Dr. Avram Goldstein
Avram Goldstein, one of the founders of INRC and an icon in the world of pharmacology, died on 1 June 2012. He played a major role in strengthening the scientific basis of the discipline of pharmacology in the middle years of the last century. He was very influential in improving the rigor of research approaches to understanding drug addiction at both the pre-clinical and clinical levels, and in persuading politicians and administrators that treatments and policies in the area of drug abuse should be based on rational scientific principles and experimental evidence whenever this was available.
Avram was born in New York City in 1919, the son of a prominent New York rabbi and a mother who he described as a ‘feminist, socialist and free-thinker” (1,2). His mother ensured that he was sent not to a strict religious school but to Walden, a progressive private school. This unusual background exposed him to the rigors of traditional Jewish intellectual life, but tempered by the drive to challenge all authority that could not survive the test of experimental confirmation or demonstration. He was something of a child prodigy, admitted to Harvard at age 15, but deferring entry for another year while he traveled in Europe and worked at a kibbutz in what was then known as Palestine. After majoring in chemistry, he entered Harvard Medical School where he became interested in pharmacology, graduating in 1943 at the height of the Second World War. After a brief internship at Mt. Sinai Hospital, he entered the US Army and was assigned to Camp Carson, Colorado; his major role was to treat frostbite and trench foot. After the war he returned to Harvard, first as a Post-Doc then as Assistant Professor of Pharmacology, and in 1947 married Dora Benedict, known affectionately to all as Dody, who was then a medical student at Harvard. Dody went on to have her own independent research program, becoming well-known for her contributions to alcohol research, and a professor of pharmacology at Stanford once the anti-neoptism rules that had blocked the advancement of many women scientists were rescinded. The marriage lasted for more than 60 years, until Dody’s death in October 2011.
In 1955, while still an Assistant Professor at Harvard, he was invited to take the chair of pharmacology at Stanford University, which was at that time moving its medical school from San Francisco to the main university campus in Palo Alto. At Stanford, Avram was instrumental in dramatically increasing the size of the medical school faculty and recruiting many very talented younger scientists to Stanford, including Arthur Kornberg as chair of biochemistry. Avram went on to play a major role in developing the educational and research programs at Stanford (1,2). He also at this time founded the journal, Molecular Pharmacology, for ASPET, and he cajoled his Stanford faculty colleagues Lewis Aronow and Sumner Kalman to write a new text, Principles of Drug Action, that emphasized the scientific foundations of pharmacology, in contrast to most other pharmacology textbooks of the time that were essentially annotated lists of drugs in the style of materia medica.
Avram’s initial research studies in pharmacology were on enzyme kinetics, where he analyzed the mechanisms of actions of inhibitors of cholinesterases, and explored enzyme kinetics (3) and the binding of drugs to proteins, but he soon became fascinated with new developments in biochemistry and for a while his lab was focused on enzyme mechanisms and the role of RNA in bacteria. At the same time, however, he was conducting studies of the effects of caffeine in human subjects, using Stanford students and their spouses as subjects in a project that was initially a class exercise on how to conduct clinical research but eventually became a series of published research studies demonstrating the extent to which adaptations in the effects of the drug occurred in some individuals after chronic use (4). He also at this time developed a method for quantifying the kinetics of opioid tolerance development in a mouse model5, that opened the way for quantitative correlations between behavioral and biochemical actions.
