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Saturday, 21.09.2019

In Memoriam
Merton Sandler (March 28, 1926 - August 24, 2014)
by
Thomas A. Ban

 

On August 24, 2017, Merton Sandler, an emeritus fellow of the American College of Neuropsychopharmacology (ACNP) passed away. Born in Sanford, Lanceshire, in the UK, Sandler received his M.D. in 1962 from the Manchester University School of Medicine in the UK. In 1973, Sandler was appointed Professor of Chemical Pathology at the Royal Postgraduate Medical School, University of London.  In 1991, he became Emeritus Professor at the University.   Merton’s primary area of research interest was in monoamine metabolism and the role of monoamines in neuropsychiatric disorders. In his early research, he studied monoamine oxidase (MAO), the enzyme itself. In the mid 1960’s, in collaboration with Moussa Youdim, he provided electrophoretic evidence that MAO was present in the brain in multiple forms. They assessed the role of these in vivo and the activity of selective MAO inhibitors. They also demonstrated the therapeutic value of the MAO B inhibitor deprenyl in Parkinson’s disease. Merton also studied trace amine metabolism extensively in psychiatric illness. He found selective decreases in tyramine and octopamine production in depression and noted an overproduction of phenylethylamine in aggressive psychopaths (Ban 2011; Sandler 2006; Sulser 2011; Youdim 2004.

Merton was a member of numerous editorial boards and learned societies.  For his scholarly contributions to neuropsychopharmacology, he received the Anna-Monika Prize, the Franz Burke International Prize for Research in Parkinson’s disease, the Arnold Friedman Research Award and the CINP Pioneer in Psychopharmacology Award.

            Merton Sandler (MS) was interviewed by David Healy (DH) for the “Oral History Series” of the ACNP at the annual meeting of the College on December 15, 1998, in San Juan, Puerto Rico (Ban 2011; Sulser 2011). The edited transcript presented here was first published in Volume Two of the series.

 

INTERVIEW

Interviewer: David Healy

San Juan, Puerto Rico, December 15, 1998

 

DH: Today is Tuesday, the 15th of December 1998, and we’re at the ACNP annual meeting in Puerto Rico. On behalf of the ACNP, I am interviewing Merton Sandler. Merton, could we begin with where and when you were born, and then we will move on from there?

MS: We can, but it was an awful long time ago, 1926 in Salford, which used to be a poor relative of Manchester; both have now spectacularly reinvented themselves!  Well, there is nothing spectacular about my own birth. I grew up; the only big break was getting a scholarship to Manchester Grammar School, which was the special school in the area and quite well known in the UK.

DH:  When you were at school, did you have any feeling for what you would ultimately go on to do?  Did you have any awareness of mental illness, biochemistry, anything like that?

MS: The answer is no!  I hated school, as a matter of fact.  I think I was one of nature’s rebels.  I hated wearing a school cap and would squash it into my pocket.  I was always caught!  I hated the discipline and I hated organized sport, but I had to do it.  When I avoided it I was duly punished. The amusing thing was, when I came to live in London years later, I was cajoled into becoming chairman of the London section of the school old boys association, the school that I thought I hated so much.  That’s the way cookies crumble.

DH:  When did you actually decide to go into medicine and, why?

MS: I was always going to go into agriculture because I was a keen little environmentalist in those days.  I still am.  But, at about the age of sixteen, I suddenly thought, I don’t know one end of a cow from another.  So, I looked around and medicine seemed rather interesting; so medicine it was.  I started in 1944, just before the war ended.

DH:  That would take you up to 1950, when you qualified?

MS: I qualified in 1949.  Next year, I will have been a doctor for fifty years.  David can you imagine; it is mind-boggling.

DH: Things would have looked completely different compared with now; drug-wise, you had extremely few treatments. Biochemistry was only just forming as a discipline; neurochemistry wouldn’t have been thought of.

MS: My whole career has been shaped by expediency and opportunism and the jobs that were available. I got into this field I suppose I’ve made a small mark in, completely by accident.  I became a soldier for two years, a national serviceman. Because I’d done a year of pathology training, the Army gave me a small hospital laboratory, but with very few routine duties.  So, another doctor-soldier, Michael Pare, who later became a very able psychiatrist, and I teamed up.  We started doing things we called research. We were enthusiastic but had no idea of research discipline.  Even so, we had a bit of luck and the Lancet published our first two papers.

DH: On what?

MS: Aminoacidurias. The first was called ‘Starvation Aminoaciduria’ and we starved for three days in the process. That was in 1953.  We had no hesitation in approaching leaders in the field such as Charles Dent for advice, which they gave freely.

DH: Why did you start to look into this area and why did you begin with amino acids?

MS: I had the crazy idea of developing a new liver function test.  I didn’t know much organic chemistry, but was fascinated by it.  I’d always had chemistry kits as a kid and made bangs and smells and things, I was a bit of a terrorist. The chemical side of things fascinated me. Paper chromatography was brand new and there was time to build equipment for it out of bits and pieces scrounged from the Army Engineers. When I left the Army, I got an intern job at a famous chest hospital, the Brompton. They had brand spanking new chromatography equipment lining the corridors and nobody knew how to work it. It was mouth-watering to see this stuff so I got it going for them!  When my internship finished I was offered a research job there.  Before the house and research job ended there was another seminal event, as far as my own life was concerned. Two friends and contemporaries at the Brompton, Alan Goble and David Hay, now Sir David Hay and the big boss of cardiology in New Zealand, moved to the National Heart Hospital and started to investigate the very first case of carcinoid syndrome ever seen in England. Remembering my enthusiasms, they came to me and said, biochemically, can you do anything for us? I said I’d have a go because the petals had started to unfold, the biochemical petals. I did a few chromatograms and we were very lucky; I got some nice data showing high concentrations of 5- hydroxytryptamine (5-HT) in the right side of the heart compared with the left. That may be one of the factors in the genesis of right-sided heart disease in carcinoid tumor syndrome. I was fired-up by this finding and became a one-man carcinoid reference laboratory.  We are getting close to psychopharmacology, but haven’t got there yet.

DH: I know.

MS: I became a psychopharmacologist very gradually and didn’t realize I had become one until ten years after I had done so.

DH: At that point, what did 5-HT look like to you?  I mean, it had been discovered by Erspamer and had been isolated by Page and Rapoport.

MS:  I met Erspamer when he came to London to give a lecture. I hadn’t realized how lucky I was, because he wouldn’t travel long distances. He gave his lecture in really execrable English but it was nice to meet this great man. 

DH: Was there any feeling then that 5-HT could be involved in mental illness?

MS: First there was a problem about nomenclature; we called it 5-hydroxytryptamine and the Americans called it serotonin. Gaddum actually called it ‘HT’ until I had the temerity to remind him that 6-hydrooxytryptamine also existed in our brains and that keeps us sane. When Michael Pare and I came out of the Army, I moved to another hospital, the Royal Free, while he got a job as a psychiatrist at St. Bartholomew’s Hospital. We teamed up again, because 5-HT emerged as flavour of the month in psychiatry, so we were very happy to oblige and do a few experiments.  In the meantime we began to understand 5-HT was inactivated in vivo by monoamine oxidase.   Monoamine oxidase inhibitors were claimed by Nathan Kline to be important as antidepressants. The whole field was brand new and Pare and I had lots of leads to follow. 

DH:  Who was Gaddum? 

MS: Gaddum started life as a mathematician and later turned to pharmacology. He was a difficult man, difficult to approach; cold and rigorous in his thinking.  There was always a barrier, you couldn’t become matey with him at all. I finally came across him a little when he was dying and  I did a consultancy at Babraham, our major Institute of Animal Science, which Gaddum directed.  

DH: Where he moved to after Edinburgh.

MS: Yes. He was director for a number of years until, in the early to 1960’s he got carcinoma of the stomach.  He was a big man with something of a pot belly and an aldermanic look.  But now, alas, he had shrunk.  He looked like Stan Laurel in Oliver Hardy’s trousers.  He was still in the lab at seven o’clock in the morning, perusing goldfish gut in a minute chamber looking for substance P, of which he was one of the discoverers some years earlier.

DH: He used to hang out with Henry Dale, Marthe Vogt and a group of other people.  Did you have much contact with this group?

MS:  I remember Henry Dale.  I saw him only once when he was chairman of one of those special University of London lectures that were so good. He introduced Rita Levi-Montalcini, who co-discovered Nerve Growth Factor and won a Nobel Prize, when she came to lecture in London in very broken English. Dale was another forceful and impressive character; he died a few years later.  The last I heard of him was at a meeting at the British Pharmacological Society. He was ninety and he couldn’t come himself so he sent a video message.  Marthe Vogt, I knew very well and she is still alive in 1998.

DH: Yes, she is.  

MS: She discovered noradrenaline in the brain and mapped its distribution; that was another very important milestone. These monoamines have really influenced my life; the catecholamines and 5-HT have, to be more precise.  Although we did have a long, hard look at the trace amines, but they didn’t amount to much in the end. We couldn’t find any evidence of a neurotransmitter role; but that is the way things turn out.  

DH: Arvid Carlsson describes coming to London in 1960, and meeting a certain amount of resistance to the idea of any clinical role for these substances; but, in essence, these people were physiologists. 

MS: You are absolutely right!  There was so much resistance to anything that might even faintly have been clinically connected.  Perhaps we ought to mention Blaschko at this juncture.

DH:  We should.

MS: Blaschko made crucial observations or inspired guesses at every point in the history of the monoamines. Blaschko was there! Even apart from his best studies of monoamine oxidase.  Blaschko was a strange chap and would think and then pronounce, with his eyes closed. We would then get a monologue issuing forth, a stream of consciousness.  And, there was good stuff in there, if you could bear to listen. But sometimes, it was all rather sleep-provoking!  Blaschko, Vogt, Feldberg and many other academics of first rank; these were the people who were kicked out of Germany by the Nazis. 

DH: Right. 

MS: Jewish, almost to a man, though not Marthe Vogt, obviously. She came from a family of pathologists. Her parents ran a brain institute in the Black Forest where Lenin died of General Paralysis of the Insane.

DH: Yes, right!

MS: They sent Lenin’s brain to the two Vogt’s, somewhere around 1922 or 1923, and they dissected it.

DH: Lenin’s brain hasn’t been with his corpse in Red Square all this time?

MS: No, it hasn’t!

DH: Right, but there were also people in this group, like John Burns.  Do you know him?

DH: J. H. Burns?

MS: I knew him, but not well. He was a great influence on British Pharmacology, a very brusque sort of individual. But he was the scientific father of people like John Vane, who trained under him at Oxford. I believe that Burn started off in London at the School of Pharmacy and then moved to Oxford in his later career. Who else did you mention?

DH: Edith Bulbring.

MS: I knew her, too.  She had one of her legs amputated before she finally died, poor old thing.  But, they seem to live to a great old age.  Feldberg, too, was an amazing influence in Physiology.

DH: Why?

MS: He was a splendid experimentalist and always had a little cigar in his mouth with two inches of ash attached. Sometimes it would drop onto the cat’s belly he was poring over. He was treated  badly by the animal rights people, in his old age, when he was careless in choosing his assistants!  An animal rights evangelist got a job, pretending to be a disciple, and you can write your own scenario!  Anyway, Feldberg was a very nice man!

DH: So you had the idea your transmitters might be important for mental illness but the older group couldn’t buy the idea fully and it took people like you, who didn’t have inhibitions imposed by the field, to pick up the ball and run with it?

