Albert Lasker Award
for Special Achievement in Medical Science

Award Presentation by Eric Kandel

Very few occasions in my professional life have given me quite as much pleasure as the privilege of introducing Seymour Kety today as the recipient of this year's Albert Lasker Award for Lifetime Achievement.

Seymour Kety has been the single most important influence on American psychiatry in the second half of this century. More than anyone else, he has changed the direction of psychiatry from a discipline embedded in social engineering and psychoanalysis into one embedded in biology and medicine. Kety's influence derives from two sources. First, from 1950 to 1956 he was the first scientific director of what was then the joint intramural program of the NIMH and NINDB. In that position he provided strong and imaginative leadership that tied psychiatric research inseparably to basic science. Second, he has made two fundamental contributions to brain science. Early in his career he developed the first reliable method for measuring cerebral blood flow. In so doing he laid the foundation for modern brain imaging. Later, he applied a novel variant of the family adoption methodology to the study of mental illness, and provided the first unequivocal evidence that schizophrenia is a genetic disease and not a defect in parenting as many psychiatrists at that time were advocating.

Let me begin at the beginning. Kety was born in Philadelphia in 1915 and attended Central High School, one of the historically great public schools in this country. He then went on to the University of Pennsylvania for both his undergraduate and his medical school studies. After an internship in Philadelphia General Hospital and a post-doctoral fellowship at the Massachusetts General Hospital, Kety returned to the University of Pennsylvania, where in Carl Schmitt's laboratory he began his now-classic studies of cerebral blood flow.

Prior to Kety's entry into the field, the metabolism of the brain, and particularly the blood flow to the brain, were poorly understood. In 1945, Kety changed all that by developing the nitrous oxide method, the first effective way for measuring cerebral blood flow. Using Fick's principle, Kety measured blood flow to the brain by observing the rate of clearance of this inert gas from the blood.

Mark Raichle, one of the pioneers of brain imaging, recently described the nitrous oxide method in the following terms:

"The impact (of the nitrous oxide method) on our understanding of the circulation and metabolism of the human brain… cannot be underestimated. Since its introduction almost four decades ago, it has been the standard for this field of research."

Kety used this method for cerebral blood, not only to study the normal physiology of the brain, but also to study disease. For example, Kety found that the brain, which comprises only 2 percent of the body weight, consumes more than 20 percent of the oxygen utilized by the body. He also found that there are major reductions in cerebral blood flow with anesthesia, trauma, and vascular disease. Surprisingly, however, Kety found that the overall blood flow was not altered in a large variety of conditions where one might expect such alterations. These conditions ranged from deep sleep, to being alert and carrying out mental arithmetic, to being mentally disorganized and suffering from schizophrenia. This led Kety to suspect that, with a global method such as nitrous oxide which measures blood flow in the whole brain, local changes restricted to specific regions of the brain might be overlooked. This caused Kety to search for ways of measuring regional blood flow. In a key article in 1951, Kety argued that it should be possible to measure regional blood flow in experimental animals by using autoradiography to measure the concentration of a diffusible radioactive tracer in the different regions of the brain. Alternatively, in humans one should be able to use a radioactive tracer in conjunction with a set of external detectors. Both of these ideas proved correct.

In 1955, Kety followed up on this idea in experimental animals. In collaboration with Louis Sokoloff, Lewis Rowland, William Landau, and Walter Freygang, Kety used I131-labeled trifluoromethane and autoradiography to visualize blood flow in 23 different regions of the cat brain. Even more interesting, they found that photic stimulation selectively increased blood flow to the various parts of the visual system. This provided the first evidence that changes in blood flow in the brain were related directly to brain activity and therefore presumably to the metabolism of the brain.

In 1977, Sokoloff carried the methodology for measuring regional metabolism one step further. He developed a technique for measuring regional glucose metabolism using radiolabeled 2-deoxyglucose, a non-oxidizable congener of glucose, whose utilization could be captured by radioautography. The deoxyglucose method made it clear that blood flow was indeed related to energy metabolism, and that regional metabolic activity could be used to chart the functional anatomy of the brain.

The idea of using metabolic imaging to trace neural activity in different regions of the brain made a tremendous impact on people's thinking. Most important, it laid the foundation for PET scanning, which made it possible to image brain function in intact, awake, thinking human subjects. In fact, the current methods for measuring regional cerebral blood flow in man with PET and SPECT are merely adaptations of the ideas, equations, and methods developed by Kety. Thus, Kety is generally recognized as the person who ushered in functional imaging of brain, a methodology which has revolutionized the study of mental processes by revealing their underlying anatomy and physiology.

In the 1960s, Kety turned his attention to the biology of schizophrenia and made a second major contribution: this time to the genetics of mental illness. During the 1950s and 1960s, psychiatry was dominated by psychoanalytic thinking, which attributed much of mental illness not to defects in the brain but to learned defects in behavior resulting from poor parenting. Part of the reason that the psychiatric community was so drawn to psychoanalysis was that, in the 1950s, the biology of mental illnesses in general and that of schizophrenia in particular were so impoverished. In a critical review of the literature on schizophrenia in 1959, Kety pointed out that there was only one biological finding in schizophrenia that seemed reliable. There was the evidence, first obtained by Franz Kalmann at Columbia, that schizophrenia ran in families and that monozygotic twins had a higher concordance for schizophrenia than did dizygotic twins.

