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Friday, 20.09.2019

In Memoriam
 E. Leong Way (1916 – 2017)
by Thomas A. Ban

 

            E. "Eddie" Leong Way passed away in the afternoon on June 12, 2917, in his home in San Francisco, four weeks before his 101st birthday. Born in Watsonville, California, USA, in 1916, Eddie Way went from studying the biologic activity of arsenic compounds in the mid 1940’s to studying the bio disposition of opiate drugs such as morphine, heroin, meperidine and methadone for about 20 years.  His main research accomplishment was proving that the two biological properties of opiates, after chronic administration, tolerance and physical dependence, had a common underlying biochemical basis in norepinephrine release (Ban 2011.) It took more than 20 years to obtain conclusive evidence, from the late 1960s to the early 1990s and shifting from in vivo to in vitro techniques (Way 1993; Way, Leoh and Shen 1968.) To provide final proof, the vas deferens of the mouse was used which has a “twitch” response to electric stimulation that is inhibited by opiates.  Way retired from the University of California, San Francisco, soon after completing this research and went on to a successful 2nd career in his 70s and 80s (Kleber 2011).

            A Life Fellow Emeritus at the time of his death, Way was elected a member of the American College of Neuropsychopharmacology (ACNP) in 1969. On December 12, 2006, he was interviewed by Lynn E. DeLisi in ACNP’s oral history project at the annual meeting of the College in Hollywood, Florida. The edited transcript of this interview was published in 2011 in volume 6 (edited by Herbert Kleber) of "An Oral History of Psychhopharmacology" and presented here (Ban 2011): 

LD: Just to begin, let me just tell you that I’m a member of the History Committee.  My name is Lynn DeLisi.  I’m a psychiatrist, a biological psychiatrist and I’m a Fellow of the ACNP.  I am very interested in the history of the ACNP and, so, I’ve been asked to interview you.  Maybe the best way to start would be if you could state your name and your current position where you are and, then, we’ll proceed from that.

EW: I go, professionally, by E. Leong Way but most of my friends know me as Eddie Way.  I’m professor emeritus of pharmacology at the University of California at San Francisco.  I was there for over 50 years and served as Chairman, from 1972 to ‘78.

LD: OK.  Well, that gives us an ending to the story that I’d like to begin with your earlier life and experiences. And if you could just begin with, maybe, a description of yourself, how you got into this field and what drove you into it in the beginning.

EW: How I made my living from drugs? How I became a pharmacologist?

LD: Well, how you got into the field and where you are today?

EW: Well, I started as chemistry major in Berkeley, but after a couple of years there, I decided that dancing atoms and  electrons are not the kind of chemistry I was interested in; even though there were a lot of Nobel Laureates in physics and chemistry on campus at the time.

LD: What year was that?  What period of time?

EW: Well, that was in the 1930s.  I enrolled in 1934 and spent two years there. But then, I decided that I was more interested in drugs, so I transferred in 1936 to the School of Pharmacy on the San Francisco campus. I received a BS in Pharmacy, which was awarded in Berkeley, because, at the time, San Francisco was still not an independent campus.  After I got my degree, I practiced Pharmacy for one year.  It was interesting and somewhat satisfying, but it wasn’t the academic and intellectual challenge I wanted. Fortunately, a graduate program in the School of Pharmacy was initiated and I became its first student to acquire an MS in 1940 and a PhD in 1942 in Pharmaceutical Chemistry.  For my dissertation, I synthesized 80 compounds, which were derivatives of organic arsenic. I tried to make organic arsenic compounds in the hope that they would find clinical applications. At the time the organic arsenical, arsphenamine 606, was used mainly for treatment of trypanosomes infections and syphilis.  And, sulfanilamide had just been introduced as an antibacterial agent for gonococcus, streptococcus and staphylococcus.  I made about 80 arseno-sulfa combinations but I wasn’t able to study them in the pharmaceutical chemistry department. However, there was a famous pharmacologist, Chauncey Leake on campus, and so I started to do research with him.

LD: When was this?

EW: 1942. Unfortunately, or fortunately, Chauncey resigned from his position as Chairman at UCSF in 1942 to become Vice President and Chairman of Pharmacology at the University of Texas in Galveston. When he left, I could not continue my studies, so I accepted a job at Merck. It was during the war and I was assigned to study the stability of vitamins.

LD: Are we talking about World War II?

EW: Yes.

LD: How did the war affect you in your career?