MS: I would say you are right. Mike Pare and I, with little learning but a great deal of enthusiasm, did just that. We took up the baton. For instance, we lined up volunteers, about a dozen junior doctors at the Maudsley Hospital and devised an experiment to test Gaddum’s hypothesis. We were the first to give 5-hydroxytryptophan (5-HTP), the precursor of 5-HT, intravenously.  In those early days, we had to use DL-5-hydroxytryptophan but in retrospect we obviously didn’t use enough.  Mike and I were not only the first to inject this material into man but we were also the first to use L-Dopa for a similar purpose. We did this together with a psychologist called Brengelmann, not long after the war ended. Brengelmann was a German of rather heel-clicking variety. I was a bit sensitive to Germans just after the war. 

Anyway, despite his origins, Brengelmann was terribly good; he had a series of psychological tests which he applied.  We gave volunteers LSD, which was all the rage in these days. LSD is an antagonist, as you know, of 5-HT. We thought that if we pretreated our volunteers with a 5-HT precursor we might suppress the schizophrenia-like symptoms one gets with LSD. Strangely enough, after five subjects, it was starting to emerge we’d got it right.  We couldn’t carry on because the sixth volunteer was a disaster; he had a bad trip on LSD and had to be held down by half-a-dozen male nurses and tranquilized. He only came back to sanity after about six months, if he ever did. In those days there were no ethical committees to pronounce on our experimental design. They were a later addition. We didn’t know we were doing anything wrong and, in those days, it was not uncommon for experimentalists to test new drugs on themselves. On one occasion, for instance, I took 1mg of reserpine intravenously. My nose became blocked and I became mildly psychotic for about a month.  We were just following Gaddum’s precept to see how far it went. I think our papers, published in the Journal of Mental Science in the late 1950’s, were a milestone. That journal later changed its name to the British Journal of Psychiatry.

DH: At this point, the monoamine oxidase inhibitors started to come on stream and suggested a new hypothesis.  Did you look at this, as well?

MS: Indeed we did!  Pare and I were unfortunate we didn’t have much of an idea how to present our data properly to get the best news coverage!  What I believe was a seminal paper was published under the disguise of a clinical trial, “A Trial of Iproniazid in the Treatment of Depressive Illness.”  We had a very interesting study design and, as I mentioned before, we also gave 5-HTP and DOPA in the lag period of two to three weeks until the antidepressant took effect. Thus, we tried to shorten the lag period by giving amine precursors, to be decarboxylated to their corresponding monoamine in situ.  Although we didn’t say it in as many words, the amine hypothesis of depressive illness was implicit in every sentence of the article.  It was what we were writing about but we didn’t emphasise the information we were imparting and it didn’t hit the headlines.  Joe Schildkraut scooped that pool seven or eight years later when he wrote a review article talking about the monoamine or norepinephrine hypothesis, as he called it.

DH: Are you sure it was Joe? What about the contributions of John Davis and Biff Bunney, because both articles came out about the same time?

MS:  I am talking about the ones that hit the jackpot in Current Contents.

DH: OK. 

MS: I am not disputing others were on the right wavelength, too.

DH: Did the 5-HTP that you gave actually help?  Did it cause lightening of affect?

MS: No.  The single dose we were in a position to give was far too small.

DH: Could your article have been taken to show that the amine lag-period hypothesis couldn’t have been right to begin with?

MS: Possibly.  I don’t think you can say that when you give such a relatively low dose, 25mg of the DL compound which was  nothing when everyone knows how much L-DOPA it takes to have any effect in Parkinson’s disease, with or without a peripheral decarboxylase inhibitor.

DH: How did the monoamine story begin to unfold, from your point of view?  Iproniazid had been discovered and there was a strong suggestion it was working because it was a monoamine oxidase inhibitor.

MS: I have always been a dedicated reader of the literature. Modesty aside, I would go through the spring edition of Federal Proceedings, with its two or three thousand abstracts, as a kind of religious devotion! 

DH: You would really go through all of that?

MS: In 1957, there was a pearl in this particular oyster.  It was an abstract by Armstrong and Shore. They left out one of the authors names in haste; Macmillan’s name should have been on that abstract, too. Anyway, that paper described, for the first time, the major metabolites, the methylated oxidatively deaminated metabolites of the catecholamines, noradrenaline and adrenaline in the urine of patients with pheochromocytoma.  You wouldn’t believe it, but up to 1957, we had no idea what happened to endogenous or administered noradrenaline and adrenaline. It was the finding in this paper of O-methylated metabolites, and particularly vanilmandelic acid (VMA), that broke the thing wide open.  Julie Axelrod was immediately on to the enzyme mechanisms involved, particularly catechol-O-methyltransferase (COMT).  And it was partially for this reason he won the Nobel Prize, and quite rightly. We made our own modest contribution to the catecholamine metabolite story then and published the very first clinical assay procedure for VMA. We soon established a corner in this research area. We were quite good at measuring these unexpected metabolites and published the first method for measuring urinary homovanillic acid, the major metabolite of dopamine and were also quickly off the mark with 4-hydroxy-3-methoxyphenylglycol (HMPG). We were very early in the gas chromatographic field which made it so easy to make measurements of trace metabolites. When I first cut my teeth in clinical chemistry, we were measuring sodium by using uranium salts that took a week to get the results! Then flame photometry came along. Things have changed surprisingly since that time.  We came along with our gas-chromatographic methods just in time for the L-DOPA revolution.  We were thus able to quantify so many of the minor metabolites of L-DOPA, and the major ones too, in Parkinson Disease.  Over the years I have followed the monoamines wherever they led.  We discovered other unconsidered trifles along the way. Amines started to be implicated in migraine for instance, and research money came from the Wellcome Trust, which was very helpful at that time. The quid pro quo was that we were to investigate the metabolism of tyramine in the brain. A very nice lady, Edda Hanington who was the Wellcome’s Assistant Scientific Secretary claimed that tyramine triggered headache in patients with so-called dietary migraine.  Maybe it did and maybe it didn’t but it just might in a few affected subjects. Anyway, this was the background to a whole series of investigations that links up with depressive illness. Our tyramine test in depressive illness, which I shall tell you about in a moment, has been a sad disappointment to me and our group. It’s too tricky to do routinely in clinical practice although it works and picks out unipolar depressive patients. Somebody should take it up again and try to find the mechanism we never discovered. 

DH: What you are saying is, there is a group of people who, with the tyramine test, show one result and others don’t.

MS: Yes; the test shows a clear deficit in one particular clinical group of depressed subjects.  The metabolism of tyramine is largely carried out by monoamine oxidase (MAO).  However, there is an important minor metabolic pathway accounting for about 10 percent of the total, involving sulfate conjugation.  We were able to show that in patients with unipolar depression, there was a significant deficit of tyramine conjugation with sulfate after an oral tyramine load.

DH: In all of them, or only certain ones?

MS:  In a statistically highly significant number.    

DH: In the ones that respond to a particular drug treatment or not?  

MH: We had difficulty tying this finding in with drug treatment response.  The result hung in the balance. I seriously think there is room for further investigation. It is an expensive test because you have to be meticulous about the precise timing of a series of urine samples. So, there are good reasons this didn’t become popular; we hadn’t worked up the technology to do the test on a specimen of blood, so that manpower was involved in the urine collection procedure.  

DH: You raised the question of tyramine, which in turn raises the cheese effect and the part played by MAO.  Can you take me through this and tell me what was your role?

MH: Well, I have written a great deal but I still don’t know whether I made any major contribution.  My colleagues and I have worked in this area for a long time, even before Johnston, who first described MAO-A and MAO-B pharmacologically in 1968.  We ourselves took a wrong track.  There were always tantalizing indications that the enzyme MAO had multiple forms and, in fact Youdim and I, in 1967, were able to produce preliminary electrophoretic evidence for such a finding. We published a series of papers pointing to different substrate preferences of the multiple forms. One of them, for instance, showed a strong preference for dopamine. With hindsight, it seems obvious those findings were artefactual, elegant artifacts true; but it is equally obvious there was a physicochemical basis for their manifestation.  Even so they didn’t bear much relationship to clinical reality.  In the 1960’s, there was considerable drug company interest in MAO inhibitors following the success of iproniazid in producing a lightening of affect in some patients with depressive illness.  One of these firms, May and Baker, synthesized a pharmaceutical agent called clorgyline and set Johnson, one of their employees, to put it through its paces.  Johnston did the work but didn’t write it up, because he became ill and died not too long afterwards in a Cambridge mental hospital. Sir Rudolph Peters, the eminent biochemist, who was a consultant for May and Baker, converted Johnson’s raw data into a seminal paper, which was published in 1968, in Biochemical Pharmacology.   Nowadays, every school boy knows that there are two isoenzymes of MAO, A and B, and clorgyline turned out to be a selective inhibitor of MAO-A.

DH: What happened next?

MS: Although clorgyline was a very good lightener of affect, it never got on to the market because there were enough similar drugs already available. The first selective inhibitor of MAO-B was that synthesized and developed by Joseph Knoll and his colleagues.   I remember how excited we all were when he first presented his paper at a meeting in the early 1970’s in Sardinia when we had an MAO Festschrift for Blaschko’s 70th birthday. Mimo Costa and I edited the Proceedings with the enthusiastic collaboration of Ghighi Gessa. We held this meeting in Sardinia, because that was Costa’s home island and it became the first psychopharmacology meeting of many.  There was this charismatic Hungarian, full of fire and passion, but it was difficult to understand a word that he was saying.  To the great interest of all of us, he unveiled the first irreversible MAO-B inhibitor, called deprenyl. Now it’s officially called selegiline although deprenyl is still, if unofficially, much more used today.  Anyway, this was the only major drug to emerge from behind what was then called the Iron Curtain and Knoll was a great PR man for the Hungarian drug group that synthesized it.  To this day he is as full of enthusiasm and fire as he always was. Moussa Youdim visited him in Budapest and obtained a sample of the drug, taking it to Birkmayer in Vienna, suggesting he might like to try it in patients with Parkinson’s disease.  Now, Birkmayer would try anything on anybody.  He was a very interesting character; I don’t know if you know anything about him? 

DH: Nothing at all.

MS:  He was thin, enthusiastic, pipe-sucking and friendly and had been an SS doctor in the late 1930’s.  When they found out he was partially Jewish, they kicked him out of the SS, which was the making of him.

DH: Right.

MS: Vienna was a very interesting place to be at that time because they have a law there has to be a post-mortem examination in every death.  So, brains from Vienna flowed forth to research laboratories of the world. One of Birkmayer’s emissaries, five feet tall, arrived at our lab wearing a top coat down to his ankles and a Homburg hat.  He was carrying two plastic store bags full of human brains, two in each that he brought through British customs.  They didn’t stop him!   

DH:  Gosh.

MS:  I will tell you more about the British Customs in a moment.

DH:  Right, keep going.

MS: When Moussa Youdim said to Birkmayer, ‘Let’s try deprenyl in Parkinson’s disease”, and I heard on the grape vine they were going to try a selective MAO-B inhibitor, my immediate response was how ridiculous, everybody knows that brain dopamine is metabolized by MAO-A, because it was in the literature. We combed the literature once more and it became obvious that the only available information on this point was in the rat.  So Vivette Glover and I went quickly to the lab and looked at some human brains. These measurements hadn’t been done before in man.  Needless to say, we found that dopamine is largely metabolized by MAO-B in man, not by MAO-A!  It just shows that man is not a rat.  That’s one of the few things I have learned in my long life.

DH: It just shows. 

MS: So, I was convinced. After the Sardinian meeting, I’d kept in close touch with Joseph Knoll.   I called him and said “Can I cadge some deprenyl from you.” He said, “Oh yes, as much as you like.”  So, I flew over to Budapest in what I called my flasher’s mac.  It was a Macintosh with large pockets. I collected two large polythene bags full of white powder and walked boldly through the British customs. Nobody stopped me and fortunately the sniffer dogs were on holiday.  I hate to think what would have happened if I’d been caught.

DH: What do you think would have happened?

