A Genome Project against Disease

Claire Fraser is changing germ fighting in the 21st century

In the four years she has led The Institute for Genomic Research (TIGR), Claire M. Fraser and her colleagues have decoded and analyzed the genes of bacteria that cause anthrax, Lyme disease, syphilis, tuberculosis, cholera, meningitis, pneumonia, ulcers, and many others. The work has put TIGR at the forefront of the new field of microbial genomics--the foundation for the treatment and prevention of disease in the 21st century. "In terms of microbial sequencing, the world leader is still TIGR," says Julian Parkhill, head of microbial sequencing at the other leader in the field, the Wellcome Trust Sanger Institute in Cambridge, England.

Numbers tell the story. Researchers around the world have decoded and published the genes of some 65 microbes; TIGR, located in Rockville, Md., just outside Washington, D.C., is responsible for nearly half of them. The institute has posted an additional 20 on its Web site and is working on 40 more.

Fraser has received some public attention, most recently in May when she announced that TIGR had decoded the genes of the anthrax strain used in last fall's terrorism episode. But her public profile contrasts sharply with that of her husband, J. Craig Venter, who founded TIGR a decade ago. She took over TIGR in 1998, when Venter left for Celera Genomics Group, where he led its effort to decode the human genome and became one of the most visible scientists of the 1990s.

Fraser has focused TIGR's efforts on microbes, mostly those that cause disease. Such research is critically important in the quest to develop new drugs. Most current drug research is based on discoveries made in the last century, says Richard A. Young, professor of biology at the Whitehead Institute and Massachusetts Institute of Technology in Cambridge, Mass. "With complete genome sequences in hand, you can take entirely new approaches to most every problem that can be studied in biology today. The work that TIGR and others are doing is creating the foundation for these future studies."

TIGR has achieved its preeminent position with thorough research. It invests substantial resources in technology to extract and purify DNA and in the software to analyze the output of its DNA machines. "The quality of the DNA sequence that you generate on these machines is absolutely dependent on the quality of the DNA preparation you use," Fraser says. As a result, TIGR's machines are generating longer and cleaner DNA sequences than its competitors--and doing it at lower cost, she says.

TIGR has nearly doubled in size since Fraser took over. Its staff has grown from 170 to 325, including about 30 PhDs. The institute's annual budget--nearly all of which comes from competition for grants from the National Institutes of Health, Energy Dept., and National Science Foundation--is about $50 million this year, up from $24 million in 1998.

If public recognition has been slow in coming, scientific recognition hasn't. Fraser has published 130 papers and serves on numerous scientific committees, NIH review boards, and editorial boards. She is one of the few women to run a major research institute. That's more than most scientists achieve in a lifetime--and Fraser is only 46.

The daughter of a high-school principal and an elementary school teacher, Fraser was born in Boston and grew up in Saugus, a Boston suburb. Her early interest in science left her feeling like an outcast in high school, but that changed when she went to study biology at Rensselaer Polytechnic Institute in Troy, N.Y. "She had an unbelievable memory and had a passion for science and research," says Barry Martinelli, an RPI hockey player who dated Fraser for several years. "She'd go to the hockey games and go to the parties, and then go back and hit the books for 48 hours straight. Scientists tend to be very rigid. She isn't like that," says Martinelli, now associate director of athletics at the University of Western Ontario in London, Ont.

At RPI, Fraser discovered the joys of research. She went on to get a PhD in pharmacology at the University at Buffalo. There she met Venter, who was an assistant professor. They married in 1981, and worked together on the biology of so-called G protein-coupled receptors, which are involved in many biological processes. In 1985, they moved to NIH, in Bethesda, Md. Venter began to study genomes, while Fraser continued work on receptors. In 1992, Venter left the NIH to found TIGR. Fraser became the institute's vice-president and the director of its microbial genomics program.

