1998 Lasker Award Recipients Honored For Their Groundbreaking Achievements

On September 25 at the Hotel Pierre in New York City, seven prominent scientists, representing a generation of landmark discoveries in biology and medicine, stepped to the podium to receive this year's Albert Lasker Medical Research Awards, a coveted honor bestowed annually since 1946 by The Albert and Mary Lasker Foundation. The research of six of this year's recipients made possible groundbreaking discoveries in the field of cancer research. The research of the seventh, who received his award for special achievement in medical science, revolutionized scientists' model for enzyme-substrate interactions, findings that had an impact on a number of disciplines. 1998 Lasker Awardees: From left, Daniel E. Koshland Jr., Paul Nurse, Janet D. Rowley, Lee Harwell, Yoshio Masui, Peter C. Nowell, and Alfred G. Knudson Jr. All three winners of the clinical medical research award played key roles in advancing scientists' understanding of the genetic basis of cancer. In the case of Nowell and Rowley, their findings collectively painted a complete picture of the first cancer-associated chromosomal abnormality. In the case of Knudson, his "two-hit" hypothesis demonstrated how certain multiple genetic mutations dictate the pathogenesis of the disease. In 1914, German cytologist Theodor Boveri became the first to propose that defective chromosomes in a single cell could cause widespread malignancies in progeny cells. But his famous work, The Origin of Malignant Tumors, was big on theory and short on examples. Definitive evidence wouldn't come until nearly half a century later with Nowell's 1960 serendipitous discovery of the Philadelphia chromosome. Nowell and his colleague, the late David Hungerford, found that the tumor cells of individuals suffering from chronic myelogenous leukemia (CML), cancer of the bone marrow, contained an abnormally small chromosome. "Nowell and Hungerford advanced the audacious proposal that cancer could arise from a mutation in a single cell," explained Lasker awards chair Joseph L. Goldstein in presenting the honor. "In other words, cancers could be cloned." Named the Philadelphia chromosome after the city in which it was discovered, the tiny, malformed chromosome 22, the first specific mutation associated with cancer, would become a reliable marker and useful diagnostic tool for CML. Initially, however, scientists didn't understand exactly how the aberration came about. Nowell and others had assumed that a deletion in the long arm of the chromosome had led to its detrimental small stature. But Rowley, using chromosome banding technology developed in the early 1970s, proved otherwise. She found that the Philadelphia chromosome was actually involved in a reciprocal translocation with chromosome 9. The two chromosomes had exchanged DNA and, in so doing, had created a new hybrid oncogene that stimulates unwanted cell growth. Rowley has continued to look for chromosome abnormalities and has found 10 of the 70 translocations now known to cause cancer in humans, including one that led to the cloning of the now-famous BCL2 gene, known to regulate programmed cell death, or apoptosis. Fellow awardee Knudson would, in the course of his research on retinoblastoma, a cancer of the retina, further elucidate cancer's genetic origins. Retinoblastoma, which affects 1-in-20,000 children, has both a hereditary and nonhereditary, or sporadic, form. Knudson's so-called "two-hit" hypothesis sufficiently explained a model of pathogenesis common to both. He essentially proposed that individuals will develop the condition if they either inherit one retinoblastoma gene and incur a second mutation after conception, or if they incur two mutations or hits after conception. Either way, both copies of the RB1 gene have to be mutated to trigger disease onset. If one gene functions normally, the cancer is suppressed. Knudson dubbed these preventive genes anti-oncogene; scientists later renamed them tumor suppressors. Knudson's theory, when it was introduced in 1971, was not without its skeptics. "I had some skepticism myself," recalls Knudson. "But it was a very simple hypothesis, and I knew that once the molecular techniques became available ... one could test it." Experimental data would confirm Knudson's findings in 1983, and in 1986 the RB1 gene was the first tumor suppressor to be cloned. Says Knudson, referring to his research as well as that of Nowell and Rowley, "One of the nice things that happened is that these findings connected cancer research and basic research more generally." And, in fact, as it turns out, to understand the role of RB1 as well as many other cancer genes and their proteins, it's important to understand how they affect the cell-cycle protein discovered by the 1998 Lasker basic medical research awardees. In the 1960s, Hartwell, Masui, and Nurse all investigated the proteins responsible for cell division. Hartwell looked to budding yeast (S. cerevisiae), Nurse to fission yeast (S. pombe), and Masui to frogs (Xenopus). The three of them converged on a similar find: a protein kinase essential to cell cycle regulation. Awards presenter Ira Herskowitz, a professor of biochemistry at the University of California, San Francisco, called the research "one of the most remarkable convergences in modern science, a