MS: I’d probably still be in jail!  Anyway, we rapidly put the first deprenyl in England through its clinical paces. I should say this work was in harness with Gerald Stern, my clinical collaborator over many years. We confirmed it worked in Parkinson’s disease and wrote a number of papers to this effect.  We did have one problem. We told our Committee on Safety of Medicines what we had done and they said, “You know this is illegal, you are using an illicit drug, brought illegally into the country.” Well, they were quite decent about it; they said we wouldn’t be prosecuted and  we could go ahead and publish.  So we did, and more or less lived happily ever after. We discovered a lot of deprenyl’s properties; the Hungarians were very appreciative and gave me an honorary doctorate!

DH: The deprenyl story is extremely interesting because it begins to look as if this drug can enhance life, in that it reduces mortality in people who are Parkinsonian. Can you take me through that particular aspect of the deprenyl story as it unfolded?

MS: This is another one of those stories of enthusiasm waning as more data become available.  I still think there could be something to it but the data are not as clear cut as they seemed in the very beginning. Knoll’s initial experimental findings were quite staggering!  His treated rats lived three hundred percent longer than untreated controls, amazing figures.  The only thing that I worried about was that he had a Vietnamese collaborator and though I am sure the experiments were done very well, the fact is that they were done in Vietnam and weren’t under Knoll’s personal control.

DH: Supervision, right.

MS: I don’t know; he did do some experiments in his own lab but I think it was the cost of so many rats that threw him. Anyway, there were others who jumped on the bandwagon.  There were preliminary clinical impressions suggesting longevity was one of the consequences of deprenyl treatment in Parkinson’s disease.  Others disagreed.  The London group of Neurologists produced data cutting right across that conclusion, suggesting that patients on deprenyl live for a shorter time than those not on deprenyl.  So, you pay you money and take your choice! 

DH:  What about it’s other actions, which have begun to emerge?   

MS:  There are fascinating laboratory data. Neuroprotective effects have been claimed….

DH: If that is true, it may herald whole new mechanisms by which psychotropic drugs could work.

MS: The whole business of neurotrophic activity is fizzing at the present. Although, I think of myself, as an archetypal monoamine man and still see monoamines in my dreams, lately I have taken a sideways step and branched out into neurotrophins.

DH:  Where did the neurotrophin story begin? 

MS:  With Rita Levi-Montalcini, who discovered Nerve Growth Factor, (NGF), many years ago, and won a Nobel Prize for it.  It’s amazing how that field has blossomed and generated a massive literature. Even so, it’s hard to slot into any clinical context, although it’s obvious to me that a possible role in depressive illness is just over the horizon. The methods are tricky and difficult and so immunological! You have to be a molecular biologist, for starters.  I’m not, as you know.  I came along too early for molecular biology, but I have young colleagues who know about these things.  With their assistance, I have crept quietly into this new area.  I don’t look on it as a new area, but rather as a continuation of an old one.

DH: The fact that different areas of research come under intense scrutiny depends, to a substantial extent, on the techniques available for their study.  The monoamines, of course, streaked ahead and left the others way behind until recently.

MS: They did.

DH: Was that because, as you imply, you had the techniques or is it an issue of we work on the things we like to work on?

MS: I put it another way, David.

DH: What?

MS: We have been struggling, for forty years, in the conceptual wilderness.  I recently wrote a review of one of your challenging books on the history and development of psychopharmacology and put it on record that we have been stuck in a conceptual mindset for forty years.  In the 1950’s there were so many major discoveries, the tricyclic antidepressants, the monoamine oxidase inhibitors, the neuroleptics, lithium- and, then nothing!  The reason is we just didn’t have the techniques perhaps; but our thinking was also repetitive. As I see it, we are at last breaking out of the vicious circle.  I am thinking specially of the neurotrophins, which you introduced into our discussion a moment ago and, in particular of BDNF, brain-derived neurotrophic factor, which shows signs of being of major importance in explaining the onset and treatment of depressive illness. There are fascinating data stemming from Yale in particular.  I am thinking of the group headed by Ron Duman who are responsible for a fascinating hypothesis, pointing to a cascade of events that would explain, incidentally, the lag period in response observed after tricyclic or monoamine oxidase inhibitor administration. This lag period, by analogy is, a sort of gear change in the cascade of events involving cyclic AMP and other important chemical steps until eventually you get to BDNF. Drugs, physical and chemical treatments like electroshock or insulin treatment, all cause a rise in BDNF concentration in animal experiments. Ethically, human data would be hard to obtain.  Stress models of depressive illness in animals, on the other hand, bring about a decrease in hypothalamic BDNF.  It’s just too bad that BDNF doesn’t cross the blood-brain barrier; we can’t think of it yet as a magic bullet.

DH: To take you back to the 1950’s, you were among others working on the first version of the monoamine hypothesis of depression, and one of the useful things observed at that time was that reserpine lowers amine levels and causes people to become depressed. Now, you took reserpine.   Can you describe the effects?

MS: It was one of the most miserable experiences in my whole life.  I was depressed, paranoid and aggressive for a month! I couldn’t breathe through my nose for a month. It really is a foul drug.  I know you have recently been promoting it, David.

DH: I am not promoting it but I am wondering if it did cause people to become clinically depressed.

MS: I can tell you from personal experience it does in some people.  I only had a small dose, half a milligram, I think, intravenously. A collaborator of mine, recently retired from being one of London’s coroners, took two milligrams, intravenously, and had to go to the hospital.  He was very, very ill.

DH: Why did he have to take two milligrams, intravenously?

MS: We were crazy!  We all did this sort of things. It is a grand tradition trying out things on yourself.  It’s come to a halt now, thank God.

DH: Do you still think it’s important for people working in the drug field to try compounds to appreciate what the issues are?

MS: I don’t know. Our reserpine experiment stemmed from trying to test one of Irv Kopin’s hypotheses on compartmentation of catecholamines and that sort of thing.  We published a paper or two out of our own discomfort! Ethical committees didn’t exist then but we don’t do it now.  Paul Ehrlich tried everything on himself didn’t he? It was a grand tradition.

DH: You used to go to Russia and you had links with Moscow and St. Petersburg.  Can you tell me how this all happened?  How were the links developed?

MS: I will tell you how it all started.  There was a biochemical congress in Moscow in 1961, and I got money from the hospital to go to it. They were building the Berlin wall at the time and Brezhnev harangued us from loudspeakers on every lamp post. From my point of view, the Congress was scientifically, a washout!  There was only one paper on monoamine oxidase, given by a young Russian called Vladimir Gorkin so I went to hear it.  There were about a dozen people in the room but it was very interesting and he and I subsequently became great friends. We were the only people that spoke a similar scientific language.  He also spoke very good English.  He died recently in Denver. I started to learn Russian in 1960 from a BBC Russian for Beginners course.  I took my young bride, who had also started to learn Russian the previous year to the Moscow Congress. The difference between us is that she is now a simultaneous interpreter in Russian.

DH: All right, good!

MS:  This has been one of the spurs that made me go to Russia more often than most people.  I have been there perhaps a dozen or more times. We have been lucky enough to obtain grants for joint work with Gorkin’s laboratory in Moscow.  So we also have young Russians descending on us, from time to time, particularly Alexei Medvedev.

DH: When did you make links with the group in St. Petersburg, with Lapin and Oxenkrug?

MS:  It must have been the late 1960s when I first got to know them both.  I tried to get Gregory Oxenkrug over to England when I visited them. They had published that paper in Lancet in 1968, suggesting that Serotonin was the bees’ knees, as far as depression was concerned; it was a very thoughtful paper and it came out of nothing.  They had no laboratory facilities to speak of.  Scientifically, they were living in the nineteenth century.  There were just a few favorite laboratories in the whole Soviet Union that had decent equipment and Lapin’s was certainly not one of them!

DH: I had the impression that to do the work they did they must have been reasonably favored? 

MS: No, but they were good hardworking and did it on minimal resources.  Maybe you should interview Lapin and Oxenkrug sometime.  That would be useful because they are quite well known names in the field.

DH: Sure.  Did you have to smuggle their articles out? 

MS: Yes, we did, some of them, at least.

DH: Could you tell me more about the ways you could help them?

MS: I tried several different ways to get the young Oxenkrug to work in my lab, and they wouldn’t let him out. I had to be interviewed by a special “academic committee”. They were quite anti-Semitic at that time, and it didn’t help that Oxenkrug was Jewish; Lapin is half Jewish, on his mother’s side, but he is properly Jewish as far as Jews are concerned in Russia.

DH: Right.

MS: Eventually Oxenkrug managed to get out to the US and a number of us were helpful to him.  We are having dinner tomorrow night; he is eternally grateful and looks on me as his big father.  Besides me Irv Kopin, Sam Gershon and Saul Schanberg have been helpful to him.  I am very pleased because he is a very bright boy and has made it in American psychiatry.  He is now a man in his fifties.

DH: The monoamine oxidase inhibitor story, has it come to an end?  What about moclobemide, which was going to be the great hope in that particular field, the reversible MAO-A inhibitor?

MS: I am sorry to say this but I think nothing of moclobemide.  If it works, which it may very well do, it works despite its reversible MAO inhibitory action which is quite weak.

DH: On that score, have we been slightly misled?  Maybe it isn’t monoamine oxidase inhibition we’re observing?

MS:  I agree with you almost one hundred percent. All drugs are dirty drugs. All drugs have multiple actions. That’s what I mean about moclobemide. I am sure it has a perfectly good mechanism of action, maybe because it is a mild antidepressant, but I can’t see that effect stemming from monoamine oxidase inhibition, which isn’t very powerful, unlike the original group of irreversible inhibitors, which kill the enzymes stone dead.

DH: Can I take you through the trace amines story because although it’s been a minor sideline for you, this is one of the mysterious groups which may in due course emerge from the shadows?  What are the trace amines?

MS: The trace amines are monoamines, very similar to all the other monoamines we have mentioned.  The difference is that 5-HT and the catecholamines, including dopamine, all have special receptor uptake and re-uptake mechanisms. The trace amines are present and some are produced in substantial amounts in the body.  Take octopamine, for instance, did you know that we excrete in our urine about as much or almost as much p-hydroxymandelic acid, the major metabolite of octopamine, as we excrete 4-hydroxy-3-methoxymandelic acid, VMA, the major metabolite of adrenaline and noradrenaline.  If you take a rabbit and give it a monoamine oxidase inhibitor, and this was done thirty years or more ago, tissue concentrations of octopamine rise greatly. There are some species of crustacean where octopamine is a known neurotransmitter with uptake mechanisms and special receptors. There are a whole host of other monoamines, the three tyramines; p-tyramine we talked about briefly, and for a time I thought it might have had something to do with the lightening of affect you get from a MAO inhibitor.

DH: Right.

MS:  We still don’t know but it’s still conceivable, especially taking our tyramine test data into account. Then there are tryptamine and phenethylamine.

DH: They have to be important.

MS: I think they are.  Gavin Reynolds and I put forward a phenethylamine hypothesis of schizophrenia in 1976.  That’s since been dragged from its graveyard by some very respectable genetic teams; they are thinking about it again and measuring phenethylamine, thinking of it as we did, as nature’s amphetamine.

DH:  Last year, I was interviewing Paul Janssen and this is what he believes in….

MS: Really.

DH:  Wasn’t it you who put the name “trace amines” to this group of compounds?

MS: Yes, we did. Alan Boulton was the original big enthusiast.  He wanted to call them “microamines” and published a letter in the Lancet, saying there were a lot of micro amines in the body and they must presumably have a function; they are present in the brain and have a discontinuous location. We know a number of reasons why they should be important.  Earl Usdin and I thought we’d try to sort the problem out. We both always liked meetings in the Caribbean, so we set one up and duly published the proceedings. We thought the term, microamines, was unhelpful, because they weren’t, so we coined the name, “trace amines”.

DH:  How do the trace amines link to polyamines?  

