Life itself

Richard Michelmore was present at the creation. Or something close to it.

When Michelmore was a plant-biology graduate student at the University of Cambridge in England in the 1970s, Fred Sanger invented the method for sequencing DNA there. For the first time, the sequences of DNA that govern the heredity of humans and all other species could be read. “I can remember Sanger’s nephew sequencing the very first plant gene,” Michelmore says. “But it took him a very long time.”

Today, the Sanger Institute is one of the world’s premier DNA-sequencing and genomics research centers in the world. There, and at similar institutes around the globe, literally millions of units of DNA—the stuff that the genes and genomes of all living things are composed—are being sequenced on a daily basis. And plant biologist Michelmore is now the director of the UC Davis Genome Center.

Still a work in progress, the Genome Center embodies the new paradigm in biological research that puts under one roof a faculty from diverse disciplines, working with the most advanced technologies for analyzing the molecular activity within living cells. This paradigm seeks to break through the mysteries underlying all the processes of life and to uncover how invisible molecules interact in complex networks to compose and maintain the living tissue of organisms, from the plants that make up your salad to the eyes and brain reading these words.

“A global approach to biology,” as the Genome Center’s brochure calls it.

The goal is nothing less than gaining a complete understanding of, and ultimately complete mastery over, the molecular action inside the cells of all types of organisms—whether microbe, plant, animal or human. Curing diseases of all manner, increasing agricultural productivity and protecting the environment are among the sought-after results in achieving these scientific breakthroughs.

In making this effort, the center is considering how this fundamental knowledge might aid, and be aided by, taking the next step: figuring out how to create life forms from the bottom up, finding the “bio-bricks” needed to construct novel organisms or alter existing ones. While scientists believe this new “synthetic biology” offers great benefits for addressing problems like pollution, they also acknowledge there’s risk in gaining this capability to engineer life itself.

Located at the bend where Interstate 80 meets Highway 113 at the southwestern edge of the UC Davis campus in Yolo County, the Genome Center occupies two floors of a recently constructed six-story building with green tinted windows. Despite all the high-technology gizmos within the center—there’s actually a machine there called a “Thermo-Electron Hybrid Linear Ion-Trap Fourier Transform Ion Cyclotron Resonance Mass Spectrometer,” or LTQ-FT for short—the most telling piece of equipment might be the foosball table in the fourth-floor lounge. “I paid for it out of my own pocket,” says center director Michelmore, “because I want to do everything I can to encourage interaction among our researchers. Interaction is the keynote here.”

When the center’s graduate students avidly take to the foosball table when it’s allowed after 5 p.m., they claim that its primary virtue for them is stress release. But the newest faculty there offer unsolicited testimonials to the Genome Center’s collaborative, interdisciplinary approach as a major draw for them in accepting their positions. “The new way to do science” by “sharing space with a mix of people doing experimental and computational work” are among the phrases expressing this appreciation.

In a way, the Genome Center is misnamed. Some might assume that a genome center performs the same task as the Human Genome Project: sequencing the DNA that makes up an organism’s genome—an organism’s entire genetic code for its own development and functioning, and its hereditary bequest to the next generation. But no genome sequencing occurs here.

Instead, the Genome Center might more aptly be understood as the post-genome center. This is a center for assessing the actions in a cell after a genome sequence, or part of it, is in hand.

A little bit of background is necessary here:

As Carl Sagan famously said of galaxies in the universe, there are billions and billions of various molecules interacting in an organism’s cell during every second of its life. Obtaining the genome sequence is just the warm-up for understanding this complex universe inside of each cell of an organism. Michelmore puts our current ignorance of a cell’s complexity in perspective this way: “If you take the average human cell and run it through the analytical machines, we do not know what half the read-out is showing us. We don’t know what they mean. So we do not know what half of you is. It’s scary.” Back in 2000, J. Craig Venter, one of the leaders of the human-genome effort, put it more bluntly: “We don’t know shit about biology.”

