Part 2: Lead Poisoning
A summer job steers Dr. Kety toward work on lead poisoning. During his residency at Philadelphia General Hospital, he publishes a paper on the lead citrate complex ion and its role in the transport of lead in the body. After winning a National Research Council Fellowship, he goes to Boston to work with Joseph Aub.
Kety: Then I got a job for the summer with a toxicologist in Philadelphia, who, among other things, had me doing urinalyses and blood studies and so forth for him. He had a little medical laboratory, but he was also a toxicologist, and he had a contract with some lead company to examine their employees for lead exposure. He had me doing the tests for lead, which consisted in precipitating the lead as a lead salt—lead chloride, I think—and then dissolving that with sodium citrate, which formed a complex ion with lead and dissolved it. It was that process which…
Kandel: Must have gotten you interested later on in lead poisoning.
Kety: It did. It got me interested in lead poisoning, but the reason it did was because I got interested in this citrate complex with lead. This was the first chelation of lead, and I thought, you know it might be possible to remove lead from the bones of patients who have lead poisoning.
Kandel: Now let me interrupt you for a second, Seymour, because I don’t know anything about this history. Were you the first one to ever discover the process of chelation?
Kety: Well, no. I guess chelation is simply finding a complex with a metal, a complex which was highly associated, has a very low dissociation constant or high association constant, so that it grabs onto the metal and keeps it in solution as a complex ion. That’s chelation. That’s a chemical process that had been known for years.
Kandel: Right. You thought of it as a way of, number one, binding lead and, number two, using it as a way of treating lead poisoning.
Kety: Exactly. And as a matter of fact, as an intern in medical school (as a medical student), I did an experiment with rats, feeding them lead and then letting them drink water which was salted with sodium citrate and then measuring the lead output in their urine. And I was very gratified to find, when I analyzed the urine, that they had put out a huge amount of lead after the citrate. That was my first sort of “ah, ha” experiment, which was very gratifying and very interesting. And I reported that at the research day at Penn. In any case, when I got to residency (internship), I had some time on my hands…
Kandel: Now the residency (internship) was still at the University of Pennsylvania?
Kety: No, it was not. The residency was at the Philadelphia General Hospital. No, I didn’t get into the University of Pennsylvania Hospital, as a matter of fact. That year, for some reason or other, although I was third in the class because I didn’t do too well in some of the clinical subjects—I was third in the class, and I was not accepted in the hospital at the University of Pennsylvania. In fact, no Jewish student was accepted that year. When you break down the list, it excluded all the Jewish students, which was rather shocking. But I went to Philadelphia General, which was a fine residency. There I had time to work on the lead citrate complex. And I studied the complex in the laboratory, measuring its association constant and some of its physical chemical parameters.
My first paper was a paper that I published in the Journal of Biological Chemistry on the lead citrate complex ion and its role in the transport of lead in the body. Because I then calculated, after finding the association constant, I found that the citrate concentration in blood with a normal diet was enough to carry a good fraction of the blood lead as lead citrate complex, and, therefore, if one were to increase the citrate concentration in the plasma, one would carry a proportionately larger amount of lead. So I did that. I treated patients, men with lead poisoning, with sodium citrate and measured the lead in their urine and found, gratifyingly enough, that the citrate increased the excretion of lead. I did this with a help of a biochemist at the hospital, Letonoff, who did the lead analyses and was extremely helpful and very supportive.
On the basis of that work, I won a National Research Council Fellowship. I was interviewed by Blalock, I remember, and I won that fellowship because I hoped to be able to use it to go to Boston and work with Joseph Aub, who was the great authority on lead poisoning. I got the fellowship, and Aub was happy to accept me in the laboratory. And then America entered the second World War, and I applied for service in the armed forces, but was rejected because of residual from the old accident and the osteomyelitis.
So I then went up to Joe Aub’s laboratory, and by that time Aub told me that, unfortunately, he was not working on lead poisoning, and I wouldn’t be working on lead poisoning much because that whole laboratory, because of the war, had turned its attention to shock. And so we worked on shock. And in Joseph Aub’s laboratory—and by the way Aub was a remarkable mentor, very wise, very fair, very supportive, very sensitive and sensible and a great man. It was a wonderful experience to be with him. His fame was not really in lead poisoning. It was in metabolism and in cancer etiology. In fact, he was head of a large laboratory at the Huntington Memorial Hospital, which was a hospital dedicated to cancer, which eventually—before I got there—became consolidated in the Massachusetts General Hospital.
Kandel: I somehow also think of him in calcium metabolism. Didn’t he have something to do with Albright…
Kety: Yes, well, he did some work with Albright, and was there with Baird Hastings. Hastings was the calcium metabolism man. It was in Aub’s laboratory that I met Zamecnik and Alfred Pope. Zamecnik was in Copenhagen at that time working with Linderstrom-Lang and becoming trained in some of the enzymatic biology that Linderstrom-Lang was famous for. And so he was away most of the time that I was in Aub’s lab, but he returned for the last third of my visit, and we became very close friends and admirers of each other. Alfred Pope was a postdoc in Aub’s laboratory at the same time that I was there, and we got to know each other very well because we were the two lowest men on the totem pole. We were assigned the scut work. We would stay up late at night taking care of the dogs, which had been put into shock, and doing blood pressures and taking samples and all that kind of thing.
Part 3: World War II Studies on Shock
Dr. Kety goes back to Philadelphia to work in the laboratory of Carl Schmidt, measuring blood flow in monkeys. He devises the nitrous oxide method to calculate blood flow in humans.
Kety: We became very much interested in the homeostatic reflexes that occurred in shock, the obvious teleological purpose of which was to preserve the blood flow to the brain and to the coronaries at the expense of blood flow everywhere else in the body. We wrote a review of this topic emphasizing these homeostatic reflexes and their purpose to save the circulation of the brain, mainly, which was published in the American Heart Journal. That review got me very much interested in (cerebral) circulation. And it happened also that I read a paper in the American Journal of Physiology by Dumke and Schmidt. Dumke was a junior scientist working with Carl Schmidt. Carl Schmidt had been my professor of pharmacology at Penn.
So that Dumke and Schmidt paper measured the cerebral blood flow in the rhesus monkey by inserting a bubble flow meter into the carotids. And they made the first measurements of cerebral blood flow in primates, which was quite an accomplishment. Well that impressed me very much. And since I planned to go back to Philadelphia when I finished my fellowship, I wrote to Schmidt and asked him if he had a place for me in his laboratory, which he indeed had because the war was on and actually the laboratory had lost a number of its members who were in the service. So I went back and worked with Schmidt on blood flow in the rhesus monkey and also in the spider monkey. But somehow this didn’t really satisfy me, because although these were the first studies of blood flow and metabolism—oxygen consumption also—once you have the blood flow and measure the AV difference, you have the oxygen consumption. In a primate, it wasn’t the same as the human, and I kept thinking how nice it would be if one could actually measure blood flow in the human brain.
In Boston, I had heard a lecture by Andre Cournand on his studies of cardiac output, clinically, at the bedside, in patients using the Fick principle, for which he eventually won the Nobel Prize. Those studies impressed me because it made me realize that it was possible with indirect techniques to make measurements that were just as accurate and just as significant as studies that could be made under surgical techniques and with anesthesia and so forth. And the Fick principle also struck me as being a useful strategy. However, if you want to use the Fick principle to measure blood flow, you’ve got to measure the AV difference of oxygen and the accumulation of oxygen in the brain. And using the Fick principle, one can then calculate the blood flow.
