Five Immunologists Garner Lasker Awards

On the 50th anniversary of the establishment of its prestigious Albert Lasker Medical Research Awards, the New York-based Albert and Mary Lasker Foundation added a United States senator to the six biomedical researchers-including five immunologists recognized for the same research subject-it chose to honor for their contributions to the medical sciences and research. The foundation's Public Service Award went to Sen. Mark Hatfield (R-Ore.), chairman of the Senate Appropriations Committee, for his commitment to advocating public funding for medical research. The five immunologists, who made key contributions to the understanding of the mechanisms of immune recognition by T cells, were selected as the recipients in the Basic Research category. They are: Peter Doherty Peter Doherty, a professor in the departments of pediatrics and pathology at the University of Tennessee's Memphis College of Medicine; Jack Strominger, a professor in the department of molecular and cellular biology at Harvard University; Emil Unanue, a professor of pathology at Washington University School of Medicine, St. Louis; Don Wiley, chairman of the department of molecular and cellular biology at Harvard, and a Howard Hughes Medical Institute investigator there; and Rolf Zinkernagel Rolf Zinkernagel, director of the Institute of Experimental Immunology of the University of Zurich in Switzerland. Barry Marshall, a clinical associate professor of internal medicine at the University of Virginia, won the Clinical Research award for his discovery that peptic ulcers are caused by the bacterium Helicobacter pylori. Barry Marshall The seven individuals were honored at a special presentation ceremony and luncheon on September 29, at the Pierre Hotel in New York City. Each award carried with it a statuette as well as a cash award. Marshall received $25,000, while winners in the basic research category shared a $50,000 award. As a senator, Hatfield was not allowed to accept the $25,000 prize accompanying his award. The contributions of the different basic research awardees span a period of more than two decades in immunology, each providing a critical piece of the fundamental puzzle of how immune-system T cells are able to recognize foreign antigens. T cells are responsible for cell-mediated immunity, whereby the body employs different cells to fight off infections. Different types of T cells (including T helper cells, cytotoxic T cells, and suppressor cells) mediate different functions to help clear various harmful agents like viruses, bacteria, and cancer cells from the body. In order to perform these functions properly, the T cells need to be able to tell the difference between self and foreign proteins. Working individually, or in collaboration with each other, these five investigators helped shed light on this recognition process. Don Wiley In a sense, says Wiley, the work began with Doherty and Zinkernagel, who "discovered a phenomenon in immunology which ignited work in the field for the next 10 to 15 years." Basically, notes Doherty, "we stumbled onto the discovery that both foreign antigens and self molecules had to be recognized for T cells to mount an immune response." "At the time, we were working on trying to define the role of the so-called cytotoxic T cells in destroying virus-infected cells, using as a model mice infected with the lymphocytic choriomeningitis virus [LCMV]," recounts Zinkernagel. "We observed that in this disease, the virus itself was not killing the cells and that, in fact, it was the T cells that were causing the damage." Furthermore, he adds, they found that "different mice differed in susceptibility to LCMV." In a series of experiments using different strains of mice, Zinkernagel and Doherty proceeded to try to pinpoint the source of the varying degrees of susceptibility. "It turned out that the different strains of mice differed only in the type of MHC -- major histocompatibility complex -- antigens on their cells," remarks Zinkernagel. "We were able to show that the T cells had dual specificities: Not only were they specific for the type of virus, but also to some part of the host's own cell -- the MHC." This seminal paper on MHC-P.C. Doherty, R.M. Zinkernagel, "Immunological surveillance against altered self components by sensitized T lymphocytes in lymphocytic choriomeningitis," Nature, 251:547-8, 1974-has been referenced in more than 1,000 subsequent publications. Emil Unanue The discovery of the association of MHC antigens with foreign proteins also helped explain Unanue's earlier discovery that "feeding protein antigens to macrophages actually resulted in a much stronger immune response [E.R. Unanue, B.A. Askonas, Journal of Experimental Medicine, 127:915, 1968]." Macrophages are cells that circulate in the bloodstream and engulf various foreign particles. Until his discovery, explains Unanue, "the dogma had been that an immune response to a protein occurred before it was taken up by the cells and digested." His finding proved that macrophages played a role in presenting foreign proteins to the immune system, rather than just clearing them from the system, as originally believed. Subsequently, Unanue also played a role in establishing that antigen-presenting cells are required to process the proteins intracellularly and then transport them to the surface to bind with the MHC antigens, where they would be recognized by the immune system. His most highly referenced paper -- E.R. Unanue, P.M. Allen, "The basis for the immunoregulatory role of macrophages and other accessory cells," Science, 236:551-7, 1987 -- has been cited more than 750 times. Jack Strominger Strominger and Wiley were honored by the Lasker foundation for their role in elucidating the crystal structures of the MHC molecules, along with their peptide complexes. The importance of these structures is that "we could immediately see exactly how the molecule worked. It clearly showed the groove where the peptides could bind to the MHC molecules and how it was possible for different peptides to bind," declares Wiley, whose lab studied the crystallography of the structures following biochemical work by Strominger's lab, which gave them the means to isolate sufficient quantities of the proteins. The first papers from Wiley's lab describing the crystal structures of MHC molecules -- P.J. Bjorkman et al., "Structure of the