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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. Lou Harris has played crucial and varied roles as a pioneer in the drug research field and has also done much to advance the careers of others. He has brought to pharmacological research a keen understanding of the role of the chemist.

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EARLY INFLUENCES

  1. Top of page
  2. EARLY INFLUENCES
  3. PHD TRAINING AND EARLY RESEARCH INVOLVEMENTS
  4. THE MOVE TO INDUSTRY
  5. EXPANDING HORIZONS
  6. THE MOVE TO CHAPEL HILL
  7. ‘DOING FANTASTIC THINGS’
  8. CAREER MOVE TO THE MEDICAL COLLEGE OF VIRGINIA
  9. NETWORKS OF INFLUENCE AND A LAPEL PIN
  10. References

Addiction (A): What forces directed you toward science?

Lou Harris (LH): As a kid, I was always interested in science. My parents bought me chemistry sets. I had a microscope and I had a small laboratory in the house. I was driven by curiosity about nature. I started high school in the 10th grade in 1942 and I graduated in 1944 from Boston Technical High. We were in an era that was quite unsettled due to the Second World War. I think my interests were always driven towards chemistry or medicine. As a volunteer at the Beth Israel Hospital, I was doing differential blood counts when I was only 15 years old. We were not a wealthy family, but middle-class. My father was in the wholesale produce business, so we always ate well but we were restricted in luxuries. So, I worked early on, in the family business with my father and my uncles.

‘As a volunteer at the Beth Israel Hospital, I was doing differential blood counts when I was only 15 years old.’

A: In what kind of role?

LH: I was about 16 when I took a part-time job in Filenes Department Store as a bundle boy after school and worked up to the point that I was actually going around collecting cash from the cashiers. It was a bonded position and unusual for a young kid like me. But then again, there was a war. There were not many people around, particularly males. I started working at the Harvard Medical School in the Department of Pharmacology as an animal caretaker in 1943. I worked there continuously to 1950. I also spent some time as a substitute teacher in my high school. The chemistry teacher was drafted and I took over supervision of the chemistry laboratory for the rather unskilled person that replaced him.

A: So your first experience in science was while you were still a high school student?

LH: Right, and I worked there until I started college at Harvard in 1950. It was actually 7 years that I worked there full time. It was quite an experience because, again in the early days, Harvard Medical School was a military base. Students in the army or navy were doing medical school in a little over two-and-a-half years. It was run like a military base. It was completely locked down all the time. Avram Goldstein was one of the many students who was in the service. He was in the navy. The place was filled with people who later became extremely well-known and productive scientists. Otto Krayer was the chair.

A: When did he come?

LH: He came in the late 1930s. He was on his way from the American University of Beirut to take a position at Peking Medical University in China as chair of the department there and stopped at Harvard to give some lectures, which he had undertaken very successfully the year before. The students liked him so much that they petitioned the medical school to hire him as chair. The chair was open because Reid Hunt, the former chair, the acetycholine scientist, became schizophrenic and had to be institutionalized. Surprisingly, they did make Krayer acting chair and associate professor of pharmacology. The pharmacology department was full of people. who represented the leading edge of pharmacological research.

A: Did you report to Krayer when you started as a high school student?

LH: Yes. He ran the department. In any case, I received a great deal of laboratory experience working with many different people in the department.

A: Was a career in pharmacology your goal when you started college?

LH: No, actually towards the latter part of my stay in the pharmacology department, an organic chemist by the name of Fred Uhle came onto the scene and I had this great interest in chemistry and started working pretty much for him. At the same time, I was doyen (head technician) of the department and took care of much of the general technical operation of the department.

A: Was Uhle in pharmacology?

LH: Yes, Uhle was in pharmacology. Reid Hunt strongly believed it was important to have a chemist in the department and Otto Krayer continued this tradition.

A: You did not yourself serve in the military?

LH: I could not get into the military because I was so myopic. I wanted to go to college but my mother had become seriously ill, and only when she died in 1950 was I relieved of that responsibility. At the urging of Uhle, Krayer, and the whole department, I applied at several colleges and was accepted at Harvard as a chemistry major. When I graduated from college, I came back to the department as a PhD candidate. My principal mentor was Uhle.

PHD TRAINING AND EARLY RESEARCH INVOLVEMENTS

  1. Top of page
  2. EARLY INFLUENCES
  3. PHD TRAINING AND EARLY RESEARCH INVOLVEMENTS
  4. THE MOVE TO INDUSTRY
  5. EXPANDING HORIZONS
  6. THE MOVE TO CHAPEL HILL
  7. ‘DOING FANTASTIC THINGS’
  8. CAREER MOVE TO THE MEDICAL COLLEGE OF VIRGINIA
  9. NETWORKS OF INFLUENCE AND A LAPEL PIN
  10. References

A: What caused you to go from chemistry (as an undergraduate) to pharmacology?

LH: Well, the PhD in pharmacology was just natural. I just continued working for the person I was working for. I worked all the time I was in college. I had to work. I had scholarship help but I had to have extra money, so I worked all through college. In 1951 and 1952, I worked at the Massachusetts General Hospital in Henry Beechers department (anesthesiology).

A: Was Beecher a part of pharmacology?

LH: Beecher had an appointment in pharmacology. I was conducting clinical chemistry on the affects of anesthesia on patients with liver damage. They were mainly alcoholics that had bleeding esophageal varicies. The protocol was well controlled because all the surgeries were held in the White Building, which was the research building, and the study was carried out by the same surgeons, physicians and anesthesiologists. What we did was typical clinical research for those days. We took large blood samples before, during and after the operations and measured everything we could measure. We were performing Van Slykes with hand-driven instruments. There were no automated machines at that time.