EW: Well, Merck employees were deferred from active duty for doing essential work. Although I got a deferral for studying vitamin stability, I didn’t think doing that was very essential, and after four months I accepted an offer to become an instructor in pharmacology at George Washington University Medical School in Washington, DC where medical students were being trained to join the Armed Forces, either in the Army or in the Navy.  I found that not only more interesting but also more satisfying. I stayed at GW for five years.  I finished my studies on the biologic activity of my arsenic compounds. I found they weren’t much good in their action on trypanosomes.  After these negative findings I shifted my research to studying narcotic drugs.  I was sort of gently nudged into the field.  At that time, meperidine, Demerol, the first synthetic opiate-like analgesic was introduced.  Meperidine, at the time known as isonipecaine, was designed to be a substitute smooth muscle relaxant for atropine but was serendipitously discovered to be analgesic.  I asked Dr. Roth, the chairman of the department who had hired me, what we know about the vagal inhibitory properties of meperidine.  He said, “Why don’t you study it on frogs, Doctor”? I tried to put him off but the week following Dr. Roth said, “Your frogs have arrived for your research, Doctor”.  I got the message, and that’s how I got hooked on narcotics for good.  When P. K. Smith succeeded Roth as chairman in 1946, he suggested I do drug metabolism studies because the field was better suited to my background and training.  P.K. was interested in acetyl salicylic acid, good old aspirin, and supported me to study the biodisposition of   p-amino-salicylic-acid. So, that’s how drug metabolism became my main research field.  I received a NIH grant that I held for about twenty years, studying the biodisposition of opiate drugs, morphine, codeine, heroin, meperidine, methadone, and 1-acetylmenthadone, LAAM.

LD: So this was the field you were working in and what you were doing. Could you tell us what you would consider your best accomplishments in research?

EW: After completing a review and a monograph on the biodisposition of morphine and its surrogates, I shifted my research to studying the two biologic properties of the opiates that develop after repeated administration: tolerance and physical dependence.

LD: What were your most exciting findings in this area of research?

EW: Providing the pharmacologic evidence that the two parameters, tolerance and physical dependence, have a common underlying biochemical basis. Clinically, tolerance and physical dependence appear to be related because when addicts develop tolerance to opiates such as morphine or heroin they also become physically dependent on the compound as evinced by a severe withdrawal syndrome shortly after drug taking is discontinued. However, some investigators have maintained that tolerance and physical dependence are not related.  Tolerance and dependence have been used as qualitative terms without quantification and, in order to relate tolerance and physical dependence to a single parameter, it was first necessary to develop experimental methodology to measure tolerance and physical dependence of morphine in the laboratory quantitatively. We developed procedures for measuring tolerance and physical dependence in mice and rats that helped open the field for scientific evaluation.  Our first paper and last papers in the area were to be most satisfying. In the first paper, we reported on methods in mice to measure tolerance and physical dependence.  Over the years we provided considerable circumstantial evidence that certain neurotransmitters could modify tolerance and would also alter dependence development.  And finally we were able to show by in vitro methods that tolerance and physical dependence have a common underlying basis related to neurotransmitter release.  I began the studies after I visited Professor Huidobro-Toro in Chili.  He had developed a morphine pellet to make mice dependent on morphine that eliminated having to inject mice repeatedly with morphine very day. By implanting a single compressed pellet underneath the skin, mice became highly dependent on morphine as evidenced by the precipitation of a severe abstinence syndrome after an injection of nalorphine, a morphine antagonist. The dependent mice became very excited and ran off the table. I decided that would be a great way to study opiate tolerance and dependence. However, Professor Huidobro’s handmade pellet was laborious to make. So I went to our pharmacist, Bob Gibson, who developed a product that could be machine manufactured, and, provide a steady release of morphine. We could easily implant thirty or forty of our pellets in our animals on Friday, go off dancing, playing golf on the weekend, and return on Monday for the evaluation of our tolerant and dependent animals. To quantify tolerance, we used an analgesic response, actually an antinociceptive effect, known as the tail flick response. A mouse would flick its’ tail away after a heat stimulus, and after the administration of an opiate, its reaction time would be delayed. After repeated doses of morphine, tolerance could be quantified by a shift of the dose response curve of morphine to the right, and the degree of shift gave a quantitative estimate of the degree of tolerance.  Physical dependence was displayed by withdrawal signs, such as weight loss and defecation, after removing the pellet but we could quantify the physical dependence easier by measuring the dose of the opiate antagonist naloxone, to precipitate jumping. Antagonist precipitated withdrawal was reported earlier by Abe Wikler, Harris Isbell and Frank Fraser.  We found the more dependent the mice became; the less naloxone became needed to precipitate the withdrawal jumping. So, having a quantitative measure of tolerance and physical dependence we demonstrated that the degree of tolerance, as shown by the increase in dose of morphine to elicit antinociception, was paralleled by a decrease in the amount of naloxone to precipitate withdrawal jumping.