To overcome this ignorance, in the late 1980s former California Institute of Technology president and Nobel laureate David Baltimore predicted and promoted “the industrialization of biology.” He foresaw the need for large-scale, high-throughput machinery to analyze these billions and billions of molecules and their real-time interactions. The Human Genome Project was the first flowering of this approach. The UC Davis Genome Center is among the more recent.

Technology being key, the Genome Center is organized into five technology cores. Each of three is devoted to analyzing one of the key molecules: DNA, RNA and protein. A fourth is represented by a tongue-twisting mouthful: “Metabolomics.” This one captures snapshots of a cell’s molecular metabolism in action. UC Davis philosopher of biology James Griesemer compares metabolomics to being able to see where everyone in New York City is going, their rate of speed and their direction, rather than just what’s happening at one subway stop.

The fifth technology core lies closest to the heart of the Genome Center’s innovations: “Bioinformatics.” In one way or another the other technology cores, which analyze real biological samples, are generating results that can be translated into computer-based data. Once encoded for the computer, the bioinformatics specialists design methods for analyzing these bio-data. Along the center’s bioinformatics corridor, not a test tube or microscope will be found—just researchers in offices and cubicles peering at their computer screens, contemplating life translated into computer code.

The Genome Center currently has 15 faculty members. It not only serves the campus’ 800-plus faculty researching some aspect of the biological world—one of the largest concentrations of biologists in the world, according to Michelmore—but the center’s research projects also serve as the engine driving its ability to keep up with the latest technological advances.

So far, it seems to be working. A recent compilation shows the Genome Center completing 150 projects for 125 different UC Davis faculty members spread across 43 different campus departments. This pleases Michelmore, who predicts a doubling of that result within the next 18 months. It also seems to be working in attracting some of the most accomplished talent to the center, researchers who came of age in the genome era, representing a new breed of scientist, ones for whom the new science paradigm is the norm.

Katie Pollard, one of the newest GenomeCenter faculty members, never has worked with monkeys, though she does have a small stuffed monkey sitting on her office shelf. But as a post-doctoral biostatistician at UC Santa Cruz in 2004 and 2005, she worked with the chimpanzee’s genome in the form of a computer code, and made a discovery that this summer received worldwide attention from scientists and the public. Comparing the chimp genome with the human genome, which are considered to be 99.5 percent alike, Pollard found regions in the human genome that showed major changes from their chimp ancestors, including at least one that involves brain development. A potentially major piece of the puzzle about how humans evolved from their primate ancestors had fallen into place.

Pollard arrived at the right place at the right time to make this discovery. “A moment of serendipity,” she calls it. She’s the daughter of a Johns Hopkins University cell biologist and a League of Women Voters of Maryland president who worked for education and health reform. For a while, Pollard balanced her interests and talents by pursuing medical anthropology and public health, at Pomona College, through internships at British health facilities and at UC Berkeley. She’d always been good at math, so getting a doctorate in public health with an emphasis in epidemiology seemed the right merger of her skills. A summer internship at the Chiron Corporation in Emeryville, which uses cutting-edge technology to analyze cancer tissue, opened her eyes to new possibilities.

“Literally, from when I started graduate school until I finished in 2003, biology was transformed,” she says. “I got excited about that.”

Luckily, she had an adviser who also “got the bug for this stuff right around the same time,” and she completed her Ph.D. with a thesis in bioinformatics and made her way to Santa Cruz.

UC Santa Cruz occupies a storied place in the genomics world. The first meeting to strategize a human-genome project occurred there in 1985. In December of 1999, when the public Human Genome Project faced a seven-month deadline to produce a first draft, the Santa Cruz computer lab of David Haussler saved the day.

When Pollard arrived in 2004, Haussler and his group were at the center of efforts to sequence and compare dozens of other animal genomes, from the fruit fly to the platypus. Weekly international conference calls occurred for each one. “There were so many genomes being finished during this period that we had a joke,” Pollard says. “ ‘If it’s Tuesday, it must be the chicken,’ we’d say, because each day of the week there would be a different conference call about a different genome—mouse or chicken or cow or dog.”

