|Claire Fraser '77
Photograph by Manuello Paganelli
By Ricki Lewis
When she was 5 years old, playing housewife in a friends mini-kitchen, Claire Fraser 77 could scarcely have imagined what she would be when she grew up. Of course, genome sequencer was not exactly a career option back then, or even just a few years ago. But since 1995, Fraser has led efforts to discover the complete genetic instructionsthe genomesof an eclectic collection of species, including a frightful list of human pathogens, several laboratory darlings, and microorganisms that lie at the crossroads of evolution.
While the sequencing of the human genome has dominated the headlines, the much bigger picture revealed in the other genomes is what excites life scientists, earning the fledgling field of genomics Science magazines breakthrough of the year designation for 2000. Fraser, a graduate of the Class of 1977, credits her years at Rensselaer with turning her on to research. And in a way, her current work in genomics harkens back to her microbiological investigations then.
Today, Fraser is president of The Institute for Genomic Research (TIGR), a not-for-profit organization headquartered in Rockville, Md. The lobby and hallways at TIGR impart an ambiance of serious science mixed with fun, with tiny stuffed tigers perched on decorative plants. The walls boast framed journal covers and spectacular posters depicting sequenced genomes, color-coded annotations categorizing key genes by functionmetabolism, biosynthesis, acquiring energy, and responding to signals. Prominent hatched areas in each genome denote genes whose functions remain to be filled in. Upstairs, the framed certificates outside Frasers office are not the usual advanced degrees of the research scientist, but the obedience school diplomas of Shadow, Cricket, and Marley, three beloved standard poodles who share the area.
At TIGR, powerful computers decipher the sequences of adenine (A), guanine (G), thymine (T), and cytosine (C), DNA building blocks that comprise genomes. Sections of the sequencegenesencode proteins, which in turn provide the functions of life. Specifically, contiguous triplets of DNA bases spell out the amino acids of particular proteins. This correspondence constitutes the genetic code, discovered in the 1960s and shared by all life on Earth. Until now, the century-old science of genetics has focused on such single genes. But genomics is an entirely new way of looking at life as a dynamic, complex interplay of molecular rules. Within genome sequences lie clues to the evolutionary past, as well as the secrets to what it takes to be alive.
Genomics will be revolutionary, changing the way we approach basic biology, medicine, agriculture, and other areas, says Fraser.
Fraser has for the most part remained quietly behind the scenes of that revolution, while her husband, J. Craig Venter, founder of TIGR and nearby Celera Genomics Group, has held the limelight for his leadership in sequencing the human genome. But Fraser is a powerhouse in her own right. And if it werent for Rensselaer, she might not be where she is today. For it was here that she was bitten by the research bug.
Genomics is an entirely new way of looking at life as a dynamic, complex interplay of molecular rules. Within genome sequences lie clues to the evolutionary past, as well as the secrets to what it takes to be alive.
The Rensselaer Years
Studying the insides of a frog in biology class started Fraser on the road to a career in the life sciences. In high school in a Boston suburb, she took every science course offered and, in those days before biotechnology, anticipated pursuing biology by way of medicine.
Throughout high school and most of college, I thought Id go to medical school. I didnt know anyone in science, Fraser recalls. She applied to several bachelors degree/MD programs, selecting the one that Rensselaer and Albany Medical College offered. She was actually on their waiting list, and planned to enroll at Rensselaer and switch to the MD track by the end of the first year. But it was not to beshe was having too much fun as a biology major
Course offerings werent all that Rensselaer held for the budding scientist. Of equal if not more importance was that I had felt like an outcast in high school, because it wasnt cool to be a woman taking so many science courses. I wasnt part of the popular group, and at that time that was still important to me. I felt very isolated. But when I came to RPI, everybody was interested in science or engineering! I felt extremely comfortable right from the beginning.
By her senior year, Fraser found another reason to love Rensselaerresearch.
Senior biology majors had two optionsto take an advanced laboratory course, or to conduct independent research. The instructor for a favorite microbiology course invited Fraser to work in the lab where he was a postdoctoral researcher, run by Lenore Clesceri, now professor emeritus of biology. Fraser, who had not seriously thought about doing research, accepted. I was really excited, because it wasnt like doing canned lab exercises, she recalls.
