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Saturday, 21.09.2019

EULOGY for ALFRED PLETSCHER (1917-2006)
By
Barry Blackwell

 

       The International Neuropsychopharmacology History Network (INHN) is dedicated to recording and learning the lessons of history to better understand and benefit the present.

       Central to those themes is the role of the pharmaceutical industry and the part played by scientists working within it. In 2006, the year of Alfred Pletscher’s death at age 90, Tom Ban and Ucha Udabe published a volume on The Neurotransmitter Era in Neuropsychopharmacology (Ban & Udabe, 2006) with 10 chapters devoted to the early contributions from inside drug companies. They invited two members of CINP’s History Committee who had “intimate knowledge about research in the pharmaceutical companies” to contribute chapters. They were Paul Janssen and Alfred Pletscher. Alfred, former Research Director of Hoffman La Roche, provided a paper, “From Inside the Pharmaceutical Industry,” perhaps the last he wrote, that became the lead chapter in that section.

       In addition to that autobiographical material, we have a firsthand account from his colleague Fridolin Sulser (Sulser, 2013) and two interviews in his own words from the Oral History of Neuropsychopharmacology, the first by Tom Ban in Volume 3 (Pletscher, 2011a) and the second by Andrea Tone in Volume 9 (Pletscher, 2011b).

       Alfred Pletscher was born in 1917 in Alstaetten in the far east of Switzerland, close to the Rhine and the frontier with Austria. He attended elementary school there and his undergraduate and graduate work in studies at the University of Zurich with semesters in Berlin (before the war in 1939), Geneva and Rome. Alfred obtained his M.D in 1942 and his Ph.D. in organic chemistry in 1948 when he worked with Nobel Laureate Paul Karer.

        After completing both degrees, he practiced medicine for five years interested both in “how biological processes work and how to apply them … I was interested in human relations and I had the idea that, with sick people, you could get, perhaps, closer relations. I became interested in how to prevent illnesses and the need to know biochemistry to understand biological processes.”

       Toward the end of 1954 he was approached by Hoffman La Roche to become their Director of Biological Research. “I was rather idealistic although you could ask, why did I then join the pharmaceutical industry, which is not so idealistic? I joined because I thought I would have more possibility to help sick people than being a general practitioner. If I found a drug we could help thousands of people, as an individual physician I could only help a few.”

       After deliberating for half a year, he chose to join Roche rather than Ciba because “it was a family owned company and the family created a very good spirit.” The owner of Roche was “Alfred’s friend, a musician, whose wife was a sculptor, while he had a cultured mind.”  He continued, “The management of the commercial department would listen to what we in research said, and that is what I liked. Otherwise I would not have joined them. Today I would not join them anymore.” (Pletscher, 2011a).

       Another factor was that Roche, unlike other Swiss companies, was more interested in pharmaceuticals than the dye industry. Roche synthesized and analyzed vitamins, but also had developed a sulpha drug and COX inhibitors, as well as iproniazid then used for tuberculosis, with which Alfred himself had been treated in 1938, while a medical student.

      At the time Alfred joined Roche there were only three drugs known to have an effect on psychiatric patients, chlorpromazine, reserpine and iproniazid, while the only known neurotransmitters were acetylcholine, serotonin and norepinephrine. “There were hypothetical concepts about receptors, but no solid physical evidence.”

       Aware of the need for more up-to-date knowledge and research, within a year of joining Roche, Alfred Pletscher arranged through his Roche colleagues at Nutley, New Jersey, to take a sabbatical in Brodie’s laboratory at the National Heart Institute where Brodie’s ground breaking research was on the brain, not the heart. Working with a junior colleague, Parkhurst Shore, they had already shown that serotonin had a function in the brain that mediated the effect of reserpine. Continuing this research, he began a series of studies on the metabolism and effects of serotonin using a new instrument, a spectrophotometer, developed by Bowman, Caulfield and Udenfriend at NIH. This work established a relationship between sedation and serotonin levels, a finding published in Science that opened up the field of neuropsychopharmacology; “a psychotropic drug affected an endogenous neurotransmitter” (Pletscher, Shore & Brodie, 1955).

       When Pletscher, in contact with Nate Kline at Rockland State Hospital, told him that reserpine and iproniazid had opposite effects on sedation and mood it triggered the evolution of the MAO inhibitors as antidepressants. And when, within a year, he returned to Roche as Director of Biological Research, “I had the necessary authority to make the development of psychotropic drugs the center of our program. I said that we should look for new psychotropic drugs with all the knowledge we have. We assembled a group of people for that research, found and developed several compounds.” This research bore fruit in work on reserpine-like neuroleptics and monoamine oxidase inhibitors for depression.

