Indeed, Selkoe, Schrieber, and Kinzler are among the scientists who have produced the greatest number of highly cited papers over the last three years, as identified by ISI's newsletter Science Watch (4:1-2, December 1993), based on a ranking from ISI's Hot Papers Database. Others on the list who have produced five or more of these papers--research articles with a substantially greater number of citations than other papers in similar disciplines during that time--are molecular neurologist Stanley Hamilton, molecular biologist Bert Vogelstein, and neuroscientists Solomon Snyder and David Bredt of Johns Hopkins; molecular biologists Benjamin Margolis and Joseph Schlessinger of New York University Medical Center; molecular biologist Tony Pawson of the University of Toronto and Mount Sinai Hospital, Toronto; and molecular neurologist George Yancopoulus of Regeneron Pharmaceuticals Inc. in Tarrytown, N.Y.
* Currently at the University of California, San Francisco, School of Medicine
Source: ISI's Hot Papers Database, November/December 1990- November/December 1993
That all of these researchers are life scientists, ISI analysts explain, is largely attributable to the fact that life scientists far outnumber physical scientists; therefore, this larger population produces a far greater number of papers in which their colleagues' work might be cited than other disciplines. Furthermore, they cite a greater average number of references within those papers compared with physical scientists.
These "hot papers" remained heavily cited over several bimonthly periods from November 1990 to November/December 1993. For example, Vogelstein, at Johns Hopkins Oncology Center, had 16 papers on which he was an author stay highly cited during this period. His most cited article (M. Hollstein, et al., "p53 mutations in human cancers," Science, 253:49-53, 1991) was cited in 700 papers by the end of 1993.
Kinzler, a coauthor with Vogel-stein on nine of these papers, also at the Hopkins Oncology Center, says their main research interest is in understanding the genetic changes that cause cancer, specifically colon and brain cancers. (For a recent example, see N. Papadopoulos, et al., "Mutation of a mutL homolog in hereditary colon cancer," Science, 263:1625-29, 1994.) Hopkins researchers Snyder and Bredt also wrote several papers together that put them on this list.
Taking an integrative approach in answering research questions and participating in interdisciplinary collaborations are keys to their success, say these highly cited authors. For example, even though these scientists categorize their work into subdisciplines--such as signal transduction or immunosuppressant biochemistry--they all agree that the strength of their labs' work is in the diversity of their staffs' backgrounds and their ability to cross boundaries in terms of subject matter, methodologies, and communication with colleagues.
For example, Schlessinger, chairman of the New York University Medical Center's pharmacology department, says he collaborates with crystallographers, geneticists, and biophysicists, both within and outside his own institution.
A prime illustration of this integrative approach is the Schreiber lab--a group that takes a chemical approach to cell biology. Schreiber, who holds a joint appointment as a professor in Harvard's chemistry and cellular and molecular biology departments, studies the use of immunosuppressants in understanding signal transduction. "Most of the people who come to my lab are interested in knowing how that field can integrate with neighboring disciplines," he says.
Schreiber explains that the major role that chemistry has played in his interdisciplinary lab is in using synthetic compounds as tools for elucidating the function of important molecules in cell types such as T cells. (For a recent example, see D.M. Spencer, et al., "Controlling signal transduction with synthetic ligands," Science, 262:1019-24, 1993.)
Another characteristic to which the researchers attribute the success of their lab--in their collective words--is their intelligent, energetic, dedicated, and creative staff of doctoral and medical students, postdoctoral fellows, and technicians.
Kinzler explains that he looks not for people who have specific skills, but for people who are bright and enthusiastic, explaining that "they will learn whatever they need to do" once they are on the job. Because of his confidence in his research team's expertise, Vogelstein exercises a relatively free rein in running his lab. "I just let them do their thing," he says.
Schreiber says that attracting highly interactive students to his lab stimulates his own work: "I find it a very exciting way to do science, as opposed to trying to do interesting things in a vacuum."
In addition to the collaborative and talent aspects of research staff, the type and timeliness--with respect to solving current human health problems--of the research itself plays a significant role in the accomplishments of the research programs, say the scientists.
For example, Selkoe, whose lab (along with other colleagues) discovered that abnormal amyloid protein deposits in brain tissue can cause certain types of Alzheimer's disease, says, "The reason there's been so much interest in the biology of Alzheimer's disease is because it's a tremendous public health problem and an enormous number of people are affected." Selkoe holds a joint appointment as professor of neurology at Harvard Medical School and as director of the center for neurologic diseases at Brigham and Women's Hospital in Boston.
