International Gairdner Awards Honor Six For Medical Science Achievements

Last Friday, the 1991 Gairdner Foundation International Awards were presented in Toronto to six scientists--three from the United States, two from England, and one from Canada. The winners, each of whom received a $30,000 prize and a small statuette, come from a cross-section of disciplines. They were recognized for contributions to medical science ranging from the growth and functioning of blood vessels and their constituent cells to the invention of a revolutionary technique for copying pieces of DNA. M. Judah Folkman, a Harvard Medical School professor associated with Children's Hospital in Boston, was cited for his contributions to the study of angiogenesis, the growth of blood vessels. Folkman's work has profound implications in the control of malignant tumors, since these tumors co-opt the body's own angiogenic processes in order to create networks of blood vessels for nourishment. Folkman's work, which began in the early 1960s when he was drafted into the Navy as a surgeon, drew a great deal of skepticism early on. "The major hurdle was changing people's minds," he recalls. "In the 1960s, it was widely believed that tumors simply widened the host blood vessels. Nobody thought that the tumors could stimulate new vessels." Folkman first hypothesized in the early 1960s that tumor growth was contingent on a supply of blood vessels, but it was several years before he could prove his theory. One of the first, and toughest, steps was developing a technique for growing endothelial cells (the cells that line blood vessels) in vitro. This task alone took Folkman and his team five years of trial and error. Today, he notes, 30 to 50 scientific papers published each week have endothelial cells in their titles, and "all of these are [grown] in vitro." Over the next several years, Folkman and his colleagues advanced and refined the techniques allowing them to study angiogenesis. The first blood vessel-promoting factor was discovered in 1983 in Folkman's lab. Since then, several more have been identified. Folkman explains that angiogenesis is highly regulated in normal body processes, such as wound healing and ovulation; after several days of brisk blood vessel growth, the process is turned off. When tumors become malignant, however, "they just pour [growth factors] out of the cell. New blood vessels come in, and the tumor can expand." In fact, he adds, "a tumor's ability to metastasize is also angiogenesis-dependent." Folkman's lab is now investigating the switching mechanisms for this process. Angiogenesis is now being targeted as a means to treat cancer. Folkman explains that angiogenesis inhibitors could be used to suppress tumors without the painful and dangerous side effects of conventional cancer therapies. Since complete turnover of endothelial cells in the human body can take up to 10 years, but only 5 to 6 days in tumors, drugs that inhibit angiogenesis would have a minimal effect outside of the tumor itself. An inhibitor isolated from a fungus by Donald Ingber, an associate professor in Folkman's lab, is being readied for clinical trials in association with the National Cancer Institute. Folkman expects angiogenesis control to have other therapeutic applications as well. Clinical trials using angiogenesis promoters to speed wound healing are under way at the University of Texas at Galveston, and angiogenesis inhibitors are being investigated for use in the treatment of arthritis, he says. Folkman, a surgeon at Children's Hospital and director of the Surgical Research Laboratory there, is the only M.D. included among this year's Gairdner Award winners. He says that the interaction between research and patient care is an integral part of his work. "I'm driven by a lot of children in this hospital here, dying of cancer," he says. "Just that fact that you're doing research gives [the children's parents] hope." Folkman, Julia Dyckman Andrus Professor of Pediatric Surgery at Harvard Medical School, earned his M.D. there in 1957, and served most of his residency at Massachusetts General Hospital. He joined the faculty of Harvard Medical School in 1967. Last year he was elected into the National Academy of Sciences and the Institute of Medicine. Robert F. Furchgott, University Distinguished Professor at the State University of New York's Health Science Center at Brooklyn, also received a Gairdner Award for research relating to blood vessels. His discovery and characterization of endothelium-derived relaxing factor (EDRF) has provided a foundation for a broad range of cardiovascular research. In 1980, Furchgott discovered that the thin layer of endothelial cells that lines blood vessels produces a substance that causes the underlying smooth muscle to relax. Furchgott and others then identified EDRF as nitric oxide. EDRF has since been implicated in other cardiovascular processes. It may slicken the walls of blood vessels, discouraging the adhesion of clot-forming platelets in the blood, and it may also inhibit cell growth that contributes to atherosclerosis. Researchers around the world are now investigating the role of EDRF in cardiovascular functioning, and the processes that control the balance of vasoconstriction and vasodilation. Furchgott earned his Ph.D. in biochemistry at Northwestern University in 1940. He held positions at Cornell University Medical College and Washington University School of Medicine in St. Louis before joining the department of pharmacology at SUNY's Brooklyn Health Science Center in 1956. David H. MacLennan, J.W. Billes Professor of Medical Research at the University of Toronto, was honored by the Gairdner Foundation for his contributions to the understanding of muscle membranes and the chemistry of muscle contraction. Muscle contraction is governed by the concentration of calcium in the muscle cell. A high concentration of calcium causes the muscle to contract. After contraction, the calcium is pumped into the sarcoplasmic reticulum (SR), an organelle in the muscle cell that functions as a storage compartment. The calcium remains sequestered until an electrical impulse from a nerve cell triggers another contraction, stimulating the release of calcium from the SR so that the cycle can begin anew. MacLennan isolated and identified nearly all of the major functional proteins of the SR responsible for pumping the calcium into the SR, storing it, and releasing it. The first SR protein that MacLennan isolated was calcium ATPase, also called the calcium pump. After accomplishing this in 1969, he went on to isolate several other calcium-binding proteins, including calsequestrin, which binds calcium during the storage phase, cal-reticulin, and sarcaluminin. In