UW lures famed researcher to lead genomics efforts
When Mark McGwire hit his 70th—and final—home run of the 1998 baseball season, Philip Ozersky was in the right place to make the catch. Traveling at 115 miles per hour, the ball caromed off the wall of the left-field Bullpen Room in St. Louis’s Busch Stadium. Ozersky played the ricochet, diving under temporary bleachers to grab the record-breaking souvenir and later auctioned it off for $3 million.
Even though his catch was like winning the lottery, Ozersky did not retire to an exotic South Sea isle to live off his millions. Instead, the St. Louis native went back to work for someone named Bob Waterston.
“It’s not like I could have gone to live in my own little island anyway, but it never crossed my mind not to return to the sequencing center. The work is so important, and the people who run this place are so good to work with, that it was a pretty easy decision to return,” the millionaire says.
This lucky Cardinals fan even now continues his work as a research technician in the sequencing laboratory at Washington University in St. Louis where scientists mapped parts of the human genome. And although the media went ga-ga over McGwire’s home run, the real record breaker came two years later, when Ozersky’s boss, Robert Waterston, and other leading scientists in the United States and England announced they had mapped the basic code to human life. Waterston and his collaborator, John Sulston, had become the Wright Brothers of sequencing—developing methods and organizations to sequence the human genome, all the while insisting that any member of the public should be able to access its mysteries via the Internet.
The promises of the human genome are astonishing—a cure for cancer, and antidote for aging, a test for predicting future maladies such as heart disease. But the genome sequence is data, not cures. And it is not at all clear how science and medicine can get from all this data to something you can pop in your mouth.
In January, Waterston said goodbye to St. Louis, Busch Stadium and his genome sequencing laboratory. He left Washington University to hold the William Gates III Endowed Chair in Biomedical Sciences and to become the first chair of the Department of Genome Sciences in the UW School of Medicine. At the UW, Waterston is being reunited with two other genome pioneers from his St. Louis days—Maynard Olson and Philip Green.
“Bob was very farsighted at a time when some people did not think genome science was real science.”
James Watson, Nobel laureate
How Waterston became a leader in the world of genomics—and how he landed in Seattle—involves twists of fate almost as lucky as Ozersky’s catch. If he hadn’t overstayed a summer sabbatical on Cape Cod (to the chagrin of his thesis adviser), if overcrowding at an English research center hadn’t sent him into another lab, if he hadn’t taken an offhand comment seriously—he might not be one of the top genetic scientists in the world and now welcomed to the UW.
Born in September 1943, Waterston grew up in the suburbs of Detroit, where he met his future wife, Pat, in ninth grade. He graduated from Princeton University in 1965, playing both basketball and football (and meeting future NBA star and U.S. Sen. Bill Bradley on the court). His college major was engineering, but in his senior year, Waterston decided he wanted to be a doctor.
While in medical school at the University of Chicago, Waterston decided to embark on a simultaneous Ph.D. track. He was fascinated by the basics of biology, and the underlying reasons for the development of traits and illnesses. “Most of my medical lectures would leave off just when they were starting to get interesting,” he says.
Waterston took an influential summer course in 1969 at Wood’s Hole, Mass., that would determine the course of his career. Scheduled to spend six weeks there, another researcher convinced him to stay for the other half of the summer (“My thesis adviser had thought this whole thing had been a lark, and just about killed me when I stayed,” he recalls.) But there was a happy ending. The guests for the second half included Sydney Brenner, a godfather of genetic studies. (He and colleagues discovered messenger RNA and he later won the Nobel Prize for his work on the genetic basis of organ development and cell death.)
“He would spellbind us every day,” Waterston says. “And this was the first summer he was talking publicly about his C. elegans work.” C. elegans is the Latin name of a tiny nematode worm that scientists study for its biological parallels to humans. Among other things, a lot can be learned about muscle from studying C. elegans. This worm would turn into an obsession for the new doctor.
Genetics pioneer Robert Waterston (left) explained some sequencing equipment to Rep. Richard Gephardt, former Democratic leader in the U.S. House of Representatives, when Gephardt visited Waterston’s lab in St. Louis. Photo courtesy of Washington University in St. Louis.
In 1972, Waterston graduated with a rare commodity: separate but simultaneous M.D. and Ph.D. degrees. After graduation, Waterston went to England for postdoctoral studies with Brenner and his worm.
Four years later, Waterston joined the faculty at Washington University in St. Louis. Already interested in genetics, he served on a committee that recruited a young geneticist, Maynard Olson.
“I was already interested in the idea of making a map of the yeast genome, which at the time was thought to be a bit wacko—but Bob was very interested,” Olson recalls.
In the early ’80s, Olson proved that his ideas weren’t so “wacko.” He created a physical map of the yeast genome by cloning overlapping fragments of DNA. His team invented revolutionary methods to do the work—methods that later served as an underpinning of the Human Genome Project itself.
Meanwhile, Waterston developed a successful laboratory in muscle research studying his nematode worm. He later went back to England with the goal of finding a new class of muscle genes. Once again, fate played a role. The traditional worm group did not have space for him, so they found him a space with John Sulston—now Sir John Sulston, and a winner with Brenner and Robert Horvitz of the 2002 Nobel Prize in Medicine. When Waterston arrived, Sulston was immersed in genome studies of C. elegans.
“He wants to change the world—like a lot of us—but unlike a lot of us, Bob is very good at it.”
