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In this occasional series, we record the views and personal experience of people who have specially contributed to the evolution of ideas in the Journal's field of interest. Tomoji Yanagita is a Japanese scientist who has for many years been a leading international figure in the study of drug self-administration by laboratory animals. He conducted postgraduate work at the University of Michigan and in his professional career did much to strengthen international understanding of the Japanese contribution in this arena.

Addiction (A): Dr Yanagita, I would like to first ask you to tell me about your family, how you grew up, where you were educated and so forth.

Tomoji Yanagita (TY): I was the first son in my family. My grandfather and father were both physicians. So I was expected to be the next generation in that tradition. During my college years I was interested in physiology. As my father did, I attended the Jikei University School of Medicine, which is located in Tokyo. While I was there  I  became  very  interested  in  pharmacology. During the year that I served my medical internship at the Red Cross Hospital, I treated my father's patients in his office when he was away at meetings. I remember being concerned about an allergic reaction observed in the patient to whom I administered penicillin. Since that time, I became interested in the adverse effects of medications such as penicillin. So my interest in pharmacology was further strengthened by this early clinical experience. Thus, I decided that I wanted to become a pharmacologist.

‘I was the first son in my family. My grandfather and father were both physicians. So I was expected to be the next generation in that tradition.’

A: In your medical school training at the Jikei University, was pharmacology taught in the same way as it is in the USA?

TY: Yes, almost.

A: You had a course in pharmacology? Did that include laboratory experiments as well as lectures?

TY: Yes, we had lectures and we did about eight experiments, both whole-animal and in vitro studies.

A: Do you remember any particular pharmacology professor who had an impact on your choice of pharmacology as your specialty?

TY: Yes, my boss. There was only one professor in the department, who was the chairman.

A: Who was that?

TY: Dr Nakao. I forgot to mention that my father received a PhD in pharmacology at the Jikei University. So he knew Dr Nakao well and encouraged me to study pharmacology with him.

A: So your father was also interested in pharmacology?

TY: Yes. Although, he practised medicine he was interested in pharmacology.

A: Was your father a specialist or was he a family practitioner?

TY: Both. Well, my father, after taking his medical training and a PhD degree in pharmacology, entered into orthopedics. He became the vice director of an orthopedic hospital in Tokyo that was owned by a professor of orthopedics at the Tokyo University. However, when my grandfather wanted to retire he requested that my father come home to take over his medical practice. Because my grandfather's clinic was in a small city it was not possible for my father to continue specializing in orthopedics. So he became a general practitioner and took over my grandfather's clinic.

A: Where was your grandfather's clinic located?

TY: In Ashikaga city, located about 100 km north of Tokyo. It is a middle-sized city with a population of 300 000.

A: Was your father the oldest son?

TY: No, but he was a physician and the only family member who could take over my grandfather's clinic.

A: Do you have any brothers and sisters?

TY: Yes, I have one sister and one brother. My brother was interested in flower gardening but I requested him to enter medical school. He did so. When he graduated from medical school I wanted to be a pharmacologist and so I asked my younger brother to take over my father's clinic. My father used to say that either one of us should take over the clinic.

A: I suspect that in Japan the father's request is usually honored?

TY: Yes. But he knew I wanted to be a pharmacologist and that I was doing well in pharmacology, so he let me go into pharmacology expecting that my younger brother could take over his clinic.

A: So your brother took over the clinic at your request? Do you ever have any regrets about making that decision?

TY: Not at all. My brother has been very successful. He is doing very well as a clinician—much better than I would have done. He is quite lucky since he has been able to retain hard-working staff members and good patients. He expanded to double my family's houses and land holdings. He has also enlarged the clinic activities so that it provides not only treatment but also rehabilitation.

A: What is his name?

TY: Khoji Yanagita

A: You sou nd like you are very proud of him.

TY: Yes, I am.

A: How long after you got your medical degree before you came to the University of Michigan?

