Cancer Research:

Cell Geneticist's Studies of Yeast Win the Horwitz

A scientist who has made fundamental contributions to understanding cell division and replication--and how these processes are altered in cancer--has won Columbia's 1995 Louisa Gross Horwitz Prize.

Leland Hartwell, a geneticist at the University of Washington, has studied a simple, one-celled organism, brewer's yeast, to tackle the difficult problem of how a cell is able to faithfully copy its genetic information and divide in two without transmitting potentially lethal errors in its genetic blueprints.

Remarkably, yeast and humans have evolved a similar mechanism for ensuring that only cells that have unerringly copied their DNA are able to proceed with cell division. Over a period of some 30 years, Hartwell has identified in yeast a series of genes and proteins that activate a complex set of checks and balances that in turn regulate the cell cycle. Mutations in these proteins are thought to underlie many forms of cancer in humans.

Since the Horwitz Prize was first presented in 1967, more than half its recipients--31 of 55--have gone on to win the Nobel Prize in Physiology or Medicine, or in Chemistry. Edward B. Lewis and Christiane Nüsslein-Volhard, who shared this year's Nobel in Physiology or Medicine, won the Horwitz in 1992.

The dinner at which the prize was scheduled to be presented by President Rupp Jan. 10 was postponed because of the recent blizzard. The award carries a monetary award of $22,000 and is given annually for outstanding research in biology or biochemistry.

As he began his research career in the late 1960s, the young geneticist was intrigued by the question of how cell growth and division always occur in the correct sequence. Couldn't there be instances where the cycle misfired, where something went wrong? Mutant cells--those with a misconstructed gene--would perform the nonmutant gene's function badly or not at all, showing scientists how the cell division process normally should work.

"He had good ideas about how to analyze the mutations and he had the vision to realize that these mutations would yield fundamental insights," said Marian Carlson, professor of genetics and development and professor of microbiology at Columbia's College of Physicians and Surgeons.

Though yeast cells have been used in research for more than 50 years as a model for more complex genetic systems, Hartwell was the first to study them to find the genes that control cell division. Yeast cells are relatively easy to manipulate, and mutants can be readily spotted and isolated for further study.

Hartwell began by identifying yeast mutations that were sensitive to temperature changes and the moment when their progress through the cell cycle stopped.

With this approach, he was able to demonstrate the sequence in which the genes must act and the fact that later steps in the cycle were dependent on the completion of earlier steps.

In 1974, Hartwell identified the gene that set in motion the cell division process in yeast. He and researchers working with other organisms next began to identify other cell division genes and the proteins that activated the cell cycle. As they compared results, the scientists found that in most organisms the cycle is enormously complex and exquisitely regulated, with some proteins activating others to create an intricate system of checks and balances.

Hartwell more recently has documented the existence of cell cycle checkpoints, control mechanisms in which incomplete early events in the cycle generate signals that inhibit later events.

If a yeast cell lacks nutrients, for example, it may well decide to delay cell division. Hartwell believes it is possible to find drugs that will emulate signals halting cell development and thus stop the growth of cancer tumors. He is also studying how defects in cellular DNA disrupt the cell cycle, sometimes leading to malignancy, and how restoration of cell cycle controls can help prevent cancer.

Born in Los Angeles, Hartwell earned the B.S. degree at CalTech in 1961 and the Ph.D. from MIT in 1964.

He held a postdoctoral appointment at the Salk Institute for Biological Studies in San Diego, where from 1964 to 1965 he conducted research with Renato Dulbecco, who won the Horwitz Prize in 1973 and the Nobel Prize in Physiology or Medicine in 1975.

He taught at U.C.-Irvine from 1965 to 1968, then joined the faculty of the University of Washington, where he has been a professor of genetics since 1973. The American Cancer Society named Hartwell its Research Professor of Genetics in 1990.

He was named a Guggenheim Fellow in 1983 and received a National Institutes of Health Merit Award in 1990. In 1992, he was one of seven scientists to receive the Gairdner Foundation International Award for Achievements in Science.

He has also received the Alfred P. Sloan Award for advances in cancer research and served as president of the Genetics Society of America in 1991. Hartwell has been a member of the National Academy of Science since 1987.

The Louisa Gross Horwitz Prize was established under the will of the late S. Gross Horwitz in memory of his mother.

She was the daughter of Samuel David Gross (1805-1889), a prominent Philadelphia surgeon who pioneered methods for suturing nerves and tendons and later served as president of the American Medical Association.

Columbia University Record -- January 19, 1996 -- Vol. 21, No. 13