LD: Why did it take you over 20 years to demonstrate that tolerance and physical dependence have a common underlying biochemical basis?

EW: We found much circumstantial evidence early that neurotransmitters, serotonin (5-hydroxytryptamine), norepinephrine, dopamine, and acetylcholine could be involved in tolerance and physical dependence, but this still didn’t prove that tolerance and withdrawal have a common underlying biochemical basis, and it took about another twenty years, and shifting from in vivo to in vitro techniques, to show it.   In the meantime, some investigators continued to maintain that tolerance and dependence were not related. They argued that the tolerance response in one system could be reduced without altering a dependence response in another system. We pointed out that such considerations are comparing apples to oranges because tolerance to various opiates effects on various systems or organs have different times of onset and degree; tolerance to the analgesic effect comes on very early and is of a high degree, whereas tolerance to pupillary constriction appears later and is of a lesser degree. To show a relationship between tolerance and physical dependence, it is necessary to measure a common parameter in both syndromes. Investigators in the UK, especially Hans Kosterlitz, used the Guinea pig ileum to study opiate action.  Earlier Paton had shown that after an electric stimulus of the ileum a twitch response occurs that is inhibited by the administration of an opiate. The model provides a surprisingly good predictor for analgesic potency experimentally and clinically.  Also, the rank order of potency yielded surprisingly good correlation with dependence liabilities in monkeys in Mo Seevers’ lab at Michigan. So, using the guinea pig ileum one can predict the addictive liability of opioid substances.  The decrease in twitch response elicited by morphine in this system is due to inhibition of acetylcholine release but found it difficult to measure. So we then decided to use the vas deference of the mouse for measuring withdrawal. The mouse vas deferens has also a twitch response to electric stimulus that is inhibited by opiates, but the neurotransmitter inhibited in this system is due to norepinephrine. . Thus, with the employment of this test, we finally demonstrated that norepinephrine release is the common underlying biochemical basis for tolerance and physical dependence. As tolerance developed more morphine was required to inhibit norephrine release and after washing out the morphine there was substantial increase in norepinephrine release. That was the last original publication from our laboratory.

LD: When was this?

EW: In 1990.

LD: In 1990?

EW: Yes and our first report, was published in 1968 or 1969.

LD: What made you stop working in this area of research?

EW: Well, I retired in 1987, and didn’t have any more research space.

LD: Why did you retire?

EW: There is mandatory retirement at age 70 but I was able to fudge almost two years.

LD: How were you able to cheat them?

EW: Well, retirement ends on June 30th and I was only 69 then but because my birthday is on July 10th, so that got me almost one additional year. Then the research grant administrators unwittingly had approved the support for my research for five years and did not realize they obligated two additional years past my mandatory retirement.

LD: This was at UCSF?

EW: At UCSF.

LD: And, they had mandatory retirement?  I thought that there was not supposed to be any prejudice against age.

EW: At that time, there was.

LD: So, what have you been doing since?

EW: Well, I got an offer to go to Japan to establish a neuropharmacology department.  My friend, Eikichi Hosoya, who was research director at Tsumara, probably the largest herbal company in the world, wanted to validate herbal medicine with Western technology. So, the way to do that in Japan is to set up and subsidize a department at an academic institution.

LD: So, you went over there?

EW: I went over there as a Professor and Chairman of the Department of Neuropharmacology at Gunma University.  As it turned out, I was a figurehead; just hired for show.  Hosoya wanted a former colleague of his at the company to be the Chairman, but the Japanese academicians opposed a person coming directly from the drug industry to be head of an academic department. To circumvent this I was hired as professor and chairman for one year and after I left another person would inherit the chair.  I wasn’t aware of this. I wasn’t very keen about going to Japan, but at the same time I wanted to be nice to my friend. So when he invited me I told him, “Well, I have a disabled daughter, so my wife would not be able to accompany me to bring her to Japan, and .I wouldn’t know what to do with my weekends.  I like to golf and dance. Get me membership in a dance club and a golf club and I would consider coming.” I thought he wouldn’t be able to meet my terms.  He replied I can get you a dance club membership, but not a golf club membership because that’s very expensive. However, he came back to me two weeks later and said, OK.  As it turned out, Tsumura made money on me. The golf club membership cost the company about a hundred thousand dollars.  However, buying a golf club membership in Japan is like buying stocks and, by the time I quit, the economy was still at its peak and the price of my membership had ballooned three fold. Too bad I couldn’t keep the membership.  It belonged to the company and not to me.