He states in his autobiographical memoir (1) that his interest in drug addiction was provoked by a lecture delivered at Stanford in 1970 by Vincent Dole, a biochemist and professor at Rockefeller University, on the use of methadone in a novel treatment of heroin addiction, but the chronology of his publications indicates that he was already shifting his focus in this direction. Nevertheless, the novel concept of a safe legal maintenance therapy for heroin addiction that was presented by Dole fascinated Avram and he saw here an opportunity to combine fundamental research on very poorly understood facets of opiate drug pharmacology - the extreme tolerance that could developed to opiate drugs and the closely related development of physical dependence - with his desire to utilize his medical training to impact a significant social phenomenon, the escalation in the use of drugs of abuse in Western societies. He now directed the work of his lab, and of his long-time assistant Louise Lowney in particular, to identification of the receptor target for morphine, noting that the stereo-specificity of opiate drug action pointed to a way of identifying the critical fraction of opiate drug present that was actually bound to functional receptor, although this was small relative to the much larger amount of drug bound by “non-specific” tissue proteins6. To address the clinical problem of heroin addiction, he started a research-based methadone treatment program serving the hitherto neglected Latino community in nearby San Jose, gaining the trust of the leaders of this community. With Barbara Judson, Priscilla Grevert, Bob Dent and others, he began to conduct experimental studies on opiate actions in human subjects.
It was at about this time that Avram joined with Hans Kosterlitz, Eric Simon, Harry Collier and Sydney Archer in founding the International Narcotics Research Club (later Conference). As described by Syd Archer in his history of INRC, on the INRC web site(7), the initial meeting of this distinguished group was held at the Hotel Euler in Basel during the 1969 International Union of Pharmacology (IUPHAR) Meeting, and at this meeting they planned for a full symposium on opiates to be presented in 1971 in Aberdeen, Scotland during a meeting of the British Pharmacological Society. Avram then hosted the next INRC meeting in San Francisco, again during an IUPHAR meeting (1972), and he became the Secretary (the position was later named President) for the next few meetings of INRC. At this time, the Secretary was by far the most important person in the Club; he arranged the venue, secured funding and developed the program. While the other Founders played very important roles in building INRC as the critical place to present novel research on the actions of opiate drugs, it was the administrative skill and organizational drive of Avram that kept the Club going during its early years.
Avram’s research group expanded substantially at this time. He brought a number of foreign scientists to his lab, including Harry Collier (for a brief sabbatical), Rudiger and Karin Schulz, Hans-Jörg Teschemacher, Brian Cox, Shinro Tachibana, Walter Fischli, and Ji-Sheng Han, recruited gifted graduate students at Stanford, including Ray Dingledine, Charles Chavkin, Maureen Ross and Carl Romano, and post-doctoral fellows from a number of disciplines, including Kent Opheim, Lakshmi Devi, Francis Leslie, Vartan Ghazarossian, Tsung-Ping Su, Susan Gentleman, Gene Baizman, Ian James, Barbara Herman, Charles Weitz and Guo-Xi Xie. This expansion was funded by the newly created National Institute on Drug Abuse, and required more space than he was able to obtain in the Stanford Medical School building1. The solution was a typical Goldstein solution; he would create a new non-profit organization to support his research, the Addiction Research Foundation, and locate this in beautiful purpose-built laboratories on the Stanford business park in Palo Alto, where the walls of the new laboratory were painted in all colors of the spectrum and the room numbers were dictated by the wavelength of wall color. He brought one component of his clinical heroin addiction treatment program to the Palo Alto campus and began an evaluation of a methadone analog, LAAM. LAAM initially appeared to offer a number of advantages over methadone, until it was later withdrawn because of unanticipated hepatic toxicity. To maintain the scientific vigor of the Foundation, Avram also recruited a world- class scientific advisory board, including Jerry Jaffe (the first White House Drug Tsar), Floyd Bloom, Arnie Mandell, Harold Kalant and others. Those working there then still remember the interesting and entertaining scientific discussions when this group visited the lab.