MS: That is a different ballpark.

DH: You’ve raised the question of trace amine production in schizophrenics and you, looked at another group you termed aggressive psychopaths, who end up in jail.  Take me through this.

MS: The phenylethylamine hypothesis of schizophrenia arose fully armed from a chat I had with a young biologist, Gavin Reynolds, I was interviewing for a job.  I gave it to him.  He is now Professor of Neuroscience. We had both been thinking along the same lines but hadn’t quite put it together; but after the interview, within a week or two, we wrote up our hypothesis for the Lancet. If you inject phenethylamine into an experimental animal, nothing much happens, but if the amine injection is preceded by a monoamine oxidase inhibitor a sequence of events follows, similar to that which follows amphetamine administration. I was about to talk about aggressive psychopaths and serendipity. At about this time, I happened to be at one of those interminable dinners at the Royal College of Physicians.  I had been seated on the end of a table and the chap, sitting next to me hadn’t turned up. The only contact was with a rather morose guy called Field I couldn’t draw into conversation. I almost had to sit on his head to find out he was a psychiatrist at one of our better prisons, Wormwood Scrubs.  At last, we started to talk and I desperately tried to dredge up what I knew about criminals, which wasn’t much.  I had just read a paper, however, which claimed that sixty percent of murderers in North Carolina had been on amphetamine. It was obviously amphetamine psychosis they were dealing with. They had become schizophrenic on amphetamines and I had never even heard of this until I started reading the whole thing up.   One thing led to another and Field and I decided to collaborate.  We set up a group of aggressive psychopaths and another group of men imprisoned for white collar crimes, fraud, cooking the books, tax evasion-normal controls, you know.

DH: The things we all do, right?

MS: We compared these two groups and, surprise, surprise the aggressive psychopaths excreted significantly more phenethylamine metabolites than controls.  The national press made quite a splash of the story at the time.  We thought we ought to repeat the experiment and went back to Wormwood Scrubs and asked if we could have a couple of dozen more of each just so we could clinch the whole thing?   But the prison gates were closed!  They got scared stiff!

DH: Too much of a splash.

MS: Yes. The prison authorities were always sensitive to too much publicity.  Well, I thought we’d finished with that one, really.  And, then, I was at someone’s dinner party.  There was a young man sitting across from me and we started talking about what we did. I got on my frustrated scientist hobby horse and complained how difficult it was doing research on prisoners.    This smooth young man was the British Minister of Transport.  His name was…

DH: Norman Fowler!

MS: Norman Fowler, yes. He said the Home Secretary is my chum; send me the papers on the case and I’ll have a word.  Nothing happened for about six weeks. And then, I got a call, “the prison gates are open.” It is nice to have influence.  So, we confirmed our earlier data and did parallel experiments in animals, comparing dominant and non-dominant monkeys, which took us out to St. Kitts where they have monkey colonies; the dominant alpha monkeys lead the pack and are the ones that carry their tails in the air. We collected blood samples and the alpha males had higher circulating concentrations of phenylethylamine metabolites.

DH: I can see that you pick your research with care, that carries you to the Caribbean.

MS: Absolutely!

DH: You used to come to the Caribbean, as well, courtesy of Nate Kline.  Tell me about that?

MS: Very true.  Nate Kline, we all remember fondly.  Nate Kline was a wheeler dealer.  He was a New York psychiatrist of flare, talent and panache.  He was a fascinating character and even quite a good psychiatrist. One of his patients, a Mrs. Denghausen, was an upstate New York millionairess, with depressive illness. Nate would give her oral tryptophan and she would cycle back to normal. And when she was relatively normal, she said “Doctor, what can I do for medical science?” So he said, “Doctors have to travel a lot and are always worried about their wives”.  He persuaded her to fund a small scientific meeting on a Caribbean island every March, “and bring your wives” along.

                           We used to line up on the beach at 8:30 in the morning in our swimming trunks under the palm trees, with just a blackboard and somebody would get up and hold forth; he would be torn to pieces by the hand-picked group of a dozen neuroscientists Nate Kline had assembled. It was hard work and wildly stimulating. Lots of contacts were made and   experiments were spawned by this gathering a .really fascinating group. Unfortunately, Mrs. Denghausen died, her husband died and Nate Kline died so that the whole thing wound up.  But, it was great while it lasted. 

DH: Before we come back to the Caribbean and the ACNP meetings, can we hop to the first CINP meeting, because you were there, weren’t you?

MS: I was, by pure chance.

DH: Tell me about that first meeting in Rome and the impact it made?

MS:  That was the first foreign scientific meeting I’d ever been to.

DH: I don’t know the date, so you better put it on record.

MS: It was 1958, because Mike Pare had been involved in some sort of drug trial for Hoffmann-LaRoche and they very kindly funded our trip..  At that time, I had never heard of the CINP; nobody had, it was the first meeting.  We were delighted to get to Rome.  We’d done some very intriguing work I think should be disinterred and looked at again.  We found a deficit of 5-HT in the platelets of phenylketonurics. Even more interesting was our control group, so-called “cerebral palsy” patients from the same children’s hospital.  I don’t know what they were really suffering from; they may have been autistic, but the fact is they had wildly differing levels of 5-HT in their platelets, some astonishingly high.  Others later confirmed that certain autistic kids have raised levels of 5-HT in their platelets and this finding has never been satisfactorily explained. There may be some mechanism that normally stops it building up and it’s being sucked up like a sponge in children with abnormally high values. What has happened to the uptake mechanism in these subjects? I don’t know,  but somebody should look into it.  Anyway, that was the paper Mike Pare and I presented to something like nine or ten people!  We were perfectly happy in Rome and we banqueted at the Villa of Mussolini’s mistress. This was the good life.  The faint whiff of corruption was in the air and it was a delight!

DH: You liked it?

MS: I loved it, yes!  It was marvelous! It was nice while it lasted, David.

DH:  After that you began to come to the ACNP meetings, which we are having here at the Caribbean?

MS: I came first in the mid-1970s and very soon after I was elected a foreign corresponding member of the ACNP. It was around the swimming pool at an ACNP meeting that David Wheatley, Alec Coppen and I, hatched the British Association of Psychopharmacology.  Perhaps I am wrong, as there are other interpretations and other stories that compete.

DH: Was this the model you wanted to reproduce?

MS: Yes, this ACNP meeting has always been the leader of the field.  There is no question in my mind it represents the front line of Psychopharmacology. I top up my psychopharmacological tanks when I come to these meetings.  They are marvelous!  The program committee has the right formula and they are good. 

DH: So, you save your air miles each year to come here?

MS: That sort of thing.

DH: There is one more angle we need to explore.  The NIH was a major mover in all this.  You had Brodie, Axelrod and people like that with whom you worked closely.  But, you were related to Brodie, is that right?

MS: Distantly.  He was a wild one, Brodie.  I will always remember the last time I saw him.  He was living in retirement in Tucson, Arizona, and had this forceful old wife who looked after and drove him.  She was like one of those pioneer women who went out west on the wagons, a rather harsh lady, and she really ran his life.  Brodie was always sorry for himself because he never won a Nobel Prize. When his former technician, Julie Axelrod, won the Nobel Prize, Brodie said to him sadly “You always kept your operations small, Julie.”  Brodie had a special room, perhaps his wife looked after it, where all his certificates and honorary degrees were pasted around the walls like a shrine, but the big one was missing!  It was very sad, really.  He made wonderful contributions to our knowledge, especially in toxicological methodology, working with Julie Axelrod and many other famous names. Brodie was the driving force, a very strange man and a bit of a junky. He took amphetamines during the day and barbiturates at night, uppers and downers. He had a very strange idea of time and would phone his associates at twelve o’clock at night to come into the lab to have discussions.  He would never put in an appearance there until around lunch time. Yes, there is a distant relationship but there isn’t much Brodie blood in my veins!

DH: Or the other way around?

MS:  Yes.

DH: Sandler blood in his veins.  Brodie was actually born in Liverpool.

MS:  And went out to Canada as a boy.

DH:  How did you rate Julie.

MS: Ah, a lovely man.   I first visited America in 1963, and Julie very kindly organized a party in my honor that night. Well, the plane was diverted to New York.  It was a mess!  So, I missed  Julie’s party, with great regret.  I had met him at that first CINP meeting. We sat next to each other on a conference bus, by chance.  I thought to myself I’d never met a man less likely to succeed and I never thought this little guy would make it. He was overdressed in the bright sunshine in a dirty old rain coat!  I have a dirty old rain coat myself but his was dirtier and older. He was obviously very hot.  The whole conference, around three hundred people in those days, was bussed out to Castelgandolfo to see the Pope.  The Pope made a speech and none of us could understand him, in Latin perhaps?  But, in fact, it was broken English. Then he died twelve days later.  It didn’t seem strange to me at that time.

DH: OK. But, there’s another issue here. You have described elsewhere the powerful role that displaced Jewish physicians and scientists, forced to leave central and eastern Europe before World War II, played in the UK, but they also played a huge role here in the US.

MS: Oh, a huge role!  During my seminal 1963 visit, when I first visited the NIH, Seymour Kety was in his prime as chief of the Laboratory of Clinical Science; he is a chap who should have won a Nobel Prize, if there had been any justice in the world.  Anyway, he assembled a random group of his colleagues to go out to lunch.  There were a dozen of us sitting around the table and by pure chance, all were Jewish!  People like Sol Snyder, Irv Kopin, Joe Fisher and Dick Wurtman all were there. Of course, I don’t know, but I suspect that Jews manifest survival genes.  They have survived, despite the odds. The individuals, who survived, evolved tricks and mechanisms which, somehow, provide the ability to see through to the heart of a problem, and not to accept revealed truth. I believe that this is the key to scientific ability. Well, it’s just as good a hypothesis as anybody else’s.  Anyway, there are a lot of Jewish scientists in the United States and an awful lot in our own field of psychiatry and psychopharmacology.  

DH: When the field coalesced, it was very much driven by clinical observation and people who were working in the basic sciences had to come in and try to explain what was going on.  At the meetings now there is an awful lot of basic science and you’re not sure of what, if any, are the clinical implications.  Do you think we have moved too far down the neuroscience route?

MS:  No I do not. I think it has become clear this is the only way to make progress; and now we have the human genome mapped.  So, it’s a new ball game completely, isn’t it? We don’t have all the pieces in the jigsaw yet, but we can be much more confident in our predictions than before.  These ACNP meetings are an eye opener now, where basic science rules. Ok!

DH: Good. Do you have any other thoughts on things we need to cover?

MS: I don’t think so. I think you have done a jolly good job, David, if I may say so.  I am happy and thank you very much for doing the job so well and courteously and I truly regret that I won't be present to witness it

 

References:

Ban TA. Preface. In: Sulser F, editor. Neuropharmacology. In: Thomas A. Ban, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Per Interviews. Volume One.   Brentwood: American College of Neuropsychopharmacology, pp. IX-XXX.

 

Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Brentwood: American College of Neuropsychopharmacology; 2011.

 

Sandler M. My fifty years (almost) of monoamine oxidase. Neuro-Toxicology 2004; 25: 5-10

 

 

Sulser F. Introduction & Dramatis Personae. In: Sulser F, editor. Neuropharmacology. In: Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Per Interviews. Volume Three.  Brentwood: American College of Neuropsychopharmacology, pp. XXXIX –LX.

 

Shorter E, editor. Neurophysiology. In: Thomas A. Ban, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Per Interviews. Volume Three. Brentwood: American College of Neuropsychopharmacology; 2011.

 

Youdim MBH. Monoamine oxidase, their inhibitors and the opening of the neurotransmitter era in neuropsychopharmacology. In: Ban TA, Ucha Udabe R, editors. The Neurotransmitter Era in Neuropsychopharmacology. Buenos Aires: Polemos; 2006. p. 107-26.