TY: Six years. After my first year at medical school I worked at the Central Hospital of the Japan Red Cross in Tokyo as an intern. After my internship, I returned to the department of pharmacology at my home university, where I did a series of studies on morphine physical dependence in rats and received my PhD in pharmacology. Then, in 1960, Professor Hosoya of Keio University—a close friend of Dr Seevers, professor and chairman of the University of Michigan Pharmacology Department—recommended to my boss that I should apply for a fellowship program set up by Dr Seevers to spend a couple years studying pharmacology at the department. Dr Hosoya thought that my research on physical dependence would fit in with Dr Seevers’ opiate research program at the University of Michigan. At first, my boss was reluctant to let me go because he wanted me to do departmental research. But finally, he accepted this offer so I could go to the University of Michigan pharmacology department.

A: Do you know when Dr Seevers began the fellowship program with the Japanese Pharmacology Society?

TY: It began in 1956. Fellows usually stayed for 2 years, so the first-year people and the second-year people would overlap. This helped newcomers to adjust to the USA.

‘I was the first fellow who took their family with them to the USA.’

A: You took your family with you to Michigan?

TY: That's right. I was the first fellow who took their family with them to the USA. The reason why they could not take family with them until that time was that we were limited in the amount of money we could take with us to the USA. It used to be limited to only $50 per person. So previous fellows couldn’t take their family with them. Also, the Japanese academia had a rather rigid and brutal view saying that fellows were going to study so it was not considered appropriate to take a family. But the year I went, the regulations changed and our family could have $200 per person. Further, I didn’t care about the academia's view, so I took my wife and 6-month-old child with me. Dr Seevers’ secretary Dorothy Overbeck commented later that, seeing my family, she wrote in the department records that ‘it's a new era. This is the first time that a postdoctoral fellow from Japan has brought his family with him’.

‘the Japanese academia had a rather rigid and brutal view saying that fellows were going to study so it was not considered appropriate to take a family.’

A: You came expecting to stay only 2 years but you stayed much longer. How was that possible?

TY: Yes, I came to the USA in June 1960 and stayed for 5 years. I will tell you, the Fulbright Scholarship took care of my own and my family's travel expenses to come to the USA and to go back home. But the returning support was effective only for 2 years. Since I stayed longer than 2 years, I had to give up the support. But Dr Seevers promised to take care of us, saying ‘you need not worry’. He made me an instructor in 1962 and that paid for my living expenses.

A: Tell me about your first experiences at the University of Michigan.

TY: Dr Seevers asked me what kind of research I would like to do. I told him that I was interested in studying opiate physical dependence in rhesus monkeys. At that time, it was impossible to use monkeys in Japan and I wanted to take advantage of the large monkey colony that Dr Seevers had for opiate research. In Japan, we couldn’t think of using such animals in the laboratories.

A: Was that because of the lack of facilities or was it an ethical issue?

TY: Not an ethical problem, we simply didn’t have the facilities for monkey research in Japan at that time. It was too costly and we could not obtain monkeys. Dr Seevers was pleased that I wanted to do research on opiate physical dependence. I found out later that that was his intention from the beginning.

A: But he wanted you to have the illusion that you were free to choose.

TY: That's right. But it was good guidance for me after all. And so I belonged to Dr Seevers’ research program!

A: Were you there when the drug self-administration studies started at the University of Michigan?