LD: Were you there just for a year.

EW: One year.

LD: I suppose you played a lot of golf and went dancing and, then, you returned to California?

EW: I was allowed to come home once a month, too.  .

LL: Were you born in America?

EW: Yes.

LD: Were you born in California?

EW: In Watsonville, a town not far south from San Francisco.

LD: Wasn’t there a wave of immigration from China that started in the early 1900's?

EW: No, it really started after the 1849 Gold Rush in California.  Chinese immigrants were welcomed and admitted to build the railroads. But when the job was finished the immigrants were no longer welcomed and excluded in 1882.  By the time my father brought my mother over in 1912 discrimination laws were still in effect against the Chinese, and, they were not revoked until 1943 and further liberalized in 1948. If you were not a US citizen, you could not bring a wife over or have property in the US. My father claimed he was a citizen by right of birth and the government had no proof to dispute his claim because in 1906, there was a catastrophic earthquake in San Francisco. Since it destroyed government records many Chinese could claim citizenship by birthright. My dad was enabled to go back to China and marry my mother and bring her over in 1912.  And, they had 8 kids who all attended college This is a great country for opportunity and social justice even though there are downsides  they become corrected if unbearably slow for many of those suffering.

LD: After a year in Japan, what did you do?

EW: Well, the director of NIDA, Bob Schuster, invited me to go there as a senior post-doctoral fellow. So, I went there for a year but I didn’t contribute very much.  I gave some advice to which not much attention was paid. But I learned to appreciate government employees much more while there.

LD: How did you become an expert in herbal pharmacology? Did you become an expert of it while in Japan?

EW: I became an “expert” in herbal pharmacology by default much before that, in the late 1950s. I did not know much herbal pharmacology before 1958.  The Communists took over Mainland China in 1948 and closed the door to the West especially the US.  We heard of some major advances in China in the first six or seven years. The American government was very much interested in the progress.  NAS and the AAAS sponsored a symposium on The Sciences in Communist China that was later published in 1960, and I was invited to speak and publish the chapter on Pharmacology.

LD: Ah, so, we’re back now in years to1958.

EW: Well, I’m telling you how I became an expert in herbal pharmacology without doing any research in it. Is this OK?

LD: Yes.

EW: After I consented to write the chapter in Pharmacology I was inundated with literature related to herbal pharmacology in China. Herbal pharmacology received great attention after Chairman Mao made the pronouncement that herbal medicine in China is a great treasure that should be developed and elevated. Tremendous efforts were made to validate herbal remedies. Pharmaceutical chemists trained in the West were adopting advanced methods to isolate the active constituents of herbs, and pharmacologists were evaluating their pharmacologic properties. Western-trained physicians were told to learn traditional medicine and traditional practitioners to learn Western medicine. There was a huge shortage of health practitioners in China in those days, especially in the rural areas, and hastily trained local practitioners “the barefoot doctors” program was invented.  It was the time of political reform movements with slogans such as the “big leap forward”, “let a hundred flowers bloom” and, when scientists who were urged to criticize what was wrong got into trouble, they “confessed” and the academicians were downgraded and put into to labor camps in the countryside.  I learned about this when I went to Hong Kong on my sabbatical in 1962 and 1963 to do research on Hong Kong addicts. While there I wanted to follow up on the earlier program in herbal pharmacology in China after the 1950s but now found virtually no literature because scientific activity had stopped. I learned this from my assistant, B. N. Mo. Benny, who had been a surgeon in China who had managed to get out of China with his wife.  He had difficulty finding work in Hong Kong but finally became a lab assistant in the physiology department.   Now how did I digress to politics?

LD: Actually, I was wondering if we could get back to more recent years.

EW: My chapter on Pharmacology in the 1960 book Sciences in Communist China qualified me to be appointed in 1974 to the NAS delegation to evaluate the status of herbal pharmacology in China. Well, that’s how I got to be an expert in herbal pharmacology. After Nixon sent Kissinger over to China to talk with Zhou Enlai, they agreed to exchange scientific knowledge between the USA and PRC. The first delegation dealt with exchange of information in medicine, and the objective of the second was to learn about the herbal pharmacology program. The head of the latter delegation was Louis Lasagna, a prominent clinical pharmacologist who was a member of the ACNP. So, I sent Lou a reprint of my publication and managed to get on the committee.  There were very few pharmacologists in the US in those years with any knowledge about Chinese herbal remedies.

LD: So you had been pretty much involved in herbal pharmacology.