A: Was Dr Beecher the head of this study?

LH: There was another person, John Bunker, who headed that study. The interesting thing about it was that we collected huge amounts of data but it was not hypothesis driven. They just collected data hoping they might find something meaningful. This is not the way to do clinical research. At the same time that I was there, there was a very bright young resident named Lou Lasagna, who started a study prompted by Nathan B. Eddy. I had nothing do with that study but I was there and there was great interest in the study. There was a close relationship between the anesthesiology department and the Committee on Narcotics and Drug Addiction, which later became the College on Problems of Drug Dependence. Scientists from Merck had come to Eddy with an idea. They had conducted a great deal of laboratory work where they thought that they could put together mixtures of the narcotic antagonist nalorphine and morphine, such that they could block the respiratory depressant effects of morphine but would leave the analgesia intact. And so Eddy came to Beecher to ask if he could test this clinically and Beecher gave the project to Lasagna. They set up a study running in 1952–53 where they were measuring postoperative pain. They were giving placebo, morphine and morphine plus nalorphine, and measuring respiratory function in addition to analgesia. Lasagna was bright enough to add nalorphine alone as a secondary control. When they looked at the results, there was absolutely no difference between morphine alone and morphine plus nalorphine on the separation between the respiratory depressant effects and analgesia. The startling thing observed was that nalorphine, by itself, was equally potent with morphine as an analgesic. That was a very important finding, because nalorphine had already been studied by the Michigan group in the dependent monkey and it had also been studied in man at Lexington. It did not support dependence. It actually precipitated withdrawal and did not have a profile of subjective effects typical of an opiate. That was the clue that we used much later to postulate that opiate antagonists might lead to non-dependence-producing analgesics.

‘They just collected data hoping they might find something meaningful. This is not the way to do clinical research.’

A: In terms of your career, was that the first time that you were involved with the pharmacology of opiates?

LH: That was the first time.

A: What was the project for your PhD thesis?

LH: The synthesis of lysergic acid and later the pharmacological evaluation of a number of unique substances which resulted from the chemistry.

A: Anything to do with drug abuse?

LH: Nothing to do directly with drug abuse. Just chemistry of the compounds. We failed in the synthesis of lysergic acid because we did not have the right single step, which was discovered by Bob Woodward, in the chemistry department at Harvard and his colleagues at Eli Lilly. What I had was some very interesting chemistry and ended up with a number of betacarbolines, substances which were related to harmine and harmaline—natural products, described as hallucinogens. My compounds, like the natural products, proved to be potent 5-HT antagonists. When I completed the chemical portion of my thesis, I had two publications in the Journal of the American Chemistry Society[1,2] but when I handed in the thesis, which was a typical organic chemistry thesis, Krayer called me in and said, ‘But Lou, you’re getting a degree in pharmacology. There's no pharmacology in this’. I went back to do some laboratory work, essentially isolated organ work on the guinea pig ileum and rat uterus [3]. Sure enough, these betacarbolines produced some very potent 5-HT antagonist effects. At the same time Peter Dews, from England, came to the department and was appointed assistant professor. He was interested in many aspects of behavioral pharmacology. He brought with him operant conditioning and also a photocell cell activity cage. I began testing these compounds, both from the point of view of observational and behavioral pharmacology with operant techniques. I conducted sleep time, barbiturate potentiation and activity cage studies. It emerged that these compounds were very interesting, because they potentiated both stimulants and depressants. That paper, which included operant pigeon studies, was published in the Journal of Pharmacology and Experimental Therapeutics[4]. That was essentially my thesis—synthesis of these compounds and some pharmacological activity.

A: So what next, with your thesis completed?

LH: We were strapped for money. I was married as an undergraduate. By the time of my graduate studies, I had a child and was awarded a National Science Foundation (NSF) predoctoral fellowship and my wife was working. When my PhD finished, Krayer said he wanted me to carry out typical postdoctoral work. He sent me to visit the laboratory of George Koelle. He and his wife were not then in the pharmacology department at the medical school. He was chair of the department in the graduate school and his laboratories were located in the basement of one of the dormitories. It was not very impressive. Great work was coming out and I was offered a typical postdoctoral fellowship. I think it was something like $3000 or $5000. Louis Fieser, the head of the chemistry department at Harvard, wanted to know what I was going to do.

A: He was a chemist?

LH: Yes. We had become very close because of a variety of things on which we worked collaboratively. He recommended Max Tishler at Merck. Al Farrar had also been in the Harvard pharmacology department, but was then at Syracuse; he thought that I should go to Sterling Drug. He was a consultant at the Sterling Winthrop Research Institute. So we set up meetings and I went to visit both companies. Merck offered me a very fine position but only as a chemist. Sterling offered me a comparable position but only as a pharmacologist. It was a time in history when Woodward, at Harvard, was rapidly expanding the chemistry of natural products, mainly medicinal in nature, and I thought there was not a great deal of future left in organic chemistry of the type that interested me. I was greatly interested in the area of central nervous system (CNS) pharmacology, a field that was expanding rapidly at that time. So, I went to Sterling.

