Abstract
Seymour S. Kety, M.D.: 1915–2000
For God's sake, let us sit upon the ground And tell sad stories of the death of kings.
—William Shakespeare
Richard II
Seymour Solomon Kety, Honorary President of the International Society for Cerebral Blood Flow and Metabolism and Honorary Editor of this journal, died May 25, 2000. This is one of those sad stories for he was in every respect a king, crowned not by divine right but by his legendary scientific achievements, outstanding statesmanship, and magnanimity of spirit. I knew Seymour for approximately 56 years as a teacher, preceptor, collaborator, colleague, and friend, and in every one of those roles he earned a level of esteem often afforded to royalty, not just from myself but from many others. He graced every field in which he worked and those with whom he worked. I know of no scientist who was so universally respected, admired, and even loved. Neuroscience has suffered a great loss.
Seymour was born in Philadelphia, August 25, 1915, and raised there in rather humble but intellectually stimulating surroundings. Residual physical limitations derived from an automobile-inflicted injury in his childhood directed him further toward intellectual pursuits, particularly in chemistry. He received all of his formal education in Philadelphia where he attended Central High School, one of the city's premier high schools, and then the college and medical school of the University of Pennsylvania. After graduation from medical school in 1940 he served a rotating internship at the Philadelphia General Hospital. It was while in medical school and later during his internship that he made the first of his many major contributions to medical science, that is, the use of citrate in the treatment of lead poisoning. Citrate forms a soluble chelate of lead that accelerates its urinary excretion. Better and more effective chelating agents are now in use, but this was the first proof of principle that chelating agents can be used in the treatment of heavy metal intoxication.
Seymour's interest in lead poisoning led him to seek and to obtain a National Research Council post-doctoral fellowship with Joseph Aub, a well-known researcher on lead poisoning at the Massachusetts General Hospital (MGH) in Boston, Massachusetts, U.S.A. By the time he arrived there in 1942, the U.S. was at war, and Aub had abandoned his work on lead poisoning switching to traumatic and hemorrhagic shock. It was there that Seymour developed an interest in circulatory physiology, particularly the cerebral circulation, which appeared to be relatively preserved in shock by regulatory mechanisms that adjusted the distribution of the reduced cardiac output to favor the brain, heart, and lungs at the expense of less vital circulatory beds. To pursue this interest he elected to forego the opportunity to remain at Harvard and in 1943 returned to The University of Pennsylvania to work with Carl Schmidt, a leading figure in the field of the cerebral circulation, who had just published his bubble-flow meter technique for the quantitative determination of cerebral blood flow (CBF) and metabolism in anesthetized monkeys. Seymour's wife Josephine, whom he married after graduation from medical school, was also a physician and a Philadelphia native. Their desire toreturn to their roots was probably also a factor in this decision.
Seymour was an instructor in Schmidt's Department of Pharmacology when I first met him in 1944 as a member of his first class in Pharmacology. He was an excellent teacher who presented lucid, stimulating lectures that emphasized the experimental procedures and findings underlying the conclusions. I still remember how he made even a lecture on analgesics exciting. He was popular with the students and readily accessible to them. As he was not much older than we were, he often joined some of the members of our class on the patio of Houston Hall, the Student Union, where we usually congregated after lunch. It was in casual conversations on those occasions that we learned of his interest in the cerebral circulation. He discussed the sampling of cerebral venous blood from the internal jugular bulb and may have been soliciting us to volunteer for the procedure, though without success.