Soon after arriving, Pollard e-mailed Haussler that she’d be interested in “getting involved in the chimp,” and Haussler immediately responded, “Great. We need a chimp person.” “Chimp was low on their priority list,” Pollard says, “because they were busy with other stuff.”

That winter she got to work on comparing the chimp and human genomes to identify areas where the two diverged. She and her team were looking for evolution’s “missing links,” the genes responsible for the emergence of the human from its primate past.

This meant working with huge data sets. Each genome is around 3 billion DNA units long. Making matters even more complicated, the researchers were going to search through the part of the DNA that doesn’t consist of genes. Human and chimp genes are so similar scientists theorized that what separated the two species must lie in the area often mischaracterized as “junk DNA.” This non-gene area is about 97 percent of all those 3 billion DNA units.

Pollard and her colleagues devised a strategy to bring evolutionary perspective to the task. They would throw the mouse and rat genomes, which are early ancestors to both the chimp and the human, into the comparison. They’d search for only those segments where the mouse, rat and chimp had remained virtually the same, but where the human had diverged substantially. That way they would know the human changes occurred in an area that evolution had otherwise long conserved.

Once they found those regions in which the mouse, rat and chimp were mostly identical, they brought the human into comparison. The result was astonishing: 200 segments showing substantial human changes. And at the top of the list was an area showing 14 changes out of a 100 units of DNA—far more than would have been expected by chance. “I immediately called in David [Haussler],” Pollard says, “and he was counting the differences and said, ‘Are you sure this is right?’ ”

Checking and re-checking confirmed the finding. “I remember looking over Katie’s shoulder in December 2004,” Haussler says, “and we were jumping up and down. There was just a lot of excitement. We had no clue what the meaning of this stretch of DNA was. But we knew we had a candidate.”

A year and a half of investigations and experiments before publishing their results showed that they had more than a candidate that might help explain how humans evolved. Pollard actually had discovered a new gene. Experiments by Pierre Vanderhaeghen, a Belgian scientist, showed that this gene is involved in embryonic brain development. Not only that, but this development is of the brain’s higher-thinking center, the cerebral cortex.

Asked whether this gene might in part be responsible for consciousness itself, Pollard replies in a measured way: “The fact that this gene isn’t highly expressed in the adult brain suggests that having it present isn’t necessary for the ongoing experience of consciousness. But it may be involved in the development of brain structures that are prerequisites for consciousness. But that’s all pretty hypothetical.”

Vanderhaeghen currently is experimenting with transgenic mice to figure out the precise function of this gene. Using a different approach, the No. 1 priority at Haussler’s wet lab in Santa Cruz is also to determine what this gene does, says Pollard.

Pollard took occupancy of her office at the Genome Center in January of 2006. When her paper on the chimp-human gene differences was published in the pre-eminent science journal Nature in August, the story was picked up all over the world. “I think that people get really excited about tying things in our DNA back to our evolutionary history,” she reflects. “When we found this thing that was so extremely changed in a human, and yet hadn’t changed almost at all for the previous 300 million years of evolution before that, well, that was cool in and of itself.

“People really like to understand our evolution as a species. We like to fancy ourselves as being advanced versions of the rest of the apes—a bigger brain, not so hairy, building computers and doing all kinds of stuff. So humans want to understand what we perceive as our superior evolutionary history. So our brain development is a part that really strikes a chord with people.”

At Davis, Pollard continues to work on finishing this project—she hints that the announcement of locating additional genes could be in the offing—even as she begins new ones at the Genome Center. She’s collaborating with scientists doing work with plants and fruit flies. She likes working with those model organisms, she says, because unlike with chimps and humans “you can quickly do cheap and ethical experiments and rapidly get results.”

Jonathan Eisen has a lot in common with Pollard. A recent recruit to the Genome Center in 2006, Eisen also grew up in Maryland with parents who were biomedical researchers, though his worked at the National Institutes of Health in Bethesda. In his first college years at Harvard University, he too pursued a career outside of biology. Despite being in the same East Asian studies seminar with the young actress Mira Sorvino, it was taking a class on evolution for non-science majors with renowned paleontologist and author Stephen Jay Gould that changed his mind. “It was probably half-way through the first lecture that I decided to bail on East Asian studies,” he recalls.