THE MOVE TO INDUSTRY

  1. Top of page
  2. EARLY INFLUENCES
  3. PHD TRAINING AND EARLY RESEARCH INVOLVEMENTS
  4. THE MOVE TO INDUSTRY
  5. EXPANDING HORIZONS
  6. THE MOVE TO CHAPEL HILL
  7. ‘DOING FANTASTIC THINGS’
  8. CAREER MOVE TO THE MEDICAL COLLEGE OF VIRGINIA
  9. NETWORKS OF INFLUENCE AND A LAPEL PIN
  10. References

A: Did you start Sterling in the drug abuse area?

LH: No, I started Sterling in the area of psychotherapeutic agents. It was at that time, of course, that Bill Dewey showed up as a technician. We had a major tranquilizer in advanced preclinical study, and several others were coming along. We also had some very interesting stimulants [5]. I think in that area at one time, we had three to four compounds in the clinic at the same time.

A: Dave Wiley was the head of CNS?

LH: Yes, I was responsible for stimulants and depressants. The analgesics were under Leonard Grumbach. When he decided to go back to academia, that area also was assigned to me. We were operating at that time with what was a relatively new concept called ‘program project teams’—consisting of a chemist, a pharmacologist, biochemist, toxicologist and a clinician. Wiley left in 1961 and I took on the entire CNS area.

A: So what was going on at Sterling when you arrived?

LH: Analgesics were very fascinating. We, early on, had a project team meeting to discuss the current status of the project. For decades, the chemists at Sterling were synthesizing meperidine derivatives. They had prepared more than a thousand of these compounds. We had developed test methods (tail-flick and hot-plate) that were very predictive of clinical activity. Even at that time, we had compounds in the meperidine series that were a thousand times more potent than morphine. The problem was that we never reached the objective of the program, which was to produce non-dependence producing analgesics; so I sat down and conducted a correlation study. Remember, this was prior to the extensive development of the concept of opioid receptors. We had eight compounds in which we had extremely good quantitative data in the tail-flick, hot-plate, analgesic activity in man and dependence liability both in animals and man. There was, just as we had known, a very high (0.93) correlation between the tail-flick, and hot-plate tests and analgesia in man. The correlations that emerged to be highest were between the tail-flick and the hot-plate tests and addiction potential (0.95).

A: How did you take things forward?

LH: At a later meeting of this project group, I presented my data and said that we were wasting our time. We were testing and bringing compounds to the clinic with a high probability that we were going to fail. The discussion came around to what direction could we go in. That was when my experience at the Mass General came into play. I told them that there were data out there—Lasagna had conducted a study and Keats repeated the study, showing that the narcotic antagonist nalorphine was a potent analgesic. It had also been shown in animals and man that nalorphine had essentially no opioid abuse potential. The only problem was that nalorphine had a pretty high incidence of psychotomimetic activity associated with it. My plea was if in all these years we failed to remove dependence liability from analgesia, we should be able to more easily remove the psychotomimetic activity from the analgesia. So we embarked on a new, large project. First of all, we did all the same tests but anything that was positive in the tail-flick and hot-plate tests was thrown out and we developed a quantitative assay for opioid antagonists.

A: And a burgeoning of new compounds?

LH: We began synthesizing narcotic antagonists. We were collaborating very closely with the College on Problems of Drug Dependence (CPDD) and National Institutes of Health (NIH) people and we began to produce some interesting compounds.

A: Co-operation with other groups?

LH: Everette May was very helpful through consulting on the synthetic chemistry at Sterling and we began making a number of benzomorphan derivatives. For instance, there was a large number of isomers isolated that had a very interesting pharmacology. In any case, we sent the 5-ethyl-N-allyl compound, a potent antagonist, to the clinic. Arthur Keats carried out the first study in man and it turned out to be equally potent with morphine as an analgesic, but it was hellishly psychotomimetic. The term ‘psychotomimetic’ associated with these compounds was a rather different one. The biggest problem with these compounds was that they produced what people described as a sense of impending doom. It was a very strange thing. They were not having hallucinations or the usual LSD type of symptoms. In any case, that was a potent antagonist. The next compound we sent to the clinic was a weak antagonist. That was a dimethylallyl compound (WIN 20228), which later became pentazocine. This compound was also sent to Dr Keats for evlauation (evaluation) [6].

‘The biggest problem with these compounds was that they produced what people described as a sense of impending doom. It was a very strange thing.’

A: What did he conclude?

LH: In his controlled double-blind clinical trial, he found good analgesia with a potency somewhat less than morphine with no reports of psychotomimetic activity. We were very, very excited about the compound because studies at Michigan and Lexington indicated that it had little or no dependence potential. We continued to work and synthesized and studied the N-cyclopropylmethyl compound [7]. That was a rediscovery of the use of the N-cycloproypl group in the analgesic area.

A: How did the cyclazocine story develop?

LH: Cyclazocine went to Lou Lasagna for the first clinical testing, which was used in postpartum pain. It turned out to be an extremely potent analgesic [8]. It had very few psychotomimetic effects associated with it at the dose they were using. We were very keen about the compound because, again, it went through Lexington and Michigan and was a very potent antagonist with little indication of dependence liability. The compound had a great deal of clinical work conducted on it. The obstetricians loved it. It did not produce any respiratory depression either in the mother or the baby.

A: Cyclazocine looked like being clinically useful in the treatment of opiate dependence?