The focus of the research was Lake George, where runoff from fertilizer and pesticides was causing eutrophication, choking the lake with algal blooms. We took soil and water samples from various points around the lake. It clearly had problems. We were looking to see if we could find isolates of one or more bacterial species with an ability to survive in the lab on fertilizer or pesticide as their sole carbon source, Fraser relates. Each student was assigned a contaminant; Fraser drew Atrazine.
Once the sampled microorganisms were growing well in the lab, the investigators would increase the concentration of the pollutant under study, and see which microbes would survive. That was 23 years ago, and it was the beginning of the whole idea of bioremediation, to identify organisms that can grow under conditions like those of the lake, then put them back into the lake to accelerate the degradation of pollutants. That is exactly what the Department of Energy is doing today, she adds.
But their tools were positively archaic by contemporary standards. Now, rather than isolating bacteria in the field and consulting Bergeys Manual of Systematic Bacteriology to identify the species, we look at it through whole genome analysis, she explains.
The sense of fun that Fraser would eventually bring to TIGR was already apparent in the Rensselaer lab of her senior year. Recalls Clesceri, Some students you really enjoy having in the lab. Others, it really doesnt make much of a difference whether they are there or not. Claire came in with her friends, and we had such a nice year. The enthusiasm she displayed was infectious.
Despite the camaraderie in the lab, Clesceri had no idea that the experience was profoundly influencing her protege. Students come to college with a limited view of life after college. Medicine is a clear-cut path with which they are familiar, but they are not able to experience research beforehand. Claire came back last year to lecture. I hadnt seen her in 20 years, and she came up to me and said, Dr. Clesceri, you changed my life!
After College, Whats Next?
Like many a biology major circa 1977, Fraser sent off her applications to medical school. But already she was having second thoughts. In early spring, I had this horrible sense that medical school would be a dreadful mistake, because I was so enthralled with research. I went into a panic. I didnt know where to go, what to follow up on, she recalls.
Once again, the mix of scientific calling and social needs surfaced. Fraser found a guidebook to graduate programs in biology and began to search for her future, with the stipulation that she stay geographically near the man she was dating, who was headed to Toronto. She laughs now when she looks back at that time, but it must have been a wrenching decision.
I was torn between seeking a top graduate school and finding a place close to him. I remember telling the director of graduate admissions at Yale, after Id been admitted, that I would be going to SUNY Buffalo instead, and why. He said, Well young lady, I hope you know what youre doing.
At Buffalo, Fraser worked on receptors for neurotransmitters. Soon after arriving, she met a young assistant professor, a biochemist named J. Craig Venter. The Toronto relationship became history, and they married in 1981. We went to a meeting for our honeymoon, and wrote a grant proposal there, Fraser recalls wistfully.
After earning her Ph.D., Fraser worked in Venters lab, continuing to investigate neurotransmitter receptors in rodents. Then in 1984, they both relocated to the National Institutes of Health (NIH) in Bethesda for intramural research positions, where they taught themselves how to sequence the genes that encode receptor molecules. The seeds were being sown for genomics.
We saw how time-consuming and subject to error manual DNA sequencing was. Applied Biosystems was developing the first automated DNA sequencers, and Craig was the first test site. He became very interested in sequencing at a much larger scale. This was also the time of formulation of the human genome project strategy, Fraser recalls.
Meanwhile, she continued her work matching receptor combinations to differing responses to alcohol exposure, and by 1989, headed an entire research section. Fraser and Venters professional interests were and remain both complementary and synergistic: He finds ways to do things faster and better, while she probes the basic mechanisms of life.
It wont lead to any immediate miracle cures, but will instead provide information that will, eventually, change the face of medicine. Genomics promises to personalize treatment of infectious disease, cancer, inherited disease, and common illnesses.
Of NIH, ESTs, and TIGR
By 1990, Venter invented a powerful shortcut to identify genes of interest without having to sequence entire genomes. Expressed sequence tag (EST) technology zeroed in on the DNA sequences that encode protein, and therefore determine an organisms characteristics. By 1992, use of the technique had doubled the number of known human genes to 2,300. While the NIH began filing patent applications for ESTs, in the hopes of eventually mining genes relevant to human health, venture capitalists tried to entice Venter away from the NIH. He resisted at first, Fraser recalls, but they both began to realize that they would have more freedom away from the government.