TIGR's first major success came in 1995, when it determined the complete genetic sequence of a microbe called Haemophilus influenzae, a cause of ear infections and meningitis in children. It was a landmark--the first time researchers had deciphered the complete genetic code of a free-living organism.

Many had predicted the project would fail. The institute was testing a new and potentially faster method of deciphering genes--a process called shotgun sequencing. The idea was to blast the genome into a mountain of small pieces that would be comparatively easy to sequence--and then put it back together. That simplified the sequencing problem, but replaced it with the difficult challenge of how to reassemble the pieces. That problem was ultimately solved with breakthrough computer software developed by Granger Sutton, who came to the institute from Bell Laboratories. The sequencing of haemophilus, which Venter calls "the experiment that changed the world," gave him the confidence to apply the methodology to the human genome.

As Fraser began to decode the genes of more microbes, she made a profound discovery. Nearly all of the microbes' genomes contained a large store of unknown genes--making up about one-third of the organisms' genes. "That was the biggest shock," she says. "At that point, we gave up any notion that if we had all the genes, we'd know how something worked." TIGR and others are now working to determine the functions of these newly discovered genes.

TIGR's research has had few practical applications yet--it's early in the game--but one example suggests where it could lead. Scientists at the biotechnology company Chiron Corp. (CHIR ) contracted with TIGR--in one of the institute's rare non-public ventures--to decode the genome for Neisseria meningitidis, a cause of meningitis. Analysis of that genome led the company to new meningitis vaccines, which are now in development.

Fraser has little patience for formality or for hierarchy. The institute's organizational lines mostly run horizontally, not vertically. "There are no walls, no departmental barriers," she says. "We're what you might find in industry, where groups are formed to tackle a particular problem. And when the task is completed, the groups go away and new groups are formed." Teamwork is crucial to the institute's success. "We're not a good place for loners, people who are more comfortable doing traditional biology," she says. "This is large-scale biology, and that means people have to come together to solve problems."

Samir Kaul prospered under that approach. He had only a master's degree in biology when he joined TIGR to work on a project to sequence Arabidopsis thaliana, a mustard plant important in agricultural research. Despite his lack of a PhD, he was quickly promoted to project director. "They recognize talent, and they cultivate it," says Kaul, who left TIGR for Harvard Business School and has just joined a venture capital firm in Boston. "I worked a lot of late hours, and you do it because you don't want to disappoint her."

One of the remarkable things about Fraser's achievement at TIGR is that she draws the highest level of work out of her staff without the promise of stock options, bonuses, or sales commissions. TIGR is a not-for-profit institute. Because nearly all of its work has been funded by the government, its research results are freely available to anyone with an Internet connection.

Fraser's work has consumed much of the time that might have gone into other, non-professional pursuits. Venter has one child from a previous marriage, but she and Venter do not have children. "There was a time when it might have happened, and it didn't, and I don't regret that," she says. The demands of her work, she says, simply made it impossible for her to be the kind of parent she wanted to be.

She does have a few diversions. She shares her office with three poodles--Shadow, Cricket, and Marley--whom she loads into her Range Rover with her every morning and evening. Instead of displaying her degrees in her office, she has framed copies of the dogs' obedience-school graduation certificates. For the past six months, Fraser has supervised the restoration of a 19th century farmhouse she and Venter bought in Maryland's Montgomery County. "I have had a blast doing it. My disappointment is that I haven't been able to do more of the hands-on work myself. My father was a handyman, and I think I picked that up from him."

Several years ago, Fraser started to paint. She has mused about quitting and going back to school. "I'd like to relearn physics," she says. Or maybe chemical engineering, she adds. Or nano-technology, or interior design, or landscape architecture. Or, to put it another way, Fraser is one of those uncommon individuals with a broad intellectual curiosity about the world and how it works. That, more than anything else, may explain her success.

Corrections and Clarifications ``A genome project against disease'' (Science & Technology, July 1) misspelled Claire M. Fraser's name in a sub-headline and table.

By Paul Raeburn in Rockville, Md.

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