At the 1944 annual FASEB meeting there was a symposium on the cerebral circulation that focused primarily with the methodology of its measurement. The dominant theme that emerged was the need for a quantitative method for determining CBF, and preferably one applicable to unanesthesized humans. At the time there were nonquantitative methods for use in humans. One was the thermoelectric flow recorder, a thermocouple in the form of a needle that could be inserted into the jugular vein to monitor changes in flow within the vein. Another was the measurement of cerebral arteriovenous O2 differences, which should vary inversely with changes in CBF if cerebral O2 consumption (CMRO2) remained constant, but could not distinguish between changes in CBF and CMRO2. The only method that quantitatively determined both CBF and CMRO2 was the bubble-flow technique of Dumke and Schmidt, and this method required not only anesthesia but such extensive surgery that its use was restricted to monkeys. Seymour attended this symposium and accepted the challenge with a unique and conceptually brilliant approach. He was aware of Cournand's application of the direct Fick principle to the determination of cardiac output in man. Cardiac output equals pulmonary blood flow, which was determined by dividing the rate of O2 uptake into the lungs by the pulmonary arteriovenous O2 difference. O2 uptake was determined by measurement of total body O2 consumption, and the pulmonary arteriovenous O2 difference was determined from measurements of O2 content in the systemic arterial blood and in the total body mixed venous blood sampled by catheterization of the right heart or pulmonary artery. Seymour reasoned that he could apply the Fick principle indirectly by introducing a chemically inert, diffusible tracer, that is, nitrous oxide, into the blood, measuring the cerebral arteriovenous N2O difference and determining the uptake of tracer into the brain. He experimentally showed that after approximately 10 minutes the brain and blood concentrations were close enough to equilibrium for brain N2O concentration to be determined from the cerebral venous concentration and the relative solubilities of N2O in brain and blood. The same principle applied to other chemically inert tracers, for example, radioactive krypton and xenon, which were used later in place of N2O. Because the method itself required sampling of arterial and cerebral venous blood, it was also relatively simple to determine from the determined CBF and their measured arteriovenous differences the brain's rates of utilization or production of oxygen, glucose, carbon dioxide, lactate, and so on. This ingenious concept resulted in the Kety-Schmidt N2O method for the measurement of CBF and metabolism in unanesthetized humans that, along with several of its applications, was published in 1948. Its impact was like a thunderclap that revolutionized research on the human brain. Numerous applications in neurology, psychiatry, and medicine led to much of our knowledge of the physiology and pharmacology of cerebral circulation and metabolism of the human brain in health and disease. Carl Schmidt, in whose department Seymour had developed the method, wrote, “…now, for the first time, the clinical physiologist is no longer at a disadvantage in studying the circulation in the human brain. As matter of fact he is now able to learn more about this, and its relation to the metabolic functions of the organ supplied, than about any other organ of the body. The change is one of the small profits of the research activities of the war years and is one more example of the benefits to be expected from giving brilliant young men opportunities to develop and test out original ideas.”
These papers were published while I was serving in the U.S. Army as a neuropsychiatrist and was undecided about what to do when I was released. The ability to study directly the human brain in healthy and mentally ill subjects was a strong attraction, so after leaving the army in 1949, I joined Seymour as a postdoctoral fellow in Julius Comroe's Department of Physiology and Pharmacology in the Graduate School of Medicine at Penn where Seymour was now a full professor. It was a fantastic experience. He was an inspiring leader. Despite his towering intellect, he never allowed it to overwhelm us. He was always humble and unpretentious and listened to everything we had to say. Often he would raise questions and patiently consider our comments even though, as we would later learn, he already knew the answers. His attitude stimulated us to think critically and deeply. A frequent comment of his was, “Well, think about it.” He valued conceptualization, originality, and uniqueness above all. In my first project on the effects of hyperthyroidism on cerebral O2 consumption, we were scooped in the publication of the surprising finding that CMRO2 was unaffected despite marked increases in total body O2 consumption. He reassured me with the comment, “Don't feel bad. It must not have been such a great idea. Someone else thought of it too.”
Seymour's office had two doors, one opening into the corridor and the other into the room where the fellows had their desks. The latter door was almost always open, and we constantly interrupted his work, which at that time was mainly on the preparation of his now classical and seminal Pharmacological Reviews article, “The Theory and Applications of the Exchange of Inert Gas at the Lung and Tissues.” One day in the summer of 1950, the door was closed while Seymour was meeting with two uniformed Coast Guard officers. All of us were curious and queried him about the purpose of their visit after they left. They were Robert Felix and Joseph Bobbitt, Director and Executive officer, respectively, of the newly formed National Institute of Mental Health (NIMH). They had come to offer him the position of Scientific Director of the Intramural Research Programs of both the NIMH and the National Institute of Neurological Diseases and Blindness (NINDB, now NINDS). When questioned whether he would consider such an offer, he indicated that he would indeed because he had always been interested in mental disease and that this would be a challenging opportunity to study it. We then asked why they would choose him, a physiologist and not a psychiatrist. He said that he had asked them the same question, and they had replied that it was for just that reason that they wanted him; they thought that the Scientific Director of a research program on mental disease should be a scientist and not a psychiatrist to ensure scientifically sound and rigorous research. After several months of deliberation, he accepted the appointment and in 1951 left Penn to undertake the organization of the Intramural Research Programs of the NIMH and NINDB.