And so TIGR was born on July 6, 1992, with an infusion of $70 million from HealthCare Investment Corp. Inc. At the same time, Human Genome Sciences (HGS), located a few miles away, formed. HGS would commercialize TIGR discoveries. For the first two-and-a-half years, all of TIGRs efforts went to a handful of people looking for therapeutic human ESTs, Fraser says. By 1995, TIGR researchers, with Venter at the helm, had amassed 170,000 human ESTs, a rich vein to tap for drug discovery.
But Fraser grew frustrated with turning over most of her receptor discoveries to HGS. She feared that the association with HGS, which would eventually end, gave the impression that TIGR was a business, rather than a nonprofit research institution. She and Venter started to form a different vision, a broader one that transcended the focus on humans and which would lead to tackling entire genomes.
It started with a conversation between Craig and Hamilton Smith, who was then at the Johns Hopkins University School of Medicine. Smith won the Nobel Prize for identifying restriction enzymes in Haemophilus influenzae. He was interested in computational aspects, Fraser says. Granger Sutton at TIGR had developed software to sort out the redundancies among individual gene sequences, and Smith thought the same approach could be expanded to sequence entire genomes. They could shatter several copies of a genome, then overlap the pieces where the sequences align to reassemble the whole.
Tremendously excited, Venter sought NIH funding to use the approach to sequence the genome of H. influenzae, a well-studied bacterium that causes childhood meningitis and ear infections. NIH trashed the proposal! They thought it was ludicrous, it couldnt be done, it was full of holes, recalls Fraser, adding that, years later, the very same people dismissed Venters claim that he could use the same strategy to sequence the human genome. By 1995, TIGR had indeed bagged the first genome, without the help of the NIH.
The genomics game was off and running. And Claire Fraser found herself back in microbiology.
Asking a researcher to choose a favorite genome is like asking a parent to choose a favorite child. Venter, after a moments thought, mentions Deinococcus radiodurans, the bacterium that can stitch together DNA fragmented by 3,000 times the radiation dose that would kill a human. Many biologists would pick Mycoplasma genitalium, whose tiniest of genomes places it on the boundary of what is alive and what isnt. Some of the genomes sequenced at TIGR hold clues to such human illnesses as Lyme disease, syphilis, peptic ulcers, cholera, and Legionnaires disease.
Claire Fraser cant pick a favorite. There have been lots of surprises. Each time we delve into a genome, we find something quite exciting, she shares. Her attention today, though, is riveted on a cousin of the malaria parasite that is having devastating effects in Africa.
Theileria parva is a tick-borne menace that causes a swiftly fatal leukemia-like illness in cattle called East Coast fever. Sequencing its genome is letting Frasers humanitarianism show. On a recent trip to Kenya, Fraser stayed long enough to get a true picture of the extent of the problem. Im glad I had the opportunity to visit the people. It is too easy to lecture and take a safari and get a sanitized view, just enjoy the scenery. Coming face to face with poverty was a profoundly moving experience, she says.
East Coast fever decimates whole herds. The disease kills more than a million cattle in 11 African nations each year, causing staggering financial losses. But it is at the family level that the impact of the disease really struck Fraser. Their entire livelihood depends on their cattle. The people are looking starvation right in the face, she relates.
The organisms genome sequence will reveal new proteins that can serve as the basis of a vaccine. Previous attempts have been stymied by the fact that many of the parasites key proteins are inside cells of the immune system and not detectable. The International Livestock Research Institute (ILRI) in Nairobi and Venters $100,000 King Faisal International Prize support the project; U.S. government agencies were not interested when Fraser approached them in 1999.
Another recent accomplishment is the sequencing of the genome of Arabidopsis thaliana, for which TIGR was part of an international consortium. The tiny relative of broccoli and cauliflower is essentially the lab rat of botany. Within its sequences of A, C, T, and G, researchers are seeking clues to how plants and animals diverged some 1.5 billion years ago. Patterns within the genome may speak volumes about evolution. Explains Fraser, Perhaps close to 60 percent of the genome is the result of gene or genome duplication. We traced it back to a possible precursor genome that was duplicated and rearranged to yield the five chromosomes that exist today.