The trouble in the case of the brain is that oxygen is used by the brain, and one couldn’t assume that the oxygen utilization was going to be constant. In fact, it was one of the things that one would want to measure in the various processes of mentation and behavior. But it offered a means of approaching the topic. Now there were two groups that used the AV oxygen difference in human beings to study either blood flow or oxygen consumption, depending upon what assumption one made. There was a group in Boston at the Boston Psychopathic Hospital that used AV oxygen differences to measure circulation to the brain. And it is true that if the oxygen consumption is constant then the cerebral blood flow will vary inversely with the AV oxygen difference, so that if the AV oxygen difference gets large, that signifies a slow blood flow; if it gets small, then that’s a rapid blood flow. And using this, they made a number of observations, some of which turned out to be valid—like finding that carbon dioxide increased cerebral blood flow. But a number of which were invalid, because of the assumption that oxygen consumption was always constant.
At the same time, a group in Albany was using the AV oxygen difference to measure oxygen metabolism in the brain. And here, they assumed that the blood flow was constant, therefore, the oxygen consumption would be directly proportional to the AV oxygen difference. So you had two groups in different parts of the country using the same measure, AV oxygen difference, one to measure blood flow assuming oxygen consumption was constant, the other to measure oxygen consumption assuming that the blood flow is constant. And the reason that neither one of these studies were highly regarded physiologically was because of the fact that oxygen itself is very strongly utilized in the functions of the brain.
It occurred to me that if one substituted for oxygen another tracer that wasn’t metabolized, an inert gas like nitrous oxide, then the amount of nitrous oxide taken up by the brain would not be influenced by the what the brain was doing, whether it was sleeping or awake, whether it was having a thought or (hallucination) or whether the blood pressure was high or low—that the uptake of this inert gas would be dependent upon certain physical characteristics, like the solubility of the gas in blood and in the brain, diffusion constants (in tissue) and so forth. I chose nitrous oxide because others had used nitrous oxide in various circulatory measurements. I worked this out, worked out the equations and the Fick principle. The Fick principle had to be converted to a differential equation instead of a mathematic equation because we were dealing now with a variable. The AV nitrous oxide difference began at zero, of course, and then became very large and then gradually diminished to a very low level as the brain became saturated with nitrous oxide at the inhaled tension.
I used 15 percent, which did not have much physiologic effect and in human beings did not produce laughter or any other observable physiologic or psychological effect. But because one was dealing now with a variable AV difference, one had to use differential equations, and so I converted the Fick principle to a differential equation. And then, we did some studies at Philadelphia General with the patients’ cooperation—explaining to them that we wanted to study their circulation to the brain and that it might not be very helpful to them, but it might be helpful eventually to other people who had disorders of the brain. I calculated the blood flow in these patients. Very few, actually about two or three patients. And then I felt that I was sure enough about the technique and the theory that I was willing to talk about it to Carl Schmidt.
Part 4: From Cerebral Blood Flow to Schizophrenia
Kety and Schmidt make the first measurements that had ever been made with cerebral flow and the oxygen consumption in the normal human brain without anesthesia, under reasonably normal physiological and psychological conditions. Dr. Kety joins Julius Comroe’s department of physiology and pharmacology in the graduate school of medicine at the University of Pennsylvania.
Kandel: You mean all of this you had pretty much worked out completely on your own?
Kandel: This’s remarkable.
Kety: Well, Carl Schmidt was a remarkable mentor because, although he had me working on some of the things that he was interested in—in fact, that’s why I had come up, to assist him in some of his studies—he allowed me complete freedom if I wanted to do any research of my own.
Kety: So I thought that I would tell Carl what I had been doing, and I did, and he was very much interested in this.
Kandel: But this must have been a major advance, Seymour. I mean he must have immediately grasped…
Kety: He saw the significance of it, I’m sure, but he also made the suggestion that wouldn’t it be nice to calibrate this technique against direct measurements. What did I think of doing this technique in conjunction with the blood flow studies in the monkey with the bubble flow meter? And I thought yes, I would. So we did. Carl set up these monkeys, and he measured the blood flow with a bubble flow meter, and I measured the blood flow with the nitrous oxide technique. And we got a very good correlation between the two. And that enabled us to publish the first paper on this nitrous oxide technique, which we published together.
Kandel: So this is in 1945.
Kety: This was ’45, yes. And then we applied this to human beings (which had been my original goal) because the human brain is so different from the lower primate brain, as opposed to the heart or the liver or the kidney, where one can have a pretty good model in lower animals. In the case of the brain, there is no animal which would give you a good model of the human brain with its ability to experience ecstasy and depression, with its ability to understand, to grasp, to reason, to remember and its ability to discuss with the observer the observations that were being made. So this was the prime driving force in these cerebral blood flow studies.
We (studied) a number of normal volunteers. These were conscientious objectors during the war, who chose to submit themselves as volunteers in scientific studies as opposed to serving in the military. And these were a very fine group of young men. We studied them, and with them we made the first measurements that had ever been made with cerebral flow and the oxygen consumption in the normal human brain without anesthesia, under (reasonably) normal physiological and psychological conditions. Then from there we went on to other subjects.
Now, the nitrous oxide technique had been developed under a grant that Carl Schmidt was getting from the Scottish Rite Masonry Organization, the northern jurisdiction of the Scottish Rite. And Carl had been getting a grant from them to study cerebral circulation in the monkey and that grant I think, may have been paying part of my stipend and so forth. But it was also supporting the research that I was doing on cerebral blood flow. And since the Scottish Rite had never asked us once to explain to them why the cerebral blood flow had anything to do with schizophrenia, I felt that the first clinical topic I wanted to take up was schizophrenia, just to indicate to them that basic research does have a practical output, even though it may not be done with that target in mind.
So we studied schizophrenia, and we made a number of observations on various types of schizophrenics, going to the state hospital in Delaware and working with Fritz Freyhan, who was a psychiatrist there and a very fine person, who collaborated with us on these studies in schizophrenia. And when we calculated the blood flow and the oxygen consumption, it turned out that these were not different from those in the normal young men, from which I concluded that it takes as much oxygen to think an irrational thought as a rational thought. But there was another conclusion that I was faced with, which was that perhaps this nitrous oxide technique had very important limitations, (one of which was that) it treated the brain as a whole and didn’t take into the consideration the tremendous wonderful…
Kety: … variety in the brain. It sent me then into thinking about…
Kandel: Regional blood flow.
Kety: Exactly! How nice it would be to do regional blood flow, local blood flow in the brain. I began thinking about that, and by that time I moved to Julius Comroe’s department. Julius Comroe had rejuvenated the department of physiology and pharmacology in the graduate school of medicine at the University of Pennsylvania, and asked me to join him. He also made me a professor, which Carl Schmidt had not yet decided to do, so I …
Kandel: So you were a full professor in Comroe’s department, Seymour?
Kety: Yes. He was gathering around him a number of people who would serve in various disciplines, and I became the head of physiology—I became responsible for physiology and pharmacology, and I was a professor in the graduate school. He had Batson in anatomy. He had Erich in pathology, and he had Drabkin in biochemistry. He did a great job with the graduate school because people who joined the graduate school were veterans of the war who returned to civilian life the GI Bill gave them the opportunity to take additional courses, which they did. Comroe’s lectures were so magnificent—and I guess some of the others were not bad either—but it was Comroe’s lectures which attracted hundreds of people to come to Penn to take them. There were people who commuted from New York to hear his lectures.
Kandel: That’s wonderful.
Part 5: Regional Blood Flow Research at NIH
Kety, Landau, Freygang, Rowland and Sokoloff publish a study of 28 regions of the cat brain.