Mark Johnston, researcher at Washington University in St. Louis
Waterston saw that Sulston had problems cloning the worm’s DNA and remembered that Olson’s lab in St. Louis had an answer. So he began working on Sulston’s project. When he returned to St. Louis, Waterston began applying Olson’s answer to Sulston’s problem. The results were excellent, and Waterston was now fully off on another track. Besides becoming a muscle scientist, he was now a genome scientist.
That was not such an obvious choice back in the 1980s, when DNA analysis was far more tedious and laborious than it is today. It represented a deliberate risk for someone who was already a successful muscle researcher. Some scientists debunked the effort to capture the human being’s genetic code. One letter to the editor in Nature said the idea was like trying “to excavate the entire country of Kenya to a uniform depth of six meters (to look for) for hominid fossils” and concluded that “any biologists who proposed such projects would doubtless be obliged to carry them out in a padded laboratory.”
Padding was not necessary for the laboratories where Sulston, Waterston and another English collaborator, Alan Coulson, labored to produce a complete physical map of the worm’s six chromosomes. In 1989, at a gathering of worm researchers, Coulson taped up a map of the worm genome that stretched along the back of the auditorium. The map ran about 40 sheets wide—held together by Scotch tape—with six rows, one row for each chromosome. The map represented an organism whose genome—the length of all its chromosomes—is 97 million base pairs of DNA.
Attending that meeting was Nobel Laureate James Watson, who in the 1950s, along with Francis Crick, discovered the helical structure of DNA. Watson was organizing efforts in various labs to map other organisms—including the human—in a project that would later be known as the Human Genome Project. Looking over their work, he became convinced that these were the men who would be able to sequence the human genome.
“It never occurred to me that they could fail,” Watson says in retrospect. “Bob was very farsighted at a time when some people did not think genome science was real science. Bob is very intelligent and very focused. Bob gets the job done.”
Waterston had mixed feelings about the project. “Muscle is a very fine field and someone else could do the sequencing,” he remembers thinking. “But it was clear there had to be a U.S. component, and because of my work on the map, I was the logical fall guy.”
Joining the team in St. Louis was Philip Green. Green was “incredibly important” to the Human Genome Project, Watson says, in part for developing computer programs still used for sequencing DNA.
Ultimately, the sequencing center at Washington University would run machines 24 hours a day, with a staff of 300. The center played key roles in the sequencing of the worm, yeast, human and, in the winter of 2002, mouse genomes.
Throughout the process, Waterston has been among those who have demanded that the data be publicly available and easily accessible for researchers around the world, without cost. In 1998, a private company, Celera, announced plans to sequence the human genome. To make back its investment, it decided to charge for access to the human genome sequence.
The challenge to public access led to a “ramping up” of the government effort. At about this time, fate entered again. In the late fall of 1998, Waterston was diagnosed with colon cancer.
“This happened at about the worst possible time,” Waterston says. He had a course of radiation and chemotherapy before a successful surgery in April 1999, just as the sequencing effort was reaching its highest gear. While convalescing at home, Waterston set up a “mini-office” and stayed in touch via conference calls. Sulston says: “As so often before, Bob dwarfed everyone with his sheer ability to cope.”
But while Waterston set aside time to recover, he also continued his work. “Part of me felt I should not give in,” Waterston says.
“Bob recognized that there was a threat to the public availability of the human genome sequence, and he adjusted accordingly,” says Marco Marra, a Waterston protégé who now directs the sequencing center at the University of British Columbia. “He did what he could to increase the speed on both sides of the pond. He accepted it as a challenge.”
While Waterston served as head of the Department of Genetics at Washington University School of Medicine, as well as director of the school’s Genome Sequencing Center, his colleagues started leaving for the West. Olson and Green both came to UW in the early ‘90s, when then-UW Professor Leroy Hood was organizing the Department of Molecular Biotechnology.
As the century turned, that department and the Department of Genetics merged into a new Department of Genome Sciences. Waterston would have been a dream candidate as its first leader, but he seemed firmly in place in St. Louis.
His road to UW partly began with good luck and impulsive conversation. Green was in Washington, D.C., on a scientific trip in the summer of 2001. He went out to dinner with Waterston and other old friends. Waterston did not know about the opening at UW; somebody else asked Green how the search for a chair was going.
“I said we were still looking. I turned to Bob and asked if he was interested. I told him he should apply,” Green says. And they left it at that.
“Phil was smiling, but of course, Phil would always smile,” Waterston says of the conversation. “But I did not forget what he said.” Eventually the UW was able to lure him away and in January he started his new job as genome sciences chair.
Olson feels Waterston is perfect for the role. The new Department of Genome Sciences includes people with expertise in model organisms, data crunching and medical research. Olson notes that Waterston bridges all those groups—for example, his model organism experience includes the worm, he writes computer programs himself, and he’s got an M.D.
“This is a wonderful constellation of brilliant people who have already proven to be very compatible with one another,” Sulston says.
“You have the nucleus of a powerhouse,” Marra says. He refers to Waterston as a legend among younger researchers. This raises a challenge: Could expectations be any higher?
Waterston says he’s not intimated. It’s a fresh chance to look ahead. “What matters is the work,” he says. “We’ll proceed the same way we did before—we’ll figure out what problems need to be solved tomorrow.”
One of Waterston’s former colleagues in St. Louis, Mark Johnston, says the consolidation of the UW departments provides a great opportunity. “It will be led by one of the three or four people who you can truly say marshaled in a revolution,” says Johnston. “Bob is very driven. Bob sees the direction where biology is going. He wants to change the world—like a lot of us—but unlike a lot of us, Bob is very good at it.”