TY: I arrived at June 1960, and the drug self-administration studies started in 1961. Prior to that, we had attempted to get monkeys to drink morphine and methadone. Then, by the end of 1960, we found that the drinking method had definite limitations because even the morphine-dependent monkeys refused to drink methadone or pethidine, probably due to the taste or flavor. Therefore, I understood that we had to adopt a different approach. At that time, Dr Weeks, a senior colleague in the pharmacology department who was working at Upjohn Laboratories in Kalamazoo, Michigan, developed an intravenous catheterization method in rats. One snowy day in the winter, Drs Seevers, Deneau, my laboratory mentor, and I visited Dr Weeks at Kalamazoo. We saw how he did the surgery and how he had devised a way of protecting the catheter that ran from the rat to an infusion pump. We realized later that adapting the IV catheter surgery for a monkey was the easiest part. The biggest challenge was how to have them be free to move about their cage and at the same time protect the catheter. So I went to the engineering department on the campus and discussed the idea of making a restraining harness and flexible arm through which the catheter could run to the outside of the monkeys’ cage. We had a primitive sketch of the idea for the harness as proposed by Dr Seevers that had been modified a little by Dr Deneau. So I was given the job of working with the engineers to develop this restraining system. We did it and I ordered a dozen! But 3 months later, when we tried to fit the monkeys into the harnesses, we discovered that the monkeys were kind of differently shaped than we had imagined. So we had to modify our design several times so that the shoulder areas would not get sore because of the weight. But we finally got something that worked.

A: So you had a dozen harnesses that you couldn’t use. Was Dr Seevers upset?

TY: No. Dr Seevers didn’t complain that much, but he said ‘be careful’. Anyway, I finally had a harness that worked and then I developed a motor-driven injection pump.

A: After you developed this system, what was the first drug that you studied in self-administration?

TY: Morphine.

A: I’m not surprised.

TY: The next drug was cocaine. Because cocaine was a powerfully addicting drug in humans. However, it was known that it did not produce physical dependence in animals. At that time, the addicting properties of drugs were believed to be attributable to the need to avoid the aversive symptoms of the withdrawal syndrome, and self-administration of cocaine in monkeys was expected to answer this question.

A: I’ve seen movies of the animals you studied in the cocaine experiment. You might want to describe the movies that you made.

TY: Monkeys really were crazy to self-administer cocaine and took an injection about every 5 minutes. After the monkeys had been self-administering cocaine for a few days, they began to have convulsions. But the convulsions did not stop them from continuing to self-administer cocaine. Many animals died after the third or fourth convulsion. One monkey took cocaine for 3 or 4 days around the clock every 5 minutes without sleeping. But on the fifth day the monkey fell asleep for over 24 hours. After that, he woke up and ate and did not show any withdrawal signs. The monkey started taking cocaine again and over the next few days showed many signs of neurotoxicity and even hallucinations. At least they appeared to be hallucinating. They behaved as if there were insects or something on the cage floor or in the air that they kept trying to catch.

‘Monkeys really were crazy to self-administer cocaine and took an injection about every 5 minutes.’

A: Were you surprised that there were not clear-cut withdrawal signs when animals stopped taking cocaine?

TY: I knew the results of Dr Seevers’ experiment on cocaine in rhesus monkeys, but I was deeply impressed by the results that there were almost no withdrawal signs except the sleeping. I was surprised by the hallucinatory manifestation.

A: When you did these experiments, were you aware that humans took cocaine in bouts and then would crash for a few days?

TY: I knew that humans used cocaine in a similar way but I imagined that humans were more cautious in their use because they would know the possible toxic consequences of cocaine.

A: You continued to study other drugs in the self-administration model. Do you remember any particular drug that interested you?

TY: Well, one dramatic drug was pentobarbital. The monkeys took it quite often and became drowsy and would continue taking the drug until they fell down unconscious. After a few minutes, they would awaken and go back to the lever pressing for more drug injections. After the monkeys were allowed to take pentobarbital for a couple of weeks, they would have convulsions if we shut off the injectors for a few hours. The monkeys became physically dependent in only 2 weeks if they were allowed to take the drug continuously.

A: There was a Japanese drug called SPA that you did research with as well. Was it an amphetamine-like drug?

TY: No, cocaine-like. However, SPA, known as lefetamine, was much less addicting and toxic than cocaine.

A: What was its therapeutic use in Japan?

TY: It was used by injection as a treatment for shoulder pain because of its local anaesthetic properties. Unfortunately, some people began to abuse SPA. The SPA abusers were interviewed by an expert psychiatrist who found that the users thought its subjective effects were much like methamphetamine. They had no experience with cocaine but methamphetamine was a well-known popular drug of abuse in Japan.