Kety: So I joined Comroe’s department, and in addition to giving lectures and participating in his new approach to medical treatment—which was the approach that was eventually adopted by Western Reserve and eventually by Harvard, where one concentrates on clinical topics and studies various basic disciplines for their input into that clinical topic. I had lots of time to do research. I proceeded to work then on developing a regional blood flow technique. At that time, I was also asked by Goodman and Gilman if I would write a review for The Pharmacologic Review, a journal which they were editors of, on anesthetic gases. I said I would like to (examine a broader topic like) inert gas exchange at the lungs and tissues, (to which they agreed). And so I wrote a review. It took me a year. I read all the literature.
Kandel: This is The Pharmacological Review of 1951 paper? Extremely influential, great paper.
Kety: That paper was influential…
Kandel: Yes. You suggested there and indicated that one might be able to measure regional blood flow with autoradiographic methods or with multiple indicators in the human brain.
Kety: I developed an equation for the distribution of an inert tracer between blood and tissues, which depended on the past history of the arterial concentration, the diffusion permeability of the tissue, the solubility of the substance or the partition coefficient between blood and the tissue, and of course on the perfusion. And that came out as a fairly complicated equation, which was similar to the charging of a capacitance with an electric input. But that equation then became the basis of measurements for (regional) blood flow that emerged from that paper. Just about the time I had submitted that paper for publication, I got a visit from Bob Felix.
Kandel: … How the cerebral blood flow method was the basis for moderate imaging methodology. So could you continue that line of thought?
Kety: Okay. I continued that work at the National Institutes of Health, where I had come down as the first scientific director. While I was there in the very first year or the second year that I was there, spending my time mainly recruiting and planning the divisions and recruiting people, I got a visit from one of the fellows in Wade Marshall’s laboratory, Bill Landau, who came to see me about whether it would be possible to measure regional blood flow. And I said, “Huh, isn’t that nice that you ask me, because it’s about time that I turn my attention to that, and I’d be happy to work with you on that.”
The first thing we tried was a clearance method, where we injected a radioactive gas dissolved in saline into the brain and attempted to measure its disappearance from the brain—a technique that I had elaborated earlier for studying muscle blood flow. But this didn’t work very well. And then I said, “Well, you know there’s another approach that is in this review, but this is going to be a much more elaborate approach. We’re going to have to make measurements of the concentration of an inert tracer in the brain. We’re going to have to slice the brain. We’re going to have to freeze the brain. We’re going to have to do autoradiography, and it is going to be very, very complicated. But if you’re willing, I will help you.” So he said yes, he was willing. He then got one of the other people in Wade’s lab, Walter Freygang and Louis Rowland, who was another post doc with Landau, interested in this. And by that time, Sokoloff, who had worked with me at Penn, in fact, had been one of my students at Penn and eventually came back and joined Comroe’s department to work with me on what I was doing, cerebral blood flow and muscle blood flow, and Sokoloff came down and joined me at NIH. So that became the team that approached the question of regional blood flow.
I knew what we would have to do would be to find a radioactive inert gas. We would have to slice, we’d have to freeze the brain, because the gas having a high vapor pressure would get lost if it wasn’t frozen in the tissue. We had to freeze the tissue, we had to slice the tissue and autoradiograph it. And I began to look around for a microtome that would cut through the skull. There were such microtomes, but it was going to take a year to have one built and so forth. In the meantime, these young men who were working with me on this, one of them, I think maybe it was Walter Freygang, said, you know, you could use a band saw. So they went down to Sears, and they bought a band saw. And we froze a cats’s head in liquid nitrogen, and we proceeded to slice the head with a band saw, which worked pretty well. And that became the technique.
So we had to find a radioactive inert gas, and the halogen compounds of methane were the place we looked first because we knew the fluorinated methanes were inert and might serve as a basis for this. We tried trifluoriodomethane, which had three fluorine atoms and one iodine atom, and the iodine atom was the radioactive one. And that was still a gas, and it was made by a process of synthesis. And Jack Durrell, who had joined us at the NIH, was a very hot biochemist, and I asked him if he would see if he could synthesize this compound for us. And he worked out a synthetic method, which was very useful. So we dissolved this gas in saline. We injected this gas into the cat. This was a conscious cat, whose head was in the bottom of a guillotine. And we drew arterial blood, and at the end of one minute, after measuring the concentration in the arterial blood over this period of one minute, the guillotine would decapitate the animal. The head would drop into liquid nitrogen and freeze. And then we would slice it with the band saw and place it against X-ray film, put that in an X-ray frame and put that in a dry ice freezer, and we’d leave it overnight and then we’d develop.
We would get densities in the autoradiogram which corresponded to the density of the radioactivity. It required a calibration, however, and I suggested that we drill holes in the frozen head and fill those holes with jell containing this radioactive iodine in various concentrations. We used the cross sections of those jells as the calibrating factor. So then we would calculate the blood flow, the regional blood flow in various regions of the head, using a densitometer and using a mechanical calculator. We didn’t have computers in those days, and we would calculate the blood flow in various ways.
So we published the first study by Landau and the rest of us in the Transactions of The American College of the American Neurological Association, and this was a study of 28 regions of the cat brain. And they were very interesting. They distributed themselves from very rapid blood flow in the inferior colliculi and the auditory cortex, down to various parts of the cortex, down to the white matter, which was about one-fifth of the average in the cortex. And we published this.
Kandel: Now in those studies, if I remember correctly, you also showed that in the visual system that flashing lights increased blood flow, which was the first evidence that you could use this to trace neuronal activity.
Part 6: NIH Team Accomplishes Imaging of Neural Activity
Studies indicate the whole visual system could be mapped functionally by means of cerebral blood flow. The team provides the first direct demonstration of Roy and Sherrington conclusion that there is a homeostatic system in the brain which increases the blood flow to meet the increased demands of metabolism.
Kety: Exactly. Now what happened here was that we noticed that the auditory system was highlighted. The auditory system, for some reason or other, had a very high rate of blood flow—all the way from the inferior colliculi, all the way through the auditory, which is the auditory center—through the medial geniculate to the auditory cortex. All of these were very high. Much higher than any other part of the brain. So the obvious explanation was that we were using a counter, a diode counter, a decade counter, and the counter was clicking away while this study was going on, and the cat was conscious. So this was simply his auditory system responding to those clicks.
So Landau deafened the cats, and even though they were quite deaf without any auditory system at all, or external auditory system and medial auditory system, the blood flow still remained very high. So it wasn’t simply listening to the clicks that did it. We found eventually that the high blood flow was the result of a very high metabolism and that these structures in the brain had very high concentrations of oxidative enzymes.
So I’m not sure that we still know why they are high in blood flow, but they certainly are. But while this was going on, Sokoloff thought, well, why not try photic stimulation. See what that does. So he set up an arrangement whereby he stimulated the cats with photic stimulation, flashing lights, and then when we did the autoradiograms and blood flows there, we found, sure enough, that the autoradiograms showed definite highlighting of the visual system now, not the auditory system as much. The visual system really, really sprang out, and so now we were dealing with the lateral geniculate, the visual cortex.
Kandel: That was a fantastically important additional observation because it really made one realize you could really map the whole visual system functionally by means of cerebral blood flow.
Kety: Well, I guess it was the first…
Kandel: Imaging of neural activity.