       While working at Roche at Basel, Alfred also taught pathophysiology to the medical faculty at the university, work that was cut short in 1957 when the Chairman of Roche asked him to leave Switzerland for New Jersey to become Director of the new Roche Research Institute in Nutley. When he asked what substances they had developed he was “told there was nothing.” In fact they had a substance on the shelf with the code name, RO5-0690 (chlordiazepoxide), but management was not interested in it… the sales manager told me there was no market for these drugs.”

       Nevertheless, the Director of Pharmaceutical Research had screened the compound in untamed aggressive cats and 20 minutes after receiving RO5-0690 they became calm but not sleepy, tranquilized without losing coordination.

       By 1958 research confirmed the benefit of Librium and the first clinical publications appeared a year later; within a short time Librium had vanquished Meprobamate and soon afterwards was followed by Valium.

       Having initiated this series of events, Pletscher was recalled to Basel in 1958 to become Director of Research for Roche International where he resumed his role as Professor at the University and his involvement at Roche broadened to extend the use of benzodiazepines in sleep and epilepsy, development of an antipsychotic (chlorprothixene) and an antidepressant (amitriptyline). In the search for further compounds, Roche collaborated with Ermino Costa at NIH and the Department of Pharmacology at the University in Basel.

       Alfred Pletscher remained as Director of Roche Research Worldwide until 1978 during which time he played a pivotal role in the development of benserazide, a decarboxylase inhibitor which enhances the effectiveness of levodopa in Parkinson’s disease (Pletscher, Gey and Burkard, 1965). He also participated in the development of antibacterial agents at Roche.

       During his entire time at Roche Alfred felt he had both freedom and flexibility in what he did. But he also acknowledged, “If you go to work for industry you have to make some compromises, you can’t work on all the drugs you are interested in, you have to work on drugs that have a big market to generate money. But you can do wonderful research… much more than at a university or in public and State situations. This is why I did not pursue my interest in drugs against malaria and tropical sleepiness but decided we should work on drugs for depression and schizophrenia” (Pletscher, 2011b).

       In 1978, at age 61, Alfred resigned from Roche to create a Department of Clinical Research at the University Hospital in Basel where he organized groups working on beta-blockers in hypertension, organ transplants in oncology and brain chemistry, as well as pursuing his own line of research using platelets as a model for the brain to study the mechanism of monoamine uptake and storage, work he began in the early 1960s.

       Alfred Pletscher remained at the University until he retired from his Chair in 1988 to become President of the Swiss Academy of Medical Sciences. He also remained a consultant at Roche, but between 1978 and 2002 industry had changed dramatically and his opinions had hardened with serious reservations. “It’s too commercial. All the decisions are made by non-scientists with the involvement of lawyers, commercial people, economists and the like. All of us are trying to make a contribution to society, I got a good salary at Roche and I’m thankful for that… my primary motivation was not profit but helping people” (Pletscher, 2011a).

       Alfred Pletscher garnered many honors, including Honorary Doctor in Paris, Geneve, Lausanne and Friborg. He also won the prestigious Marcel Benoit Prize, the Science Prize of Basel and the CINP Pioneer in Psychopharmacology Award.

       In recent publications multiple authors from outside the pharmaceutical industry have commented on a radical shift from science and research creativity to commercial interests with the complicit support from  psychiatrists in academia (Blackwell, 2016). So, it is sad to have corroboration of this trend after 1980 by a distinguished scientist who spent almost a quarter century of his highly creative and productive career in industry between 1954 and 1978. 

References:

Ban TA, Ucha Udabe R (Eds.) the Neurotransmitter Era in Neuropsychopharmacology. Buenos Aires: Polemos Editorial; 2006, 28-37.

Blackwell B, Corporate corruption in the psychopharmaceutical industry on INHN.org in Controversies 09.01.2016

Pletscher A. Release of 5-hydroxytryptamine by benzoquinolize derivatives with sedating action. Science 1957; 126: 507.

Pletscher A. In Series Ed. Ban TA, The Oral History of Neuropsychopharmacology Vol.3 Ed.Sulser F. Brentwood Tennessee ACNP; 2011 a,: 420- 433.

Pletscher A. In Series Ed. Ban TA,The Oral History of Neuropsychopharmacology Vol.9 Ed.Blackwell B. Brentwood Tennessee ACNP; 2011 b: 269-275.

Pletscher A, Shore PA, Brodie BB. Serotonin release as a possible mechanism of action of reserpine. Science; 1955: 122: 374-372.

Pletscher A, Gey KF, Burkard WP. Inhibitors of monoamine oxidase and decarboxylase of aromatic acids. In Eicher O, Farah A, Eds. Handbook of Experimental Pharmacology, Vol.19. Berlin: Springer: 1965, 593-735.

Sulser F. In INHN.org at First Hand Accounts; Alfred Pletscher. 11.28.2013.

 

June 15, 2017