LH: Yes. It was at that time that Bill Martin, at Lexington, together with Abe Wickler, postulated that if you could extinguish drug-seeking behavior, then the addicts would stay off the drugs. Bill Martin proposed that what we should do was to completely withdraw heroin addicts: give them large doses of an antagonist and then let them go out in the community to test heroin injections. They would gain no effect as there was an antagonist on board. After repeatedly gaining no effect, their drug-seeking behavior would cease. He picked cyclazocine for this [9]. Nalorphine and levorphan were the only two others that were available. Naloxone and naltrexone were not available at that point. Cyclazocine was ideal, because it had the property of good oral bioavailability and was long-lasting. He began raising the dose of cyclazocine in these addicts and he could show very quickly that he could completely block morphines activity, but as he raised the dose to 10 or 20 times the dose that was analgesic, he began to obtain psychotomimetic effects. This information spread through the addict and therapeutic communities very quickly. The drug was killed at that point because of the psychotomimetic activity.

EXPANDING HORIZONS

  1. Top of page
  2. EARLY INFLUENCES
  3. PHD TRAINING AND EARLY RESEARCH INVOLVEMENTS
  4. THE MOVE TO INDUSTRY
  5. EXPANDING HORIZONS
  6. THE MOVE TO CHAPEL HILL
  7. ‘DOING FANTASTIC THINGS’
  8. CAREER MOVE TO THE MEDICAL COLLEGE OF VIRGINIA
  9. NETWORKS OF INFLUENCE AND A LAPEL PIN
  10. References

A: Despite that setback to your work?

LH: We undertook a great deal of interesting work and at one time had 12 compounds in clinical trial at the same time. That was before the new Food and Drug Administration (FDA) regulations made things much more difficult. In the analgesic area we worked very closely with Nathan Eddy and the Committee at that time [10]. We had embarked on a large new research program.

A: The next questions that attracted your attention?

LH: In the early 1960s, a young chemist from Arthur D. Little showed up at our door with an interesting proposal. The federal government, under the philosophy of John Kennedy, had decided that the United States was going to wage humane warfare. They were going to lessen the reliance on atomic bombs and killing people. What they started was called an ‘incapacitating agent program’. The commander in the field was supposed to be able to look over and say: “Theres the enemy over there”, and could drop some sort of munition which would incapacitate but not kill them. They would quickly revive and be taken off to interment camps. Edgewood Arsenal was set up as the base for this research and a number of request for proposals (RFPs) were put out and the government was interested in getting supplies of the active principle of marijuana. Arthur D. Little had worked out a large-scale extraction process using large columns to separate out the material. That was their tie to the incapacitating agent project, as the active principal of marihuana was one of the priority agents.

‘The commander in the field was supposed to be able to look over and say: “There's the enemy over there”, and could drop some sort of munition which would incapacitate but not kill them.’

A: And your group became involved?

LH: Arthur D. Little approached us to see whether we would become partners with them. When the Arthur D. Little people approached us we had an anticholinergic compound which was extremely safe and potent, as well as the analgesic agonists and antagonists, major tranquilizers and stimulants, which could fit into an incapacitating agent program. Arthur D. Little had entered into the marihuana field which we greatly desired to pursue. Thus, we started a joint program, which included cannabinoids, anticholinergics, opiate agonists and antagonists, stimulants and major tranquilizers. All the work was conducted under security clearance and the project continued at Sterling after I left, but my contact with Arthur D. Little and the program continued at North Carolina, where I had a security-cleared facility.

THE MOVE TO CHAPEL HILL

  1. Top of page
  2. EARLY INFLUENCES
  3. PHD TRAINING AND EARLY RESEARCH INVOLVEMENTS
  4. THE MOVE TO INDUSTRY
  5. EXPANDING HORIZONS
  6. THE MOVE TO CHAPEL HILL
  7. ‘DOING FANTASTIC THINGS’
  8. CAREER MOVE TO THE MEDICAL COLLEGE OF VIRGINIA
  9. NETWORKS OF INFLUENCE AND A LAPEL PIN
  10. References

A: What prompted you to leave Sterling?

LH: For one thing, I missed the academic life, particularly the training of graduate students. While Sterling pharmacologists were involved in giving lectures at Albany Medical College, there was little other interaction. In addition, I was beginning to get a little restless because the only way you could advance in industry, at that time, was to go up the administrative ladder and I thought I had much more to accomplish scientifically. One of my thesis committee members at Harvard, Paul Munson, took over as chairman of the pharmacology department at the University of North Carolina (UNC). He knew I was restless. Krayer also knew I was ready to return to academia, so they convinced me to join the University of North Carolina at Chapel Hill School of Medicine as an associate professor of pharmacology.

A: That was in 1966.

LH: Well, I actually got down there the end of 1965, before Christmas. It was there that Munson had decided to create a department that was going to be first-rate. There was no graduate degree granting ability in pharmacology. The former chair did not believe that a PhD in pharmacology was a legitimate degree. His opinion was that you gained an MD degree and went out and obtained research experience. Paul Munson had different ideas and planned a strong doctoral program. He also planned to create a department that was divided into divisions and I was, of course, to head the CNS division. It was at that point that I began recruiting people into the program as faculty members to support this division.

A: What was the major research interest at that time?

LH: The major research interest was still analgesics. We were not allowed to take anything of the Sterling research to UNC.

A: You continued to be interested in narcotic antagonists?

