What you do in life, says Dr. Michael Gottesman, is affected by two forces -- the path or trajectory you consciously choose and unpredictable events. "The trick," says Gottesman, "is to keep track of the trajectory while unexpected forces buffet you hither and yon."

Gottesman is the Deputy Director for Intramural Research at NIH. The intramural -- from the Latin words for "within the walls" -- community includes some 11,000 people who work in NIH's hospital, in its research and clinical laboratories, and in its offices. The community includes about 6000 doctors and scientists and about 5000 support persons; the annual budget of the program is $1.3 billion.

Administrative activities occupy five of Gottesman's days each week; on the other two, he is in his laboratory. Juggling the administration of science with doing science is not easy, and many researchers never take on administrative tasks. But Gottesman says he felt it was his responsibility and obligation to both the public and to his fellow scientists to accept administrative assignments.

Gottesman's office is the "nerve center" for the intramural community, and his broad-ranging responsibilities -- which he assumed in 1993 -- are much like those of a university dean. For starters, he oversees and coordinates activities among the 6000 researchers on the NIH campus, making sure that the work they do is of the highest quality, that the training they receive is the best, that they treat each other and the people and animals included in their experiments properly, and that they are aware of opportunities, meetings, and other activities on the campus and elsewhere. In addition, he participates in budget discussions with Congress and in the complex process of "technology transfer" by which discoveries that are made in NIH laboratories or clinics move into the marketplace as new diagnostic tests and improved treatments for diseases.

Gottesman's first taste of administration came in 1990 when he was a researcher at the National Cancer Institute and was appointed Chief of the Laboratory of Cell Biology. In 1992, he was asked to serve as the acting director of the National Center for Human Genome Research until a permanent director could be recruited. He suspects he was chosen for the position because of his "calm nature and skills in management;" he has a strong background in genetics, but the position was definitely outside his specialty area -- the study of cancer cells and their growth. He says the position was "relatively easy to step into because there were good people in place, the program was running itself, decisions were made collegially, and the project stayed on target."

A typical day in the Deputy Director's office includes meetings at NIH and elsewhere, one-on-one appointments, phone and e-mail conversations, and communications with members of the intramural community through several media. Gottesman is the publisher of The NIH Catalyst, a bimonthly magazine for the intramural researchers that, like its biochemical namesake, "makes a small investment and gets a lot back." The Catalyst along with publications from his office on the World Wide Web and through an electronic listserve distribution address issues that are important for NIH scientists -- policy matters, upcoming meetings, problems and their solutions, job opportunities, personnel changes, and so on.

Gottesman's e-mailbox gets about 50 new messages each day, all of which he tries to answer within 24 hours. "E-mail," he says, "has led to a sea change. Everyone can be in touch with anyone." One recent exchange dealt with the arrangements for using the synchrotron -- an accelerator that blasts charged particles onto target materials -- at Brookhaven National Laboratories. Gottesman was involved because the beam time was to be shared by researchers from four NIH institutes, and he was coordinating the time-sharing schedule. Other exchanges dealt with personal concerns of individual researchers, policy discussions among the senior leadership at the NIH, and arrangements for reviewing the programs in intramural laboratories.

"The rewards of administrative work are immediate," says Gottesman. "It is fun, because the feedback is positive and the effects are obvious." He adds that the rewards associated with laboratory research and patient care are different. "Research has distant rewards. And, when I saw patients, every interaction was positive even if I didn't do a thing but just stop by."

Gottesman considers that both his presence in his laboratory and his absence from it benefit the young researchers -- called fellows -- who work with him. "It is an enormous opportunity for them to learn how to do their own thing," he says, "to become independent and to have 'space.' However, they still need a senior scientist to provide overall direction for them and take an interest in their work."

Gottesman's group is investigating how cancer cells express their malignant natures. They are focusing on a gene called MDR1 and the protein it produces -- P-glycoprotein.

P-glycoprotein molecules sit on the surfaces of many cells, stop toxic chemicals from entering them, or pump toxins out (please click on the picture) if they get inside. The "purpose" of these gatekeeper molecular pumps may be to protect cells from random natural toxins that pop up in the environment.

But, on cancer cells in patients, p-glycoprotein molecules are liabilities, not assets.

Many tumors mass-produce P-glycoprotein. When the surface of a tumor cell is studded with P-glycoprotein molecules, chemotherapy -- the strategy for killing tumor cells by treating patients with toxic chemicals -- is not effective, because the chemicals never get inside the target cells to exert their killer effects.

How do these molecular pumps operate? Can they be turned down or off in tumor cells so that chemotherapeutic drugs could regain some of their power for stopping tumor growth? Can the pumps be primed or introduced into normal cells when people are receiving chemotherapies to protect the normal cells from "innocent bystander" deaths?

Gottesman says it remains to be seen whether manipulation of P-glycoprotein and MDR1 will be effective in the treatment of human cancers. Often when a new toxic chemical is discovered or developed, it works well for a time but then stops. Taxol, for example, seemed at first to be a wonder drug for ovarian and other tumors. But, he adds, "after several courses of treatment, taxol is a wonderful substrate for the P-glycoprotein pump, which may be expressed in surviving cells and pumps taxol right out of the types of cells that it once could kill."

In most cases, says Gottesman, successful control of tumor cells probably will depend on some combination of toxic chemicals "that nature hasn't seen yet" and statistics -- the chance that any given cell will become resistant.

Chance has a real, though unpredictable, place in the success of laboratory experiments and in the treatment of diseases. It has a well-known role in the accomplishments of the scientists who conduct experiments: "Chance," said Pasteur, "favors only the mind that is prepared." It has a not-insignicant impact on every person's life.

One chance event for Gottesman, one of those "unpredictable events" in life's trajectory, was meeting his wife, Susan, who is a geneticist and "soulmate. Her interests complemented mine," says Gottesman, "and I have learned a great deal from her." Another chance event was that the Gottesmans' decision to move to NIH in 1976 -- they had worked at NIH in the early 1970s as well -- worked out well for both of them. That move was made when Susan was offered "a real job" and Michael took a chance and came along.

"There is no knowing," says Gottesman, "when you will find out which precise direction you will take in life. But when it happens, go with it and give it your best effort."