A: Did you think when you were in Michigan that you would be able to continue primate research in Japan?

TY: No, I didn’t. Dr Seevers wanted me to continue my research studies at the University of Michigan. But I told him that I felt I should go back home and contribute my experience to new drug development in Japan. Although at the University of Michigan I did research on drugs of abuse, I also learned about pre-clinical studies for new drug development including the toxicological studies that must be done in animals before a drug is tested in humans. I knew that Japan did not have natural resources such as iron and oil but did have chemical and biological technology. Therefore, I thought that Japan should try to take a leadership role in the pharmaceutical industry. Well, as you know, we have become very productive in building ships and cars and not very competitive in the pharmaceutical industry. So much for my predictions!

A: When you returned to Japan, did you keep in touch with Dr Seevers?

TY: Yes, he was very helpful to me when I returned to Japan. He arranged for me to get a subcontract from his NIH grant so that I could start a small primate research laboratory at the Central Institute for Experimental Animals in Kawasaki. To supplement the funds that Dr Seevers provided, I started a research unit that did contract studies on drug properties such as abuse liability, toxicity, pharmacodynamics and pharmacokinetics in animals for pharmaceutical industries. I continued to do primate self-administration studies but did research with all species of animals for the work. Subsequently, the Japanese government made new regulations that mandated drug self-administration studies with all new medications that had central nervous system (CNS) effects. For over 30 years, those studies were conducted in my laboratory.

A: I have heard people in the USA say that you could not get a drug on the market in Japan unless Yanagita approved.

TY: That is not true! Only for the abuse liability of CNS-acting drugs.

A: Well, when you came back to Japan did you know that you were going to have a job? You were gone for 5 years, what did the university say about that?

TY: The university kept my position open. My boss was waiting for me to set up a laboratory and be promoted to full professorship. But when I found out that the university couldn’t handle monkeys I said, ‘I’m sorry I cannot come back to the university because I have this contract research program and I have to have a monkey laboratory’.

A: So you went to the Central Laboratory for Experimental Animals in Kawasaki in 1966 and you were there for how many years?

TY: For 30 years. I was there until 1996.

A: You worked there for 30 years and you had support from the pharmaceutical companies for whom you did research?

TY: Yes. But also I was supported in part by the government.

A: Did the government support you for basic research or for applied research?

TY: Funds from the Ministry of Education were for basic research, and those of the Ministry of Welfare and Public Health were rather for applied research.

A: Were there many people who were trained in your laboratories?

TY: Training was not our major focus, but we did have more than 10 post-doctoral fellows from Japan as well as from other countries.

A: Did you maintain a position at Jikei University during those years?

TY: Yes, I gave a lecture over there several times a year. In 1992, I became a part-time professor.

‘When I opened up my laboratory in 1966 it was the only contract laboratory for pharmacological and toxicological studies. In 1996, there were about 50 laboratories.’

A: Why did you retire from the Central Institute? Is there an age in Japan when you must retire?

TY: There was no age limitation. The major reason was it became more difficult to maintain the laboratory. That is, because of the hard competition it became more difficult to continue the basic research and I tended to do only the contract studies. When I opened up my laboratory in 1966 it was the only contract laboratory for pharmacological and toxicological studies. In 1996, there were about 50 laboratories.

A: Are there any laboratories in Japan where dependence studies are done today?

TY: Yes, when I closed my section at the Central Institute I moved all the dependence facilities and monkeys and also the lab staff in my group to where I am working today.

A: Is that at the university?

TY: No, that is a private contract laboratory called Ina Research, Inc. ‘Ina’ is the name of a city in the Nagano Province, where the company's main laboratories are located.

A: Do you go there often?

TY: Once a month for 2 days for face-to-face meetings and discussions with lab staff. Although it is only once a month, I am in daily communication by mail or e-mail. I check all study protocols, experimental data, progress reports and final reports to be submitted to the sponsors.

A: Your office here in Tokyo is at the university?

TY: No, it's in the Tokyo office of Ina Research, Inc.