Avram’s contributions to opiate drug research are many. His strategy for identification of opiate receptors6 provided the approach that was later exploited by the Snyder, Terenius and Simon groups to demonstrate the presence of opioid receptor in brain. Avram had used a 14C-labeled opiate reasoning that the apparent affinity of the major opiate drugs for the opiate receptor was about 1 µM. We now know that in the absence of sodium the affinity of many opiates is close to 1 nM. The Snyder, Terenius and Simon groups used very high-specific activity tritium-labeled opiate drugs, enabling them to identify opioid receptors despite their low tissue concentration, and to demonstrate that this binding was stereo-specific. Avram was one of the first to recognize that an endogenous ligand for opiate drug receptors was likely to be a small peptide, and his laboratory first demonstrated the presence of opioid activity in extracts of the pituitary gland, describing different pituitary extracts that displaying the opiate-like properties of what are now known as b-endorphin (8) and dynorphin (9). This was when he posted copies of the sheet music for Handel’s “He shall Purify” from the Messiah on the lab walls to exhort the group to greater productivity (2). He quickly recognized that b-endorphin had already been isolated by Cho Hao Li in San Francisco in his work on ACTH and related peptides, but that its opioid activity had not previously been appreciated (10). Purification of dynorphin took a long time because of its very high receptor affinity and its extraordinary stickiness at surfaces of all kinds, but it was eventually achieved (11).
The lab had some interesting discussions on the differing properties of the receptors mediating the actions of dynorphin and morphine. In 1975, Hans Kosterlitz and colleagues had published studies suggesting that the receptors mediating enkephalin effects in guinea pig and mouse vas deferens were different. Avram was initially opposed to the proposal that there was more than one type opioid receptor, largely on the grounds that the concept offended Occam’s razor. However, repeated exposure during lab meetings (held during the summer around the swimming pool of the Goldstein home on the Stanford campus) to data from studies on receptors in different peripheral tissues eventually persuaded him that one receptor could not explain the data and he became an enthusiastic advocate for multiple opioid receptor types. With Charles Chavkin, he demonstrated convincingly that dynorphin was an endogenous ligand with high selectivity for the kappa opioid receptor (12).
In the clinical arena, the careful quantitative evaluation of the effectiveness of methadone and LAAM treatment programs provided some of the best evidence that these programs were a very cost-effective way to address the growing problem of heroin addiction. He also contributed significantly to the development of science policy. He advised Jerry Jaffe, then working in Nixon’s White House, on how to bring the troops home at the conclusion of the Vietnam War without introducing a major heroin abuse epidemic to the USA. The solution was a reliable device for detecting the presence of opiate drugs in the urine of all troops before they were repatriated; those whose urine sample did not pass the test were not permitted to return until they could provide a clean urine sample1. He was a very strong advocate for the establishment of methadone maintenance programs at public expense in all communities where heroin addiction was rampant. He served on NIDA Council and was consulted often by NIDA Directors. With Harald Kalant he began to think about national policies that would reduce illicit drug use (13), and this eventually developed into a book seeking to explain drug addictions to a national audience (14). His reputation in this area resulted in his being invited to offer a primer on drug addiction biology and treatment approaches to General Barry McCaffrey, Bill Clinton’s Director of National Drug Control Policy.
Avram could be intimidating to some and loved to debate weighty topical issues with those up to the challenge. He acquired something of a reputation of being difficult to work with, and he did not hesitate to use his height and impressive intellect to achieve his goals. He frequently expressed his disdain for committees (1). However, for those who had the pleasure of working closely with him (after surviving his initial probing for intellectual weakness), Avram could be the most instructive, friendly and supportive of mentors. He used his very considerable ability to charm to great effect, whether it was to persuade a post-doc to try once more to solve an intractable problem (always with a novel approach offered by Avram), or in his approaches to potential private donors for the Addiction Research Foundation, or in his interviews with reporters, or in his persuasion of politicians that it was in their best interests to treat drug addiction as a disease rather than a punishable offence, because the former approach might be effective but the latter had been a proven failure.
