as if any smart kid out there can make polio or smallpox in their homes. These are complicated viruses—yet there seems to be this idea floating around that you can just order DNA and whip up a virus as if it were a cake. That is untrue. Could somebody who wants to hurt people make such a virus? Of course. Will one be made? I don’t know, but silence isn’t going to help us prevent it or respond. We need to be talking.”
It didn’t take long for me to realize that he was right. Synthetic biology will never fulfill its promise unless it is discussed and understood by the society it is designed to serve. If not, the cycle of opposition and denialism will begin anew. Scientists will insist that research is safe and the benefits clear. A chorus will respond: how do you know? Wimmer was right about the difficulty of making viruses too, particularly in the quantities necessary for a weapon. He wouldn’t put it this way, but he believes the best defense is an offense. To protect ourselves from new diseases, including those introduced purposefully, we will need vaccines that can stop them. And to do that, scientists must understand how the parts work. (Which in the end has been the goal of his polio research.)
Before meeting Wimmer I had asked Drew Endy what he thought of the controversial research. Endy, whose fundamental approach to biological engineering is to learn by doing, has also tried to synthesize novel viruses to better understand how they work. “If it was just a single virus then I could see people wondering why he did it,” Endy said. “But if you look at the arc of Eckard’s research he has used synthesis to make viruses that have hundreds of mutations which attenuate their activity. Those changes can help lead to rapid vaccine responses.” Vaccines are made in a couple of basic ways. Live, attenuated vaccines are often the most effective; they are composed of a virus that has been weakened or altered in order to reduce its ability to cause disease, but they can take years to develop. Wimmer introduced a modern version of that approach: a synthesized virus that had been mutated could train antibodies without causing harm. Indeed, the Defense Advanced Research Projects Agency (DARPA) has a program under way to develop vaccines “on demand,” in large quantity, and at low cost, to interdict both established and new biological threats.
“You have to remember,” Wimmer said in reference to his original paper, “2002 was a super-scary time after 9/11 and the anthrax attacks. I think the fear that people expressed was in not knowing the goals of the research. By 2005, people seemed more comfortable with the idea that there was a legitimate reason to reconstruct something like the 1918 flu virus in order to create a vaccine. With polio, which really doesn’t affect people, it is still harder to explain that we use the research to make vaccines.
“But our approach was to remodel the virus,” he went on. “I have said before—and this is true of synthetic biology in general—we have to understand that it provides wonderful solutions to terrible problems. And it can also lead to the synthesis of smallpox and polio.” Many of Wimmer’s original critics have come around to his point of view. In 2008, he was elected a fellow of the American Association for the Advancement of Science for “discovering the chemical structure of the poliovirus genome, elucidating genetic functions in poliovirus replication and pathogenesis, and synthesizing poliovirus de novo.”
Wimmer’s polio research did spark a discussion about whether synthetic biology could be used for bioterrorism; the answer, of course, is yes. If a group of well-trained scientists want to manufacture polio—or even the more complicated smallpox virus—they will be able to do so. (It should be noted, but often is not, that an evil scientist—or country—does not need fancy new technology or much money to cause widespread terror and death. Anthrax spores exist naturally in the soil. They can be extracted, grown, and turned into remarkably effective weapons with far less effort than it would take to create a lethal organism from scratch.) While creating deadly viruses from modern tools—or using them to revive smallpox—presents a compelling horror story (and rightfully so), more prosaic weapons, both biological and conventional, are easier to use, highly effective, and more accessible. “It doesn’t take the fanciest technology to cause destruction,” Wimmer said. “I think we all saw that on September 11.”
FOR DECADES, people have described the exponential growth of the computer industry by invoking Moore’s law. In 1965, Gordon Moore predicted the number of transistors that could fit onto a silicon chip would double every eighteen months, and so would the power of computers. When the IBM 360 computer was released in 1964, the top model came with eight megabytes of main memory, and it took enough space to fill a room. With a full complement of expensive components the computer could cost more than $2 million. Today, cell phones with a thousand times the memory can be purchased for less than a hundred dollars.
In 2001, Rob Carlson, then a researcher at the University of Washington and one of synthetic biology’s most consistently provocative voices, decided to examine a similar phenomenon: the speed at which the capacity to synthesize DNA was growing. What he produced has come to be known as the Carlson Curve, which mirrors Moore’s law, and has even begun to exceed it. Again, the effect has been stunning. Automated gene synthesizers that cost $100,000 a decade ago now cost less than $10,000. Most days, at least a dozen used synthesizers are for sale on eBay—for less than $1,000.
As the price of processing DNA drops, access (and excitement) rises. Between 1977, when Frederick Sanger published the first paper on automatic gene sequencing, and 1995, when Craig Venter published the first bacterial genome sequence, the field moved slowly. It took the next six years to complete the first draft of the immeasurably more complex human genome, and six years after that, in 2007, scientists on three continents began mapping the full genomes of one thousand people. George Church’s Personal Genome Project now plans to sequence one hundred thousand. (Church is convinced that, in exchange for advertising, companies will soon make genomes available to anyone for free—a model that has certainly worked for Google.) His lab has been able to sequence billions of DNA base pairs in the time it would have taken Sanger to sequence one. “This is not because George or Craig Venter got ten billion times smarter in fifteen years,” Endy said. “It’s because the capacity of the tools have exploded.”
In 2004, when he was still at MIT, Endy and his colleagues Tom Knight and Randy Rettberg founded iGEM, the International Genetically Engineered Machine competition, whose purpose is to promote the building of biological systems from standard parts like those in the B
ioBricks registry. In 2006, a team of Endy’s undergraduate students used those tools to genetically reprogram E. coli (which normally smells awful) to smell like wintergreen while it grows and like bananas when it is finished growing. They named their project Eau d’E Coli. By 2008, with hundreds of students from dozens of countries participating, the winning team—a group from Slovenia—used biological parts that they had designed to create a vaccine for the stomach bug Helicobacter pylori, which causes ulcers. There are no such working vaccines for humans. (So far, the team has successfully tested their creation on mice.)
This is open-source biology, where intellectual property is shared freely. What’s freely available to idealistic students, of course, would also be available to terrorists. Any number of blogs offer advice about everything from how to preserve proteins to the best methods for desalting DNA. Openness like that can be frightening, and there have been calls for tighter regulation—as well as suggestions that we stop this rampant progress before it becomes widely disseminated. Carlson, among many others, believes that strict regulations are unlikely to succeed. Several years ago, with very few tools but a working charge card, he opened his own biotechnology company, Biodesic, in the garage of his Seattle home—a biological version of the do-it-yourself movement that gave birth to so many computer companies, including Apple.
“It was literally in my garage,” Carlson told me. The product enables the identification of proteins using DNA technology. “It’s not complex, but I wanted to see what I could accomplish using mail order and synthesis.” A great deal, it turned out. Carlson designed the molecule on his laptop, then sent the sequence to a company called Blue Heron that synthesizes DNA. Most instruments he needed could be purchased easily enough on eBay (or, occasionally, on LabX, a more specialized site for scientific equipment). “All you need is an Internet connection and a credit card,” he said.
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