A more immediate outcome of the Arabidopsis project is the sense of cooperation that evolved as researchers realized that the competition common in science was no longer appropriate. Genomics has changed the face of biology. The level of science going on now cant ever be done by one or a few individuals. Very territorial scientists had to come together in the most wonderful way, for an international collaboration. Many different disciplines are working together, learning each others language, says Fraser.
The Impact of Genomics on Health Care
Although the number of genomes sequenced at TIGR exceeds two dozen, with other research groups around the world contributing more, the general public is, naturally, most interested in the human genome. How will knowing the sequences of DNA bases nestled in the nucleus of a human cell improve lives? It wont lead to any immediate miracle cures, but will instead provide information that will, eventually, change the face of medicine. Genomics promises to personalize treatment of infectious disease, cancer, inherited disease, and common illnesses.
Instead of treating symptoms as other patients have been treated, a genomics approach will make possible not only a very specific diagnosis, but a prediction of how a person will respond to a particular treatment. Fraser offers an example of this new paradigmher fathers experiences with infections related to diabetes. One time, my dad developed a systemic infection through a break in the skin. Was it strep? Staph? Nobody could find the antibiotic sensitivity of these organisms. A couple of times he ended up with infections that were methicillin-resistant Staphylococcus aureus, and hed spend a week on intravenous methacillin, when it wouldnt work. It was frustrating how limited his care was because of insufficient information.
Treating hypertension is another example of how genomics information can target and shorten treatments. Standard drugs are given to everyone, including diuretics and beta blockers. But these dont work for all. It is a waste of time and money to keep going to the next line of treatment until they stumble upon something that works. It is an empirical process not based on knowing anything about the particular patient, explains Fraser.
Genomics will also be important in preventing adverse drug reactions, the fourth leading cause of death in the U.S. Fraser turned down taking a once-a-week anti-malarial drug for her recent Kenya trip because of a possible severe side effect, opting instead for a five-week regimen of an older, better-studied drug. Eventually, shortcut genome maps based on variable DNA bases in a populationcalled single nucleotide polymorphisms, or SNPswill reveal who will react dangerously to particular drugs.
A New View of Biology
It might be 10 years before enough disease-causing genes are described, and SNP maps generated, for genomics to noticeably affect routine medical practice. In the meantime, genomics has opened up an entire new world for biologists to explore. Ironically, the genome sequences revealed so far show how little we really know.
In his 1966 book Of Molecules and Men, Francis Crick, co-discoverer of the structure of DNA, wrote that once we knew all of the genes of an organism, such as a simple bacterium, we would understand how life works.
It was not to be. Much of each genome sequenced still remains a mystery; witness those hatched areas on the posters along the halls of TIGR, genes that have no known counterparts among other species. The idea that, once you have a sequence, you will also have brilliant insights just isnt true, Fraser says. Yet, at the same time, sequenced genomes indicate that organisms can get along on very streamlined genetic instructions. A yeast cell functions using a mere 6,000 types of proteins, a fruit fly 13,000, and a human just about 40,000.
What can it all mean? How can scant blueprints embedded within reams of what appears to be genetic gibberish encode something as complex as life? By comparing genomes to discover what they share and how they differ, researchers are beginning to glimpse how life has diversified.
Each genome is like a little bit of recorded history of evolution. We see a continuum from species to species; were not all that different. Yet each genome is different, and interpreting the differences will be a real challenge, says Craig Venter.
The clues are being laid out, genome by genome. Over evolutionary time, some starting set of instructions written in DNAburied in the genomes of organisms living todayhas been copied, expanded, and modified in millions of variations. And Claire Fraser, who had her first taste of research at Rensselaer, is at the forefront of this new biological science that is deciphering the mysteries hidden within genomes.
Ricki Lewis is the author of Human Genetics: Concepts and Applications, in its fourth edition (McGraw-Hill Higher Education, 2001), and other textbooks. She is a contributing editor to The Scientist. She has a PhD in genetics.