human class-I histocompatibility antigen, HLA-A2," Nature, 329:506-12, 1987; and P.J. Bjorkman et al., "The foreign antigen-binding site and T-cell recognition regions of class-I histocompatibility antigens," Nature, 329:512-18, 1987 -- have been cited in nearly 2,000 subsequent articles. Several other papers to emerge from these laboratories since then have also been cited highly. "I think our work has been useful because it allows immunologists to think more clearly and accurately on how the immune response works," Wiley asserts. "It has an impact on understanding not only bacterial and viral infections, but also tissue transplantation, and, increasingly, the immune response to tumor growth," he adds. This year's basic research winners hail from highly diverse backgrounds, both geographically and academically. Doherty, 55, trained as a veterinary surgeon at the University of Queensland in Australia -- receiving a BVSc. in 1962 and an MVSc. in 1968 -- before getting a Ph.D. from University of Edinburgh, Scotland, in 1970. From 1972 to 1975 he was a research fellow at the John Curtin School of Medicine, Canberra, Australia. While there, he collaborated with Zinkernagel on their award-winning discoveries. Since then, he has held appointments in both the United States and Australia. Among numerous honors, he was elected a fellow of the British Royal Society in 1987, and was also a winner of the prestigious Gairdner Foundation International Award in 1986. Like the Lasker, the Gairdner award is considered a "Nobel predictor" prize. Zinkernagel, 51, received an M.D. from the Faculty of Medicine at the University of Basel in 1968, and completed a postgraduate course in tropical medicine at the University of Zurich in 1971. He worked at the John Curtin school as a visiting fellow in the department of microbiology from 1973 to 1975. during this time he also obtained a Ph.D. degree from the Australian National University. He was a scientist in the department of immunopathology at the Scripps Clinic and Research Foundation, La Jolla, Calif., from 1976 until 1979, when he joined the University of Zurich. Among his international honors, he has also been a recipient of a Gairdner award. A native of Cuba, Unanue, 61, obtained his M.D. from the University of Havana School of Medicine in 1960, before coming to Presbyterian University Hospital in Pittsburgh as a medical intern in 1961. He received his research training at the Scripps Clinic and the National Institute for Medical Research in London. From 1970 to 1984, he served as a professor of pathology and immunology at Harvard Medical School, and has held his present position at Washington University since 1985. He has been a member of the National Academy of Sciences since 1987 and a fellow of the American Academy of Arts and Sciences since 1989. Strominger, 70, graduated with an M.D. from Yale University in 1948, interning and doing research at the Washington University School of Medicine from 1948 to 1951. He subsequently worked there from 1955 to 1964, and then moved to the University of Wisconsin Medical School as a professor of pharmacology until 1968, when he came to Harvard. He was elected to the National Academy of Sciences in 1970 and the American Philosophical Society last year. Like Doherty and Zinkernagel, Wiley, 55, is a winner of a Gairdner award. He holds a Ph.D. in biophysics from Harvard (1971), where he has held the positions of assistant, associate, and full professor of biochemistry and biophysics. Since 1987, he has also been a Howard Hughes Medical Institute investigator at Harvard. He was elected to the National Academy of Sciences in 1991. The winner of the clinical award may perhaps be best remembered for his rather unorthodox methods of research. "I couldn't successfully infect animals to test the pathogenicity of the bacteria -- so I did the experiments on myself," relates Marshall, recounting that he orally ingested the bacteria and "was sick for a week or two after that." His initial interest in the subject was sparked when "doing a rotation in gastroenterology," as a medical registrar at the Royal Perth Hospital in Australia. He was able to establish a connection between the occurrence of gastritis and the presence of novel spiral organisms in the gastric fluid. These organisms were later named Helicobacter pylori. Marshall subsequently developed a rapid enzyme test to detect the bacterium, and also worked out an antibiotic regime for curing the ulcers. His seminal paper identifying the ulcer-causing bacteria has been cited nearly 750 times (B.J. Marshall, J.R. Warren, "Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration," Lancet, 1:1311-15, 1984). Marshall obtained his bachelor's degree in medicine from the University of Western Australia in 1974 and worked in Australia as a physician until 1986. Since 1986, he has been a physician at the University of Virginia. Marshall has also been named as the winner of the 1995 John Scott Award by the city of Philadelphia, to be presented November 16 at the American Philosophical Society. The Lasker Foundation's Public Service Award was established with the intent of honoring individuals who have promoted the cause of medical research in the government, or have been instrumental in enhancing the public's awareness of advances in medical sciences and public health via lay publications or television. Past winners have included Huntington's disease researcher Nancy Wexler in 1993, scientist and writer Lewis Thomas in 1989, and medical advice columnist Eppie Lederer -- Ann Landers -- in 1985. Mark Hatfield This year's winner, Sen. Hatfield, was recognized for his energetic support of biomedical research in Congress. During his appropriations committee chairmanship from 1981 to 1987, funding for the National Institutes of Health increased at an average rate of 10 percent per year, despite federal cutbacks in other departments, and proposed cuts of the NIH budget. He was responsible, along with Sen. Tom Harkin (D-Iowa), for shaping the Harkin-Hatfield amendment in 1993, which, had it been passed, would have established a stable, non-appropriations-based fund for health research (B. Spector, The Scientist, Nov. 14, 1994, page 8). (The Scientist, Vol:9, #20, pg., 8 , October 16, 1995) (Copyright © The Scientist, Inc.)

Five Immunologists Garner Lasker Awards

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