The Clinical Center was soon to open, and Seymour had what he considered almost unlimited resources in space, budget, and positions. He approached the organization of the program in characteristic Kety fashion, cautiously, deliberately, systematically, and with great humility. He was uncertain about how best to study mental disease but had faith that more basic, fundamental knowledge of the structure and functions of the nervous system would be needed. Therefore, he emphasized basic science and relegated most of his resources to laboratories organized along more or less traditional disciplinary lines. He did not pretend to be expert in all the disciplines. Instead, he exhaustively consulted leaders in these disciplines to identify outstanding candidates whom he might recruit as laboratory chiefs. Once they were appointed, he gave them full authority and support to direct their own laboratories as they chose. Laboratory chiefs were selected not because they had been working in the latest, most fashionable, so-called “hot” research areas, but because they had demonstrated originality and abilities to recognize and solve good problems. He was not very impressed by wish-fulfilling descriptive research driven more by desire than by insight. His acumen in his selection of laboratory chiefs, as well as many of their staffs, was eventually confirmed; one won a Nobel prize, three received Lasker awards, and close to a dozen, if not more, were elected into the National Academy of Sciences.
While engaged in the organization of the research programs of the NIMH and NINDB, Seymour also collaborated with several biochemists in Europe and the U.S. in efforts to bring recognition and respect to the field of neurochemistry. Their efforts resulted in the initiation in 1954 of biennial Neurochemical Symposia, later transformed into the International Society for Neurochemistry, the founding of the Journal of Neurochemistry in 1956, and the establishment of the International Brain Research Organization in 1960.
Seymour had reserved a small amount of laboratory space for his own research. Because the nitrous oxide method measured only average blood flow and metabolic rates in the brain as whole, it could not localize changes in discrete regions of the brain. Therefore, he undertook the development of a method to measure local cerebral blood flow that was based on his theory of inert gas exchange between blood and tissues that he had previously derived. With the help of several research fellows, he ingeniously translated his theories into a functional method for measuring local CBF. The method could have been used with any freely diffusible, chemically inert tracer, but they settled on 131I-labeled trifluoroiodomethane, a gas with the requisite properties. Localization within the brain was achieved by a unique quantitative autoradiographic technique that limited its use to animals. The method and its use to determine local CBF in individual structural and functional units of the brain in conscious and anesthetized cats was first reported in 1955. When used to examine the effects of visual stimulation, the autoradiograms clearly visualized the increases in CBF in the visual pathways and provided the first examples of functional brain imaging.
Because the trifluoroiodomethane method was designed for use with autoradiography, it could be used only during uptake of tracer by the tissues. Its underlying principles, however, were equally applicable to clearance of tracer from tissues and had, in fact, been applied by Seymour in 1949 to the determination of blood flow in the muscle of humans by the clearance of 24NaCl from its site of injection. The 24NaCl method could not be used in brain because 24NaCl is not freely diffusible across the blood-brain barrier, but it was later adapted by Lassen, Ingvar, and colleagues for use with radioactive gases, first radioactive krypton and subsequently xenon. The 133Xe method has been used extensively and effectively as a clinical and research tool for several decades. More recently, the trifluoroiodomethane method has been resurrected for human use, but with 15O-labeled water as the tracer and PET scanning in place of autoradiography, and is widely used in the functional brain imaging of cognitive processes in humans. All of these fantastic new developments in neurobiology derived from Seymour's pioneering work.
In 1956, Seymour stepped down from the position of Scientific Director to become the Chief of the Laboratory of Clinical Science (LCS). Having completed organizing the Institutes' Intramural Basic Research Programs, he no longer felt challenged. As he put it, he no longer enjoyed the role of “deciding where to put the broom closets.” There were also other reasons. He had been impressed by developments in psychopharmacology, particularly those involving the monamine neurotransmitters and the actions of psychotomimetic drugs, such as LSD, mescaline, indole derivatives, and others. There were suggestions at the time that abnormal metabolites of amino acids or epinephrine might be involved in schizophrenia. There were a few reports that, although flawed and inconclusive, suggested genetic influences in schizophrenia. This information reinforced his suspicion that schizophrenia was a biochemical disorder. He, therefore, established in the LCS a program of research on the biology of schizophrenia. To carry out some of his studies he contracted for the first commercial synthesis of radioactive epinephrine and norepinephrine which later proved to be of immense value to Julius Axelrod, a member of the LCS, in his Nobel Prize winning research.