LH: Yes. First of all, one of the key things we found at Sterling, which later turned out to be the key in discovering endogenous opioid systems, was the electrically stimulated guinea pig ileum. I had gone through the literature and found that Peyton and Schaumann had both published papers on the activity of opiates on the guinea pig ileum. I ran a huge series of compounds, including isomers, and showed a very high correlation between the effects of opioid antagonists in the guinea pig ileum and analgesia in man [11]. At that time, except for the postulation that there were multiple receptors, there was very little known about receptors. We had the hypothesis of multiple receptors from Bill Martin at Lexington about the possibility of mu, kappa and sigma receptors. Mu was morphine, kappa was ketocyclazicine, which was one of the early compounds that we had and were very excited about and sigma was for SKF10,074. Our hypothesis was that these compounds were working through neurochemical systems in the brain that we already knew about (adrenergic, 5-HT and cholinergic systems). We expended a great deal of effort and produced a great deal of good science on interactions between opiate agonist, antagonists and the cholinergic system, the adrenergic system and the 5-HT (serotonin) systems in the brain [11].

A: Did you have funding?

LH: Well, Sterling had promised me money but they reneged on the promise to get me started. I did receive an initial small grant from the CPDD. I applied to NIH and received the first grant on narcotic antagonists from the National Institute on Neurological Diseases and Blindness (NINDB). The National Institute on Drug Abuse (NIDA) did not exist at that time. We also had some funds from Arthur D. Little to support the incapacitating agent program. I then applied for NIH support for cannabinoids and received the first cannabionoid research grant that was given by NIH.

‘DOING FANTASTIC THINGS’

  1. Top of page
  2. EARLY INFLUENCES
  3. PHD TRAINING AND EARLY RESEARCH INVOLVEMENTS
  4. THE MOVE TO INDUSTRY
  5. EXPANDING HORIZONS
  6. THE MOVE TO CHAPEL HILL
  7. ‘DOING FANTASTIC THINGS’
  8. CAREER MOVE TO THE MEDICAL COLLEGE OF VIRGINIA
  9. NETWORKS OF INFLUENCE AND A LAPEL PIN
  10. References

A: And from that base you were able to do good work?

LH: In the period 1968–69 we were doing fantastic things. No one had conducted any real pharmacology on cannabinoids and we had an excellent supply of Δ9-THC through Arthur D. Little and the Sheehan Institute and Sharps Associates (SISA) group. We had a variety of newly synthesized compounds which permitted extensive structure activity studies [12,13]. We had isomers which allowed stereospecific studies, which led later to an early postulation of a cannabinoid receptor [14]. We discovered the phenomenon of tolerance. At the time we started working in the area, it was believed that marijuana produced reversed tolerance. That is, one became more sensitive to its activity as you used it for prolonged periods. We completely shot that down and found a remarkable tolerance, particularly in behavioral studies [15]. We carried out tolerance in a number of species and demonstrated that it was not metabolic tolerance; not like the barbiturates. These studies continued unabated after our move to the Medical College of Virginia [16,17].

‘At the time we started working in the area, it was believed that marijuana produced reversed tolerance . . . We completely shot that down.’

CAREER MOVE TO THE MEDICAL COLLEGE OF VIRGINIA

  1. Top of page
  2. EARLY INFLUENCES
  3. PHD TRAINING AND EARLY RESEARCH INVOLVEMENTS
  4. THE MOVE TO INDUSTRY
  5. EXPANDING HORIZONS
  6. THE MOVE TO CHAPEL HILL
  7. ‘DOING FANTASTIC THINGS’
  8. CAREER MOVE TO THE MEDICAL COLLEGE OF VIRGINIA
  9. NETWORKS OF INFLUENCE AND A LAPEL PIN
  10. References

A: So your laboratory at UNC had two major focuses—one on narcotic antagonist analgesics and one on cannabinoids?

LH: Yes. At that point, NIDA was created and came out with an announcement for center grants. We put together what I thought was a very fine center grant from North Carolina. It went through review but at that time, I decided to move to the Medical College of Virginia (MCV). I did not think it was ethical to leave the center grant in review when I and much of the research group were moving to another site. So I withdrew the center grant and at the behest of NIDA, resubmitted much of it as an R01 with a different cast of characters. It was a very large R01 because the center program ended by the time we were settled in. In any case, they approved the grant and that supported a very large program in the area of CNS pharmacology at the MCV.

A: That grant was funded shortly after you arrived at MCV.

LH: Right. It gave a remarkable opportunity. It permitted us to build up a large group here at the MCV. Bill Dewey, of course, came with me. Billy Martin completed his doctoral research at MCV, went to Europe and returned as a faculty member. Bob Balster and Mario Aceto, who was with me at Sterling, were recruited. In addition, we had a very close relationship with the College on Problems of Drug Dependence. In 1973, Dr Seevers was about to retire at Michigan. That was where the animal dependence testing facility for the opiates and other drugs was located. Dr Eddy and the committee were concerned that the facility might be shut down because the university was not overjoyed with it. They asked me whether we could set up a parallel testing facility at MCV and thus we established a colony of dependent monkeys at MCV. Michigan scientists were extremely helpful, and it was at that point that we recruited Mario Aceto to be in charge of that program. Mario went to Michigan to learn how to carry out the work. We trained some technicians and the colony was set up. At that same time, we began to set up other testing facilities such as self-administration and drug discrimination. We obtained a contract from NIDA to maintain a colony of morphine-dependent monkeys and support a testing procedure that included analgesic agonist and antagonist testing, self-administration drug discrimination and others. This work was carried out as a contract to test compounds that were submitted from the various regulatory agencies [NIDA, FDA, DEA and the World Health Organization (WHO)], the pharmaceutical industry and academia [18]. We also started a very large graduate program. We repeated our experience at North Carolina. Our interaction with the College on Problems of Drug Dependence was increased because we had an excellent rapport with the organization—starting at Sterling, going to North Carolina and then coming to MCV/VCU (Virginia Commonwealth University).

