W. Edwin Fann: A History of The Tennessee Neuropsychiatric Institute
Fridolin Sulser (1926 – 2016) on the Tennessee Neuropsychiatric Institute
The following is an extract from an interview with Fridolin Sulser conducted by Leo E. Hollister on May 9, 1997, in Nashville, Tennessee, for the Oral History series of the American College of Neuropsychopharmacology. The edited interview was published in: Sulser F, editor. Neuropharmacology. Volume Five. (In Ban TA, editor. An Oral History of Neuropsychopharmacology. The First Fifty Years, Peer Interviews). Brentwood: American College of Neuropsychopharmacology; 2011, pp. 501-15.
LH: I gather you were at the International Congress in Moscow where Marshall Nirenberg presented his findings on the genetic code.
FS: No, I was not there but I was at NIH when Matthaei and Nirenberg discovered the genetic code. That was in 196I or 1962. They were just around the corner from me. After I became an immigrant I went to work for two and a half years at Burroughs Wellcome in Tuckahoe, New York, as head of their pharmacology department. But, as you can imagine, working in industry was not for me. It's not my life style. So, when Dan Efron told me Allan Bass at Vanderbilt was entertaining the development of a Psychopharmacology Research Center I thought that's a good opportunity for me to go back to academia and get closer to psychiatry. This was in 1965.
LH: Sometimes we underestimate the influence administrators have, because Dan was nothing but a scientific administrator. Yet he was the one who encouraged Allan to start the Tennessee Neuropsychiatric Institute (TNI) and recruit you.
FS: Administrators, if they're smart, can do a lot by channeling things in the right direction. I think that top administrators, who are also scientists, should have membership in the ACNP as real members, and not just as administrative members. Some of them have made tremendous contributions to the field.
LH: For a very long period of time, in this country, nobody employed by industry could ever hope to be President of the Pharmacology Society. John Burns was one of the very first people from industry to be asked.
FS: In 1958, when I came to this country, you could not even become a member of the Pharmacology Society if you were working in industry.
LH: That's never been a bias in the ACNP. Len Cook and Larry Stein were both connected with industry while they were President, and one of the guys running for president this year is also connected with industry. I don't think we've had any biases in that respect.
FS: I don't think so, either.
LH: So, after you left Burroughs Wellcome, you went to Tennessee?
FS: Yes, I went to Tennessee.
LH: That was what year?
FS: 1965. Then I could develop my own research, in industry, I could not. And at NIH I worked with Brodie. So, this was a tremendous opportunity.
LH: You had to come down here, take a vacant space, and turn it into a laboratory?
FS: Space at the State Hospital had to be turned into labs at the beginning. We got a center grant from NIMH with the enthusiastic support of Dan Efron. And the State of Tennessee gave us money to renovate the place. We had good space and we got good people to come to work in the Institute; post doc's like Elaine Sanders-Bush, Susan Robinson, Dorothy Gallagher and Phil Mobley. All these people went through TNI. Then Jerzy Vetulani came from Poland, and Janowsky.
LH: Dave Janowsky from San Diego?
FS: No, Aaron Janowsky from Oregon. We developed a very effective basic research group.
LH: Didn't Jerzy Vetulani go back to Poland?
FS: Yes, he went back.
LH: Is he a Chair somewhere?
FS: He is the Scientific Director of the Polish Academy of Sciences in Krakow.
LH: What did you start doing when you came here?
FS: The first thing we did was ask the question why antidepressant drugs take so long to work. I was convinced that norepinephrine uptake inhibition per se had probably nothing to do with the therapeutic activity of these drugs, because uptake inhibition and the reversal of the reserpine syndrome take place rapidly. I had one of my graduate students during my first-year at Vanderbilt look at how fast uptake inhibition in vivo occurs. We gave imipramine and a few minutes later the uptake of norepinephrine was blocked. So, I concluded this could not be directly responsible for the therapeutic activity.
LH: Also, uptake into the nerves is especially fast.
FS: Yes. We looked for other mechanisms that take longer to produce an effect. This is when Earl Sutherland, another one of my heroes, with his cyclic AMP second messenger concept, came into the picture.