 

 

 

January 11, 2018In Memoriam

Merton Sandler (March 28, 1926 - August 24, 2014)

by

Thomas A. Ban

 

On August 24, 2017, Merton Sandler, an emeritus fellow of the American College of Neuropsychopharmacology (ACNP) passed away. Born in Sanford, Lanceshire, in the UK, Sandler received his M.D. in 1962 from the Manchester University School of Medicine in the UK. In 1973, Sandler was appointed Professor of Chemical Pathology at the Royal Postgraduate Medical School, University of London.  In 1991, he became Emeritus Professor at the University.   Merton’s primary area of research interest was in monoamine metabolism and the role of monoamines in neuropsychiatric disorders. In his early research, he studied monoamine oxidase (MAO), the enzyme itself. In the mid 1960’s, in collaboration with Moussa Youdim, he provided electrophoretic evidence that MAO was present in the brain in multiple forms. They assessed the role of these in vivo and the activity of selective MAO inhibitors. They also demonstrated the therapeutic value of the MAO B inhibitor deprenyl in Parkinson’s disease. Merton also studied trace amine metabolism extensively in psychiatric illness. He found selective decreases in tyramine and octopamine production in depression and noted an overproduction of phenylethylamine in aggressive psychopaths (Ban 2011; Sandler 2006; Sulser 2011; Youdim 2004.

Merton was a member of numerous editorial boards and learned societies.  For his scholarly contributions to neuropsychopharmacology, he received the Anna-Monika Prize, the Franz Burke International Prize for Research in Parkinson’s disease, the Arnold Friedman Research Award and the CINP Pioneer in Psychopharmacology Award.

            Merton Sandler (MS) was interviewed by David Healy (DH) for the “Oral History Series” of the ACNP at the annual meeting of the College on December 15, 1998, in San Juan, Puerto Rico (Ban 2011; Sulser 2011). The edited transcript presented here was first published in Volume Two of the series.

 

INTERVIEW

Interviewer: David Healy

San Juan, Puerto Rico, December 15, 1998

 

DH: Today is Tuesday, the 15th of December 1998, and we’re at the ACNP annual meeting in Puerto Rico. On behalf of the ACNP, I am interviewing Merton Sandler. Merton, could we begin with where and when you were born, and then we will move on from there?

MS: We can, but it was an awful long time ago, 1926 in Salford, which used to be a poor relative of Manchester; both have now spectacularly reinvented themselves!  Well, there is nothing spectacular about my own birth. I grew up; the only big break was getting a scholarship to Manchester Grammar School, which was the special school in the area and quite well known in the UK.

DH:  When you were at school, did you have any feeling for what you would ultimately go on to do?  Did you have any awareness of mental illness, biochemistry, anything like that?

MS: The answer is no!  I hated school, as a matter of fact.  I think I was one of nature’s rebels.  I hated wearing a school cap and would squash it into my pocket.  I was always caught!  I hated the discipline and I hated organized sport, but I had to do it.  When I avoided it I was duly punished. The amusing thing was, when I came to live in London years later, I was cajoled into becoming chairman of the London section of the school old boys association, the school that I thought I hated so much.  That’s the way cookies crumble.

DH:  When did you actually decide to go into medicine and, why?

MS: I was always going to go into agriculture because I was a keen little environmentalist in those days.  I still am.  But, at about the age of sixteen, I suddenly thought, I don’t know one end of a cow from another.  So, I looked around and medicine seemed rather interesting; so medicine it was.  I started in 1944, just before the war ended.

DH:  That would take you up to 1950, when you qualified?

MS: I qualified in 1949.  Next year, I will have been a doctor for fifty years.  David can you imagine; it is mind-boggling.

DH: Things would have looked completely different compared with now; drug-wise, you had extremely few treatments. Biochemistry was only just forming as a discipline; neurochemistry wouldn’t have been thought of.

MS: My whole career has been shaped by expediency and opportunism and the jobs that were available. I got into this field I suppose I’ve made a small mark in, completely by accident.  I became a soldier for two years, a national serviceman. Because I’d done a year of pathology training, the Army gave me a small hospital laboratory, but with very few routine duties.  So, another doctor-soldier, Michael Pare, who later became a very able psychiatrist, and I teamed up.  We started doing things we called research. We were enthusiastic but had no idea of research discipline.  Even so, we had a bit of luck and the Lancet published our first two papers.

DH: On what?

MS: Aminoacidurias. The first was called ‘Starvation Aminoaciduria’ and we starved for three days in the process. That was in 1953.  We had no hesitation in approaching leaders in the field such as Charles Dent for advice, which they gave freely.

DH: Why did you start to look into this area and why did you begin with amino acids?

MS: I had the crazy idea of developing a new liver function test.  I didn’t know much organic chemistry, but was fascinated by it.  I’d always had chemistry kits as a kid and made bangs and smells and things, I was a bit of a terrorist. The chemical side of things fascinated me. Paper chromatography was brand new and there was time to build equipment for it out of bits and pieces scrounged from the Army Engineers. When I left the Army, I got an intern job at a famous chest hospital, the Brompton. They had brand spanking new chromatography equipment lining the corridors and nobody knew how to work it. It was mouth-watering to see this stuff so I got it going for them!  When my internship finished I was offered a research job there.  Before the house and research job ended there was another seminal event, as far as my own life was concerned. Two friends and contemporaries at the Brompton, Alan Goble and David Hay, now Sir David Hay and the big boss of cardiology in New Zealand, moved to the National Heart Hospital and started to investigate the very first case of carcinoid syndrome ever seen in England. Remembering my enthusiasms, they came to me and said, biochemically, can you do anything for us? I said I’d have a go because the petals had started to unfold, the biochemical petals. I did a few chromatograms and we were very lucky; I got some nice data showing high concentrations of 5- hydroxytryptamine (5-HT) in the right side of the heart compared with the left. That may be one of the factors in the genesis of right-sided heart disease in carcinoid tumor syndrome. I was fired-up by this finding and became a one-man carcinoid reference laboratory.  We are getting close to psychopharmacology, but haven’t got there yet.

DH: I know.

MS: I became a psychopharmacologist very gradually and didn’t realize I had become one until ten years after I had done so.

DH: At that point, what did 5-HT look like to you?  I mean, it had been discovered by Erspamer and had been isolated by Page and Rapoport.

MS:  I met Erspamer when he came to London to give a lecture. I hadn’t realized how lucky I was, because he wouldn’t travel long distances. He gave his lecture in really execrable English but it was nice to meet this great man. 

DH: Was there any feeling then that 5-HT could be involved in mental illness?

MS: First there was a problem about nomenclature; we called it 5-hydroxytryptamine and the Americans called it serotonin. Gaddum actually called it ‘HT’ until I had the temerity to remind him that 6-hydrooxytryptamine also existed in our brains and that keeps us sane. When Michael Pare and I came out of the Army, I moved to another hospital, the Royal Free, while he got a job as a psychiatrist at St. Bartholomew’s Hospital. We teamed up again, because 5-HT emerged as flavour of the month in psychiatry, so we were very happy to oblige and do a few experiments.  In the meantime we began to understand 5-HT was inactivated in vivo by monoamine oxidase.   Monoamine oxidase inhibitors were claimed by Nathan Kline to be important as antidepressants. The whole field was brand new and Pare and I had lots of leads to follow. 

DH:  Who was Gaddum? 

MS: Gaddum started life as a mathematician and later turned to pharmacology. He was a difficult man, difficult to approach; cold and rigorous in his thinking.  There was always a barrier, you couldn’t become matey with him at all. I finally came across him a little when he was dying and  I did a consultancy at Babraham, our major Institute of Animal Science, which Gaddum directed.  

DH: Where he moved to after Edinburgh.

MS: Yes. He was director for a number of years until, in the early to 1960’s he got carcinoma of the stomach.  He was a big man with something of a pot belly and an aldermanic look.  But now, alas, he had shrunk.  He looked like Stan Laurel in Oliver Hardy’s trousers.  He was still in the lab at seven o’clock in the morning, perusing goldfish gut in a minute chamber looking for substance P, of which he was one of the discoverers some years earlier.

DH: He used to hang out with Henry Dale, Marthe Vogt and a group of other people.  Did you have much contact with this group?

MS:  I remember Henry Dale.  I saw him only once when he was chairman of one of those special University of London lectures that were so good. He introduced Rita Levi-Montalcini, who co-discovered Nerve Growth Factor and won a Nobel Prize, when she came to lecture in London in very broken English. Dale was another forceful and impressive character; he died a few years later.  The last I heard of him was at a meeting at the British Pharmacological Society. He was ninety and he couldn’t come himself so he sent a video message.  Marthe Vogt, I knew very well and she is still alive in 1998.

DH: Yes, she is.  

MS: She discovered noradrenaline in the brain and mapped its distribution; that was another very important milestone. These monoamines have really influenced my life; the catecholamines and 5-HT have, to be more precise.  Although we did have a long, hard look at the trace amines, but they didn’t amount to much in the end. We couldn’t find any evidence of a neurotransmitter role; but that is the way things turn out.  

DH: Arvid Carlsson describes coming to London in 1960, and meeting a certain amount of resistance to the idea of any clinical role for these substances; but, in essence, these people were physiologists. 

MS: You are absolutely right!  There was so much resistance to anything that might even faintly have been clinically connected.  Perhaps we ought to mention Blaschko at this juncture.

DH:  We should.

MS: Blaschko made crucial observations or inspired guesses at every point in the history of the monoamines. Blaschko was there! Even apart from his best studies of monoamine oxidase.  Blaschko was a strange chap and would think and then pronounce, with his eyes closed. We would then get a monologue issuing forth, a stream of consciousness.  And, there was good stuff in there, if you could bear to listen. But sometimes, it was all rather sleep-provoking!  Blaschko, Vogt, Feldberg and many other academics of first rank; these were the people who were kicked out of Germany by the Nazis. 

DH: Right. 

MS: Jewish, almost to a man, though not Marthe Vogt, obviously. She came from a family of pathologists. Her parents ran a brain institute in the Black Forest where Lenin died of General Paralysis of the Insane.

DH: Yes, right!

MS: They sent Lenin’s brain to the two Vogt’s, somewhere around 1922 or 1923, and they dissected it.

DH: Lenin’s brain hasn’t been with his corpse in Red Square all this time?

MS: No, it hasn’t!

DH: Right, but there were also people in this group, like John Burns.  Do you know him?

DH: J. H. Burns?

MS: I knew him, but not well. He was a great influence on British Pharmacology, a very brusque sort of individual. But he was the scientific father of people like John Vane, who trained under him at Oxford. I believe that Burn started off in London at the School of Pharmacy and then moved to Oxford in his later career. Who else did you mention?

DH: Edith Bulbring.

MS: I knew her, too.  She had one of her legs amputated before she finally died, poor old thing.  But, they seem to live to a great old age.  Feldberg, too, was an amazing influence in Physiology.

DH: Why?

MS: He was a splendid experimentalist and always had a little cigar in his mouth with two inches of ash attached. Sometimes it would drop onto the cat’s belly he was poring over. He was treated  badly by the animal rights people, in his old age, when he was careless in choosing his assistants!  An animal rights evangelist got a job, pretending to be a disciple, and you can write your own scenario!  Anyway, Feldberg was a very nice man!

DH: So you had the idea your transmitters might be important for mental illness but the older group couldn’t buy the idea fully and it took people like you, who didn’t have inhibitions imposed by the field, to pick up the ball and run with it?

