In Memoriam: Seymour Lieberman, Hormonologist, Chemist and Humanist (1916−2012) National Academy of Sciences of the United States of America, Member, and Endocrine Society, President, 1974−1975

Seymour Lieberman died in New York, the city he loved, on October 8, 2012. He was nearly 96 years old. After more than 35 years at the Departments of Biochemistry and of Obstetrics and Gynecology at Columbia University, College of Physicians and Surgeons (P & S), he directed at St. Luke's Roosevelt Institute an active biomedical research laboratory until his final days. An archetypical scientist, his memory will remain an exceptional inspiration for those devoting their lives to making new discoveries and concerned about their significance to humanity.

Born in Manhattan and steadfastly rooted there after his early studies, he was part of a Jewish family and a proponent of secular humanism. Very respectful of others' opinions, even though he was a faithful supporter of Israel and very much interested in politics, he never opened a conversation on those matters and he did not take the liberty to share his critical views with colleagues and friends. We had to guess his views from his behavior, vigorous and warm-hearted at the same time. His family incessantly admired him. His wife Sandra Spar died in 1993, and he is survived by his son Paul, a psychiatrist married to Genie Bailey and father of 2 children, Jacob and Alyson, and by his sister Marilyn Moreinis.

Lieberman graduated from Brooklyn College in 1936 and then went to the University of Illinois, renowned for its excellence in organic chemistry, the scientific discipline that he had cherished since his youth and that was central to his life's work. Having gained experience in microscale-organic chemistry, he was hired by Oskar Wintersteiner, an Austrian chemist working at P & S and one of the discoverers of the steroid hormone progesterone. This first job marked Lieberman's introduction to the steroid field. His doctorate in organic chemistry with Carl Noller at Stanford University dealt with saponin and sapogenin. Thereafter, he worked 4 years at Harvard University in the laboratory of Louis Fieser, a giant of steroidal chemistry. After World War II, Lieberman went to Switzerland and spent a year in Basel with the immense discoverer of corticosteroids, Tadeus Reichstein. During this postdoctoral period, he met, worked with, and published with a number of the greatest steroid specialists of this time.

Seymour Lieberman, Columbia University (1970).

Returning to New York in 1947, Lieberman worked at the Sloan-Kettering Institute under the direction of Konrad Dobriner, and they produced a number of remarkable discoveries on human steroids found in healthy and ill human beings; in particular, they studied changes related to cancers. In 1951, he was hired in the Department of Biochemistry of Columbia University and from then on continued to work on steroids for more than 60 years at P & S (as associate dean for a period) and then at Roosevelt Hospital (president of their Institute of Health Science), always passionate for the diverse pathophysiological activities of these versatile molecules. He became Professor of Biochemistry in 1962. His laboratory was also connected with the Department of Obstetrics and Gynecology (Ob-Gyn), and he developed, with a number of biochemists and physicians, novel medical and biochemical approaches of exceptional quality. Uninterested in the acquisition of personal wealth, he formed a very complementary research partnership with Raymond Vande Wiele, a gynecologist from Belgium who became Head of Ob-Gyn.

Lieberman received many prestigious awards for his contributions to the field (eg, the Pincus Prize, the Roussel Prize, the Ciba Award, and the Fred Konrad Koch Award from the US Endocrine Society and the Sir Henry Dale Medal from the British Society of Endocrinology). Elected president of the Endocrine Society (1974−1975), he introduced many bright young researchers there, becoming their advocate in the Society that was so invigorated by his leadership. It was therefore not a surprise when in 1977, he was selected to be a member of the National Academy of Sciences of the United States of America. A great supporter of public scientific debates, he created a weekly “Journal Club” at Columbia, which was “the” place to attend for clinical biochemical researchers interested in steroids, whether working in or visiting the New York area: it was a formidable launching pad for the scientists from at least 20 different countries who worked with him.

