Harmony in the Lab

The Scientist 14[17]:19, Sep. 4, 2000 NEWS Harmony in the Lab Kinzler-Vogelstein group is single-minded in goal of beating cancer By Eugene Russo Photo:©Marty Katz Bert Vogelstein (bearded, third from upper left) and Ken Kinzler (center, directly in front of Vogelstein), surrounded by therir labmates. Asked why his laboratory has had a string of successes in the last decade, making it one of the most recognizable oncology labs in the world, Johns Hopkins University's Bert Vogelstein answers straightforwardly. "That's easy," he says, pausing slightly as if for dramatic effect. "It's the people." Vogelstein graciously credits his 18 postdoctoral and 5 predoctoral students, picked five a year from a group of more than 200 applicants, for not only competently doing the laborious grunt work required of any research lab, but for supplying many of the ideas and much of the creativity that keeps the group on the cutting edge of cancer research. He worries that the public commonly thinks of scientists as lone, long-distance runners who make discoveries after excruciating solitary struggles. "If I were to make an analogy with sports, I'd say I'm kind of a mountain climber," remarks Vogelstein, beaming. "And each of the posts I put up was not laid there by me, but by one of our former graduate students or postdocs or someone from another lab." Vogelstein, a Howard Hughes Medical Institute investigator and professor of oncology at the university's school of medicine, and the lab's co-principal investigator (PI) Ken Kinzler, an associate professor of oncology at Hopkins, aren't shy about their laboratory's ultimate objective: They're looking to find a cure for cancer and to improve the management or treatment of cancer along the way. "We don't have a great interest in basic science other than where we think it'll meet those goals," says Kinzler, who started working with Vogelstein in 1983 as a graduate student. Basic science questions that appear to be little more than intrinsically interesting are the lab's lowest priority. It is a philosophy that may make some hard-core basic scientists shudder. "We look at the cancer problem not as an intellectual puzzle, although it is one to be sure," explains Vogelstein. "But really the primary motivation for studying it is because it's a disease that affects people." Myriad Accomplishments The Kinzler-Vogelstein lab is in a two-story suite of a dozen offices, conference rooms, and workstations on the fifth floor of a new Johns Hopkins medical school research building overlooking East Baltimore. It also overlooks, on one side, the site of their former lab, a one-story renovated supermarket from which they moved this past January. "I used to tell people I worked in the deli," says former graduate student and current postdoc Victor Velculescu, referring to the checkered, shiny floor of his former workstation. The roomy new facility, complete with a pool table paid for by Vogelstein, affords ample space for all 27 lab members. The lab area contains the usual cell biology goodies--including a tissue culture room, a microscopy room, a room for tasks involving radioactivity, and a PCR room with some two dozen machines. The conference room houses not only the expected table for the group's twice-weekly lunchtime discussions, but a satellite-linked big-screen TV around which lab members congregate to watch the occasional soccer game. Kinzler, Vogelstein, and their labmates are trying to better understand several cancers by focusing on the genetic mechanisms of colorectal cancer. Colon cancer is a good model, says Vogelstein, because it is common and has clear genetic components and because researchers can easily extract tumors from various stages of the disease. In the last 10 years, the lab's translational approach has turned up some rather significant finds. The researchers have helped delineate the pathway of the colon cancer-associated adenomatous polyposis coli (APC) tumor suppressor gene, and they've showed that it regulates the c-MYC oncogene, a connection that could suggest treatment targets.1 In research started prior to Kinzler's joining the faculty, they also explore the pathway of p53, the most frequently mutated tumor suppressor in human cancers. Kinzler calls the cloning of the APC gene the lab's most important contribution to cancer research.2 But asked what accomplishment has had the greatest impact on a variety of fields, Kinzler points to the lab's 1995 development of a unique method now widely used to study gene expression in human cells.3 Called SAGE (serial analysis of gene expression), the method uses portions of cDNA expressed sequence tags (ESTs), which link physical and genetic maps, to confirm whether a piece of DNA comes from a given RNA transcript. SAGE works 30 times faster than conventional EST-based searches. It has been crucial to several of the lab's projects, including studies of APC and c-MYC. The technology is free to academic investigators and available to those in industry for a fee via Genzyme Molecular Oncology, the company to which Hopkins licensed the technology (Kinzler and Vogelstein have a financial stake in the company). Findings related to APC, p53, and SAGE haven't only gotten the attention of the press, but of the scientific community as well. According to the Institute for Scientific Information's Web of Science, several of the lab's papers, including several related to p53's role in several cancers,4,5 are among the most cited in all of oncology. Partners in Science Though Kinzler and Vogelstein claim that the students are the secret to success, several postdocs point to the duo's selfless mentorship as the lab's driving force. "They're the Lennon and McCartney of science," says postdoc Chris Torrance, referring to the their complementary styles. During a discussion over sushi at a harborside restaurant in Baltimore