A: Tell us more about your interactions with CPDD over the years.

LH: I first attended a meeting of the Committee on Drug Addiction and Narcotics in 1961 as a drug manufacturers representative from Sterling Drug. Subsequently I was involved in many different ways. In 1990, I became Chair-Elect of CPDD and Chairman in 1991, when the organization became the College on Problems of Drug Dependence. In 1992 I was past-chair, and in 1993 had no official role other than continuing to edit the proceedings. This continued to 1999, when I was again elected to the Board and became President-Elect in 2001, President in 2002 and Past-President in 2003. In 2002, I stepped down as editor of the proceedings and was replaced by Bill Dewey. My formal relationships with the College Board ended in 2004.

NETWORKS OF INFLUENCE AND A LAPEL PIN

  1. Top of page
  2. EARLY INFLUENCES
  3. PHD TRAINING AND EARLY RESEARCH INVOLVEMENTS
  4. THE MOVE TO INDUSTRY
  5. EXPANDING HORIZONS
  6. THE MOVE TO CHAPEL HILL
  7. ‘DOING FANTASTIC THINGS’
  8. CAREER MOVE TO THE MEDICAL COLLEGE OF VIRGINIA
  9. NETWORKS OF INFLUENCE AND A LAPEL PIN
  10. References

A: Let us discuss interactions with individuals and groups which were initiated while at North Carolina and helped to formulate the development of the department at MCV.

LH: Early on in North Carolina there was a great deal of interest in LSD and other psychotomimetic compounds. At that time, it was decided by the government to institute regulations that LSD, even for animal work, had to have a human IND. Sandoz, who owned the compound, decided that they would no longer provide supplies of the drug, so they told the US government ‘if you want to do research on this stuff that's fine. Well provide you the supplies and you decide whos going to get it. Thus, NIMH and the FDA set up an IND system and a Psychotomimetic Advisory Committee [PAC] was established. Jonathan Cole chaired it and I served on it from the beginning. The governing body was the NIMH. It started with LSD, but it soon grew to include psilocybin and a number of other hallucinogens such as mescaline, which were being widely abused. Somewhat later the committee also became responsible for the distribution of Δ9-THC, the active principle of marijuana.

A: Were you involved with WHO at that time?

LH: No, the WHO interaction started much later. I can remember one time while serving on the PAC, I received a call from Nathan Eddy asking me or telling me that he had heard that I was going to an international meeting in Europe (Amsterdam). Some months before that, Eddy had called and asked me whether I would join him and Dr Seevers at a meeting of an organization in Montreal, Canada. I went to Montreal, where there was a meeting of the International Narcotic Officers Enforcement Association (INOEA). I made a short presentation and answered numerous questions. Eddy insisted that I join this organization; and so I became a member of INOEA. They issue a lapel pin. When he called me about going to pick up the package in Milan, he told me to make sure I wore that lapel pin when I went through customs so they would not open my luggage. I delivered the package to him in Washington. I asked him what it was. He said it was 1 kg of lysergic acid, the precursor of LSD (which was an enormous supply). They supplied the whole research community with LSD out of that sample.

‘he told me to make sure I wore that lapel pin when I went through customs so they would not open my luggage.’

A: You became interested in control issues?

LH: In 1971 the United Nations initiated the creation of the 1971 Convention on Psychotropic Substances. The Single Convention on Narcotic Drugs covered only opiates, cocaine and coca leaves and cannabis, and represented the only international control of abused substances. However, one of the things that was lacking in the Single Convention was all the new abused substances that were introduced in the 1960s. We began having world-wide problems with amphetamines during that period, as well as new barbiturates, meprobamates, the benzodiazepines and LSD and other hallucinogens. The structure of the active principal of marijuana was identified. None of this fitted into the Single Convention, so they initiated the Psychotropic Convention to cover all the newer substances that were not covered by the Single Convention. At the same time, the United States was in the process of modifying its drug abuse laws. My interests in the US law were grounded in the fact that there was no provision under the Single Convention for scientific input into control decisions. We did a great deal of lobbying. I appeared at a senate hearing to lobby for the inclusion of a scientific basis into the Controlled Substances Act for scheduling of drugs. We won that battle.

A: What was the role of the United States in controlling substances at that time?

LH: There was no DEA at that time; it was the Bureau of Narcotics and they were governed by the international treaties and a variety of congressionally mandated individual laws. There was no overarching US law to cover the field. When the law was passed, control shifted from the Treasury Department to the Justice Department. The science section was delegated to the Secretary of Health, Education and Welfare, now Health and Human Services. He had under his perview the NIH and FDA, and he made the decision to delegate the authority for science and public health to a combination of NIDA and FDA. At the same time, similar language was incorporated into the UN Convention. In that case, WHO was given the role for scientific and public health input. In order to do this, WHO utilized their Expert Committee on Drug Dependence (ECDD). I was an appointee to the ECDD and personally involved with most of their meetings from 1977 to 1994 often as chairman or rapporteur [19].

A: We were talking about how the relationship with the various scientific organizations such as the WHO, etc. affected the decision to seek funding in this department.

LH: I think that my participation as a consultant at the WHO, the FDA and the multi-disciplinary grant and testing program from NIDA had a large influence on my department. However, when I came to VCU, we created the department much as in UNC along divisional lines.

A: You also had a strong involvement with NIDA?