Seymour's research at the NIMH was interrupted in 1961 when he accepted the position of Chairman of the Department of Psychiatry at Johns Hopkins University. However, after one year he returned to his position as Chief of the LCS at NIMH and resumed his research on schizophrenia, this time focused on the question of genetic contributions to the disease. Previous studies had failed to disentangle convincingly the roles of “nature and nurture.” He conceived of the brilliant idea of studying the adoptive and biological family lines of schizophrenics who had been adopted at birth. The necessary data were available in the Danish Case Registry, and he, in collaboration with colleagues at the NIMH and in Denmark, initiated such studies. In 1967, he left NIMH for Harvard University where he first became Director of Psychiatric Research, MGH, then Director of Laboratories for Psychiatric Research, Mailman Research Center, McLean Hospital, and finally Professor of Neuroscience in the Department of Psychiatry. In 1983, he retired from Harvard and returned to the NIMH from which re-retired in 1996. Throughout all of these decades and all of his moves he continued his studies on adopted schizophrenics. The results demonstrated far greater incidence of the disease in the biological than in the adoptive family lines, thus providing unequivocal evidence of a major genetic component in the etiology of schizophrenia. These studies represent not only an outstanding contribution to our understanding of schizophrenia, but their underlying strategy and design provided a research model that has been followed in studies of a number of other psychiatric disorders.
Seymour Kety's legacy encompasses at least three different areas of his endeavors. As a physiologist, he made extraordinary contributions, primarily to the field of cerebral circulation and metabolism but with much broader ramifications. As a wise and adroit statesman, he developed at the NIMH and NINDB outstanding research programs in neuroscience, contributed substantially to the recognition of neurochemistry as a respectable and important field of neuroscience, was a powerful force for the development of biological psychiatry, and was a sage counselor serving on countless advisory boards and committees. Finally, as a psychiatric geneticist, he conceptualized and developed a model of study for distinguishing contributions of nature and nurture in the etiology of mental disease and used it to prove the existence of a strong genetically determined vulnerability to schizophrenia.
There is, in addition, Seymour Kety the man. His professional achievements gained him enormous international recognition and acclaim. He received many awards, honorary degrees, and honorary titles and was elected into some of the most honorific societies, including the U. S. National Academy of Sciences, the American Academy of Arts and Sciences, and the American Philosophical Society. In 1999, he received his last award, the Lasker Award for Special Achievement in Medical Science, which touched him deeply. However, none of these honors changed him. He remained the same humble, modest, self-effacing, unselfish, considerate, generous, and warm human being that he was when I first met him 56 years ago. He remained readily accessible to all and never used his razor-sharp intellect to overwhelm or intimidate. He was intensely loyal and supportive of his colleagues and truly relished their successes. Perhaps, he was kept humble by his wife Josephine, a master of one-liner repartee. For example, Seymour once expressed surprise that a new research fellow from India had appeared unimpressed when Seymour had proudly escorted him through NIH's newly opened Clinical Center, the world's largest all-brick building furnished with the most modern hospital facilities. Her response was, “Did you ever hear of the Taj Mahal?” When Seymour, as Scientific Director of the NIMH, was inclined to accept a free psychoanalysis paid for by the Institute, she asked, “Suppose they offered you a free appendectomy. Would you take it?”
The Ketys were generous and genial hosts and would often entertain at their home. These were always delightful experiences full of scintillating conversation and humor. Seymour had an enormous reservoir of jokes and amusing anecdotes that he enjoyed telling and occasionally used to make a point. The Ketys were great art lovers, and Seymour was enamored of good food and wine, particularly the traditional French cuisine. He lamented the subversion of the classical rich French sauces by the advent of the nouvelle cuisine or cuisine minceur.
Some of his fondest memories were of the great meals he had had in the 3-star restaurants listed in the Guide Michelin. In short, Seymour was as a great a human being as he was a scientist.
Seymour is survived by his wife Josephine (Gross) Kety, daughter Roberta Kety, son Lawrence Kety, and two grandchildren. He will be greatly missed not only by them, but also by his many colleagues and friends whose lives he influenced and enriched. As Stanton said about Lincoln, “Now he belongs to the ages.”