Life: The Next Generation

Drew Endy

Courtesy of Sriram KowitzFor Drew Endy, heading up the Massachusetts Institute of Technology Synthetic Biology Working Group is like being "the lifeguard at the gene pool." Working with prefabricated snippets of DNA pulled off a freezer shelf, Endy and his MIT colleagues are attempting to design and construct new living systems.Their agenda, explains Endy, is twofold: "First, let's see if we can learn more about existing systems by rebuilding them." Next, he'd like to "take natural living systems and try to reimplement them according to our own designs and purposes." Potential applications, though not necessarily Endy's personal wish list, include generating biological machines that could clean up toxic waste, detect chemical weapons, perform simple computations, stalk cancer cells, lay down electronic circuits, synthesize complex compounds, and even produce hydrogen from sunlight.Endy, 34, brings to the venture a solid background in engineering, with degrees in civil and environmental engineering and a PhD in biochemical engineering from Dartmouth College. "I like building stuff," Endy shrugs, and he set his sights on living systems because they're more impenetrable than structures of concrete and steel. "No other domain of my physical existence is so boxed off from my understanding," he says, "and I think if I can build biological systems, I'll understand them better."His initial foray into building biological systems was centered on modeling. In particular, Endy studied the behavior of the T7 virus that infects bacteria. He worked on predicting what would happen if he altered its genome in "nontrivial ways," for example by adding a feedback loop designed to boost a particular part of the virus's developmental pathway. The turbo-charged virus, Endy surmised, would grow faster than its wild type relative does.But when he did the necessary experiments, Endy discovered that his predictions were all wrong. "This was the beginning of the dim, dismal period of reflection and depression," he says.This is where Roger Brent comes in. Brent, director of the Molecular Sciences Institute (MSI) at University of California, Berkeley, heard Endy give a talk about his work. "It was 'like at first sight,"' he recalls, and he invited the young engineer to come to MSI to regroup. There, Endy had a major revelation: "I came to the conclusion that natural biological systems are not optimized to be easy to describe, manipulate, measure, model, interact with, understand, or direct according to human intention." He decided that if he were going to do any of those things, he'd have to assemble his own biological systems from the ground up."Worst-case scenario, it's a complementary approach to traditional discovery science," says Endy. "Best-case scenario, we get systems that are simpler and easier to understand and are easier to extend and redirect in the future." Spoken like a true engineer, who prizes simplicity above all else."There's an old joke," says Tom Knight, cofounder of the MIT synthetic biology group and one of Endy's coconspirators. "A biologist and an engineer perform experiments and discover that the system is more complex than initially thought. The biologist says, 'Great, I'll write a paper.' The engineer says, 'Damn. How do I get rid of that?'""The engineering gene is missing from most biologists," laments Knight. "So from my perspective that makes Drew an exciting person. And he works his butt off." What's more, "I think a stable job will do him good," quips Sydney Brenner, MSI founder and now professor at the Salk Institute for Biological Studies, La Jolla, Calif.MIT is a fine place for such activities. "The intellectual excellence of the engineers who animate MIT make it a wonderful place," says Brent. "And in the biology building, Drew is surrounded by people he can learn from."MIT's legendary hacker culture can only feed the bioengineering bonfire. "Synthetic biologists want to do things for hacker reasons, because they're cool or elegant,"says Brent. "The hacker culture of playfulness has a great deal to teach biology."Since moving to MIT, Endy has continued to play with T7. He and his lab mates Leon Chan and Sri Kosuri have done a total overhaul of the viral genome, physically separating all of its genetic elements. In the wild type organism, genes often overlap – a situation that Endy, as an engineer, can't abide. The result: a redesigned virus that grows, but not that well. Endy isn't sure what he will do with the new T7, but he's encouraged that their manipulations didn't kill the thing outright.Endy also has launched an even more ambitious project. He is developing a repository of interchangeable biological parts that can be snapped together like Legos to produce devices and systems that act as toggle switches, oscillators, or other nifty molecular gadgets. The standardized parts, which Knight and Endy