Avram had many interests inside and out of science. He came to be good friends with Ji-Sheng Han at a time when relations with China were more difficult than today. A prominent plaque resides on the wall outside the Neuroscience Research Institute of Peking University memorializing Avram’s donation, upon his retirement from laboratory research, of a substantial amount of lab equipment and furnishings to the new Institute. To help teach pharmacology to medical students he wrote a book on biostatistics in 1964. Although titled “an introductory text”, it was anything but. The beautiful arguments and logic that characterize this book can best be appreciated after years of routine use of statistics in the lab, and they contrast starkly with the more contemporaneous “how-to” menu-driven books on the subject. Avram dug deeply into the subjects that interested him. Flying his own plane gave him great satisfaction and he used this frequently to travel to meetings on the west coast for many years. Not content with simply learning to fly, he became a certified flight instructor and then an instrument flight instructor, publishing three lengthy teaching manuals in the process.
INRC owes Avram a debt of gratitude for his insistence on the highest scientific standards at the initial meetings of the Club, establishing a tradition that has continued as the club became a Conference. Under his leadership it became in the late 1970s the critical place to present new data relating to the actions of opiate drugs and opioid peptides, and the tradition of frank discussion has continued under the succeeding leadership. The success of the Conference today can be attributed to the strength of Avram’s leadership in the initial years. We remember him with gratitude and affection.
Brian Cox, Charles Chavkin, Lakshmi Devi & Ray Dingledine
1. The biographical details here are taken from Avram’s wonderful autobiographic reminiscences: Goldstein A, A rewarding research pathway, Annu. Rev. Pharmacol. Toxicol. 37: 1-28, 1997.
2. More biographical details can be found on the Stanford University web site autobiography:http://med.stanford.edu/ism/2012/june/obit-goldstein.html
3. Goldstein A. The mechanism of enzyme-inhibitor-substrate reactions illustrated by the cholinesterase-physostigmine-acetylcholine system. J. Gen Physiol 27: 529-580, 1944.
4. Goldstein A, Warren R, Kaizer S. Psychotropic effects of caffeine in man. I. Individual differences in sensitivity to caffeine-induced wakefulness. J. Pharmacol. Exp. Ther. 149: 156-159, 1965.
5. Goldstein A. and Sheehan P. Tolerance to opioid narcotics. I. Tolerance to the “running fit” caused by levorphanol in mice. J. Pharmacol. Exp. Ther. 169: 175, 1969.
6. Goldstein A, Lowney LI, and Pal BK. Stereospecific and non-specific interactions of the morphine congener levorphanol in subcellular fractions of mouse brain Proc Natl Acad Sci USA 68: 1742-47, 1971.
7. Archer S. The early history of the INRC (1969-1975). http://www.inrcworld.org/history.htm
8. Teschemacher, H.-J., Opheim, K., Cox, B.M. and Goldstein, A. A peptide-like sub-tance from pituitary that acts like morphine. 1. Isolation. Life Sci. 16:1771-1776, 1975.
9. Cox, B.M., Opheim, K., Teschemacher, H.-J. and Goldstein, A. A peptide-like substance from pituitary that acts like morphine. 2. Purification and properties. Life Sci. 16:1777-1782, 1975.
10. Cox, B.M., Goldstein, A., & Li, C.H. Opioid activity of a peptide, β-lipotropin-(61-91), derived from β-lipotropin. Proc. Natl. Acad. Sci USA 73: 1821-1823, 1976.
11. Goldstein, A, Fischli W, Lowney LI, Hunkapiller M, Hood L. Porcine pituitary dynorphin: complete amino acid sequence of the biologically active heptadecapeptide. Proc. Natl. Acad. Sci. USA 78:7219–23, 1981.
12. Chavkin C, James IF, Goldstein A. Dynorphin is a specific endogenous ligand of the k opioid receptor. Science 215:413–15, 1982.
13. Goldstein A, Kalant H. Drug policy: striking the right balance. Science 249:1513–21, 1990.
14. Goldstein A. ADDICTION: From Biology to Drug Policy. New York: Freeman. 321 pp., 1994.