Kety: Yes. Now others had shown an increase in activity with functional activity. As a matter of fact, Ralph Gerard had made an observation, I think, that somebody who had an AV aneurysm in his brain near the visual system, that the aneurysm would produce a bruit when he used his eyes, when he read. And Carl Schmidt had shown with a thermostromuhr in the monkey, or in the cat, that increases in blood flow were associated with changes in the function. Oh, but Roy and Sherrington did the initial study where they found that functional activity increased the blood flow. At least they drew that conclusion from their observation of blood flow or blood volume, and drew the remarkable conclusion that there is a homeostatic system in the brain which increases the blood flow to meet the increased demands of metabolism. So here was the first…
Kandel: Direct demonstration.
Kety: We published the results of the autoradiographic studies in cats in 1955, and I continued to think and plan about how that could be applied to human beings. I even thought also of how that could be used in a measurement of metabolism, oxygen consumption, and I thought of using an oxygen electrode and regional blood flow and somehow between the two, between measuring the oxygen in the tissue and the blood flow, I might somehow be able to calculate what the oxygen metabolism was. But that wasn’t too promising, and in the meantime, Lou (Sokoloff) was thinking of looking at metabolism by studying glucose metabolism. The development of the deoxyglucose technique was (largely) the work of Sokoloff with input and help from Reivich. I had really nothing to do with that. I can take no credit for it. It was done, as a matter of fact, after I left the NIH and went up to Harvard. I went on a sabbatical to Europe. I went to the College de France, where I was a visiting professor for a year. And that was in ’66 and ’67. And then after that, I didn’t come back to the NIH, but I was offered a chair at Harvard and accepted that. So I had left the laboratory essentially when Lou and Reivich began working with…
Kandel: Let me jump in for one second, Seymour. But isn’t it correct to say that the equations that you worked out in the ’51 paper were important for the development of the deoxyglucose method and for subsequent PET scanning? I don’t want to take anything away from Lou’s fantastic contribution, I just want to understand the intellectual connection.
Kety: No, they were not. Lou had to develop an entirely different equation, (based on) entirely different principals, because the uptake of deoxyglucose is not a matter of simple diffusion and solubility. There he had to deal with enzyme kinetics, and he developed that on the basis of his knowledge of enzyme kinetics, which he got after his sabbatical at the College de France several years later. But the only thing he got from (his earlier work with us was) the importance of regional blood flow and how the (autoradiograms of the brain, properly calibrated, gave us) regional concentrations of a tracer. (On the other hand, my 1951 equations led to the PET technique in the hands of Marcus Raichle for regional cerebral blood flow by what he called “the autoradiographic technique.” For the deoxyglucose technique, Sokoloff used autoradiograms that were also calibrated as we had done.) But that was it. Otherwise, he had to start from scratch, and he decided to start with glucose.
The first thing he did was to inject radioactive glucose and see the kinds of pictures that he got with radioactive glucose. (But) I don’t think he even went as far as getting pictures, because he quickly realized that glucose was not an inert tracer. It was quickly, (almost) instantaneously metabolized. So what he got was a hodgepodge of carbon dioxide and various glucose (metabolites), distributed all over the brain in a random kind of way. So he had to give that (approach) up. Then he learned about deoxyglucose and how deoxyglucose served as a substitute for glucose in metabolism because it was taken up through the same mechanism, it passed tissue membranes, under the same transport mechanisms as glucose itself, and it became phosphorylated. But once it was phosphorylated, it was trapped, and it stayed in the tissue. And that, he realized, was the way to go about it.
Part 7: Sokoloff Comes Up with Optical Dominance Columns
His work with Reivich at the University of Pennsylvania leads to the subsequent wider development of PET scanning.
Kety: So working with Reivich, they got radioactive deoxyglucose labeled with C14, and they injected it, and they realized that they had to inject it for some time so that they would entrap enough of the deoxyglucose in the tissues to be measurable (while the blood levels fell to a low level). Then they made autoradiograms and, sure enough, they found that this was giving them very nice pictures. As a matter of fact, it was giving them nicer pictures than the regional blood flow technique had given us, because we were using a diffusable tracer, and the tracer, once it got into the tissue, didn’t stay in the tissue, but began to diffuse out of the tissue, so it made the outlines a little fuzzy. This (the deoxyglucose) was trapped in cells and made very sharp autoradiograms. I guess the most dramatic (result they obtained)…
Kandel: The optical dominance columns.
Kety: (Laughs.) He did that. (He made visible in the visual cortex what Hubel and Wiesel hypothesized from electro-physiological recordings.) And they were just gorgeous. I invited Sokoloff up to Boston after I arrived there, and he gave a conference for us at MGH. I invited Wiesel and Hubel to that conference, and they said, well, we can come to that, but actually we we’d like to have Sokoloff come to the medical school and give a conference here. And the conference he gave at the medical school was a great hit because everybody was struck by those optical dominance columns. They were exactly what Hubel and Wiesel predicted would be the case, but had never demonstrated. It was just magnificent, and Hubel remarked that those pictures took the place of a thousand electrodes.
Then Lou had the question of applying this technique to man, which again, he did entirely independently of me. He did this with Reivich and they also co-opted a group of very competent scientists in other disciplines. Lou was unable to do this at NIH for some reason or other. He was tied with studies of thyroxine and its effect on metabolism, and to do this properly in human beings would require that he really tear his laboratory apart and build a new laboratory. And Reivich was in a position to do just that, having come to the University of Pennsylvania and having access to a cyclotron and (the makings of) a PET scanner.
Kandel: How did those studies lead to the subsequent wider development of PET scanning? How did Marcus Raichle get involved?
Kety: Marcus Raichle got involved purely on the basis of blood flow (measurement. When Landau went back to St. Louis, he told his colleagues about the work he did at NIMH.) The regional blood flow technique was the thing that caught (Raichle’s) eye. And, in fact, in his first studies, where he applied that technique to human beings, he called it the autoradiographic technique. But it (went beyond the) autoradiographic technique. It was positron emission tomography. What Lou did earlier was very important also for brain imaging, because (after demonstrating it in monkeys, he turned to man). His first paper, which was with Reivich, Kuhl and with Wolf, who was a super synthetic chemist, who synthesized deoxyglucose labeled (with) radioactive fluorine. And the fluorine 18 is a positron emitter, but they weren’t using it in positron emission in their first experiment. Instead they used it as a means of reducing collimated beams of gamma rays, which they could detect externally. So they used an external counter, and they measured the emitted gamma ray, but not simultaneously and not using the beautiful technique of positron emission.
Kandel: Right. Seymour, I want to leave this topic, but before I do that I want to try to summarize and have you make sort of a final set of comments on imaging methodology. So beginning in ’45 and until 1955, you worked on cerebral blood flow. And you realized from the studies of cerebral blood flow in humans that certain disorders like schizophrenia didn’t show any overall changes in blood flow compared to normal, which made you realize that there is a dimension that you were overlooking, where the nitrous oxide method is conventionally used, and that is, there may be regional differences that were being diluted out. And so you turned to developing regional blood flow, which you first did with autoradiography with Lou Sokoloff (and Landau and Rowland).
And that showed that there are regional differences in blood flow, and that had two consequences. One is it allowed you to see how the blood flow of distinctive regions of the brain varied with one another, and two, you picked up serendipitously the finding that blood flow is correlated with activity. And therefore, the blood flow technique became more than just measuring blood flow. It became the first objective visible marking technique that allowed you to visualize activity in the brain and delimit the human brain. And Lou went on to further improve that methodology with the deoxyglucose method, and that was ultimately applied to humans in terms of PET scanning.
Kety: It was more than improving the methodology. It was really a radical departure. It was a branch.
Kandel: Okay, let me restate it. I didn’t mean to de-emphasize its importance. But based upon the insight that regional blood flow was important, Lou went on to develop a new methodology that allowed you to get regional blood flow measurements much easier and crisper.
