The 1999 Lasker Awards

Editor's Note: This year's winners of the Albert Lasker Medical Research Awards were honored for their achievements at an Oct. 1 luncheon at the Hotel Pierre in New York. Three researchers were recognized for their work on ion channels, two for their development of a novel hypertension medication, and one for a lifetime of contributions to neuroscience. Following are three stories on the winners. More information is available on the Web at www.laskerfoundation.org. Basic Award Recognizes Ion Channel Research Two of this year's Albert Lasker Basic Medical Research awardees, Bertil Hille and Clay Armstrong, conceived of a remarkably simple model for the mechanisms governing the body's ion channels--pores in cells that facilitate all electrical signals--and therefore all thinking and movement. A third awardee, Roderick MacKinnon, confirmed and expanded on that model by using X-ray crystallography to supply a picture of the potassium channel. In the 1950s, Sirs Alan Lloyd Hodgkin and Andrew Fielding Huxley started to elucidate the ionic mechanisms involved in excitation and inhibition of the nerve cell membrane. Through studies in the squid giant axon, Hodgkin and Huxley, who jointly garnered the Nobel in physiology or medicine in 1963, discovered how electrical conductance controls the action of nerve cells. But they hadn't proposed a physical mechanism, a molecule-based concept for what the membrane was doing. "A lot of people didn't care," said Hille, a professor of physiology and biophysics at the University of Washington. "But both Clay and I imagined molecules. We didn't know particularly what molecules, but we were thinking in terms of billiard balls and machines and wanted to realize it as a mechanical device." Hille and Armstrong, now a professor of physiology at the University of Pennsylvania, began working on the problem independently in 1964. They theorized that there must be separate, selective pores on the axon membrane to select for sodium or potassium. But it wasn't possible to actually see the ions in action, only to detect the electric current they produced. "It was entirely a black box problem," Hille explained. Armstrong devised a model for how ion channels control the movement of ions, and Hille worked on the mechanism of channel selectivity. From left (top): David W. Cushman, Seymour Kety, and Miguel A. Ondetti; (bottom) Bertil Hille, Clay Armstrong, and Roderick MacKinnon Armstrong was the first to suggest that drugs may block ion channels by physically plugging the pores. In the 1970s, his team developed its findings into a theory called the "ball-and-chain" model, which held that channels had one-way valves. Ions, triggered by a change in voltage, enter the cell by knocking out the peptide "ball" that corks the channel, and remain in the cell once the charge has ceased and the channel is recorked a millisecond later. Initial doubts as to the model's validity were wiped away when researchers confirmed it years later. Hille first investigated ion channel selectivity by using neurotoxins to alter channel function in frog nerve axons. He was able to block sodium channels while leaving potassium channels open--and vice versa. "I took it to be an argument that sodium and potassium channels aren't the same hole." He later illustrated channel recognition by showing how channels are sized to accept a particular ion type. "I sort of felt like I was an ion and I was walking through this corridor and it was getting narrower and I had to sort of map out where the bumps were." Hille went on to describe the molecular interaction of local anesthetics and sodium channels. The work of Armstrong and Hille drove MacKinnon, now a professor at the laboratory of molecular neurobiology and biophysics at Rockefeller University, to work on ion channel structure. When he started his research in the early 1980s, MacKinnon, then at Harvard, worked on cloned ion channels, mutating them to test for gating and selectivity. "He was doing just wonderfully," said Hille. "And then suddenly he bagged the whole thing." Reasoning that his ultimate objective was to go after the structure of the pore, MacKinnon decided take a riskier, more direct approach. In a bold career move, he took a position at Rockefeller and began the tricky and laborious task of crystallizing the potassium channel, a process which, at the time, he knew very little about. But the gamble paid off just last year when his group found the potassium channel structure.1 MacKinnon points out that the results were much more than confirmatory. "Most of the features of the channel no one could have ever put together without seeing it." "I think we're just at the beginning of the study of ion channels," Armstrong said in accepting his award. "There are legions of channels whose specific functions have yet to be elucidated. And we also have to think of the interaction of ion channels with other proteins." 1. R. MacKinnon, "The structure of the potassium channel: molecular basis of K+ conduction and selectivity," Science, 280:69-77, April 3, 1998. Roderick MacKinnon Seymour Kety Wins Lifetime Achievement Award Fifty years ago, one man began research that would go a long way toward anchoring the field of psychiatry on more solid biological footing. This year's winner of the Albert Lasker Award for Special Medical Research Achievement, Seymour Kety, performed two key studies that would help demonstrate that mental disorders are influenced by biology and genetics, and not just environment as was widely believed at the time. Kety was also the inaugural scientific director of the National Institute of Mental Health (NIMH). Kety's first major accomplishment: using nitrous oxide to measure blood in the brain and identify brain regions that receive more or less blood in various psychological conditions. His second: an elegant twin study that proved to both scientist and layperson the significant role of genetics in the onset of schizophrenia. "These discoveries came at a time when psychiatry was really focused on environmental contributions to mental illness," said current NIMH director Steven E. Hyman. "Many of the ideas were dominated by psychoanalytic thinking .... He really stepped outside of the dominant paradigm." Scientists had attempted previously to monitor cerebral blood flow by measuring oxygen consumption. But their method wrongly assumed that oxygen consumption remains constant, when in fact it varies with brain activities. Kety's technique, developed in 1945, got around this roadblock by tracking the clearance rate of nitrous oxide, an inert gas that's not metabolized by the brain. He then applied the technique to certain conditions: hypertension, to find out how