Specifically, he says, his lab's research has been referenced by colleagues so often because, by using a simple cell-culture system for analyzing soluble amyloid protein, they have found a possible diagnostic tool for testing predisposition to Alzheimer's disease and screening for possible therapeutic drugs. (See C. Haass, et al., "Amyloid beta-peptide is produced by cultured cells during normal metabolism," Nature, 359:322-25, 1993, which is also a hot paper.)
Schlessinger, who studies the role of molecular receptors in the signal transduction pathway of normal and diseased cells, attributes part of his lab's achievements to the fact that he studies the underlying workings of fundamental life processes. "One of the most urgent subjects in biology is understanding basic mechanisms which relate to growth and differentiation, and if you're able to figure out such mechanisms, the rewards will be very high," he explains.
"For the last 15 years we've been trying to understand how receptor tyrosine kinases are activated [in the signal transduction pathway of cells], and by knowing what they do we can also figure out what goes wrong in cancerous cells," he says. (For example, see J. Schlessinger, A. Ullrich, "Growth factor signaling by receptor tyrosine kinases," Neuron, 9:383-91, 1992.)
Kinzler describes his lab's research as question-driven rather than capability-driven. "We define the question first and worry about how to do it later." As a result, the lab's research "has crossed a lot of borders," Kinzler adds, referring to his lab's practice of learning whatever methods are necessary to fully answer their questions, such as using several types of models-- from yeast to mice.
Researchers say that another distinguishing feature of their labs is their commitment to open communication. This exchange has many elements, they say, such as discussing research in progress; including all levels of staff--from students to principal investigators--in the dialogue; holding both formal and informal meetings; and, again, adopting an integrative approach.
On the formal side, Kinzler's and Vogelstein's staffs attend weekly joint meetings--whose format is roughly similar to the lab meetings described by the other researchers. "We discuss the literature and get feedback on ideas and interpretation of results. Half of the meeting is devoted to a critical survey of the literature and the other half is devoted to a presentation of new data by one person," says Vogelstein.
Schreiber stresses that participants in his joint chemistry- biology lab meetings make a special effort to communicate their work to others outside their area of research.
On the informal side, Bredt, previously a doctoral and medical student in Snyder's lab and since January an assistant professor of physiology at the University of California, San Francisco, Medical School, says of Snyder's lab, "The vast majority of learning happens at the benchside where people just informally discuss their daily progress."
Kinzler also tries to maintain close contact with the people in his lab. "Whatever level you're at--even at the principal investigator level--it's helpful to talk to people about your experiments, so you don't forget something." However, he adds, "As a result, I don't travel very much."
More generally, Schlessinger mentions that all modes of scientific communication--listening to speakers at meetings, reading journal articles, talking with colleagues in the lab, for example--"somehow synergizes other thoughts" and inspires him intellectually.
Promoting a creative environment that doesn't discourage new interpretations or approaches is also part of a healthy, productive lab, say the researchers. The open climate of Snyder's lab at Johns Hopkins, where Bredt used to work, is one example.
"We [took] on people who aren't so structured in the way they think about science, but are rather more open to new ideas," says Bredt, who studies how the gas nitric oxide functions as a neurotransmitter in the brain. (See D.S. Bredt, et al., "Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase," Nature, 351:714-8, 1991, also a hot paper.) He traces this practice back to Snyder's Nobel Prize- winning adviser, Julius Axelrod.
Bredt explains that researchers were originally resistant to the idea that nitric oxide could actually be made and used by the body. However, spurred by the fact that nitric oxide had been discovered in the bloodstream as a regulator of blood pressure, his group investigated whether nitric oxide is used as a neurotransmitter in the brain.
Likening the brain to a computer with precisely defined connections between circuits, he says, "nitric oxide is the wrong thing that you'd imagine being used in the computer because it doesn't go between the wires--it affects all the wires in a given area--and there's no computer element like that."
Because nitric oxide is a gas "it doesn't go specifically from one cell to another like all other known neurotransmitters," Bredt says. "Instead, it diffuses out in a sphere in brain tissue so it affects all cells in a defined area." Explaining nitric oxide's possible role in learning, he adds "when [a person's] experience goes through a circuit in the brain, that circuit becomes strengthened and it is thought that nitric oxide mediates this process."
Related to the idea of fostering a creative, uninhibited lab environment is the custom of promoting healthy debate and independent thinking among team members. "I expect people to argue with me when they don't like an idea," Kinzler says. "It's funny, we don't have very much [personal] feuding in the lab, but people will argue about scientific points and it's enjoyable," he says, "once you get used to it."
NYU's Schlessinger encourages new trainees in his lab to find their own related research project by spending their first few weeks talking with their new colleagues: "When a new person comes to the lab, I really do not make this person work on what I think is important. I want them to choose."