Kety: No. Roy and Sherrington had pointed out that there was an increase in blood flow with an increase in functional activity, but they assumed that the reason for that was that the increased functional activity was associated with an increase in metabolism and…
Kandel: And what Lou was able to show was that there actually was an increase in metabolism with activity.
Kety: And it was the increase in metabolism, which produced vasodilating substances, which increased the blood flow. That was the great contribution that Roy and Sherrington made. It was all theoretical. They really had very little clear cut evidence for any of it, except for swelling of the brain in certain regions. And Lou then set about to measure the metabolism. And he did this by examining the metabolism of glucose, and he did this by developing a technique that trapped the glucose in the brain in the form of an inert non-further-metabolized (tracer): deoxyglucose phosphorylated.
Kandel: So let me restate this. So what you and Sokoloff in the Freygang study showed was that there was increased regional blood flow. Lou then went on using the deoxyglucose to show there actually were regional differences in metabolism, and that this was correlated with activity. And that further opened up the method of correlating activity in different regions of the brain in human subjects with mental activity, with mental processes.
Kety: It was not so much Freygang. It was Lou and …
Kandel: Lou, Rowland, Freygang and Landau. I was just using it as an abbreviation for that short transaction paper.
Part 8: Serial Colored Images and Theories of Schizophrenia
Sokoloff also calculates regional glucose metabolism and displays the metabolism, not as a table with numbers, but as a colored photograph with the measurements of metabolism spelled out in colors of the spectrum. In 1950s and early 1960s, two schools of thought prevail: 1) Parents teach their children to be schizophrenic, and 2) the disease has some origin in genetics.
Kety: Freygang was not really one of the major contributors in that work. But Lou did something else that was important for brain imaging. (With the help of a few color and computer experts) he then developed mathematical computerized techniques whereby he could convert the readings of radioactivity that they got from the photomultiplier tubes (into regional) concentrations of deoxyglucose from which they could then calculate (regional glucose metabolism). He was able then to display the (metabolism), not as a table with numbers, but as a colored photograph with the measurements of metabolism spelled out in colors of the spectrum.
Kandel: Right. So he could use serial colored images to indicate the degree of activity in different regions of the brain.
Kandel: I remember those images. They were very beautiful, and they really set the standard for how subsequent imaging was done.
Kety: That’s right. Exactly.
Kandel: Good. So I want to leave this topic, if it’s okay with you. So is there is anything else that we need to cover? Any one or two particular highlights that we have omitted, before we go on to the genes and mental illness studies?
Kety: I think we ought to mention Raichle, who picked up the regional blood flow (equations), and he applied (them) to human beings using O15 oxygen water as the tracer. And the O15 water became then a much more appropriate measure of regional activity because it was so instantaneous. The deoxyglucose technique took 45 minutes of equilibration before one actually made the measurements, so what it measured was the integrated functional activity over that period of 45 minutes, whereas with the O15 autoradiographic technique that Raichle had developed, one could make several of these measurements in the course of a minute. Rapid, temporal resolution. He also used the color computer techniques that Sokoloff… And as a matter of fact, for normal mentation and behavioral studies, the O15 water technique was the one that really became the standard (for functional activity). Raichle worked with a neurologist… an outstanding psychologist..
Kandel: Oh, he worked with Posner, Michael Posner. Outstanding. Those classic papers and then ultimately theScientific American book. Good, so lets go back now and pick up the other major strands of research in which you have pioneered, and that is the application of genetic techniques to the study of mental illness. Maybe you could begin by describing what the scene was before you got the idea that adoption studies would be a useful way of resolving the genetic contribution to mental illness. So what was the scene in the late 1950’s and early 1960’s?
Kety: Well, the scene was divided into two schools of thought. The vast majority of psychiatrists were influenced very strongly by Frieda von Reichmann and by Ted Lidz, and they believed (and told the parents of patients) that schizophrenia was something that parents taught their children. And this produced in them a terrible feeling of guilt. As a matter of fact, there was a book published recently called Madness on the Couch, which takes the whole psychoanalytic movement to task and blames the psychoanalytic movement for having produced a whole generation of parents of schizophrenics with terrible guilt feelings that they had caused the schizophrenia by how they raised the children. And on the other hand, there was some indication in the minds of some psychiatrists, but mainly in other disciplines, that schizophrenia was not simply a simple learning experience—of learning poor stratagems, (incorrect social attitudes, poor interpersonal relations, bizarre thinking, even hallucinations and delusions) from (schizogenic) parents—but that schizophrenia had an origin in genetics. And this was based upon two types of (observations).
One, was the fact that schizophrenia ran in families. This had been observed by Kraepelin and by Bleuler. And both of these assumed that there was a hereditary component in schizophrenia, which explained it running in families. And then along came Freud, who emphasized the experiential input into development of the brain and personality and mentation. And these same observations because grist in the mill of the psychoanalysts who preferred to think of schizophrenia as something that was taught. As far as schizophrenia running in families, that fit in very well with Ted Lidz’s theory, because that simply proved that the (schizophrenogenic) parents were teaching children to be schizophrenic. Also it ran in families because families shared the same environment. So even those who didn’t subscribe to the psychoanalytic theory, but still believed that schizophrenia was an environmental defect, could say, well, they share the same environment and that’s why it runs in the family.
The twin findings were actually a little better because these findings indicated that monozygotic twins have a high concordance rate for schizophrenia, what used to be thought of as 85 percent. But when corrections were applied, and when the studies were done more carefully, it turned out that around (40 to) 50 percent of monozygotic twins are concordant with schizophrenia. Whereas on the other hand, the dizygotic twins shared the risk for schizophrenia to the same extent that siblings shared the risk for schizophrenia, so that there was a 10 percent concordance for schizophrenia in dizygotic twins and a (40 to) 50 percent concordance in monozygotic twins. And this was perfectly compatible with genetic factors, of course, because the monozygotic twins share the same genes. The dizygotic twins share 50 percent of their genes, as do siblings, so the concordance rate in DZ twins is the same as it is for siblings.
Part 9: Adoption Studies
Dr. Kety conducts a study of adoptees in Denmark and finds that schizophrenia ran in the biological family, but not in the adoptive family of the subjects.
Kety: Now the environmental people could still be unconvinced by the twin studies, because it was quite obvious that monozygotic twins share much more of their environment than do dizygotic twins. They look alike. Their parents treat them alike. They dress them alike. They parade them in a double perambulator. They go to the same school. They have the same teachers. They have the same friends. They sleep in the same room. They sleep in the same bed. And much more environment is shared by monozygotic than by dizygotic twins. In fact, there was a study of twins published by a group in Chicago, a study of normal twins, which made the point that monozygotic twins shared very much more of their environment. That being the case, then the high concordance rate in monozygotic twins could very easily be simply the result of the shared environment.
Now I decided to write a review of the biological, biochemical theories of schizophrenia, which were rampant at the time. At that time, despite the psychoanalytical school, there were still a substantial number of people who were approaching schizophrenia from the biological point of view and were doing quick, and somewhat dirty (poorly controlled), experiments to prove to themselves that schizophrenia was a biological problem. And this included an awful lot of weird findings, which never panned out. There was the effect of the urine of schizophrenics on spiders’ webs, and presumably the spider injected with the urine of a schizophrenia wove a different web pattern than the normal.
