Rick Wilson can proudly claim to have been part of the breakthrough that led to the sequencing of the first human genome. In fact, Wilson's genome center at the Washington University School of Medicine helped provide more than a quarter of the sequence data for the Human Genome Project.
Prior to that, his lab also made significant inroads toward the completion of other genomes, including those of S. cerevisiae and C. elegans. But perhaps the work that promises to have the most immediate and tangible push toward getting genomics close to the bedside is his research targeting cancer. "We got started on cancer gene resequencing back in late 2001 working with an oncologist here at Washington University, Tim Ley, and we started out trying to resequence a few hundred genes that we thought would be involved in AML," says Wilson. "We also started a project in 2003 with Harold Varmus to do a similar analysis of a couple hundred genes in lung adenocarcinoma. That study included the discovery of EGFR mutations in patients who responded well to kinase inhibitor drugs, one of three papers published about the same time that showed the role of EGFR mutations in that drug's actions."
That same Varmus project turned into what is now the Tumor Sequencing Project, which has been undertaken by the three large US genome centers and has already published several results on lung adenocarcinoma mutations. The project was also one of the driving forces for The Cancer Genome Atlas project, co-funded by the US National Cancer Institute and NHGRI. The cancer atlas project has been focused initially on brain cancers and ovarian carcinoma, both of which have received major contributions from work done by Wilson's group.
In addition, the acute myeloid leukemia project blossomed into the first cancer genome that was published in its entirety. The results of these efforts appeared last November in Nature, where Wilson and his colleagues described the complete genome of a woman who died of AML. "By sequencing her entire genome we found 10 somatic mutations — all cancer-related in one way or another," he says. "This has really shifted the paradigm now to the thought of actually doing whole genome sequencing in the substantial number of cancer genomes."
The early days
Long before he became a cancer genomics pioneer, Wilson was a young PhD student pursuing T-cell receptor biology, which led him rather serendipitously to a postdoc position in Lee Hood's lab at the University of Washington. As a graduate student, Wilson had also done a lot of DNA sequencing work in Bruce Roe's lab at the University of Oklahoma, and Hood's group was just attempting to develop ways to automate DNA sequencing. "I think Lee was interested in me for that experience, so we made a deal that I could work on both. … So I ended up spending most of my time on the sequencing thing," Wilson says. "But this was right at the beginning of the big discussions of whether or not we should sequence the human genome [and] obviously the development of technology to make sequencing possible to the level that we need for the [Human] Genome Project was the center of attention."
During his graduate student days, Wilson worked with some instructors who would micromanage his research efforts and perch over his shoulder every step of the way. That experience strongly informed the way he runs his own lab and the kind of postdocs he looks for. "When it was time for me to pick a place to postdoc, I wanted someone that was very hands off. … I got a lot out of that experience so I kind of have the same philosophy," he says. "I want to give these guys resources and general direction, but I really like when young scientists can find their own path with minimal need for course correction."
When it comes to applicants to his lab, Wilson says the prerequisites for consideration are that they must be enthusiastic and bright with a sufficiently strong background in molecular biology and genome analysis — and who are also motivated to contribute beyond the minimum. "It's great if there are people with relevant experience, and that doesn't mean if they want to come and work on cancer genomes that they've done cancer genomes before," he says. "But if they've got some experience in something that's going to feed nicely into that and dovetail into a career path, those are guys that would get my attention."
Wilson hopes that his postdocs come away from their time in his lab with a real appreciation for teamwork and the value of open-minded leadership. "There's always somebody to contribute, and it's important that you have your own plan, but you can do a lot by working with others," he says. "We've really all been born of the genome project over the last 15 to 20 years and so a lot of our efforts are collaborative, and you can get a lot out of that and I hope they take that with them."
About his former postdocs, Wilson is at once unreservedly proud of and impressed by their achievements and progress. Here are just a handful of -investigators who cut their teeth under his tutelage.
Group leader for SNP research, GlaxoSmithKline
"A really smart kid from Oklahoma, she worked on a lot of things at the genome center and really contributed a lot to sequencing efforts of the human genome," Wilson says. "Stephanie is a player in the human genetic variation arena trying to understand how different polymorphisms might associate with different types of susceptibility in disease or drug reactions."
Research assistant professor, Genome Sequencing Center, Washington University School of Medicine
"She came to St. Louis with her husband, who had taken a faculty position at WashU, and we hired her as a postdoc where now she heads up our cancer genomics analysis group," he says. "So she took point on a lot of the analysis on the AML genome. She was the first author on the TSP sequence mutation paper that came out in November and contributed to the TCGA paper we published last year. She's really a leader in cancer genome analysis; she is a top gun."
Group leader, Genome Sequencing Center, Washington University School of Medicine
"Vince has done a really great job and sort of co-leads our tech development group, where Elaine Mardis is the director — and she's pretty busy, so Vince really holds down the fort. He's been a fabulous addition to our senior scientific staff," Wilson says.
Senior scientist, British Columbia Cancer Agency
"Marra has matured a lot. He's gone from being an earthy C. elegans biologist back in the early 1990s to a really polished and brilliant human geneticist and molecular biologist," Wilson says. "He's done a great job with the genome science center up there."
Research assistant, Washington University School of Medicine, and assistant director at the genome center
"Makedonka came over as a nematologist from Macedonia and wanted to come here to work on parasitic nematodes. [She] spent a lot of time working on parasitic nematode genetics, but has recently moved into the human microbiome analysis group," Wilson says. "She currently heads up a new group called integrative genomics, and she's made some great contributions into the analysis and annotation of various metagenomic and microbial samples."