the 1980s, MacLennan and colleagues cloned the DNA encoding many of these proteins, allowing them to express the proteins for further studies. In more recent work, MacLennan's lab has cloned and sequenced the gene encoding yet another SR protein, the calcium- release channel. This protein opens to allow calcium to flow out along a concentration gradient into the cytoplasm of the cell so that muscle contraction can occur. MacLennan has also demonstrated the involvement of this protein in malignant hyperthermia, a hereditary, potentially fatal condition marked by a severe reaction to anesthetics used during surgery. Patients with malignant hyperthermia probably have a mutation in the gene encoding the protein, allowing the uncontrolled release of calcium into the cell, says MacLennan, causing the rigid muscles and dangerously rapid rise of body temperature (up to 117 degrees Fahrenheit) typical of the condition. While this condition has been treatable during surgery for many years, MacLennan would like to develop a diagnostic genetic test for the disease that could identify people with the condition prior to experiencing a dangerous reaction. However, this will be a difficult undertaking, says MacLennan, since there are probably several mutations responsible for the condition. MacLennan received his Ph.D. in biochemistry from Purdue University in 1963. He was on the faculty of the University of Wisconsin from 1964 until 1969, when he joined the University of Toronto. The remaining 1991 Gairdner Award winners were recognized for their contributions to molecular biology. Two, Sydney Brenner and John E. Sulston, shared a citation for establishing the nematode Caenorhabditis elegans as a model for studying the genetic control of development (The Scientist, Sept. 30, 1991, page 23). Brenner, director of the Medical Research Council's molecular genetics unit in Cambridge, England, began work with C. elegans in the mid-1960s, when he recognized the need for an experimental organism simple enough to study its genetics and development in extensive detail. C. elegans, with a limited and fixed number of cells (959) and a transparent body allowing observation of cell division, fit the bill. By the time Sulston, a staff scientist at the MRC, joined Brenner's lab in 1969, Brenner had already done extensive work on the genetics of the organism. Sulston was one of a group of researchers who worked with Brenner investigating various aspects of C. elegans. By painstakingly observing and recording every cell division that the organism underwent during development, Sulston and colleagues drew up a lineage map indicating the genealogy of each cell. By 1983, the group had successfully mapped the genome of the organism. Sulston says that it is important to recognize the role of technology in the success of their work. "Very often a lot of work in biology is technology-driven," he says. Important to Sulston's work was the development of the differential interference contrast microscope. This microscope, which simultaneously passes two beams of polarized light through a subject, achieves great contrast but requires no stains or other invasive procedures. "The effect is, you see a beautiful, seemingly shadowed landscape," says Sulston. "The thing is quite happy to continue living and growing in the beam." Sulston and his team at the MRC are now sequencing the genome of C. elegans. He says that they have sequenced about 0.1 percent of the 100 million base pairs that make up the genome. Sulston earned his Ph.D. at the University of Cambridge in 1966. Brenner completed his doctoral degree at Oxford University in 1954, and joined the MRC in 1957. Brenner also received a Gairdner Award in 1978 in honor of his fundamental contributions to molecular biology. In the early 1960s, Brenner proved the existence of messenger RNA; he proposed that a single amino acid is coded by a sequence of three nucleotides; and he demonstrated that a particular triplet, known as the "nonsense codon," signifies the end of a translation process. Brenner and Frederick Sanger, who won Gairdner Awards in 1971 and 1979, are the only two people to win the Gairdner Award more than once. The sixth 1991 Gairdner Award went to Kary Mullis, now a private consultant based in La Jolla, Calif. Mullis invented the polymerase chain reaction (PCR), a technology for copying sequences of DNA that has revolutionized genetics and molecular biology. Mullis developed PCR in 1983, when he worked for Cetus Corp. in Emeryville, Calif. PCR allows the rapid and unlimited amplification of a sequence of DNA. In contrast, traditional cloning methods are slow, tedious, and often unsuccessful. The technique, which takes place in a test tube, relies on a heat-stable DNA polymerase called Taq1, extracted from Thermus aquaticus, a bacterium that lives in deep-sea thermal vents. After a piece of target DNA is denatured, separating its two strands, short primer oligonucleotides, complementary to sequences at opposite ends of the target sequence, are introduced. Taq1 and a mixture of nucleotides are added, and the enzyme attaches the free nucleotides onto the single strands of target DNA, creating two identical strands of DNA where there was just a single strand. These strands then serve as templates for the next round. Twenty PCR cycles can generate one million copies of a single sequence of DNA in a relatively short period of time. Since PCR was introduced in 1985, it has furthered a wide range of biotechnology and molecular biology research. It has been used, for example, to identify mutations in human disease-related genes, to amplify tiny samples of genes for forensic analysis, and to speed diagnostic tests for diseases such as AIDS. Mullis joined Cetus in 1979 and left the company in 1986. In 1987 he established his own biotechnology consulting firm, the La Jolla-based Nucleic Acid Chemistry Co. He earned his Ph.D. in biochemistry at the University of California, Berkeley, in 1972. The Gairdner Foundation was established in 1957 by James Arthur Gairdner, a Canadian stockbroker and industrialist. The awards were initially given to researchers in the fields of arthritis, rheumatism, and heart disease, but have since expanded to recognize achievements in a wide range of areas. Of the 218 scientists who have won the awards since 1957, 39 have subsequently received a Nobel Prize. This year's Nobelists in physiology and medicine, Erwin Neher and Bert Sakmann, who shared the Nobel for their development of patch-clamp technology, allowing the observation of cellular ion channels, both won Gairdner Awards in 1989.

International Gairdner Awards Honor Six For Medical Science Achievements

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