There were findings that schizophrenics had certain biochemical substances in their urine that were not present in normal urine. Then there were occasional tests for schizophrenia. There was the Akerfelt test which came out of Sweden. A young psychiatrist named Akerfelt found that when he added a certain dye to the plasma of schizophrenics, the plasma turned pink to red, as opposed to normal, where it didn’t change color. This was published first in The New York Times, and it was stated that you could tell not only the presence of schizophrenia, but how severe the schizophrenia was, because the sicker, the redder.
But in the course of reviewing all of the biochemical theories, I came to the conclusion that there was no really good evidence for a biological basis for schizophrenia, except what evidence there was from the genetic point of view. There I cited the studies of Kallman on twins and pointed out that (in spite of) all the alternative explanations, the twin studies seemed to carry the greatest weight. And it was in that review that I said perhaps another approach is feasible, and that is an approach based on the study of adoptive people who become schizophrenic and an examination of their two families. If schizophrenia runs in families, what family will it run in, in the case of an adopted person who became schizophrenic, who derived his genes from one family and lived with his environment in another family?
Kandel: So this was the first attempt to sort of separate environmental and genetic factors by using an adoption strategy for the study of the genetics of schizophrenia.
Kety: Right. I laid out in that review certain requirements. I pointed out that one would have to be very careful to do blind studies to avoid ascertainment bias and subjective bias, that one would have to use a national sample and instead of looking for adoptive people among schizophrenics, which would be the wrong way of going about it, one should look for schizophrenia among adoptive people. And in order to do that, I indicated that this would probably require a national sample. So having written that and having made that prediction, I then spent some time going between John Hopkins and the NIH, because I had finally accepted the chair of psychiatry at Johns Hopkins and was commuting back and forth because I still had work going on in the laboratory at NIH. And I was also living in Bethesda before we had moved to Baltimore. But in the course of those drivings back and forth, I had the opportunity to muse about this thing, and I began to think about this theory of studying schizophrenia from an adoption standpoint.
Eventually, we discovered, or we learned, that Denmark was the place where we could do the study. We couldn’t, obviously, do a study like that in America where people move very easily, where records are not kept in any one single place, and where we would have had difficulty collecting a national sample. But we learned from Sarnoff Mednik about the records that are kept in Denmark. And in 1962, I flew over to Denmark and met with Fini Schulsinger, who was the head of psychiatry at the big Kommunehospital in Copenhagen, and he introduced me to the various records that are kept in Denmark, where they have a record of all legal adoptions. Where they had a record of anybody who was ever admitted to a mental hospital or to a mental clinic. Where they had a wonderful population register, where you could trace people through their whole lifetime and members of their household. And it was obvious that that was a place where we could do this study. And so with our assurances of complete confidentiality (and with Schulsinger’s active collaboration), we were given access to these records.
Kandel: So what were the major results in those studies, Seymour?
Kety: Well, the major results were that schizophrenia ran in the biological family, but not in the adoptive family. And the incidence of schizophrenia in the biological relatives of adoptive schizophrenics was exactly the same as the incidence of schizophrenia in the relatives of schizophrenics who were naturally reared. So one didn’t need anything else but the genetic factor to account for the familial tendency of schizophrenia. It showed no more schizophrenia in adoptive relatives than in the general population.
Kandel: There were two other findings in there that I wonder if you would comment on. One is the 50 percent concordance in homozygotic twins, and two, the finding that the biological relatives had a broader spectrum of disorder than just classical schizophrenia—the development that you were so important in outlining of the schizotypal.
Kety: Yes. By the way I didn’t mention that I was joined in the (studies of the two families of schizophrenic adoptees by David Rosenthal and Paul Wender at the NIMH, besides Schulsinger in Denmark)… I had left Hopkins after a year, regretfully because I very much appreciated that university and that medical school and the traditions of that department, but my stomach just didn’t care for administration as much as that, especially administration of a clinical department. So I came back to the NIH. And as soon as I came back, I began to organize this kind of adoption study.
I spoke to David Rosenthal, who was interested in the genetics of schizophrenia and had been toying with the idea of studying the offspring of schizophrenic mothers. And he told me about Paul Wender, who was a young psychiatrist, a postdoc, working at St. Elizabeth’s who was already engaged in a study of the adoptive parents of schizophrenics. He wanted to examine Lidz’s theory that the adoptive parents of schizophrenics were psychopathic and transmitted their psychopathy to the kids by how they reared them. So he was trying to pull together a group of adoptive parents of psychotic children. We decided with our various interests that we could work together, and so we formed a team in the Intramural Program.
Part 10: Ramifications Of the Study
Kety’s adoption study provides convincing evidence in a broad humanistic biological context that not only convinced people that there was a genetic contribution to schizophrenia, but made them realize that this genetic contribution in no way questioned that environmental factors also could contribute to the illness.
Kandel: But return to the findings. The concordance and the schizotypal.
Kety: What we found, we had decided that the first problem was how you define schizophrenia. We decided that we would use the psychiatric diagnosis of schizophrenia. That was the standard psychiatric diagnosis in DSM 2 (American Diagnostic and Statistical Manual, 2nd edition), which was chronic schizophrenia, the kind that was described by Kraepelin and Bleuler. Then there was the group of borderline schizophrenia and then there was acute schizophrenia. We decided that we would use the three schizophrenias that were described in DSM 3: chronic schizophrenia, borderline schizophrenia and acute schizophrenia.
We decided that we would make our diagnoses according to those three categories and see what turned up. And what turned up was that in the relatives of the chronic schizophrenic adoptees, there was a high incidence of chronic schizophrenia, but an even higher incidence of borderline schizophrenia, and no acute schizophrenia. It was only in the biological relatives of the chronic schizophrenics that we found that. If we looked at the (biological relatives of the) borderline schizophrenics, we found one or two chronic schizophrenics, but more borderline schizophrenia. And if we looked in the relatives of the adoptees we had diagnosed with acute schizophrenia, we didn’t find any schizophrenia. So we concluded from that that acute schizophrenia was probably not part of the schizophrenia (spectrum, but) an acute psychosis of unknown origin that was not related to schizophrenia. But the borderline schizophrenia, we felt was definitely genetically related to schizophrenia because we found more of these borderline schizophrenics than even chronic schizophrenics in the relatives.
Kandel: So the data seemed to suggest that what was really inherited was really not the cause of the symptomatology, but this broader predisposition, this schizotypical behavior. I mean, that was a fascinating result.
Kety: But in that we were simply confirming Bleuler, who pointed out…
Kandel: Right, that a lot of the relatives behaved peculiarly.
Kety: Exactly. He found more schizophrenia-like symptoms in the relatives who had brought the patient into the hospital than he found in the normal population …
Kety: Right, but your conclusion was the one that we drew.
Kandel: That has had wide ramifications within psychiatry since then. I mean it now applies also to affective illness, to manic depressive illness, that there is a spectrum of disorder. In fact, in many areas one sees this turning up.
Kety: Yes. We did an adoption study of affective disorder and found essentially the same thing—that there was a higher incidence of affective disorder in the biological relatives of the adoptees than there was in the control biological relatives or in the population in general or in the adoptive relatives.
Kandel: Isn’t it fair to say, Seymour, that the current view we have of major mental illness, of schizophrenia, of the affective disorders, of anxiety states, as being biological illnesses—that a major turning point in that understanding came out of those rigorous genetic studies that began at the NIMH, and then were confirmed by lots of other groups?