LH: Yes. Shortly after Bob Schuster took over as director of NIDA, he was confronted by a dramatic increase in research funding by the Institute. It became apparent that the staff lacked the personnel and managerial skills to handle the very large increase in grant applications. Bob then asked me to spend a year at NIDA to help in the situation. I did so and we managed successfully to have all the grants reviewed on time and all the paperwork completed to add a significant number of new investigators and research directions to the Institutes portfolio. I then continued to act as Senior Scientific Advisor to the Director under both Bob Schuster and Alan Leshner.

A: Would you talk a little about how the NIDA testing facility was a benefit to the department, or how its development was attractive to recruit scientists interested in this field?

LH: While the department had the multi-disciplinary grant, extensive support for marijuana research, the testing program, and particularly having primates available, was a key to attracting people to join our faculty. Bob Balster came, I believe, in 1974. He was attracted, in major part, by this program. He had been one of the pioneers in setting up self-administration studies in the monkey and he attracted a large number of individuals who have gone on to fine careers. In addition, our work on the cannabinoids received a tremendous amount of a national and international attention and this was very helpful in recruiting first-rate faculty.

A: Would it be true to say that over the years your department at MCV developed world leadership?

LH: The immunotoxicology program also became very interesting. I think that we were able to have a multi-disciplinary organization, but with a heavy emphasis on substances of abuse which led to our becoming one of the leading departments in the world. We were very proud of that accomplishment.

‘we were able to have a multi-disciplinary organization, but with a heavy emphasis on substances of abuse which led to our becoming one of the leading departments in the world. We were very proud of that accomplishment.’

A: So looking back, would you say that there were very few departments of pharmacology whose major emphasis has been in the area of drug abuse?

LH: In the early days, in my opinion, only three departments were heavily involved: Michigan, under Mo Seevers, Chicago under Danny Freedman, and us. I think, subsequently, clones from these departments have established their own groups independently. From Michigan, Julian Villarreal went on to set up a large program in Mexico and Tomoji Yanagita in Japan. Bill Woolverton set up at Mississippi. Charles France set up first at Louisiana and then moved on to Texas. Schuster and Johanson went to NIDA and more recently to Wayne. The whole field began to be dominated by people who came out of these departmental laboratories.

A: What about the contributions from your department in the area of drug abuse and training of future scientists?

LH: One of the strong points of the training program was that we trained people for multiple roles in research. Our graduates progress probably equally among industry, government service and academia.

A: The key to success?

LH: It was a philosophy of common purpose, shared responsibility and shared credit. I do not think we have ever become known as a single-person department, as many departments have become. It was also a philosophy of research, a spirit of togetherness and pushing back the frontiers of science, working hard, working together. It is a hallmark of the department and my success as a scientist, as a scientist administrator. I just think a department of pharmacology should always have either a resident chemist or a strong relationship with chemists and that, too, contributed to our success.

A: You do not have an age bar?

LH: In response to the suggestion that the department is made up of a coherent group, it might be suggested that the department is in many ways top-heavy with older people at this time. Everette May is 90, I am 78, Mario Aceto is 70, Ed Bowman is 78, Bill Dewey is 70. These are people all associated in the substance abuse field, who are still working actively in the field because of an environment that has been created at MCV to support substance abuse research. It should be noted, however, that with the exception of Bill Dewey, the others are now un-tenured part-time faculty.

A: Could you say a little more about how the early experiences affected this success?

LH: I think that from the early days at Harvard, from the time I was a technician there, particularly the influence of Otto Krayer and Fred Uhle on the need to have rigorous, technically sound science. Krayer once said to the medical school at Harvard, as a whole, that medicine without science is nothing. I think, starting back with the re-organization of the American Medical Schools, this has been a truth that we would like to stick to. I also think another area that we have always been involved in is development of new therapeutic agents, whether medications for the treatment of substance abuse or medications for the treatment of cardiovascular disease or the treatment of convulsions. We have had a very strong interrelationship between the pharmacology, neurology and neurosurgery departments at this institution working in the area of anticonvulsants, and the area of head injury and what could be done about them. Also with the school of pharmacy, for many years we had a center for drug discovery and development supported by the Virginia Center for Innovative Technology based in the pharmacology department that reached out across the whole university in many departments. And that again, as a cornerstone, this idea of multi-disciplinary research, putting together the efforts of scientists and various disciplines or subdisciplines and melding it together to produce a solid body of scientific scholarly work, that has been vital.

‘Krayer once said to the medical school at Harvard, as a whole, that medicine without science is nothing.’

A: Any negatives about having a department emphasizing drug abuse work as opposed to some other area?

LH: Well, I think that the big downside of this is the fact that it was very difficult at this institution to get the clinicians interested in this field. The substance abuse patient population is a very difficult one to deal with. Most hospitals and clinical departments really do not want to have anything to do with this group of sick people. There is no public support for research on the treatment of substance abuse in this country. We have a whole body of public-spirited people supporting epilepsy, cardiovascular disease, cancer, psychoses, everything under the sun, but there is no support group out there which is supporting research and treatment progress in the area of substance abuse. Until recently, we have had very little push in that direction. I think it is important to point out that NIDA, unlike all the rest of the National Institutes, has no support for research coming from the public itself and all of the research in this area is supported by NIDA. I believe the number is 85% of all the research in the entire world.

A: In your immensely busy and productive life have you ever been able to find time to do anything but push back the frontiers of science, or has leisure been the casualty?

