Albert Lasker
Basic Medical Research Award

Award Description

Lee Hartwell, Yoshio Masui, and Paul Nurse
For pioneering genetic and molecular studies that revealed the universal machinery for regulating cell division in all eukaryotic organisms, from yeasts to frogs to human beings.

Lee Hartwell is a yeast man—a connoisseur of Saccharomyces cerevisiae, or budding yeast, that are essential for brewing beer and baking bread. But Hartwell sees neither brew nor bread in these simple organisms. Rather, he sees something even closer to the core of life itself. By studying yeast, Hartwell has seen the cell cycle up close and has identified genes that are crucial to controlling the intricate program of instructions by which a cell grows, rests, and divides to replicate itself.

Paul Nurse is also a yeast man—a scientist whose work with fission yeast, or Schizosaccharomyces pombe, also revealed previously unknown things about how genes regulate the lives of cells. Among Hartwell's discoveries in budding yeast is a gene called CDC28 that cells need in order to progress through their various stages of division. Nurse and his colleagues discovered a nearly identical gene in fission yeast, cdc2 , that performs a similar regulatory role. Then Nurse not only showed that the CDC28 and cdc2 genes make proteins that are functionally like one another; he also identified the first protein in humans whose role in the cell is analogous to the role of the proteins in yeast.

Meanwhile, Yoshio Masui, whose experimental work has focused on frogs, discovered a protein, called maturation promoting factor (MPF), in the cytoplasm of cells that control cell division in the fertilized eggs of frogs.

Each of these discoveries—occurring in the late 1960s and early 1970s—is important in and of itself. But more important still was the observation that Masui's MPF contains a protein that is like the yeast proteins discovered by Hartwell and Nurse. That a similar protein exists in humans brings the research full circle. If ever there was a set of stories that offer compelling evidence of how organisms are related to each other, from the lowly yeast to the higher frog, these are the stories. Ultimately, the implications of this research to human medicine would become clear.

Hartwell's early decision to focus on budding yeast was an easy one. "At the time it was the only eukaryotic cell [or cell with a nucleus] for which the basic genetics had been worked out. So it was a good starting point and I've always seen yeast as a model organism for human biology," Hartwell says. As budding yeast pass through various stages of development, the bud protruding from the organism changes in size, giving scientists a remarkable and quite visible way to follow the outward signs of the cell cycle.

At the University of Washington Department of Genetics, Hartwell discovered many of the genes that are essential to the development of yeast, whose function is to operate successively to assure that the cell reproduces according to an orderly system in which step A must be completed before the cell moves on to step B, and so on. Hartwell also discovered "checkpoint genes" that are called upon to function when the essential genes do not function properly. In the normal course of the cell cycle of any organism, errors are likely to occur as information encoded in DNA is passed along. Sometimes the DNA is damaged or some essential process, such as assembling the machinery to distribute chromosomes, is delayed.

The checkpoints are transient stops that enable the cell to monitor whether it has accurately accomplished everything it needs to do, and to make necessary repairs, before continuing its progression through the cell cycle. Like the intricate steps in a complex dance, the healthy development of the cell, which ends with cell division and the creation of daughter cells, depends on good choreography.

For a cell, errors that go undetected and, therefore, unrepaired, are not to be desired. But for a geneticist like Hartwell, errors that result in mutant cells are a gold mine of information. Learning when and why the cell cycle goes awry (often leading to the uncontrolled growth that is characteristic of malignancy) is the centerpiece of Hartwell's work.

The conviction that the development of cells (including human cells) could be discerned from yeast was "a fairly risky assumption," Hartwell says, looking back on the early days of his career in the 1960s. In retrospect it is clear the risk was well worth taking. Now, after 30 years with yeast, Hartwell is committed to the application of knowledge that he and his many disciples have acquired. Last year, he became president and director of the Fred Hutchinson Cancer Research Center in Seattle, where he is spearheading a drug discovery program based on detailed knowledge of the cell cycle.

Paul Nurse, who is director-general and head of the Cell Cycle laboratory at the Imperial Cancer Research Fund in London, is also concentrating on the application of basic science to human disease after a long, productive career as a yeast geneticist. Unlike Hartwell, who took what might be called a "holistic" approach to studying everything he could about budding yeast, Nurse quickly zeroed in on what he believed to be the most important regulatory pathway in fission yeast—like Hartwell's organism, but a yeast that is elongated and divides in the middle, like links of sausage.

Nurse focused his attention on a mutant form of fission yeast that makes very small cells (Nurse named them "Wee"), which go through certain stages of the cell cycle with unusual speed—at times dividing in half the time other yeast require. Nurse discovered three different proteins, each encoded by separate genes, that control the rate at which the cell enters the M (for mitosis) phase of the cycle—the point in the cycle when cells divide to create two daughter cells. Each of these proteins acts on the important cdc2 protein that Nurse recognized as the key protein regulating this phase of the cell cycle.

The essence of science is not only to make important observations but also to find connections among discoveries to achieve a synthesis of ideas. This, clearly, is one of Nurse's principal contributions, for it was he who saw that he and Hartwell and Masui, working in different types of yeast and in the frog, had each found equivalent proteins that are key to cell division. His subsequent identification of a similar protein in human beings clinched his achievement as a synthesizer.

As a young man, Yoshio Masui took a sabbatical from Konan University in Japan to study enzymes that control development in a laboratory at Yale, where his work on frog oocytes began. Initial studies showed that division of a cell that will give rise to an egg (an oocyte) could be stimulated by the hormone progesterone, but it only worked when the surface of the eggs were exposed to progesterone—not when the hormone was injected directly into the oocytes.

Masui concluded that progesterone acting on the egg's surface must affect something in the cytoplasm of the cell that, in turn, stimulates cell division. He set out to find that "something," which turned out to be an activity in the cytoplasm that he called MPF, without knowing precisely what it was. After his sabbatical at Yale, Masui continued his research at the University of Toronto and found that MPF is a protein.

Ultimately, Masui and his students developed techniques for preparing highly concentrated extracts of egg cytoplasm which then made it possible to analyze cell cycle processes biochemically, and to purify MPF. From there came the observation that Masui's MPF from frog eggs was analogous to the CDC28 and cdc2 proteins in yeast. It took about 15 years to make the journey that began with the identification of MPF as an agent that could stimulate the cell cycle to the discovery of its molecular composition. Masui remained on the faculty of the University of Toronto for most of his professional life until his retirement in 1997.