Kety: Yes, I guess. In any case, the adoption studies confirmed the conclusions from the twins studies and from the family studies that previously had been only inferences, but without clear support. But once the adoption studies came out, they confirmed that interpretation. So that you can say that although the adoption studies may have made all of the evidence much more crisp and much more irrefutable, the previous evidence contributed very substantially to the idea that these disorders…
Kandel: Yes. Let me perhaps restate it, and then maybe you might comment on it some more. There is no question that prior to your getting in the game, there was already genetic evidence suggesting that schizophrenia and manic depressive illness had a genetic basis. They were confronted by three problems. One is, as scientific studies in their own right, they had the weakness that they only showed correlations of illnesses in the family. They showed that these illnesses ran in families, but they could not dissect out the contribution of learning vs. genes in that context. Number two, since the analysts, and particularly people like Lidz and Fromm-Reichmann, were emphasizing the acquired nature of mental illness, either they ignored that evidence or used it as supporting the notion that, look, this is exactly like we told you. It runs in families because the parents are teaching it to the kids.
And third, there was a general suspicion after the second World War of any genetic argument that applied to mental processes because genetics had been so misused by the Germans in the eugenics movement that any mention of genetic determinants of behavior was looked upon with great scepticism and concern. And that what your study was able to do was to provide absolutely convincing evidence in a broad humanistic biological context that not only convinced people that there was a genetic contribution, but made them realize that this genetic contribution in no way questioned that environmental factors also could contribute to the illness.
Kety: That’s a very beautiful summary.
Kandel: Well, good (laughs).
Kety: I didn’t even mention the stigma derived from the Nazis.
Kandel: Yeah. I am really sort of very struck with that. Seymour, speaking about the humanistic thing, I want to go on to the final topic. I’m sorry, is there anything else that we’ve left out on the genetics of mental illness?
Kety: Well no, from that, of course, stemmed molecular genetics. But these have not yet come up with anything which is universally accepted as being crucial.
Part 11: Back To Basics
As scientific director of the Intramural Program at NIMH, Kety emphasizes the importance of fundamental science.
Kandel: But that puts schizophrenia and depression only in the same category as other complex illnesses. I mean these are very difficult disorders, but certainly the fact that there is such strong evidence from the family studies made people like Eric Lander and other outstanding human geneticists interested in these problems. Let me go on to the last point, and that is your role, your leadership of American psychiatry. I’m going to outline what I see as your contribution, and I’d like you to sort of elaborate on it.
What you have meant to me and to my generation is that… you came from biology, and yet you brought with you an enormous sort of humanistic concern for people as people. So you didn’t take sort of a narrow-minded blood and guts biological approach as did the people who were interested in, lets say, lobotomies or electroconvulsive shock or insulin therapy. Sort of the precursors of modern biological thinking in psychiatry. You actually emphasized, particularly at NIMH, the importance of social factors in mental illness. And always in your studies of the genetics of mental illness you emphasized that. So I wonder whether you would comment, number one, on your leadership role at the NIMH, your leadership role at Hopkins, your role at Harvard, and do this in the context of combining sort of biological thinking from which you derived with the broader humanistic concern that psychiatry confronts us with.
Kety: Well yes, I think that was a reasonable statement of one phase of my contributions from the time I became scientific director of the Mental Health Institute. But I wouldn’t say it was the most important phase. That is, the humanistic bringing in the social and behavioral sciences was not the most important thing that I did. It’s true that when I set up the laboratories in the Intramural Program, the first laboratory I established was the laboratory of socio-environmental studies.
Kandel: Clauson’s laboratory.
Kety: With Clauson as its chief. And I did that because that was the area I was most deficient in and which I thought had to be emphasized, in any case. But then from there I went on and established laboratories of the various basic disciplines. I think the important concept that I brought into focus was the importance of basic research and the futility of premature application of inadequate knowledge to the clinical problem itself. So on that basis, with these remarkable facilities, which Dr. Felix turned over to me with a blank check, saying that this was going to be the greatest institute on the brain and behavior that the world had ever seen. Realizing that it was certainly going to be largest institute, whether it was the greatest, had to be seen later, but with these tremendous facilities the best thing I could do with them was to recruit very good people who were concerned with the basic disciplines of physiology, anatomy, biochemistry, pharmacology, sociology, molecular biology, psychology, and allow these people to follow their own noses in terms of what they felt was important.
Kandel: Okay, Seymour, so you were speaking about the quality of the people that you were able to recruit to the Intramural Program and that the thing you take most pride in is your emphasis on the importance of fundamental science and your insistence that one not make premature movements toward clinical situations before one really understood the scientific underpinnings.
Kety: Right, now I did this against two very severe antagonists. One was the major group of psychiatrists who, of course, were worried that the National Institute of Mental Health was moving in a direction which they felt was an erroneous direction. And interestingly enough, I was also resented by the smaller group of people who were doing biological psychiatry, because…
Kandel: Many of them are charlatans.
Kety: (Laughs.) That’s a very strong word. Some of them were charlatans, but many of them were just led by the feeling that some finding that they make by accident (and seems plausible), has to be the answer to schizophrenia. But aside from those two antagonisms, there was a feeling on the part of people in basic research that, ah ha, here’s an opportunity now for making a contribution to schizophrenia. And here’s an opportunity for working in the field of schizophrenia where I make the decisions of what to work on and where my basic research is appreciated and seen as something which is essential to an understanding of schizophrenia—and which may ultimately make a major contribution to schizophrenia.
So with the announcement of the appointment of the scientific director and that we were recruiting people, I received applications, dozens and dozens of applications, not from too many senior scientists, but from young scientists who were enthralled with the idea. People who had been trained, lets say, in physical chemistry and were looking for an offer for a job. And one of such people was Alex Rich. Alex Rich was working with Linus Pauling, and he had done beautiful work with Linus Pauling, but he needed to find an opportunity. Well, he was very intrigued with the possibility that his work could contribute. So he came to apply for a job, and we had a conversation, and he told me about his theories of the template, the protein template, on which memories could be laid down and how this protein template was constructed out of amino acids. We didn’t know about DNA at that time. I spoke to Linus Pauling and got a very high recommendation for Alex. And in the same way a number of young people came and were appointed. Occasionally I appointed somebody who was already on the scene.
One such person was Wade Marshall. Wade Marshall had been a brilliant neurophysiologist who developed severe psychosis. I think Wade was probably a typical severe chronic schizophrenic, and he spent time in a mental hospital. But he restored himself partially, but as Bleuler would say, not restitutio ad integrum. But he became capable of handling himself, capable of doing research, capable of carrying out a research program. And when it came time to appoint a chairman of physiology, I had to look the problem squarely in the face and say, why not Wade Marshall, even though that idea might be appalling to some people. I felt that Wade deserved the support of the Mental Health Institute. If a former schizophrenic did not deserve the support of the Mental Health Institute, where else would he get support? So I made him director of the laboratory of physiology. Now you’re in a position to say how affective Wade was, because you were one of Wade’s primary and prized products.
Part 12: Impact on a Generation
Dr. Kety comments on his assistance in the careers of scientists in the Intramural Program, and Dr. Kandel talks about the impact Kety’s work had on an entire generation.
Kandel: Well, he was wonderful to me and to Alden Spencer, and as you know I would not be doing science today if it wasn’t for the fact that I had such a spectacular experience at the NIMH in his lab. It was clear he was peculiar, but it was also clear that he was an extremely generous and wonderful man who had very high ethical standards and very high standards for science and was extremely supportive of people. So I benefitted enormously from being in his lab.
Kety: So that was by no means a bad…
Kandel: No, no, and many people felt the same way. They all felt that, you know, he had problems, usually not with people in his lab. He was just odd and peculiar, but that he set a wonderful example by just basic integrity and generosity that went a very long way.