LH: Leisure has not been a complete casualty. I enjoy golf, although I play badly and, until recently, was joined frequently by my wife. We also swim regularly for exercise and enjoy fine food, both at home and dining out. We are avid art collectors and support the work of students in the VCU School of the Arts. We like the theatre, opera and classical music and attend performances on a regular basis. We travel extensively, both nationally and internationally, often combining pleasure with business. Finally, through our Family Foundation, we support biomedical research and training, especially on the causes and treatment of dyslexia and other learning disabilities.

References

  1. Top of page
  2. EARLY INFLUENCES
  3. PHD TRAINING AND EARLY RESEARCH INVOLVEMENTS
  4. THE MOVE TO INDUSTRY
  5. EXPANDING HORIZONS
  6. THE MOVE TO CHAPEL HILL
  7. ‘DOING FANTASTIC THINGS’
  8. CAREER MOVE TO THE MEDICAL COLLEGE OF VIRGINIA
  9. NETWORKS OF INFLUENCE AND A LAPEL PIN
  10. References
  • 1
    Uhle, F. C. & Harris, L. S. (1956) The synthesis of alpha-methylamino acids. Journal of the American Chemistry Society, 78, 381384.
  • 2
    Uhle, F. C. & Harris, L. S. (1957) The synthesis and cyclication of alpha-methylamino (4-carboxy-3-in dole)-propionic acid. Journal of the American Chemistry Society, 79, 102109.
  • 3
    Harris, L. S. & Uhle, F. C. (1960) 4-substituted indoles as antagonists to 5-hydroxy-tryptomine and to the veratrine response. Journal of Pharmacology and Experimental Therapeutics, 128, 358362.
  • 4
    Harris, L. S. & Uhle, F. C. (1961) Enhancement of amphetamine stimulation and prolongation of barbiturate depression by a substituted pyrid (3,4-B) indole derivative. Journal of Pharmacology and Experimental Therapeutics, 232, 251257.
  • 5
    Harris, L. S., Clarke, R. L. & Dembinski, J., (1963) Benzyltetrahydrofurfurylamines. A new series of psychomotor stimulants. III. The pharmacology of d-threo-a-benzyl-N-ethyltetrahydrofurfurylamine-(zylofuramine). Archives Internationale de Pharmacodynamic et de Therapie, 146, 392405.
  • 6
    Archer, S., Albertson, N. F., Harris, L. S., Pierson, A. K., Bird, J. G., Keats, A. S. et al. (1962) Narcotic antagonists as analgesics. Science, 137, 541543.
  • 7
    Harris, L. S. & Pierson, A. K. (1964) Some narcotic antagonists in the benzomorphan series. Journal of Pharmacology and Experimental Therapeutics, 143, 141148.
  • 8
    Lasagna, L., Dekornfeld, T. & Pearson, J. W. (1964) The analgesic efficacy and respiratory effects in man of a benzomorphan ‘narcotic antagonist’. Journal of Pharmacology and Experimental Therapeutics, 144, 1216.
  • 9
    Martin, W. R., Gorodetzky, C. W. & Mcclane, T. K. (1969) An experimental study in the treatment of narcotic addicts with cyclazocine. Clinical Pharmacology and Therapeutics, 7, 455465.
  • 10
    Harris, L. S. (1986) Nathan B. Eddy Memorial Award Lecture. Problems of Drug Dependence, 67, 413.
  • 11
    Harris, L. S. (1970) Central neurohumoral systems involved with narcotic agonists and antagonists. Federal Proceedings, 29, 2832.
  • 12
    Dewey, W. L., Harris, L. S., Howes, J. D., Kennedy, J. S., Granchelli, F. E., Pars, H. G. et al. (1978) Pharmacology of some marijuana constituents and two heterocyclic analogues. Nature, 226, 12651267.
  • 13
    Harris, L. S., Dewey, W. L. & Razdan, R. K. (1977) Cannabis, its chemistry, pharmacology and toxicology. In: Martin, W., ed. The Handbook of Experimental Pharmacology Drug Addiction, Vol. II, pp. 45. 371–429. Berlin, Germany: Springer-Verlag.
  • 14
    Harris, L. S., Carchman, R. A. & Martin, B. R. (1978) Evidence for the existence of specific cannabinoid binding sites. Life Science, 22, 11311138.
  • 15
    Mcmillan, D. E., Harris, L. S., Frankenheim, J. M. & Kennedy, J. S. (1970) 1-Trans-delta-tetrahydrocannabinol in pigeons: tolerance to the behavioral effects. Science, 169, 501503.
  • 16
    Martin, B. R., Dewey, W. L., Harris, L. S. & Beckner, J. S. (1976) H-delta-9-tetrahydrocannabinol tissue and subcellular distribution in the central nervous system and tissue distribution in peripheral organs of tolerant and nontolerant dogs. Journal of Pharmacology and Experimental Therapeutics, 196, 128144.
  • 17
    Aceto, M. D., Scates, S. M., Lowe, J. A. & Martin, B. R. (1996) Dependence on Δ9-tetrahydrocannabinol: studies on precipitated and abrupt withdrawal. Journal of Pharmacology and Experimental Therapeutics, 278, 12901295.
  • 18
    Annual Reports (19752005) Proceedings of the Committee (College) on Problems of Drug Dependence. National Academy of Sciences, Washington, D.C. 1975–1978 and National Institute on Drug Abuse, Rockville, MD, 1979–2005.
  • 19
    World Health Organization (WHO) (197794) Technical Report Series. Geneva: WHO.