By Meredith W. Salisbury
To this day, Dick McCombie remembers the sinking feeling he had as he checked, day after day, the post office box he had rented. The registration deadline drew closer and closer — still no responses. “What do you do,” he thought at the time, “at a meeting where nobody comes?”
It was 1989, and he and Craig Venter were planning the first Genome Sequencing and Analysis Conference, which was held at Vienna, Va.’s Wolf Trap Farm Park. An NIH grant covered hotel costs and even some traveling money for speakers.
Obviously, McCombie’s fears were never realized. Some 90 people showed up for the meeting, which in retrospect was a Who’s Who of sequencing. McCombie pulls out a photo from it and ticks off the people he recognizes: Senator Pete Domenici, who was one of the speakers; Venter; Jack McConnell; Jim Watson; Mike Hunkapiller; Sydney Brenner; Bob Waterston; John Sulston; Walter Gilbert; and Claire Fraser. Talks at the conference were along the lines of, “We think we’re going to sequence this cosmid, and we’re hoping to be done by next year,” McCombie recalls.
Today, McCombie, 48, is a professor at the Cold Spring Harbor Laboratory, where his reputation as one of the founding figures of genomics continues to grow. He’s also in a joint program with Stony Brook and Brookhaven, and he gives lectures at New York University.
“He has that vision,” says Rob Martienssen, a colleague at Cold Spring, who has collaborated closely with McCombie over the years. “He knows what’s important and how to get there.”
Never Boring
W. Richard McCombie — who never goes by William, also his father’s name, “because my mother wanted unambiguous yelling possibilities,” he jokes — had no doubts about his path as a scientist. After growing up in Michigan and Ohio, he headed to Indiana to attend Wabash College, where he so loaded up on science classes to finish his biology degree along with minors in physics and chemistry that at one point he had seven labs in a semester. “There’s not a whole lot else to do in west-central Indiana in the winter,” he laughs.
After finishing up in ’77, he pursued graduate work at the University of Michigan, where he met his wife. A postdoc at the University of Texas at Austin got him interested in working with bacteria as an energy source, so he went to Phillips Petroleum in Oklahoma for a couple of years in the late ’80s and worked on “high-level, heterologous gene expression.” The work he did there, including some vector development, is now sold by Invitrogen with its yeast expression system.
Throughout his research, McCombie realized his own interest lay in working on completely new concepts. “I always looked for organisms that didn’t have a standard toolkit with them,” he says.
Phillips halted McCombie’s research in a biotech cutback, offering him a non-research position elsewhere in the company. “It was one of those really great things,” he says. “It gave me a kick to get me moving.”
And finally, McCombie knew what he wanted to work on: neurobiology. He wound up in 1988 as a senior staff fellow in Craig Venter’s section at NIH, “primarily to clone and overexpress neurotransmitter receptors so they could be crystallized for study.”
Long story short, no one ever got the crystallization project to work. But in the meantime, McCombie got sucked into the sequencing projects Venter’s lab was plugging away on — he learned from Claire Fraser how to do mammalian tissue culture — and unexpectedly found that genomics was exactly the uncharted terrain he’d been looking for. “It was exciting, it was frustrating, it was never boring,” he says.
The sequencing work was nothing if not challenging. There were two heavy projects in particular that totaled to some 200 KB. “When you get 200 KB, all of a sudden we looked at the sequence and it really hit me that I had no idea what to do with this,” McCombie says. The research had been going on for nearly two years and was so consuming that he remembers one day staying at the lab so late and heading back in after a quick rest at home that he got stuck twice in the same DC morning rush-hour traffic.
Fission Visions
By then, McCombie’s NIH days were almost over. He was already looking at other opportunities when Venter left for TIGR, offering McCombie a position with him at the new institute. Most of Venter’s lab made the migration, but McCombie had always wanted his own lab, so he declined.
He seriously considered an industry-side offer, but in the fall of ’92 chose Cold Spring Harbor, where he would get his lab with the mission of sequencing fission yeast. One problem, though, was the inherent conflict in getting genome grants with Jim Watson heading up both NHGRI and Cold Spring Harbor. And ultimately, McCombie says, fission yeast was never given priority — he worked on it a little, but most of the sequence was done in Europe.
But if McCombie had done fission yeast, he might not have been available to work on Arabidopsis in collaboration with Washington University, which was one of the projects that made him so well known in the genomics field. McCombie, an avid photographer still proud that his nighttime-blizzard shot made it into the Cold Spring annual report, became director of the lab’s sequencing center. Under his stewardship, the center worked on bits of the human genome as well as major efforts in mouse and rice.
His plant work, in which he worked with Martienssen, also led to a new concept: removing methylate DNA for improved sequencing. That became the basis for Orion Genomics, a St. Louis-based ag genomics venture started by McCombie and Martienssen of Cold Spring and John McPherson and Rick Wilson of WashU.
Meanwhile, McCombie had been one of the people noticing the grumblings about lack of science at GSAC meetings. “I remember saying, ‘Why don’t we have our own meeting?’ and people started saying, ‘I’ll put money up for that.’” He remains on the board of directors for the Advances in Genome Biology and Technology conference at Marco Island, known in some circles as the “anti-GSAC.”
“He’s a remarkable guy,” Martienssen says. “What’s really striking about Dick is he’s very innovative — the first to do a number of things,” including working on the first large-scale EST. “What he’s doing now is he’s developing finishing strategies … to finish genomes without necessarily having the templates,” Martienssen adds. “As he likes to say, ‘We led you into this quagmire, now we have to get you out.’”
Indeed, McCombie sees the genome as a starting point. The new challenge is to figure it all out: that’s why his lab is shifting to experimental validation, combining computational work with wetlab experiments. As he thinks about comparative genomics, figuring out gene function, and continued technology development, McCombie says, “I’m actually more excited about the field than I have been in a while. I think it’s getting ready to take off into some interesting directions that we don’t even know what they’ll be.”