Like Pollard, he also had a revelatory moment as a graduate student when the possibilities of the new biology came into focus. “I was using standard molecular methods to clone genes out of different organisms. Then [Nobel laureate] Hamilton Smith gave a talk at Stanford in 1994 or 1995, saying that his group was sequencing whole genomes of organisms. It just blew me away. I’m spending months sequencing a thousand base pairs [DNA units] of one gene, and they’re using these big machines and computers and other stuff to read whole genomes of organisms.

“I basically immediately dropped almost everything I was doing and switched to bioinformatics. I almost did no more lab work after that.”

Eisen wasn’t interested in primates but focused on the other end of the evolutionary spectrum: bacteria and microorganisms. He joshes that those working on mammal genomes are behind the curve. “Katie’s stuff is really cool. But they’re way late in the game. The bacterial people, we have genomes of 500 bacteria. And they’re excited that they have a second primate? Big deal. The bacteria won the game in terms of genome sequencing. There are multiple genomes from every group of bacteria, and we’ve had them for years.”

But Eisen gets serious when he suggests that the bacterial genomes may have a more important immediate effect than the human and other animal genomes. “The causative agents of almost all infectious diseases are microbes,” he explains. “If you wanted to attack those microbes, or to diagnose an infection, you need the genomes from those microbes, not the human genome. The human genome is obviously incredibly important to medicine. But for a lot of the ‘low-hanging fruit’ in medical studies, having the genomes of these microorganisms turns out to have probably been more important than having the human genome.”

In 1998, Eisen secured a position at Venter’s The Institute for Genomic Research in Rockville, Md., where he pursued his microbial interests for the next eight years. Eisen had three priorities at TIGR. He developed methods to bring an evolutionary perspective to genomic studies, similar, he says, to Pollard’s work. He also developed his interests in a class of microorganisms known as “extremophiles”—that is microbes that live in extreme environments such as thermal vents at the bottom of oceans. His third area was studying symbiotic microorganisms that live inside of other organisms. It is this last research area that is showing results that might have impact in Northern California, even possibly saving the region’s vineyards.

Eisen and his colleagues recently published a study about an insect known as the glassy-wing sharpshooter. This insect feeds off of the root system of plants. In so doing, it can pick up and transmit a bacteria responsible for Pierce’s disease.

“Pierce’s disease is really bad,” Eisen says. “If your vineyard is found to be infected with Pierce’s disease, and the U.S. Department of Agriculture knows about it, they will want you to burn the whole thing. If one of the big vineyards comes down with Pierce’s disease, that’s billions of dollars in economic damage right there.”

What confounded scientists was that this insect carrier of Pierce’s disease only fed off the nutrient-poor root system of plants. There was no way it could obtain the nutrients it needed to survive from that diet. But how then did it survive?

With a collaborator at the University of Arizona, Eisen sequenced the genome of a bacteria living inside the glassy-wing sharpshooter’s gut. Just as predicted, it turns out this bacteria produces the nutrients the sharpshooter needs. “Not only is this really cool biologically,” says Eisen, “but in terms of attacking the sharpshooter, now we have a target.”

Such a target, he explains, is significant because instead of spraying chemical insecticides all over California to kill the insect, a specific antibiotic might be developed to attack the bacteria living inside the sharpshooter’s gut. This kills the sharpshooter, while at the same time reducing the risks to people and other insects posed by the more toxic insecticides.

In addition to finishing this work, Eisen is studying communities of microorganisms, including ones in humans. This work relates to human intestinal transplants for people suffering from severe Crohn’s disease or irritable-bowel syndrome—people who are going to die without the transplant. Many of these transplants aren’t working out. One suspicion for their failure is that the sterilization of the organ in preparation for the transplant kills off the microorganisms needed for the human gut to function. Eisen will be developing model systems to figure out how these microbial communities form and function, in the hopes of solving this problem and helping to make transplants work.