MS: I would say you are right. Mike Pare and I, with little learning but a great deal of enthusiasm, did just that. We took up the baton. For instance, we lined up volunteers, about a dozen junior doctors at the Maudsley Hospital and devised an experiment to test Gaddum’s hypothesis. We were the first to give 5-hydroxytryptophan (5-HTP), the precursor of 5-HT, intravenously.  In those early days, we had to use DL-5-hydroxytryptophan but in retrospect we obviously didn’t use enough.  Mike and I were not only the first to inject this material into man but we were also the first to use L-Dopa for a similar purpose. We did this together with a psychologist called Brengelmann, not long after the war ended. Brengelmann was a German of rather heel-clicking variety. I was a bit sensitive to Germans just after the war. 

Anyway, despite his origins, Brengelmann was terribly good; he had a series of psychological tests which he applied.  We gave volunteers LSD, which was all the rage in these days. LSD is an antagonist, as you know, of 5-HT. We thought that if we pretreated our volunteers with a 5-HT precursor we might suppress the schizophrenia-like symptoms one gets with LSD. Strangely enough, after five subjects, it was starting to emerge we’d got it right.  We couldn’t carry on because the sixth volunteer was a disaster; he had a bad trip on LSD and had to be held down by half-a-dozen male nurses and tranquilized. He only came back to sanity after about six months, if he ever did. In those days there were no ethical committees to pronounce on our experimental design. They were a later addition. We didn’t know we were doing anything wrong and, in those days, it was not uncommon for experimentalists to test new drugs on themselves. On one occasion, for instance, I took 1mg of reserpine intravenously. My nose became blocked and I became mildly psychotic for about a month.  We were just following Gaddum’s precept to see how far it went. I think our papers, published in the Journal of Mental Science in the late 1950’s, were a milestone. That journal later changed its name to the British Journal of Psychiatry.

DH: At this point, the monoamine oxidase inhibitors started to come on stream and suggested a new hypothesis.  Did you look at this, as well?

MS: Indeed we did!  Pare and I were unfortunate we didn’t have much of an idea how to present our data properly to get the best news coverage!  What I believe was a seminal paper was published under the disguise of a clinical trial, “A Trial of Iproniazid in the Treatment of Depressive Illness.”  We had a very interesting study design and, as I mentioned before, we also gave 5-HTP and DOPA in the lag period of two to three weeks until the antidepressant took effect. Thus, we tried to shorten the lag period by giving amine precursors, to be decarboxylated to their corresponding monoamine in situ.  Although we didn’t say it in as many words, the amine hypothesis of depressive illness was implicit in every sentence of the article.  It was what we were writing about but we didn’t emphasise the information we were imparting and it didn’t hit the headlines.  Joe Schildkraut scooped that pool seven or eight years later when he wrote a review article talking about the monoamine or norepinephrine hypothesis, as he called it.

DH: Are you sure it was Joe? What about the contributions of John Davis and Biff Bunney, because both articles came out about the same time?

MS:  I am talking about the ones that hit the jackpot in Current Contents.

DH: OK. 

MS: I am not disputing others were on the right wavelength, too.

DH: Did the 5-HTP that you gave actually help?  Did it cause lightening of affect?

MS: No.  The single dose we were in a position to give was far too small.

DH: Could your article have been taken to show that the amine lag-period hypothesis couldn’t have been right to begin with?

MS: Possibly.  I don’t think you can say that when you give such a relatively low dose, 25mg of the DL compound which was  nothing when everyone knows how much L-DOPA it takes to have any effect in Parkinson’s disease, with or without a peripheral decarboxylase inhibitor.

DH: How did the monoamine story begin to unfold, from your point of view?  Iproniazid had been discovered and there was a strong suggestion it was working because it was a monoamine oxidase inhibitor.

MS: I have always been a dedicated reader of the literature. Modesty aside, I would go through the spring edition of Federal Proceedings, with its two or three thousand abstracts, as a kind of religious devotion! 

DH: You would really go through all of that?

MS: In 1957, there was a pearl in this particular oyster.  It was an abstract by Armstrong and Shore. They left out one of the authors names in haste; Macmillan’s name should have been on that abstract, too. Anyway, that paper described, for the first time, the major metabolites, the methylated oxidatively deaminated metabolites of the catecholamines, noradrenaline and adrenaline in the urine of patients with pheochromocytoma.  You wouldn’t believe it, but up to 1957, we had no idea what happened to endogenous or administered noradrenaline and adrenaline. It was the finding in this paper of O-methylated metabolites, and particularly vanilmandelic acid (VMA), that broke the thing wide open.  Julie Axelrod was immediately on to the enzyme mechanisms involved, particularly catechol-O-methyltransferase (COMT).  And it was partially for this reason he won the Nobel Prize, and quite rightly. We made our own modest contribution to the catecholamine metabolite story then and published the very first clinical assay procedure for VMA. We soon established a corner in this research area. We were quite good at measuring these unexpected metabolites and published the first method for measuring urinary homovanillic acid, the major metabolite of dopamine and were also quickly off the mark with 4-hydroxy-3-methoxyphenylglycol (HMPG). We were very early in the gas chromatographic field which made it so easy to make measurements of trace metabolites. When I first cut my teeth in clinical chemistry, we were measuring sodium by using uranium salts that took a week to get the results! Then flame photometry came along. Things have changed surprisingly since that time.  We came along with our gas-chromatographic methods just in time for the L-DOPA revolution.  We were thus able to quantify so many of the minor metabolites of L-DOPA, and the major ones too, in Parkinson Disease.  Over the years I have followed the monoamines wherever they led.  We discovered other unconsidered trifles along the way. Amines started to be implicated in migraine for instance, and research money came from the Wellcome Trust, which was very helpful at that time. The quid pro quo was that we were to investigate the metabolism of tyramine in the brain. A very nice lady, Edda Hanington who was the Wellcome’s Assistant Scientific Secretary claimed that tyramine triggered headache in patients with so-called dietary migraine.  Maybe it did and maybe it didn’t but it just might in a few affected subjects. Anyway, this was the background to a whole series of investigations that links up with depressive illness. Our tyramine test in depressive illness, which I shall tell you about in a moment, has been a sad disappointment to me and our group. It’s too tricky to do routinely in clinical practice although it works and picks out unipolar depressive patients. Somebody should take it up again and try to find the mechanism we never discovered. 

DH: What you are saying is, there is a group of people who, with the tyramine test, show one result and others don’t.

MS: Yes; the test shows a clear deficit in one particular clinical group of depressed subjects.  The metabolism of tyramine is largely carried out by monoamine oxidase (MAO).  However, there is an important minor metabolic pathway accounting for about 10 percent of the total, involving sulfate conjugation.  We were able to show that in patients with unipolar depression, there was a significant deficit of tyramine conjugation with sulfate after an oral tyramine load.

DH: In all of them, or only certain ones?

MS:  In a statistically highly significant number.    

DH: In the ones that respond to a particular drug treatment or not?  

MH: We had difficulty tying this finding in with drug treatment response.  The result hung in the balance. I seriously think there is room for further investigation. It is an expensive test because you have to be meticulous about the precise timing of a series of urine samples. So, there are good reasons this didn’t become popular; we hadn’t worked up the technology to do the test on a specimen of blood, so that manpower was involved in the urine collection procedure.  

DH: You raised the question of tyramine, which in turn raises the cheese effect and the part played by MAO.  Can you take me through this and tell me what was your role?

MH: Well, I have written a great deal but I still don’t know whether I made any major contribution.  My colleagues and I have worked in this area for a long time, even before Johnston, who first described MAO-A and MAO-B pharmacologically in 1968.  We ourselves took a wrong track.  There were always tantalizing indications that the enzyme MAO had multiple forms and, in fact Youdim and I, in 1967, were able to produce preliminary electrophoretic evidence for such a finding. We published a series of papers pointing to different substrate preferences of the multiple forms. One of them, for instance, showed a strong preference for dopamine. With hindsight, it seems obvious those findings were artefactual, elegant artifacts true; but it is equally obvious there was a physicochemical basis for their manifestation.  Even so they didn’t bear much relationship to clinical reality.  In the 1960’s, there was considerable drug company interest in MAO inhibitors following the success of iproniazid in producing a lightening of affect in some patients with depressive illness.  One of these firms, May and Baker, synthesized a pharmaceutical agent called clorgyline and set Johnson, one of their employees, to put it through its paces.  Johnston did the work but didn’t write it up, because he became ill and died not too long afterwards in a Cambridge mental hospital. Sir Rudolph Peters, the eminent biochemist, who was a consultant for May and Baker, converted Johnson’s raw data into a seminal paper, which was published in 1968, in Biochemical Pharmacology.   Nowadays, every school boy knows that there are two isoenzymes of MAO, A and B, and clorgyline turned out to be a selective inhibitor of MAO-A.

DH: What happened next?

MS: Although clorgyline was a very good lightener of affect, it never got on to the market because there were enough similar drugs already available. The first selective inhibitor of MAO-B was that synthesized and developed by Joseph Knoll and his colleagues.   I remember how excited we all were when he first presented his paper at a meeting in the early 1970’s in Sardinia when we had an MAO Festschrift for Blaschko’s 70th birthday. Mimo Costa and I edited the Proceedings with the enthusiastic collaboration of Ghighi Gessa. We held this meeting in Sardinia, because that was Costa’s home island and it became the first psychopharmacology meeting of many.  There was this charismatic Hungarian, full of fire and passion, but it was difficult to understand a word that he was saying.  To the great interest of all of us, he unveiled the first irreversible MAO-B inhibitor, called deprenyl. Now it’s officially called selegiline although deprenyl is still, if unofficially, much more used today.  Anyway, this was the only major drug to emerge from behind what was then called the Iron Curtain and Knoll was a great PR man for the Hungarian drug group that synthesized it.  To this day he is as full of enthusiasm and fire as he always was. Moussa Youdim visited him in Budapest and obtained a sample of the drug, taking it to Birkmayer in Vienna, suggesting he might like to try it in patients with Parkinson’s disease.  Now, Birkmayer would try anything on anybody.  He was a very interesting character; I don’t know if you know anything about him? 

DH: Nothing at all.

MS:  He was thin, enthusiastic, pipe-sucking and friendly and had been an SS doctor in the late 1930’s.  When they found out he was partially Jewish, they kicked him out of the SS, which was the making of him.

DH: Right.

MS: Vienna was a very interesting place to be at that time because they have a law there has to be a post-mortem examination in every death.  So, brains from Vienna flowed forth to research laboratories of the world. One of Birkmayer’s emissaries, five feet tall, arrived at our lab wearing a top coat down to his ankles and a Homburg hat.  He was carrying two plastic store bags full of human brains, two in each that he brought through British customs.  They didn’t stop him!   

DH:  Gosh.

MS:  I will tell you more about the British Customs in a moment.

DH:  Right, keep going.

MS: When Moussa Youdim said to Birkmayer, ‘Let’s try deprenyl in Parkinson’s disease”, and I heard on the grape vine they were going to try a selective MAO-B inhibitor, my immediate response was how ridiculous, everybody knows that brain dopamine is metabolized by MAO-A, because it was in the literature. We combed the literature once more and it became obvious that the only available information on this point was in the rat.  So Vivette Glover and I went quickly to the lab and looked at some human brains. These measurements hadn’t been done before in man.  Needless to say, we found that dopamine is largely metabolized by MAO-B in man, not by MAO-A!  It just shows that man is not a rat.  That’s one of the few things I have learned in my long life.

DH: It just shows. 

MS: So, I was convinced. After the Sardinian meeting, I’d kept in close touch with Joseph Knoll.   I called him and said “Can I cadge some deprenyl from you.” He said, “Oh yes, as much as you like.”  So, I flew over to Budapest in what I called my flasher’s mac.  It was a Macintosh with large pockets. I collected two large polythene bags full of white powder and walked boldly through the British customs. Nobody stopped me and fortunately the sniffer dogs were on holiday.  I hate to think what would have happened if I’d been caught.

DH: What do you think would have happened?