LH: He did most of his work on cyclic AMP at Case Reserve in Cleveland, didn't he?
FS: That's correct. He was a man with a vision. It was Earl who first talked to me about cascades in the CNS in which the interaction of a transmitter with receptors is only the first step, the step that activates these cascades. And this was before G proteins; we didn't know about them at the time. And while Earl was here at Vanderbilt he put the receptor for norepinephrine on the enzyme adenylate cyclase.
LH: So, nobody knew about G proteins then?
FS: No, the pivotal role of G proteins in signal transduction was discovered later by Rodbell and Gilman. Then, in a conversation one evening over Jack Daniels, with a fire burning in the hearth, Earl said, “If I were you, I’d look beyond the synapse at these cascades and the role they play in the action of antidepressants.” Obviously his favorite one, was the cyclic AMP cascade.
LH: At that time cyclic AMP was the only second messenger, wasn't it?
FS: It was the only one and it was difficult to measure the activity of the second messenger system. We didn't have a radioimmunoassay, so we had to use enzymatic reactions to measure cyclic AMP. It was very, very complicated and time consuming. Alan Robinson was involved in that. Then we discovered that if we gave antidepressants chronically on a clinically relevant time basis there was an adaptation going on at the level of the β-adrenoceptor-coupled adenylate cyclase systems. This was in 1975, 25 years ago. It was a tremendously interesting discovery. The sensitivity of a receptor to an agonist was measured by the activation of adenylate cyclase. We found the number
of receptors in the membrane was changed after chronic administration of antidepressants. Prior to this Lefkowitz and others discovered that receptor sensitivity was regulated by phosphorylation.
LH: So you had shown that the number of receptors decreased.
LH: But the decreased number of receptors was not the consequence of the decreased sensitivity.
FS: Rather the decreased sensitivity of the adenylate cyclase system was the consequence of the decreased number of receptors. So the first thing we found at Vanderbilt was that the number of receptors decreased. This led to the receptor regulation hypothesis and all kinds of other research. Importantly, we discovered that antidepressant treatments, tricyclics, MAO inhibitors and ECT, given on a clinically relevant time basis, reduced the responsiveness of the beta adrenoceptor-coupled adenylate cyclase system to norepinephrine in limbic and cortical structures of the rat brain and that chronic, but not acute treatment with noradrenergic antidepressants, down-regulated the biologically active form of the transcription factor, CREB-P, in the frontal cortex of the rat, indicating a net deamplification of the beta adrenoceptor – cyclic AMP cascade. Conceptually, these studies switched the emphasis on the mode of action of antidepressants and on the pathophysiology of affective disorders from acute presynaptic to delayed postsynaptic second messenger mediated cascades and opened up the gateway for subsequent studies of events beyond the receptors including changes in gene expression. A little later, when Phil Mobley joined our lab, we realized we had to incorporate the glucocorticoids in our work, because, stressful life events can precipitate depressive reactions. So we started to look at glucocorticoids and found that changes in glucocorticoids were changing the sensitivity of the receptor system to catecholamines. That led to the norepinephrine- glucocorticoid link hypothesis of affective disorders. The role of serotonin we did not understand for a long time. That changed when Berridge demonstrated that serotonin, through serotonin receptors we now know are 5HT2A and 5HT2c, activates phospholipase C, generating 2 second messengers, inositol-triphosphate (IP3) that mobilizes calcium and diacylglycerol, which activates protein kinase C.
LH: That was in the late 1960's?
FS: Yes. Then, Elaine Sanders-Bush, who worked with me, started looking at serotonin and serotonin receptors. I took care of the catecholamines and she took care of the indoles. We found that the two systems, the noradrenergic and serotoninergic systems converged after the receptors. And that was absolutely fascinating. Norepinephrine through the adenylate cyclase system
activated protein kinase A, that initially phosphorylates the receptor in the membrane, and causes desensitization of the system. Serotonin, through phospholipase C activation, made IP3 and diacylglycerol, which activates protein kinase C, and, we found that protein kinase C and protein kinase A have a cross talk with each other. Moreover, we found in human fibroblasts, using the transcription factor CREB as a target, that both the activation of the cyclic AMP- protein kinase A pathway by the beta agonist isoproteronol and the activation of the protein kinase C pathway by the phorbol ester PMA caused phosphorylation of nuclear CREB, and that this phosphorylation is additive in nature.
