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MERTON SANDLER
Interviewed by 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 ManchesterGrammar 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 NationalHeartHospital 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 monoamineoxidase. Monoaminoxidase 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 monoamineoxidase. 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 MaudsleyHospital 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 ofDepressive 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 monoamineoxidase 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.