Like Pollard, Eisen is at the Genome Center in part because of its unique setup. “The idea is better than anything being done at any of the other places in Northern California,” Eisen says. “I like the idea of bringing together people from different fields that all believe in technology-driven science,” he says, quickly adding, “Science is the key word there.”

Eisen views this new approach as needed for the transition phase now underway in biology. “You can view this as sort of the equivalent of when all the explorers left Europe in boats and went to every possible continent and island and found all these animals and plants. They were basically discovering the organism list for the planet. We’re basically at that phase with the molecular underpinnings of organisms now. We’re mapping the terrain.”

All this molecular mapping has opened up a possibility that even the bravest of the old explorers couldn’t have imagined. On a recent November morning, the Genome Center hosted a talk by Pamela Silver, the director of the Harvard University graduate program in systems biology. The title of her lecture points to a current trend in biology that suggests an even more radical transformation of the field: “Designing Biological Systems.”

In just a few years, the idea of using this newly discovered molecular data to create novel life forms or create new capacities in existing life forms has swept through biology as the latest thing. It already has a name: synthetic biology.

“There’s a kind of convergence going on between genomics, molecular biology and nanotechnology,” explains Griesemer, who is researching this emerging field. “I wouldn’t be surprised if 10 years from now chemists were able to synthesize living beings that are completely artificial.”

Among potential applications, Griesemer mentions “a tiny machine that worked as a monitor for biomedical purposes. If you could build little sensors that could circulate around the body and detect events that are potentially harmful or even clean things up, wouldn’t it be great?”

Michelmore hopes to fill one of two remaining Genome Center vacancies with a synthetic biologist. “Synthetic biology has a long way to go,” he says, “but has a lot of potential. If you can construct standardized components that have a predictable performance, can they be put together to provide novel biological functions in the context of a living cell? That’s an area I’m particularly interested in.”

Michelmore restrains himself from suggesting possible synthetic-biology targets that lie outside his field of research, such as biomedical monitors inserted in the body. But pressed to provide an example of a goal that a lay person might understand, Michelmore mentions bio-energy. “Clearly bio-energy is a big deal right now,” he says. “I’m quite sure that some of the technologies we have here will help in those investigations.” With plants’ renewable energy source as a biological model, Michelmore is suggesting that such a system potentially could be synthesized and incorporated into cells to serve as an alternative to fossil fuels. “There’s certainly a number of challenges,” he says. “But I don’t think they’re insurmountable. I think we’ll have a big impact in an eight- to 15-year time frame.”

Michelmore is aware of the concern about the risks that might come from synthesized life, as is Griesemer. “Because living things can undergo processes of evolution by natural selection,” Griesemer explains, “if you create new forms of life, they’re going to be evolving by natural selection. But we won’t know anything about them.”

If such unintended effects pose a risk, Eisner foresees other types of potential harm. “It certainly seems like people could use it for terrorism, theoretically,” he says. “But I don’t see that they would do that rather than just getting anthrax from the soil, because that would kill a lot of people and you don’t need any money.” Eisen also mentions the possible accidental release of a synthetic microbe. “There’s no doubt that someone’s going to make some bacteria in the lab that’s going to get out and attack some crop plant or degrade the plastic in electronic wiring or something. It’s just clearly going to happen, because bacteria can do lots of stuff as it is. Whether or not it has a Frankenstein effect or is just annoying is hard to predict.”

Out of such concerns, Eisen is part of a group, funded by the Department of Defense, now trying to figure better methods for detecting when people try to do bad things with synthetic biology. A major report on the risks and benefits of synthetic biology, funded by the respected Alfred P. Sloan Foundation, also is due out in the next few weeks.

But even with such risks, Eisen is tremendously hopeful that synthetic biology can speed up our understanding of how the complex molecular networks of a living cell work. “We’re at that point in biology where we see all these things happening in a cell but we don’t understand why or how. We don’t know the rules of the game. Synthetic biology is a tool that can test everything and help us figure out those rules more quickly and more easily.

“We now have the tools to study everything that’s going on. A lot of thought and experiments are still required. But we’re at the transition phase where you can actually answer questions.”