with several students, postdoc Ben Park expanded on Vogelstein's powers of guidance by explaining his reputation as the "Jedi Master." When trainees first come to the lab, they're encouraged to meet with as many of their labmates as possible to try to decide on a project. Somehow, though, inevitably the trainee ends up picking one of the ideas already on Kinzler and Vogelstein's list of potential projects. But Vogelstein staunchly denies having any real command of the force. "I wish I had that power," he says, laughing. "Many of us spend a lot of time around the lunch table ... trying to figure out what makes this lab such a great place to work," says three-and-a-half-year postdoc Phil Buckhaults. Buckhaults chalks it up to the co-PIs' knack for picking bright, team-oriented people with limited egos. Wanna-be postdocs reportedly have been very persistent at times in their efforts to get an interview; Kinzler and Vogelstein generally don't answer their phones. The chosen are no doubt very bright, not to mention driven. Examples are many: Last November, Velculescu won the Young Scientists Prize, sponsored by Amersham Pharmacia Biotech and the journal Science, for spearheading the development of SAGE. He's organizing a meeting in Baltimore, to take place Sept. 18, at which more than 150 scientists will discuss the particulars of the SAGE method, SAGE applications in a variety of organisms and disease systems, and the bioinformatics and data analysis aspects of the technology. In an effort led by postdoc Hai Yan, the lab has recently developed a technique that could dramatically improve testing for genetic susceptibility to colon and possibly other cancers.6 By separating the alleles of relevant genes to prevent one allele from masking the other, as can often happen with conventional testing, investigators improved test accuracy for the two types of hereditary colon cancer, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. The technique, called conversion, separates the alleles by fusing human cells that might contain the defective gene with a special strain of mouse cells. Yet some students claim that it's the relatively low-pressure team atmosphere that provides for a positive working environment. Five-year postdoc Wei Zhou, who worked at a large, competitive lab at Emory University as a graduate student, notes that because everybody in the Kinzler-Vogelstein lab has his own project, the competition is minimal. Unlike some PIs, Kinzler and Vogelstein choose not to have their students go head to head on the same project. The two also foster good working relations through several lab activities--out of their own pocket, they pay for a yacht club membership for the lab, occasionally buy postdocs symphony or baseball tickets, and even provide a Delaware beach house for lab members to share. Vogelstein admits that he provides these things, in part, out of guilt; he and Kinzler hope to ease the possible strain resulting from the limited earnings of the average postdoc or graduate student. The lab's most famous activity: the participation of some of its members in an all-oncologist rock band called Wildtype. A sign in the foyer outside the offices of Vogelstein and Kinzler displays band members' nicknames. For the past four years, Ken "Big Sticks" Kinzler (drums), Bert "Rockin' Doc" Vogelstein (keyboard), and postdocs Ellie "Diva" Carson-Walter (lead vocals) and Chris "Slow Hand" Torrance (guitar) have taken part in the band, which was formed at a Christmas party four years ago by former lab member Patrice "Power Play" Morin (guitar), now an investigator at the National Institute on Aging. The band, which takes over the conference room every Tuesday to practice, plays at science conferences, National Association of Science Writers gatherings, and the occasional bar. Even here, though, the science is not forgotten: All proceeds go to a cancer research charity. Though they've shown a bit more aptitude for studying cancer, Kinzler and Vogelstein seem to approach their music much like they approach their research: very seriously and with every intention of making improvements. Despite his lab's major finds, though, Vogelstein acknowledges that real cures for cancer will be much more elusive than the elucidation of genetic blueprints of the disease. He sums up the revolution in cancer research of the past two decades in one sentence: Cancer is, in essence, a genetic disease. Moving from understanding to application will be the ultimate challenge. Although paradigms in genetics research for discovering the relationship between genotype and phenotype have been well established, few paradigms, says Vogelstein, exist for applications. "The only thing I'm pretty sure about now is that the approaches being taken are unlikely to be the final answer," he comments, before turning the discussion back toward the up-and-coming researchers in his and other labs. "It's going to require some young person 25 years old who doesn't know that something can't be done." The key to future successes, Vogelstein seems to insist, is the very same as the key to past successes: It's the people. Eugene Russo can be contacted at erusso@the-scientist.com. References 1. N. Halim, "Hot Papers: Converging Pathways," The Scientist, 14[11]:20, May 29, 2000. 2. K.W. Kinzler et al., "Identification of FAP locus genes from chromosome-5q21," Science, 253:661-5, 1991. 3. V.E. Velculescu et al., "Serial analysis of gene-expression," Science, 270:484-7, 1995. 4. J.M. Nigro et al., "Mutations in the p53 gene occur in diverse human-tumor types," Nature, 342:705-8, 1989. 5. S.J. Baker et al., "Chromosome-17 deletions and p53 gene-mutations in colorectal carcinomas," Science, 244:217-21, 1989. 6. H. Yan et al., "Conversion of diploidy to haploidy: individuals susceptible to multigene disorders may now be spotted more easily," Nature, 403:723-4, Feb. 17, 2000.