A: So is the research you conduct at Ina your primary work these days?

TY: That's right, excluding the days that I have lectures or meetings. All my personal belongings, including the books, computers and all the rest of the equipment that I need, are there. So that's my main office. At the university I have a shared office.

A: I would be interested in your thoughts about Dr Seevers and his role in both your life and in Japanese pharmacology. Addiction never interviewed Dr Seevers and it would be interesting to hear your reflections about him, as I know that you feel he was an important person in your life.

TY: Yes indeed! I think he was a kind of Uncle Sam to Japanese pharmacology. After the war, he came to visit Japan as an American delegate to provide medical education. Many people came for training, particularly pharmacologists. At that time, Japan was in the post-war turmoil and coming into a new era. So the American mission had a special importance. All Japanese people, particularly in the medical field, had the highest regard for them. Dr Seevers wanted to help Japan to be restored in medical training and research, particularly in his specialty of pharmacology. He visited Japan three times with the same mission. He thought the best way to help Japan develop in the area of pharmacology was to provide the best training for young pharmacologists in the USA. So he set up a program to provide 2 years of training in the department of pharmacology at the University of Michigan. He solicited funds from both the pharmaceutical industry and the federal government to cover the expenses of Japanese post-doctoral Fellows to study in his department. He made a major contribution to the advancement of pharmacology in Japan as well as in the USA.

A: I’ve been told that when Dr Seevers would come to Japan he would be treated very well because he had provided this training for so many years to so many people.

TY: Over the years, about 40 Japanese pharmacologists came to study at the University of Michigan. Most of them became professors and chairmen of pharmacology departments. They became known as the Michigan Group and were considered very prestigious. There was some degree of jealousy from those who did not get to go to Michigan.

‘Over the years, about 40 Japanese pharmacologists came to study at the University of Michigan.’

A: The Japanese academic system is reputed to be rigid and authoritarian. What was your experience as a young academician? Has the system changed today?

TY: In a word, the chairman of a medical school department was the almighty person—‘god’—and the university could not interfere with him in any way. The university appoints a professor but once appointed they cannot terminate them. The professor can award PhD degrees to those on his faculty whose research is deemed worthy of this honor. The professor also determines where you will work. If he doesn’t like you, he can send you to a low-prestige place to work. The absolute authority of the professor is a long-observed tradition in Japan. The competition for becoming a departmental chair is intense. Universities compete to get one of their faculty members appointed. This extends their sphere of influence. Usually, the top-ranked university has the prestige to recommend who will become the next chair in other universities. But things changed a lot. Nowadays, it's not quite this way. If a chair is too authoritarian, promising young researchers will not go into that department. Times have changed since I was a young pharmacologist.

A: Dr Yanagita, you have had an incredible career of over 45 years as a pharmacological researcher, scholar and policy maker. In retrospect, are there things that you would have liked to do differently?

TY: Well, I was not certain whether I should go into medical practice or do pharmacological research. But pharmacology was certainly fun! I would have got bored treating patients with common diseases every day. So I decided to go into pharmacology and give my father's clinic to my younger brother. And I never regretted this decision. For me, I got the best end of the bargain! I have had very good fortune. The fact that I could go to Dr Seevers’ laboratory and do drug dependence studies was marvellous luck. It gave me the ability to study toxicology in a unique way—the psychotoxicity of drugs at doses the animals self-administered. I was able to support my research here in Japan for over 45 years. So I have no regrets. I am quite satisfied.

A: Do you intend to stop working soon?

TY: Not totally. I am, again, very lucky that I can work as much as I want, sometimes a little more than that, but generally I do as much as I want to do. Yes, so long as I can work I will continue to work. Fortunately, I have a good staff. They are good people and seem to be happy with me and give me all kinds of privileges. So I work for Ina Research, Inc., half of the time and the other half of my time I spend in scientific activities, public service, writing and working with professional societies.

A: We all look forward to your continuing contributions to science and policy.

TY: Thank you very much!