MS: I’d probably still be in jail!  Anyway, we rapidly put the first deprenyl in England through its clinical paces. I should say this work was in harness with Gerald Stern, my clinical collaborator over many years. We confirmed it worked in Parkinson’s disease and wrote a number of papers to this effect.  We did have one problem. We told our Committee on Safety of Medicines what we had done and they said, “You know this is illegal, you are using an illicit drug, brought illegally into the country.” Well, they were quite decent about it; they said we wouldn’t be prosecuted and  we could go ahead and publish.  So we did, and more or less lived happily ever after. We discovered a lot of deprenyl’s properties; the Hungarians were very appreciative and gave me an honorary doctorate!

DH: The deprenyl story is extremely interesting because it begins to look as if this drug can enhance life, in that it reduces mortality in people who are Parkinsonian. Can you take me through that particular aspect of the deprenyl story as it unfolded?

MS: This is another one of those stories of enthusiasm waning as more data become available.  I still think there could be something to it but the data are not as clear cut as they seemed in the very beginning. Knoll’s initial experimental findings were quite staggering!  His treated rats lived three hundred percent longer than untreated controls, amazing figures.  The only thing that I worried about was that he had a Vietnamese collaborator and though I am sure the experiments were done very well, the fact is that they were done in Vietnam and weren’t under Knoll’s personal control.

DH: Supervision, right.

MS: I don’t know; he did do some experiments in his own lab but I think it was the cost of so many rats that threw him. Anyway, there were others who jumped on the bandwagon.  There were preliminary clinical impressions suggesting longevity was one of the consequences of deprenyl treatment in Parkinson’s disease.  Others disagreed.  The London group of Neurologists produced data cutting right across that conclusion, suggesting that patients on deprenyl live for a shorter time than those not on deprenyl.  So, you pay you money and take your choice! 

DH:  What about it’s other actions, which have begun to emerge?   

MS:  There are fascinating laboratory data. Neuroprotective effects have been claimed….

DH: If that is true, it may herald whole new mechanisms by which psychotropic drugs could work.

MS: The whole business of neurotrophic activity is fizzing at the present. Although, I think of myself, as an archetypal monoamine man and still see monoamines in my dreams, lately I have taken a sideways step and branched out into neurotrophins.

DH:  Where did the neurotrophin story begin? 

MS:  With Rita Levi-Montalcini, who discovered Nerve Growth Factor, (NGF), many years ago, and won a Nobel Prize for it.  It’s amazing how that field has blossomed and generated a massive literature. Even so, it’s hard to slot into any clinical context, although it’s obvious to me that a possible role in depressive illness is just over the horizon. The methods are tricky and difficult and so immunological! You have to be a molecular biologist, for starters.  I’m not, as you know.  I came along too early for molecular biology, but I have young colleagues who know about these things.  With their assistance, I have crept quietly into this new area.  I don’t look on it as a new area, but rather as a continuation of an old one.

DH: The fact that different areas of research come under intense scrutiny depends, to a substantial extent, on the techniques available for their study.  The monoamines, of course, streaked ahead and left the others way behind until recently.

MS: They did.

DH: Was that because, as you imply, you had the techniques or is it an issue of we work on the things we like to work on?

MS: I put it another way, David.

DH: What?

MS: We have been struggling, for forty years, in the conceptual wilderness.  I recently wrote a review of one of your challenging books on the history and development of psychopharmacology and put it on record that we have been stuck in a conceptual mindset for forty years.  In the 1950’s there were so many major discoveries, the tricyclic antidepressants, the monoamine oxidase inhibitors, the neuroleptics, lithium- and, then nothing!  The reason is we just didn’t have the techniques perhaps; but our thinking was also repetitive. As I see it, we are at last breaking out of the vicious circle.  I am thinking specially of the neurotrophins, which you introduced into our discussion a moment ago and, in particular of BDNF, brain-derived neurotrophic factor, which shows signs of being of major importance in explaining the onset and treatment of depressive illness. There are fascinating data stemming from Yale in particular.  I am thinking of the group headed by Ron Duman who are responsible for a fascinating hypothesis, pointing to a cascade of events that would explain, incidentally, the lag period in response observed after tricyclic or monoamine oxidase inhibitor administration. This lag period, by analogy is, a sort of gear change in the cascade of events involving cyclic AMP and other important chemical steps until eventually you get to BDNF. Drugs, physical and chemical treatments like electroshock or insulin treatment, all cause a rise in BDNF concentration in animal experiments. Ethically, human data would be hard to obtain.  Stress models of depressive illness in animals, on the other hand, bring about a decrease in hypothalamic BDNF.  It’s just too bad that BDNF doesn’t cross the blood-brain barrier; we can’t think of it yet as a magic bullet.

DH: To take you back to the 1950’s, you were among others working on the first version of the monoamine hypothesis of depression, and one of the useful things observed at that time was that reserpine lowers amine levels and causes people to become depressed. Now, you took reserpine.   Can you describe the effects?

MS: It was one of the most miserable experiences in my whole life.  I was depressed, paranoid and aggressive for a month! I couldn’t breathe through my nose for a month. It really is a foul drug.  I know you have recently been promoting it, David.

DH: I am not promoting it but I am wondering if it did cause people to become clinically depressed.

MS: I can tell you from personal experience it does in some people.  I only had a small dose, half a milligram, I think, intravenously. A collaborator of mine, recently retired from being one of London’s coroners, took two milligrams, intravenously, and had to go to the hospital.  He was very, very ill.

DH: Why did he have to take two milligrams, intravenously?

MS: We were crazy!  We all did this sort of things. It is a grand tradition trying out things on yourself.  It’s come to a halt now, thank God.

DH: Do you still think it’s important for people working in the drug field to try compounds to appreciate what the issues are?

MS: I don’t know. Our reserpine experiment stemmed from trying to test one of Irv Kopin’s hypotheses on compartmentation of catecholamines and that sort of thing.  We published a paper or two out of our own discomfort! Ethical committees didn’t exist then but we don’t do it now.  Paul Ehrlich tried everything on himself didn’t he? It was a grand tradition.

DH: You used to go to Russia and you had links with Moscow and St. Petersburg.  Can you tell me how this all happened?  How were the links developed?

MS: I will tell you how it all started.  There was a biochemical congress in Moscow in 1961, and I got money from the hospital to go to it. They were building the Berlin wall at the time and Brezhnev harangued us from loudspeakers on every lamp post. From my point of view, the Congress was scientifically, a washout!  There was only one paper on monoamine oxidase, given by a young Russian called Vladimir Gorkin so I went to hear it.  There were about a dozen people in the room but it was very interesting and he and I subsequently became great friends. We were the only people that spoke a similar scientific language.  He also spoke very good English.  He died recently in Denver. I started to learn Russian in 1960 from a BBC Russian for Beginners course.  I took my young bride, who had also started to learn Russian the previous year to the Moscow Congress. The difference between us is that she is now a simultaneous interpreter in Russian.

DH: All right, good!

MS:  This has been one of the spurs that made me go to Russia more often than most people.  I have been there perhaps a dozen or more times. We have been lucky enough to obtain grants for joint work with Gorkin’s laboratory in Moscow.  So we also have young Russians descending on us, from time to time, particularly Alexei Medvedev.

DH: When did you make links with the group in St. Petersburg, with Lapin and Oxenkrug?

MS:  It must have been the late 1960s when I first got to know them both.  I tried to get Gregory Oxenkrug over to England when I visited them. They had published that paper in Lancet in 1968, suggesting that Serotonin was the bees’ knees, as far as depression was concerned; it was a very thoughtful paper and it came out of nothing.  They had no laboratory facilities to speak of.  Scientifically, they were living in the nineteenth century.  There were just a few favorite laboratories in the whole Soviet Union that had decent equipment and Lapin’s was certainly not one of them!

DH: I had the impression that to do the work they did they must have been reasonably favored? 

MS: No, but they were good hardworking and did it on minimal resources.  Maybe you should interview Lapin and Oxenkrug sometime.  That would be useful because they are quite well known names in the field.

DH: Sure.  Did you have to smuggle their articles out? 

MS: Yes, we did, some of them, at least.

DH: Could you tell me more about the ways you could help them?

MS: I tried several different ways to get the young Oxenkrug to work in my lab, and they wouldn’t let him out. I had to be interviewed by a special “academic committee”. They were quite anti-Semitic at that time, and it didn’t help that Oxenkrug was Jewish; Lapin is half Jewish, on his mother’s side, but he is properly Jewish as far as Jews are concerned in Russia.

DH: Right.

MS: Eventually Oxenkrug managed to get out to the US and a number of us were helpful to him.  We are having dinner tomorrow night; he is eternally grateful and looks on me as his big father.  Besides me Irv Kopin, Sam Gershon and Saul Schanberg have been helpful to him.  I am very pleased because he is a very bright boy and has made it in American psychiatry.  He is now a man in his fifties.

DH: The monoamine oxidase inhibitor story, has it come to an end?  What about moclobemide, which was going to be the great hope in that particular field, the reversible MAO-A inhibitor?

MS: I am sorry to say this but I think nothing of moclobemide.  If it works, which it may very well do, it works despite its reversible MAO inhibitory action which is quite weak.

DH: On that score, have we been slightly misled?  Maybe it isn’t monoamine oxidase inhibition we’re observing?

MS:  I agree with you almost one hundred percent. All drugs are dirty drugs. All drugs have multiple actions. That’s what I mean about moclobemide. I am sure it has a perfectly good mechanism of action, maybe because it is a mild antidepressant, but I can’t see that effect stemming from monoamine oxidase inhibition, which isn’t very powerful, unlike the original group of irreversible inhibitors, which kill the enzymes stone dead.

DH: Can I take you through the trace amines story because although it’s been a minor sideline for you, this is one of the mysterious groups which may in due course emerge from the shadows?  What are the trace amines?

MS: The trace amines are monoamines, very similar to all the other monoamines we have mentioned.  The difference is that 5-HT and the catecholamines, including dopamine, all have special receptor uptake and re-uptake mechanisms. The trace amines are present and some are produced in substantial amounts in the body.  Take octopamine, for instance, did you know that we excrete in our urine about as much or almost as much p-hydroxymandelic acid, the major metabolite of octopamine, as we excrete 4-hydroxy-3-methoxymandelic acid, VMA, the major metabolite of adrenaline and noradrenaline.  If you take a rabbit and give it a monoamine oxidase inhibitor, and this was done thirty years or more ago, tissue concentrations of octopamine rise greatly. There are some species of crustacean where octopamine is a known neurotransmitter with uptake mechanisms and special receptors. There are a whole host of other monoamines, the three tyramines; p-tyramine we talked about briefly, and for a time I thought it might have had something to do with the lightening of affect you get from a MAO inhibitor.

DH: Right.

MS:  We still don’t know but it’s still conceivable, especially taking our tyramine test data into account. Then there are tryptamine and phenethylamine.

DH: They have to be important.

MS: I think they are.  Gavin Reynolds and I put forward a phenethylamine hypothesis of schizophrenia in 1976.  That’s since been dragged from its graveyard by some very respectable genetic teams; they are thinking about it again and measuring phenethylamine, thinking of it as we did, as nature’s amphetamine.

DH:  Last year, I was interviewing Paul Janssen and this is what he believes in….

MS: Really.

DH:  Wasn’t it you who put the name “trace amines” to this group of compounds?

MS: Yes, we did. Alan Boulton was the original big enthusiast.  He wanted to call them “microamines” and published a letter in the Lancet, saying there were a lot of micro amines in the body and they must presumably have a function; they are present in the brain and have a discontinuous location. We know a number of reasons why they should be important.  Earl Usdin and I thought we’d try to sort the problem out. We both always liked meetings in the Caribbean, so we set one up and duly published the proceedings. We thought the term, microamines, was unhelpful, because they weren’t, so we coined the name, “trace amines”.

DH:  How do the trace amines link to polyamines?  

MS: That is a different ballpark.