high blood pressure affects blood flow in the brain; and schizophrenia, to compare healthy with severely schizophrenic patients. Here the technique had a serious limitation. "It turns out it takes just as much oxygen to think the irrational thought as it does to think the rational thought," notes Kety. Several seemingly opposed conditions demonstrated similar rates of cerebral blood flow. By focusing on total blood flow in the brain, the technique averaged out blood flow differences in different brain regions. Kety therefore proposed detecting regional blood flow by measuring or detecting a diffusible radioactive tracer. Subsequent animal experiments demonstrated the feasibility of this technique and provided the first evidence for the correlation between blood flow changes in the brain and brain metabolism. Kety's innovations laid the foundation for the now invaluable methods of functional brain imaging, positron emission tomography (PET) and single-photon emission computed tomography (SPECT). To prove genetic risk factors are associated with schizophrenia, Kety carried out twin studies in the 1960s on a population sample from Denmark, a country with a relatively homogeneous population and remarkably well-kept medical records. He found that the biological relatives of adopted twins with schizophrenia had a higher incidence of disorder than did their adopted families, which suggested that genetics play a large role in disease onset. This was welcome news for parents of schizophrenics who had been taught by psychoanalysts that their own poor child-rearing practices had caused the disease. According to Kety, it wasn't unusual for parents of schizophrenics to approach him after talks and say emphatically, "Thank you, thank you, Dr. Kety. I had been given the idea that it was my responsibility, that I caused the schizophrenia." But Kety's achievements extended outside of the laboratory. "The most important thing that I did was to establish the intramural program of research at the [NIMH]," he said, accepting his award at the luncheon. Although Kety had a hard time convincing veteran scientists to come to Bethesda to work for the government, many young investigators accepted the challenge. During his term as NIMH director, 1950-1956, Kety promoted basic research studies related to psychiatry. "We were more interested in good research than so-called relevant research," he said. As with his own scientific research, Kety had to overcome opposition in the field: "One good friend told me, 'Don't put another nail in the coffin of psychiatry.'" As it turns out, Kety's contributions did far more to enrich the field than to stifle it. Clinical Award Given for Blood Pressure Medication This year's winners of the Albert Lasker Clinical Medical Research Award, David W. Cushman and Miguel A. Ondetti, undertook a long and laborious search to find a new class of drugs now used by millions to treat hypertension and congestive heart failure. In the late 1960s, Cushman and Ondetti, both now retired research scientists from Bristol-Myers Squibb in Princeton, N.J., started working on angiotensin converting enzyme (ACE) inhibitors. They wanted to block the enzymes that turn angiotensin I into a peptide called angiotensin II, a vasopressor that raises blood pressure by constricting blood vessels and inducing the release of the salt-retaining steroid aldosterone. Cushman, an enzymologist, and Ondetti, a protein chemist, were actually assigned the task by Squibb on the advice of then Squibb consultant Sir John Vane, a 1982 Nobel Prize winner in physiology or medicine. Based on research done in a Royal College of Surgeons laboratory in London, Vane suggested that Squibb investigate the potential ACE-inhibiting power of peptides extracted from the venom of the Brazilian viper Bothrops jararaca. The venom induces a hemorrhagic shock that causes blood pressure to plummet, as was suggested by the deaths of several Brazilian banana plantation workers bitten by the snakes. "The marketing department was against the project," Vane recalled in an interview at the Lasker awards luncheon. "They were wrong, of course." But success didn't come easy for Cushman and Ondetti. Initial work with a novel ACE assay developed by Cushman yielded a nine-amino-acid peptide called teprotide. Although teprotide was a relatively effective ACE inhibitor in clinical trial patients injected with the drug, it was too large a molecule to be orally active. Widespread use wasn't feasible, and the project was shelved. In 1974, a little over a year later, Cushman and Ondetti restarted the project almost by happenstance. Cushman had come across a paper in the journal Biochemistry that described a new potent and specific inhibitor of the gastrointestinal enzyme carboxypeptidase A.1 He and Ondetti saw the promising possibility of designing an analogous simple chemical compound that could inhibit ACE. "We persisted even though our first effort looked to be incomplete and useless, because the clinical researchers told us that we [would] have a promising drug at the end of the rainbow," Ondetti said. But this time around, instead of searching for the structure of agents that could inhibit ACE, Cushman and Ondetti directed their attention toward the structure of the angiotensin converting enzyme itself. The end result was a small, orally active compound called captopril. "We thought it was a mistake," said Cushman of the first tests on captopril. The drug's inhibitory effects were so strong that Cushman and Ondetti initially assumed that they'd gotten the dilution wrong. Repeat tests suggested otherwise. Captopril entered clinical trials in 1977 and was approved by the Food and Drug Administration in 1981. According to Cushman, the drug, which initially brought in $1 billion a year and currently garners more than $500 million annually, has been a model for several subsequently developed ACE inhibitors. The team's success has also inspired other medical research teams to attempt so-called "rational drug design," the development of drugs based not on serendipity, but on a deliberate step-by-step investigation employing rational, chemical principles. "[Our] story's complicated," Cushman said, "but the real exciting thing that we've been able to do ... is see [our] very simple conceptions about nature turn into ... the development of a drug that saves a number of lives and continues to help people." 1. L.D. Byers, R. Wolfende, "Binding of by-product analog benzylsuccinic acid by carboxypeptidase A," Biochemistry, 12:2070-8, 1973. Eugene Russo can be contacted at erusso@the-scientist.com.

The 1999 Lasker Awards

Basic Award Recognizes Ion Channel Research

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