call BioBricks, are items familiar to most molecular biologists: pieces of DNA that act as transcriptional start and stop signals, RNA polymerase binding sites, or open-reading frames that encode a useful protein.When strung together, BioBricks form handy little devices, for example an inverter that uses a repressor protein to flip an incoming signal. The "current," in this case, is defined by the number of RNA polymerase molecules that run along the DNA wire (a measure of gene transcription). When the input signal is high (i.e., lots of polymerase driving transcription), the inverter makes mounds of repressor protein, which shuts down gene expression, and thus the output signal is low. Ultimately, the group would like to amass a large collection of these readymade parts and devices, which can then be picked off the shelf and linked in tandem to suit the investigator's needs.There's only one problem: "Nothing works," says Endy. Individual devices, such as the inverter, function correctly. But hooking them together to produce anything more complex, such as an oscillator that makes a bacterium blink on and off, has been less successful. "Honestly, I think that's to be expected," he says. "What we're doing is scavenging and harvesting things from nature. The probability that they'll be perfectly matched just isn't very high." A part scammed from Salmonella might not interface seamlessly with something from Pseudomonas, Escherichia coli, Arabidopsis, or a mouse, for that matter.Nonetheless, Endy remains unperturbed. "Engineers learn best by trying and failing, and we've been failing more than anybody, so we're learning a lot." He and his team are now trying to figure out how to tune their parts, to guarantee that they're all running at the same "voltage."In the meantime, Endy and his fellow biological engineers are learning how to think about potential misuses of the technology. For the past two years, Endy and Knight have run a course in which they challenge students with the task of designing a useful biological system. Early on, the instructors toyed with a "phage wars" theme; student teams would build synthetic viruses, toss them into a pot of bacteria, and let them battle for supremacy. "We decided right away that this would be a bad idea," Endy says. Although reminiscent of engineers' beloved robotics competitions, the goal was too explicitly destructive. "I don't think that humanity can afford to stumble into a modern bioweapons race," he says.Such concerns reverberate within the synthetic biology community, which is currently debating whether to organize a conference to discuss how to regulate the proper use of the technology. As a first step toward self-policing, Endy says he will work only with DNA-synthesis facilities that screen all their orders to make sure that they're not providing the raw materials to build a pathogen.Instead of building rampant replicators, Endy would like to construct counters made of DNA and protein that can keep track of how many times a cell divides. Such cellular odometers could be used to study how gene expression changes as cells age or to program cancer cells to self-destruct after 200 rounds of replication.Researchers are now ramping up their ability to synthesize long stretches of DNA, the raw material that synthetic biologists use to build their machines. Full bacterial genomes should be produced within a year or so, and Endy expects that eukaryotic chromosomes and genomes will follow within the decade. This timeline is fine by him, because "learning what it is we want to make is going to take at least as long and probably much longer."The consequences could be profound. "I think that synthetic biology – the ability to manipulate biological systems – will be as important to the 21st century as ability to manipulate bits was to the 20th," says Brent. "And Drew is doing what needs to be done to help bring that into being. He has the talent and resources to get something important going, and we want him to succeed. We want him to transform the world."For his part Endy remains more circumspect. "It'll be cool if we can pull it off," he says. "We might fail completely. But at least we're trying."And if things don't work out, Endy could have a future in television. The young scientist was recently approached by Warner Brothers to audition for the role of the Professor in the upcoming, reality TV-style remake of "Gilligan's Island." Endy claims he lost interest in the project when he learned that Paris Hilton would not be playing the role of Ginger. More likely, he realized that his participation would almost certainly guarantee that he'd be dogged for the rest of his professional career: "He could build a supercomputer with restriction enzymes and spit, but he couldn't get them off the island."Karen Hopkin khopkin@the-scientist.com

Life: The Next Generation

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