truly unifying discovery in which it was seen that yeast, frogs, and humans share universal machinery for regulating cell division." Hartwell was the first to put the now invaluable yeast model system to use. "I wasn't confident that yeast would be as good a model for human cells as it has become, but there just wasn't any choice," explains Hartwell. At the time, yeast was the only eukaryotic organism whose genetics were well understood. According to Hartwell, the relatively recent flood of DNA sequencing information has demonstrated the high degree of genetic similarities across species and has confirmed the tremendous utility of the yeast system. Using yeast, Hartwell discovered dozens of novel genes--including one that generated a regulatory cell-cycle protein called CDC28. Masui's path to discovery wasn't quite so direct. While working on frog cells in the 1960s at Yale University, he found that he could stimulate cells to give rise to oocytes, or eggs, using progesterone, but only when he exposed the hormone to the surface of the cells; injecting the hormone had no effect. Masui theorized, and subsequently confirmed, that progesterone triggers cell division via some substance in the cytoplasm that he called maturation promoting factor (MPF). Not until a surge of finds in the 1980s, which Masui referred to as the "big bang," was the molecular identity of MPF identified. Nurse effectively unified the cell cycle research of Masui and Hartwell while adding a crucial bit of his own. He discovered three proteins in fission yeast that all acted on a protein called cdc2 to control the rate at which the cell enters mitosis. More importantly, Nurse realized that Masui and Hartwell had found analogous proteins in their own research: CDC28 and an ingredient in MPF very similar to both CDC28 and cdc2. Nurse went on to identify and isolate a similar protein in humans. "What has given me the greatest pleasure in receiving this award is the privilege to share it with two such fine scientists," said Nurse in accepting the trophy. For Hartwell, most gratifying was that the award indicated that he had "made a contribution" to his field. That contribution included not only the yeast model and CDC28 protein, but his 1980s discovery of cell checkpoint genes, genes that halt the cell cycle at certain points to make repairs and ensure healthy cell development. Goldstein, in presenting the medical science special achievement award to Koshland, divided the awardee's life into three "acts": biochemist, institution builder, and communicator of science. Koshland the biochemist revamped the popularly accepted model of enzyme-substrate interaction. In 1957, he rejected the accepted lock-and-key model proposed by Emil Fischer, the winner of the Nobel Prize in chemistry in 1902, and introduced his own induced-fit model or, as Koshland dubbed it, the hand-in-the-glove model. As the names suggest, the lock-and-key model held that enzymes were rigid molecules that admitted only specially shaped substrates, while the induced-fit model suggested that enzymes wrap around substrates. "Too big a hand [the substrate] won't fit, and too little a hand won't fill out the glove [the enzyme]," says Koshland. The induced-fit model, which wasn't validated until the 1970s, when scientists were able to see the enzymes at work with the advent X-ray crystallography, turned out to be not only correct, but useful in understanding other mechanisms such as feedback regulation and hormone interactions. Koshland went on to show that very small confirmational changes between enzyme and substrate, as little as one angstrom, were enough to trigger big consequences in the cell--a finding that had implications for understanding evolution. As Koshland explains, gradual adaptive change of organisms requires that there be a mechanism for tiny incremental change at the molecular level. In the mid 1970s, Koshland the "institution builder" reformed a struggling University of California, Berkeley biology program. He combined several small departments into three large ones to encourage the cross-disciplinary academic approach that had become increasingly important with the then oncoming revolution in recombinant DNA and gene cloning. Several years later, Koshland left Berkeley to become an eminent "communicator of science" during a 10-year (1985-1995) stint as editor of Science magazine, a job he enjoyed immensely. The 78-year-old Koshland has perhaps added a fourth act to his long career by returning to the lab to continue work on enzymes. One current project involves using improved enzymes to clean up harmful chlorine compounds such as DDT. In another, Koshland is attempting to employ enzymology to stymie the accumulation of harmful, neuron-slaying amyloid-ß protein deposits in Alzheimer's sufferers. "When I was a kid I really enjoyed puzzle solving," said Koshland at the Lasker awards luncheon. "I'm still a kid. I still enjoy puzzle solving just as much as I did before, and I'm still a little bit astonished that I actually get paid to do it, and even more astonished that I get an award. My cup runneth over at the moment." Peter NowellLee Hartwell Alfred C. Knudson Daniel Koshland Yoshio Masui Paul Nurse Janet Rowley

1998 Lasker Award Recipients Honored For Their Groundbreaking Achievements

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