LH: So you linked the activity of the serotonin system with the norepinephrine system?
FS: Yes. We're trying, now, to see what all this means. Paul Greengard at Rockefeller, who was previously at Yale, has shown that the final common pathway of signal transduction is the phosphorylation process, so the question now is, what is phosphorylated and what is less phosphorylated after desensitization, and what are the consequences of all this in the next compartment of the cell, in the nucleus. Presently, we're looking into this. Paul Rossby and I developed the hypothesis that behavior is put together by programs of gene expression. It's a large program, it's like a huge orchestra in which there are twenty thousand players (genes) and there are first violins, first cellos, the horns and so on. This is well coordinated in" normal" people like you and me. Now, if the horn comes on at the wrong time, you have dissonance. We feel in depressed people, because of stress or whatever, the plasticity of the system is lost in response to increased input; what the drugs do is help to adapt by restoring the plasticity at the level of gene expression. At the present time, we are trying to develop methods to identify the first violins and the cellos. In other words, developing methodology to measure programs of gene expression that are activated by transcription factors, phosphorylated by the kinases. Hopefully, one of these days, we will understand what's going on. The work with transcription factors is new and people don't talk about it yet, because it is very complicated. There are about two thousand eukaryotic transcription factors. Once translocated to the nucleus, they will affect only genes that have responsive elements in the promoter area (nuclear receptors).
LH: Are c-fos, c-jun genes further down the line?
FS: Yes.. A transcription factor, like CREB, turns genes with CRE elements in their promoter region on via the beta adrenoceptor-cyclic AMP cascade. One will always turn on groups of genes, in other words, the first violins, the second violins etc. The question is, what are these genes and,
importantly, what are their products doing. That's not easy to find out. We need new methodology; but this is where the field is going. Finally, you can envision the development of drugs that affect or restore faulty programs of gene expression.
LH: So we got away from the synapses.
FS: Yes, all the way to the nucleus. There's already fascinating work in this area from Michael Greenberg's lab at Harvard. Michael has shown that fos-b, which is a transcription factor like fos-c and jun-c, is very important for the complex behavior of nurturing in animals. Normal animals, and this was done in mice, after they give birth, collect their off-spring, put them in the nest, put their body over them to keep them warm and nurture them. If you knock out just one transcription factor, fos-b, they don't do those things anymore because nurturing behavior is interrupted. This is absolutely fascinating. By knocking out one transcription factor, the olfactory stimulus of smelling the pups doesn't work any longer.
LH: This knock out gene technique is fantastic. Who is the Japanese fellow who is using the knock out gene technique in studying behavior? The one who won the Nobel Prize.
FS: I don't remember his name either. The task in the future is to apply these sophisticated techniques in an intelligent way to behavioral problems.
LH: His name was Tonegawa.
FS: Yes, Tonegawa. So, this is where the field is moving; from presynaptic events in the 1960's, to membrane receptors in the 1970's, to second messenger mediated activation of protein kinases in the 1980's, and, now, we are moving to the last compartment, the nucleus. That's where the action is now.
LH: That's an enormous amount of progress and you've been part of all of it.
FS: It is enormous progress if you think about it. At the time I entered the field there was nothing known about cascades. When I was at the NIH in the late 1950s we were still grinding up whole brains of rats, just to measure serotonin or norepinephrine. There was nothing known about presynaptic events such as uptake, receptors, receptor subtypes. There was little or nothing known about protein kinases, G proteins, transcription factors, not to speak about the organization of the genes and how they're turned on and off.
LH: And, we still don't know anything about the gene products.
FS: That research will not be easy to do because those products are proteins, and the functions of proteins are difficult to study.
LH: You're still at the Tennessee Neuropsychiatric Institute?
FS: No, I'm in the Department of Psychiatry at Vanderbilt University. 1 have my laboratories there and my grant was renewed this fall for another five years.
November 1, 2018