DH: You’ve raised the question of trace amine production in schizophrenics and you, looked at another group you termed aggressive psychopaths, who end up in jail.  Take me through this.

MS: The phenylethylamine hypothesis of schizophrenia arose fully armed from a chat I had with a young biologist, Gavin Reynolds, I was interviewing for a job.  I gave it to him.  He is now Professor of Neuroscience. We had both been thinking along the same lines but hadn’t quite put it together; but after the interview, within a week or two, we wrote up our hypothesis for the Lancet. If you inject phenethylamine into an experimental animal, nothing much happens, but if the amine injection is preceded by a monoamine oxidase inhibitor a sequence of events follows, similar to that which follows amphetamine administration. I was about to talk about aggressive psychopaths and serendipity. At about this time, I happened to be at one of those interminable dinners at the Royal College of Physicians.  I had been seated on the end of a table and the chap, sitting next to me hadn’t turned up. The only contact was with a rather morose guy called Field I couldn’t draw into conversation. I almost had to sit on his head to find out he was a psychiatrist at one of our better prisons, Wormwood Scrubs.  At last, we started to talk and I desperately tried to dredge up what I knew about criminals, which wasn’t much.  I had just read a paper, however, which claimed that sixty percent of murderers in North Carolina had been on amphetamine. It was obviously amphetamine psychosis they were dealing with. They had become schizophrenic on amphetamines and I had never even heard of this until I started reading the whole thing up.   One thing led to another and Field and I decided to collaborate.  We set up a group of aggressive psychopaths and another group of men imprisoned for white collar crimes, fraud, cooking the books, tax evasion-normal controls, you know.

DH: The things we all do, right?

MS: We compared these two groups and, surprise, surprise the aggressive psychopaths excreted significantly more phenethylamine metabolites than controls.  The national press made quite a splash of the story at the time.  We thought we ought to repeat the experiment and went back to Wormwood Scrubs and asked if we could have a couple of dozen more of each just so we could clinch the whole thing?   But the prison gates were closed!  They got scared stiff!

DH: Too much of a splash.

MS: Yes. The prison authorities were always sensitive to too much publicity.  Well, I thought we’d finished with that one, really.  And, then, I was at someone’s dinner party.  There was a young man sitting across from me and we started talking about what we did. I got on my frustrated scientist hobby horse and complained how difficult it was doing research on prisoners.    This smooth young man was the British Minister of Transport.  His name was…

DH: Norman Fowler!

MS: Norman Fowler, yes. He said the Home Secretary is my chum; send me the papers on the case and I’ll have a word.  Nothing happened for about six weeks. And then, I got a call, “the prison gates are open.” It is nice to have influence.  So, we confirmed our earlier data and did parallel experiments in animals, comparing dominant and non-dominant monkeys, which took us out to St. Kitts where they have monkey colonies; the dominant alpha monkeys lead the pack and are the ones that carry their tails in the air. We collected blood samples and the alpha males had higher circulating concentrations of phenylethylamine metabolites.

DH: I can see that you pick your research with care, that carries you to the Caribbean.

MS: Absolutely!

DH: You used to come to the Caribbean, as well, courtesy of Nate Kline.  Tell me about that?

MS: Very true.  Nate Kline, we all remember fondly.  Nate Kline was a wheeler dealer.  He was a New York psychiatrist of flare, talent and panache.  He was a fascinating character and even quite a good psychiatrist. One of his patients, a Mrs. Denghausen, was an upstate New York millionairess, with depressive illness. Nate would give her oral tryptophan and she would cycle back to normal. And when she was relatively normal, she said “Doctor, what can I do for medical science?” So he said, “Doctors have to travel a lot and are always worried about their wives”.  He persuaded her to fund a small scientific meeting on a Caribbean island every March, “and bring your wives” along.

                           We used to line up on the beach at 8:30 in the morning in our swimming trunks under the palm trees, with just a blackboard and somebody would get up and hold forth; he would be torn to pieces by the hand-picked group of a dozen neuroscientists Nate Kline had assembled. It was hard work and wildly stimulating. Lots of contacts were made and   experiments were spawned by this gathering a .really fascinating group. Unfortunately, Mrs. Denghausen died, her husband died and Nate Kline died so that the whole thing wound up.  But, it was great while it lasted. 

DH: Before we come back to the Caribbean and the ACNP meetings, can we hop to the first CINP meeting, because you were there, weren’t you?

MS: I was, by pure chance.

DH: Tell me about that first meeting in Rome and the impact it made?

MS:  That was the first foreign scientific meeting I’d ever been to.

DH: I don’t know the date, so you better put it on record.

MS: It was 1958, because Mike Pare had been involved in some sort of drug trial for Hoffmann-LaRoche and they very kindly funded our trip..  At that time, I had never heard of the CINP; nobody had, it was the first meeting.  We were delighted to get to Rome.  We’d done some very intriguing work I think should be disinterred and looked at again.  We found a deficit of 5-HT in the platelets of phenylketonurics. Even more interesting was our control group, so-called “cerebral palsy” patients from the same children’s hospital.  I don’t know what they were really suffering from; they may have been autistic, but the fact is they had wildly differing levels of 5-HT in their platelets, some astonishingly high.  Others later confirmed that certain autistic kids have raised levels of 5-HT in their platelets and this finding has never been satisfactorily explained. There may be some mechanism that normally stops it building up and it’s being sucked up like a sponge in children with abnormally high values. What has happened to the uptake mechanism in these subjects? I don’t know,  but somebody should look into it.  Anyway, that was the paper Mike Pare and I presented to something like nine or ten people!  We were perfectly happy in Rome and we banqueted at the Villa of Mussolini’s mistress. This was the good life.  The faint whiff of corruption was in the air and it was a delight!

DH: You liked it?

MS: I loved it, yes!  It was marvelous! It was nice while it lasted, David.

DH:  After that you began to come to the ACNP meetings, which we are having here at the Caribbean?

MS: I came first in the mid-1970s and very soon after I was elected a foreign corresponding member of the ACNP. It was around the swimming pool at an ACNP meeting that David Wheatley, Alec Coppen and I, hatched the British Association of Psychopharmacology.  Perhaps I am wrong, as there are other interpretations and other stories that compete.

DH: Was this the model you wanted to reproduce?

MS: Yes, this ACNP meeting has always been the leader of the field.  There is no question in my mind it represents the front line of Psychopharmacology. I top up my psychopharmacological tanks when I come to these meetings.  They are marvelous!  The program committee has the right formula and they are good. 

DH: So, you save your air miles each year to come here?

MS: That sort of thing.

DH: There is one more angle we need to explore.  The NIH was a major mover in all this.  You had Brodie, Axelrod and people like that with whom you worked closely.  But, you were related to Brodie, is that right?

MS: Distantly.  He was a wild one, Brodie.  I will always remember the last time I saw him.  He was living in retirement in Tucson, Arizona, and had this forceful old wife who looked after and drove him.  She was like one of those pioneer women who went out west on the wagons, a rather harsh lady, and she really ran his life.  Brodie was always sorry for himself because he never won a Nobel Prize. When his former technician, Julie Axelrod, won the Nobel Prize, Brodie said to him sadly “You always kept your operations small, Julie.”  Brodie had a special room, perhaps his wife looked after it, where all his certificates and honorary degrees were pasted around the walls like a shrine, but the big one was missing!  It was very sad, really.  He made wonderful contributions to our knowledge, especially in toxicological methodology, working with Julie Axelrod and many other famous names. Brodie was the driving force, a very strange man and a bit of a junky. He took amphetamines during the day and barbiturates at night, uppers and downers. He had a very strange idea of time and would phone his associates at twelve o’clock at night to come into the lab to have discussions.  He would never put in an appearance there until around lunch time. Yes, there is a distant relationship but there isn’t much Brodie blood in my veins!

DH: Or the other way around?

MS:  Yes.

DH: Sandler blood in his veins.  Brodie was actually born in Liverpool.

MS:  And went out to Canada as a boy.

DH:  How did you rate Julie.

MS: Ah, a lovely man.   I first visited America in 1963, and Julie very kindly organized a party in my honor that night. Well, the plane was diverted to New York.  It was a mess!  So, I missed  Julie’s party, with great regret.  I had met him at that first CINP meeting. We sat next to each other on a conference bus, by chance.  I thought to myself I’d never met a man less likely to succeed and I never thought this little guy would make it. He was overdressed in the bright sunshine in a dirty old rain coat!  I have a dirty old rain coat myself but his was dirtier and older. He was obviously very hot.  The whole conference, around three hundred people in those days, was bussed out to Castelgandolfo to see the Pope.  The Pope made a speech and none of us could understand him, in Latin perhaps?  But, in fact, it was broken English. Then he died twelve days later.  It didn’t seem strange to me at that time.

DH: OK. But, there’s another issue here. You have described elsewhere the powerful role that displaced Jewish physicians and scientists, forced to leave central and eastern Europe before World War II, played in the UK, but they also played a huge role here in the US.

MS: Oh, a huge role!  During my seminal 1963 visit, when I first visited the NIH, Seymour Kety was in his prime as chief of the Laboratory of Clinical Science; he is a chap who should have won a Nobel Prize, if there had been any justice in the world.  Anyway, he assembled a random group of his colleagues to go out to lunch.  There were a dozen of us sitting around the table and by pure chance, all were Jewish!  People like Sol Snyder, Irv Kopin, Joe Fisher and Dick Wurtman all were there. Of course, I don’t know, but I suspect that Jews manifest survival genes.  They have survived, despite the odds. The individuals, who survived, evolved tricks and mechanisms which, somehow, provide the ability to see through to the heart of a problem, and not to accept revealed truth. I believe that this is the key to scientific ability. Well, it’s just as good a hypothesis as anybody else’s.  Anyway, there are a lot of Jewish scientists in the United States and an awful lot in our own field of psychiatry and psychopharmacology.  

DH: When the field coalesced, it was very much driven by clinical observation and people who were working in the basic sciences had to come in and try to explain what was going on.  At the meetings now there is an awful lot of basic science and you’re not sure of what, if any, are the clinical implications.  Do you think we have moved too far down the neuroscience route?

MS:  No I do not. I think it has become clear this is the only way to make progress; and now we have the human genome mapped.  So, it’s a new ball game completely, isn’t it? We don’t have all the pieces in the jigsaw yet, but we can be much more confident in our predictions than before.  These ACNP meetings are an eye opener now, where basic science rules. Ok!

DH: Good. Do you have any other thoughts on things we need to cover?

MS: I don’t think so. I think you have done a jolly good job, David, if I may say so.  I am happy and thank you very much for doing the job so well and courteously and I truly regret that I won't be present to witness it

 

References:

Ban TA. Preface. In: Sulser F, editor. Neuropharmacology. In: Thomas A. Ban, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Per Interviews. Volume One.   Brentwood: American College of Neuropsychopharmacology, pp. IX-XXX.

 

Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Brentwood: American College of Neuropsychopharmacology; 2011.

 

Sandler M. My fifty years (almost) of monoamine oxidase. Neuro-Toxicology 2004; 25: 5-10

 

 

Sulser F. Introduction & Dramatis Personae. In: Sulser F, editor. Neuropharmacology. In: Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Per Interviews. Volume Three.  Brentwood: American College of Neuropsychopharmacology, pp. XXXIX –LX.

 

Shorter E, editor. Neurophysiology. In: Thomas A. Ban, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Per Interviews. Volume Three. Brentwood: American College of Neuropsychopharmacology; 2011.

 

Youdim MBH. Monoamine oxidase, their inhibitors and the opening of the neurotransmitter era in neuropsychopharmacology. In: Ban TA, Ucha Udabe R, editors. The Neurotransmitter Era in Neuropsychopharmacology. Buenos Aires: Polemos; 2006. p. 107-26.

 

 

 

January 11, 2018