EW: After the chapter on Pharmacology I was invited by the noted scientist and author, Joseph Needham, to write a volume on herbal pharmacology for his series Science and Civilization in China for Cambridge University Press. Like a dumb fool, I was flattered and accepted. I thought it would be relatively easy; I would read some Chinese scientific publication on herbal pharmacology and adapt them using Western terminology. As a preliminary I wrote a couple of articles providing a perspective along such lines and a suitable preface for my book that was published in 1996. As I dug deeper in my subject I learned that more than a thousand years ago the Chinese had noted six types of drug interactions that correspond to certain Western terms as agonist, antagonist, partial agonist, additive action and potentiation. But, unfortunately I have not been able to find any data to support any of these notions.

LD: Are you still actively writing on herbal pharmacology?

EW: After I published Perspective in 1996, I realized that it would be difficult to write a scholarly treatise on the subject but perhaps I might write a semi popular presentation in which I wouldn’t have to support with original data.

LD: Do you have any thought on where the future is going to take us in science?

EW: A lot depends on the global economy. China has emerged as a major power and it’s pretty obvious that scientific programs will be influenced by economics and politics.  The current social capitalism has enabled in recent years extraordinary advances in science whereas in the US the free enterprise system is beginning to have problems.  Yes, capitalism has been most successful in helping the welfare of people, since the industrial revolution, but I think it’s beginning to hurt us unless we change having a system focused on profit and dependent on an ever increasing population which spawns greedy corrupt CEOs.  When you have a system dependent on profit and focuses on profit, health care and education costs increase but so do corrupt CEOs.  Bill Gates and Warren Buffet are notable exceptions and are doing a lot of things that the government can’t.

LD: This is economics and world politics.  I’m just wondering what you think about research in the future?

EW: Research on drugs is also is going to be more globally supported increasingly by dependency on technology in the private sector.

LD: More global research.

EW: Beside the NIH there are several private foundations like the Pharmaceutical Manufacturers Research Foundation and the Howard Hughes Foundation promoting more global research on drugs. My brother and I have now started one to promote US.-China relations using education to help develop leaders. The free enterprise system has been very important in promoting such goals but a system based on profit has its limitations and I don’t know how long such a system can last.  China has a recorded history of about 4,000 years with four or five great empires lasting 300 to 400 years. The Industrial Revolution spawned capitalism so for less than 200 years with US the leader for most of the past century.  So, how much longer will the free enterprise system prevail with constant increasing cost of living and the gap between the rich and poor widening?

LD: Since this is an interview for the ACNP, I was wondering when you became a member of the ACNP?

EW: In 1969 and I’m a Life Fellow Emeritus.

LD: Were you one of the founding members?

EW: No, ACNP started in 1961.  I already belonged at that time to two pharmacology societies. I was founding member of those two organizations: the International Narcotic Research Conference (INRC) the “C” used to stand for club but we have grown and the College on Problems of Drug Dependence (CPDD).

LL: Is there anything you’d like to tell me that we’ve missed, or something you’d like to tell people regarding the future?

EW: More knowledge and experience applied with common sense results in wisdom. That’s why I say that Bill Gates and Warren Buffet have the wisdom to serve people.  Bill Clinton is doing more now than at the time when he was President, because he’s now doing it globally.

LD: Jimmy Carter, also.

EW: Yes.

LD: Well, thank you very much.  I think this was very helpful for the ACNP and for the future.

EW: Thank you.

 

References:

Ban TA, editor. An Oral History of Neuropsychopharmacology, Volumes 1- 12. Brentwood: American College of Neuropsychopharmacology; 2011.

Ban TA. Preface. In Kleber HL,editot.  Addiction. Volume Six. (Ban TA,editor. An Oral History of Neuropsychopharmacology.) Brentwood: American College of Neuropsychopharmacology: 2011, pp. ix-xxvi.

Kleber HD. Introduction and Dramatis Personae. In: Kleber H, editor. Addiction. Volume Six. (Ban TA, editor. An Oral History of Neuropsychopharmacology,) Brentwood: American College of Neuropsychopharmacology; 2011, pp. xxxv-lxxvi.

Way EL interviewed by Lynn E. DeLisi. In Ban TA, editor. An Oral History of Neuropsychopharmacology, Volume Six. (Kleber HD, editor. Addiction).  Brentwood: American College of Neuropsychopharmacology; 2011, pp. 366-76.

Way EL. Opioid tolerance and physical dependence and their relationship. In: Herz A, editor. Handbook of Experimental Pharmacology 1993; 104: 1573-96.

Way EL, Leoh HH, Schen FH. Morphine tolerance, physical dependence and synthesis of brain 5-hydroxytryptamine. Science 1968; 162: 1290-2. 

 

October 12, 2017