Historic Achievement

The Albert and Mary Lasker Foundation this year has chosen as the recipients of its prestigious Winged Victory statuettes three researchers who, according to awards program director Jordan U. Gutterman, exemplify "persistence and tenacity, intuition and intelligence." The New York-based foundation presented its Albert Lasker Clinical Medical Research Award to John A. Clements, Julius H. Comroe, Jr. Professor of Pulmonary Biology and a professor of pediatrics at the University of California, San Francisco. The Albert Lasker Basic Medical Research Award was bestowed on Stanley B. Prusiner, a professor of neurology and biochemistry at UC-San Francisco. The foundation gave its Albert Lasker Special Public Health Award--which had been presented only four times previously in the program's 49-year history--to Maclyn McCarty, an emeritus professor of bacteriology and immunology at Rockefeller University. In addition to the inscribed statues, each winner received a $25,000 prize. The presentation took place at a luncheon in New York City on September 30. Health and Human Services Secretary Donna E. Shalala was the keynote speaker. "All three are wonderful human stories in science," proclaims Gutterman, who is also chairman of clinical immunology and biological therapy at the University of Texas M.D. Anderson Cancer Center in Houston. A Lasker award, believed by many to be the most significant United States biomedical science prize, is generally viewed as a "predictor" of the Nobel Prize. Fifty-one Lasker recipients have gone on to win the coveted Swedish honor. The Lasker Foundation was established in 1942 by Albert Lasker, the late owner of the Lord & Thomas advertising agency, and his wife, Mary, an enthusiastic advocate of biomedical research. This year's awards were the first to be given since Mary Lasker's death this past February (B. Spector, The Scientist, March 21, 1994, page 3). In her address at the luncheon, Shalala paid tribute to Mary Lasker: "One of Mary's greatest skills was her ability to hold public officials to a very high level of service and excellence. And when it came to the government's commitment to science and knowledge, she left little room for people to weasel out of those commitments. "From Franklin Roosevelt to Bill Clinton, Mary Lasker made sure that presidents and Cabinet secretaries knew the value of science to this country." The award to McCarty celebrates the 50th anniversary of the landmark discovery that genes are made of DNA (O.T. Avery, C.M. MacLeod, M. McCarty, Journal of Experimental Medicine, 79:137-58, 1944). McCarty conducted this research along with Rockefeller colleagues Oswald T. Avery and Colin M. MacLeod, both now deceased. The trio, originally aiming to find a cure for pneumonia, determined that DNA was the substance that controlled the reproduction of pneumococcus--a breakthrough that launched the modern age of molecular biology and genetics. According to the Philadelphia-based Institute for Scientific Information (ISI), this paper has been explicitly referenced in more than 1,000 subsequent articles. It long ago became part of the common wisdom of the field. Joshua Lederberg, University Professor at Rockefeller, has called the group's discovery "an outstanding example of the feedback of clinically motivated inquiry into the most basic issues of fundamental biological science" (J. Lederberg, The Scientist, Feb. 21, 1994, page 11). "It was an authentic discovery of a problem as well as a solution," says Lederberg. "It wasn't a problematic issue except in the minds of one group." He notes that, at the time, it was unclear that one could go about determining what genes are made of. The profound significance of the paper took years to be appreciated, partially because it was published during World War II, and partially because the journal in which it appeared was not widely read by pure geneticists. The group's findings were also challenged by several detractors, who claimed that there was not enough evidence to support the trio's conclusion. "People didn't get it," marvels McCarty, now 83. He recalls being the second presenter at a meeting at Johns Hopkins University in 1949, at which he was to discuss the DNA research. At the beginning of the event, the room was packed. But after the first lecture--on the use of Dramamine to treat seasickness--"the sound of people leaving the hall was so loud that I had to delay the start of my paper." When he finally began speaking, "there were about 35 people left." Another factor hindering widespread acceptance of the work was Avery's reluctance to personally promote it. "His view of [self-promotion]--practiced for many years before, as well--was to get the information published with the best possible proof of the point and let the interpretations fall where they may," McCarty reminisces. Ironically, although Avery received a Lasker award in 1947, he was cited "for distinguished service through studies on the chemical constitution of bacteria" rather than his DNA work. McCarty followed the 1944 paper with two articles describing his preparation of a purified pancreatic DNase (M. McCarty, Journal of General Physiology, 29:123-39, 1946) that, in nanogram quantities, would inactivate the transforming substance (M. McCarty, O.T. Avery, J. Exp. Med., 83:89-96, 1946). This evidence backed up the conclusions of the original article. In 1946, he left Avery's group to head a Rockefeller lab investigating streptococcal infections and rheumatic fever. The Lasker Foundation's Gutterman says the award to McCarty is intended "not only to honor the work, but to honor the field and publicize what's going on." Although the discovery occurred half a century ago, Gutterman points out, only recently has an understanding developed of "how cells act, how organisms develop, what normal physiology is, and how disease develops." McCarty, a member of the National Academy of Sciences (NAS) and the Institute of Medicine (IoM), received his M.D. degree from Johns Hopkins in 1937 and came to Avery's Rockefeller lab as a research fellow in 1941. He recounts his memories of the DNA work in his book The Transforming Principle (New York, W.W. Norton & Co. Inc., 1985). Prusiner was cited for identifying a new class of pathogens, which he named prions. He has reported that these infectious agents are implicated in diseases marked by slow onset with progressive deterioration of the brain and nervous system, including scrapie, a disease affecting sheep; as well as Gerstmann-Strussler-Scheinker disease (GSS), Creutzfeldt- Jakob disease, and kuru in humans. Prusiner defined the prion in a 1982 paper, "Novel proteinaceous infections particles cause scrapie" (Science, 216:136-44), which has been cited in more than 425 subsequent studies. This work was greeted by skepticism in certain scientific circles. The pathogen, he maintained, was composed only of protein; he did not find DNA or RNA in the prion, contradicting the general belief that all living organisms contain genes. Further fueling doubts among some of Prusiner's colleagues was his assertion that prion diseases can be inherited as well as infectious. Moreover, he concluded that the normal prion protein has a different shape from the disease form. This, too, was heretical, because it had long been thought that each protein has only one natural conformation. According to Gutterman, Prusiner's award also recognizes his "many years of very, very painstaking work [amid] a lot of opposition." In the early 1980s, the researcher and his prion theory were the subject of uncomplimentary articles in the scientific and popular press. His detractors maintained that the agent at work in these diseases was a slow-acting virus. While some investigators continue to look for a virus, the scientific community now generally accepts the idea of prions, which are now studied by many former proponents of alternative hypotheses. Prusiner "was all by himself against the world to prove the point," comments Pierluigi Gambetti, a professor of pathology at Case Western Reserve University School of Medicine who studies prion diseases. The copious data Prusiner produced ultimately won over the skeptics, says Gambetti, noting that he himself originally "had trouble understanding the mechanism." The "breakthrough" that shifted his perspective, recalls Gambetti, was Prusiner's results with transgenic animals. "The deeper I got into this, the more controversy there was, the more people got angry, the more I wanted to figure out what this [prion] was," says Prusiner. "I couldn't figure out a better problem to work on." Prusiner, 52, received his M.D. from the University of Pennsylvania in 1968 and then moved to UC-San Francisco, where he did an internship and a residency in neurology. "Today, I believe, it is very unlikely that my initial research would have been funded by NIH, because so little money is available for basic biomedical research," he said at the awards presentation. "The truly innovative proposals by young people don't have a chance anymore, at least I believe that to be the case." The general acceptance of the prion hypothesis in the past few years has manifested itself in the form of numerous significant prizes given to Prusiner, among them a Gairdner Foundation International Award, the Richard Lounsbery Award from NAS, a Charles A. Dana Award for Pioneering Achievements in Health, and a Christopher Columbus Quincentennial Discovery Award in Biomedical Research from the National Institutes of Health. He was elected to NAS and IoM in 1992. The Lasker Foundation recognized Clements, 71, for discovering lung surfactant, a soap-like mixture of lipoproteins that coats the lungs and prevents them from collapsing, in 1957. The paper reporting on this discovery (J.A. Clements, "Surface tension of lung extracts," Proceedings of the Society for Experimental Biology and Medicine, 95:170-2) has been cited in more than 340 papers; like McCarty's seminal DNA paper, it has become textbook knowledge. In 1959, researchers Mary Ellen Avery and Jere Mead of Harvard University found that respiratory distress syndrome, a leading cause of death in premature infants, develops because the babies are born before their lungs start producing surfactant. The condition resulted in the death of Patrick Bouvier Kennedy, the two-day-old son of President John F. and Jacqueline Kennedy, in 1963. In 1961, Clements and colleagues identified the major lipid component of surfactant, which led to attempts by multiple groups to synthesize the substance. In 1985, Clements developed a synthetic surfactant. The artificial substance, called Exosurf, was licensed to Burroughs Wellcome Co. of Research Triangle Park, N.C., and received Food and Drug Administration approval in 1990. "Now it has been demonstrated that surfactant-replacement therapy has reduced infant mortality to the lowest it's been, in the U.S. and in most industrialized countries," says Harvard's Avery, a member of the 1994 Lasker awards jury. Clements acknowledges that science rarely proceeds at a pace sufficiently rapid to enable a researcher to see favorable clinical results of his basic investigations in his own lifetime: "I recognize that fact every day. I think of all the people toiling in the vineyards--a lot of them work harder than I work; most are a lot smarter. [Therefore] I have to consider that Lady Luck played a role." For example, he notes, it was serendipity that led him to study the pulmonary system in the first place. During the Korean War, he volunteered for military service and was assigned to the U.S. Army Chemical Center in Edgewood, Md. At the time, government scientists were studying the effects of nerve gases, fearing that the Soviets might use them in chemical warfare. "I was assigned the task of figuring out how nerve gases affected the lungs. I had no particular interest in how the lungs worked up to that point." Following the war, Clements remained at the Army Chemical Center as a staff member until 1959. He has been at UC-San Francisco since 1961. An NAS member, he has received a Gairdner Award and a Christopher Columbus Discovery Award, among other honors. Clements stresses that many aspects of surfactant remain to be investigated: " 'Surfactant' tends to imply that it is something simple, but--no pun intended--we've only scratched the surface. We know so little about it at this point." Among the knowledge that remains to be gained, he says, is the role the substance plays in recovery from injury to the adult lung as well as in the lung's response to disease. At the Lasker awards luncheon, Clements announced that he would donate the honorarium to the United Nations International Fund for Children's Relief. In the stories of all three award-winners, Gutterman maintains, there runs a common theme: the "spinoff back and forth between basic and clinical research." In order to ensure future breakthroughs, he declares: "We have to have environments for these discoveries to be made, and we have to have long-term investments."

Historic Achievement

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