Kety: Right, and this was the way Bill Landau felt and a number of his postdoctoral fellows felt. Cantoni came to see me. He was also a relatively senior scientist. He had already become well known because of his studies with s-adenosylmethionine and the transmethylation process, and he needed a job because his boss was leaving Western Reserve and taking a position in another university, and he was unable to bring his whole laboratory there. And Cantoni impressed me very much. And so he became head of pharmacology, but it was a different kind of pharmacology.
Kandel: Seymour, I would like you to comment on two additional people whom I think you actually appointed somewhat later, when you had stepped down as Intramural Director and went back to full time research as head of the laboratory of clinical investigation. That is, in addition to Sokoloff, whom you had brought along as a junior person and who developed extensively and very powerfully, you also helped the career of Julie Axelrod and Ed Evarts. And I wonder if you would just comment briefly, and Irv Kopin, maybe those three people you might comment on.
Kety: Okay, I interviewed Ed Evarts and approved his appointment. I think he went first to Marshall’s laboratory with him, and then he eventually came to the new laboratory that was being established. In fact, he became the temporary chairman of the laboratory of clinical science because he was a psychiatrist and a basic scientist. And Ed Evarts, of course, became an outstanding neurophysiologist.
Julie Axelrod came to see me from Steve Brodie’s laboratory where he had been working for some years and asked if there was an opportunity for him in the new Mental Health Institute. And I said well, of course, because I had known of Julie Axelrod’s work with Brodie and rumor had it that a lot of the work that he did with Brodie was really his work, which Brodie shared the credit for. And I said, but I don’t think there is—we’ve already appointed somebody in pharmacology—and I don’t think there is a place with a position for you, an important enough position for you, in the basic research program. Let me call Steve Brodie. I called Steve Brodie and Steve said, “Oh yes, Julie is ready to work on his own. I give him my hearty recommendation,” which was very decent of Steve. So I sent a memorandum to Bob Cohen telling him that I would recommend that he appoint Julie Axelrod to his clinical program and that there was a laboratory in the clinical program that Julie could easily head, and that was a little laboratory of biochemistry that had been started in Bob Cohen’s laboratory.
And eventually Bob Cohen did ask Julie to come and visit or he asked Ed Evarts to go and visit Julie, and they appointed Julie Axelrod. And for a while he worked in the clinical program, but when I stepped down from the scientific directorship and headed up this laboratory of clinical investigation, I was very eager to bring Julie into that laboratory—which I did. And it was in that laboratory that he did the beautiful work he accomplished, which led to the Nobel prize. I can’t take any credit for that work. I can simply indicate that, as Julie indicates, that by pointing out some of the less exact work that was being done with the metabolites of epinephrine as causing schizophrenia, which I thought was absurd, by pointing out that we didn’t even know the normal metabolism of epinephrine, and these guys were already talking about the abnormal metabolism.
Kandel: But weren’t you also… First of all, not only did you call attention to the importance of studying the normal metabolism, but didn’t you bring labeled epinephrine and norepinephrine to the NIH so that people could study it both in humans and in experimental animals?
Kety: I was interested in studying the metabolism of epinephrine in the human body, and in order to do this, I had to get an epinephrine or a norepinephrine of unheard of specific activity because we had to inject this into human beings. And these were very powerful compounds, and we had to inject tracer amounts with enough radioactivity that we could count. So we needed a new kind of norepinephrine, one that was not labeled with C14, but labeled with tritium. And I wrote to a number of places and finally got New England Nuclear to agree to synthesize the radioactive tritiated norepinephrine for us. The interesting thing was, however, that by the time that had arrived, Axelrod had already worked out the metabolism.
Kandel: That’s wonderful. Seymour, so we have really covered sort of a lot of ground. Are there any other high points that you would like to comment on?
Kety: Well, I really think the thing that I’m proudest of is the feeling that I have, and which is shared by some people, that I played a major role in turning the whole field of psychiatry around from the emphasis, overemphasis of life experience and the disregard of biology toward biological underpinnings of mental illness. And also turned psychiatry around so that it became interested in and competent to do good research, good scientific research, controlled research, not based on testimonial, not based on half-baked ideas, and so that today psychiatry is an honorable branch of scientific medicine.
Kandel: That’s what really stands out in my mind. As you know, I was interested in psychoanalysis before I came to NIMH, and it just absolutely turned me around.
Kety: You mean you were not interested in basic neurobiology?
Kandel: No, not at all. I had done a few months as an elective in medical school, but I went to medical school in order to become a psychoanalyst.
Kety: Isn’t that interesting.
Kandel: Yeah, but I’m not alone. I think your impact affected my whole generation. I think I must have told you this, Seymour, that when I came to the Mass Mental Health Center there were no rounds at all. There were no outside people ever invited in, and I thought this was ridiculous, and I agitated and after a while, Ewalt, who was a sensible guy, agreed to that. And the first topic I wanted to discuss, because I had heard you give a sensational talk at the NIH, was the genetics of mental illness. There was not a single psychiatrist in Boston that knew anything about it. I called you. You could not come at that particular date that we had set aside, so I went back and I looked around and the only person who could do it was Ernst Mayr, the biologist. He did a very good job. He knew Kallman’s work. This was before you had done any empirical work yourself. So this was I think 1961.
But anyway, I don’t want to get into this, but that community was completely unaware, uninterested in the genetics of mental illness. And it’s just completely changed. When I was a resident, you could not be a chairman of a department unless you were a psychoanalyst. Now if you’re a psychoanalyst, you have a very difficult time being a chairman of a department of psychiatry. It’s made an enormous influence on psychiatry.
Kety: Fritz Redlich used to tell an interesting story. In his day, in the old days, if you wanted to have an analysis you would tell the professor that you were going fishing and you had to take a day off. Nowadays, in his current period if you wanted to go fishing, you would tell the chairman of the department … (Laughter.) The other thing that I am very proud of is that I realized recently looking over the list of members of the National Academy of Sciences…
Kandel: How many of them had come through the NIMH Intramural Program.
Kety: More than 20 guys in the Academy served time in the Mental Health Intramural Program, and that was really amazing, I thought.
Kandel: So many of the major contributors from Sol Snyder on have really come through those labs. It was a spectacular place. It was really wonderful. Seymour, anything else that we should touch?
Kety: I don’t think so. You certainly have touched them all.
Kandel: Well, thank you very much. It’s really been wonderful, both for sentimental and historical—and intellectual—reasons to take this journey with you.
Key Publications of Seymour Kety
Kety, S.S. and Schmidt, C.F. (1948) The nitrous oxide method for the quantitative determination of cerebral blood flow in man: theory, procedure and normal values. J. Clin. Inv. 27: 484–492.
Kety, S.S. (1951) The theory and applications of the exchange of inert gas at the lungs and tissues. Pharm. Rev. 3: 1–41.
Kety, S.S. (1959) Biochemical theories of schizophrenia; a two-part critical review of current theories and of the evidence used to support them. Science 129: 1528–1532, 1590–1596.
Landau, W.M., Freygang, W.H., Rowland, L.P., Sokoloff, L., and Kety, S.S. (1955) The local circulation of the living brain; values in the unanesthetized and anesthetized cat. Trans. Am. Neur. Assn. 80: 125–129.
Kety, S.S. (1961) The academic lecture: The heuristic aspects of psychiatry. Am. J. Psy. 118: 385–397.
Kety, S.S., Wender, P.H., Jacobsen, B., Ingraham, L.J., Jansson, L., Faber, B., Kinney, D. (1994) Mental illness in the biological and adoptive relatives of schizophrenic adoptees: Replication of the Copenhagen study in the rest of Denmark. Arch. Gen. Psy. 51: 442–455.