Although the finding that schizophrenia ran in families was certainly compatible with the operation of genetic factors, the available data fell far short of proving it. Lots of things run in families. Wealth runs in affluent families and pellagra used to run in poor families. But neither of these is genetically transmitted. In fact, the family and twin data that existed in 1960 confounded genetic and environmental contributions, with the result that most psychiatrists dismissed Kalmann's finding and thought that schizophrenia was a style of aberrant thinking that children learned from their parents.

This all sounds bizarre in hindsight, and it created a terrible sense of guilt in the parents of children suffering from schizophrenia. But let me remind you of the historical setting for these social arguments. In the early days of human genetics at the beginning of the 20th century, a number of the major participants were eugenicists. This eugenic perspective was distorted by the Nazis and exploited by them to achieve racial parity. This exploitation was spearheaded by German psychiatrists who, even before Hitler came to power, had started to sterilize mentally defective and schizophrenic patients and wanted to extend these practices to their first-degree relatives. Franz Kalmann, a German-born psychiatrist who had provided much of the initial evidence for a genetic contribution to schizophrenia, came from the German school of psychiatry, and although he left Germany to escape the Nazis, his finding aroused suspicion and scorn. As a result, in the period following World War II, the idea that genes could influence any aspect of behavior was unacceptable to the vast majority of psychiatrists and to most people in American society at large.

Kety therefore tried to think of a rigorous way to disentangle genetic from environmental influences and realized that a well-designed adoption study would do just that. He appreciated that an adoptee shares his genetic endowment with his biological family, but he shares his environment with another family, his adopted family. If schizophrenia runs in families because of shared genes, schizophrenia should be found to occur more frequently in the blood relatives of schizophrenic adoptees, their biological parents, siblings, and half-siblings. But if, on the other hand, schizophrenia was caused by learning or other components of the family environment, it should be found more frequently in the foster family which raised the adoptee. Thus, by studying schizophrenic adults who were adopted early in life and raised by foster families, Kety could determine whether the schizophrenic adoptees acquired the genes of their blood relatives or learned the disease from their foster relatives.

Using an excellent sample from Denmark where the population is homogeneous and where there are excellent psychiatric records, Kety and his collaborators David Rosenthal and Paul Wender found that the blood relatives of adoptees who had developed schizophrenia showed a 12-fold greater prevalence of schizophrenia than did the blood relatives of normal adoptees. Moreover, there was no schizophrenia at all among the foster relatives who had raised the schizophrenic adoptees.

These studies permanently turned the tide in thinking about schizophrenia. They showed unequivocally that genetic factors play a key role in the etiology of schizophrenia and that rearing had no role in the development of the disorder. Finally, the studies also demonstrated that schizophrenia occurs along a phenomenological continuum, the schizophrenic spectrum, or schizotypal behavior. Kety found that many of the blood relatives of the schizophrenic adoptees were not overtly psychotic but were nevertheless odd; they were very suspicious and shy, clinically reminiscent of borderline schizophrenia. It is now clear that schizotypal behavior represents a group of non-psychotic borderline behavior patterns which cluster genetically with schizophrenia.

The introduction of the idea of a spectrum disorder has greatly altered thinking in clinical psychiatry about other types of mental illness because the design of adoption studies is simple and straightforward. Investigators in other areas employed it to study mood disorders, antisocial personality, alcoholism, and attention deficit hyperactivity disorder. In all of these disorders, the spectrum notion emerged. Kety himself extended these approaches to affective disorders, specifically unipolar depression, and he found an eight-fold increase in unipolar depression among biological relatives of depressed adoptees and a 15-fold increase in suicide among the biological relatives of depressed adoptees.

Let me end my comments by saying a word about Kety's leadership role. As the first Scientific Director of the NIMH, Kety created a powerful and original research program that brought together the very best in the biological and in the behavioral disciplines related to mental health. His leadership of the Intramural Program established a powerful scientific basis for psychiatry that the field still enjoys, while producing major advances in the basic neurosciences. Twenty scientists recruited to or trained in the basic science program were later elected to the U.S. National Academy of Sciences; among these are Louis Sokoloff, who went on to win the Lasker Award, and Julius Axelrod, who won the Nobel Prize.

Because of his extraordinary leadership capabilities, Kety, who had no clinical training in psychiatry, was invited to head one of the great psychiatry departments in the world, the Department at Johns Hopkins. He accepted this position and started to rebuild the department in a very exciting way. But towards the end of the first year, he began to think that his lack of clinical training was a handicap, and he resigned his position as Chairman at Hopkins and returned to a research position at the NIH.

When I asked him about this later, Seymour said, with typical modesty, "Look, I simply didn't know enough clinical psychiatry. A resident would call me up and say, 'Dr. Kety, I have a patient who is threatening to jump out the window. What shall I do?' I frankly didn't know what to say to that resident." To which I could not help replying, "Seymour, you are overestimating how much psychiatrists know. All you had to do was to tell the resident to shut the window!"

Finally, all of us who have interacted with Seymour Kety both at the NIH and later at Harvard were struck by one further trait that characterizes him as a colleague, as a mentor, and as leader of a scientific community, and that is his remarkable thoughtfulness and generosity of spirit, especially toward younger colleagues. It is for this reason that the Lasker Foundation and the scientific community at large take such pleasure in honoring Seymour Kety today, not for a single discovery but for a lifetime of contributions. For in honoring Seymour Kety, we are not only honoring the most important contributor to Biological Psychiatry of the second half of this century, but we are also celebrating a great human being and a great style of research. We are here recognizing a specific example of how the best in personal and scientific values can be achieved.