Laboratory of Seymour Lieberman (Departments of Biochemistry and Obstetrics and Gynecology), PNAS, Columbia University, New York (1962). Seated from left to right: Cecile Weiss, Eleanor Wallace, MD, Dr Seymour Lieberman, Dr Etienne Baulieu, Dr Raymond Vande Wiele, Margaret Welch, Dr. Paula Zimmering. Standing: Agnes Hausinger, Lois Jackson, Dr Erlio Gurpide, Eric __, Edna O. Connell, Dr Penti Siiteri, Achille Hendrikx, MD, Dr John Carpenter, William Kelly, PhD, Dr Edouard Volte, Dimitri __, Harold Calvin, PhD, Dr Paul MacDonald, Otto Gonzalez, Ernestine Gruia, Elsie Ewen.

Lieberman's success was largely due to his skills as both a marvelous classical educator and a courageously innovative discoverer.

As an educator, he had a ceaseless interest and a sincere admiration for the achievements of other scientists. Ever perceptive, his thoughtful and fair remarks, although quite often critical, were offered with kindness and were truly enlightening. His son Paul would say that he was not afraid to aim for greatness in his activities; nonetheless, he was never bitter or antagonistic in such a competitive field. He remained true to his teachers and predecessors and was sincerely proud of his students and their successes.

His influence as a discoverer grew steadily throughout his career because of his timely involvement in novel technologies and revolutionary concepts. For instance, he was among the first to synthesize tritium-labeled derivatives of steroidal hormones/metabolites that could be administered without risk to ill or healthy human patients, thus permitting in vivo studies based on the isotopic dilution technology of secretion rates of hormones and drug metabolism. By chance, I was working in his laboratory when he decided to concentrate a large part of his efforts on the use of these synthetic radioactive steroids. His enthusiasm was extreme as one of the first appropriate counters had just become available to his laboratory. This simplified the identification of molecules in in vitro experiments (metabolism and crystallization) and improved quantitative precision. Furthermore, studies of in vivo hormone distribution and metabolic transformations of steroids became possible and were successfully conducted in his group. With the help of Erlio Gurpide and Jonah Mann, Seymour Lieberman was then able to write a new chapter in the history of endocrinology, addressing our understanding of in vivo human hormonal metabolism. Both the strict rigor he imposed to define quantitatively and qualitatively the appropriate compounds and the clever mathematical approach of the proposed protocols have been and still remain of great utility to this day. They demonstrate that endocrinology can provide biomedicine a methodology of general interest, applicable in particular to in vivo pharmacology in human beings.

In his enduring association with the immunologist Bernard Erlanger that dates from the start of his career, Lieberman was also the first to successfully chemically synthesize conjugated protein-steroid molecules of relevant antigenicity. This allowed for the development of novel, sensitive, and specific methods of quantification of steroid hormones, their metabolites, and their synthetic derivatives, further facilitating the study of hormonal functions both in vitro and in vivo.

Among the very many themes of Lieberman's activities, I cannot resist reporting in detail on dehydroepiandrosterone (DHEA). “Our overlapping interest with this enigmatic secretion product of the adrenals was the starting point of our continuing and gratifying association,” he declared. Indeed, because of DHEA, an extraordinary relationship developed between Seymour and me. Of course I had, even prior to knowing him, been enthralled by his personality. But this was completely natural, considering his exceptional scientific and personal qualities! We had each been independently interested in the same scientific matter for quite some time, which could have degenerated into an unpleasant competition. During the late 1950s, Seymour Lieberman and his colleagues, in particular Raymond Vande Wiele, worked extensively on the steroid, 3β-hydroxy-Δ5-androstene 17-one, that is DHEA, originally named “dehydroisoandrosterone” according to L. Fieser. Its adrenal production in human beings was enigmatic as it could not be identified in extracts from the adrenal tumors thought to be responsible for its abundance in the blood and urine since DHEA disappears after their surgical ablation. I resolved the paradoxical situation by finding that adrenal tissue itself produces dehydroepiandrosterone sulfate (DHEA-S), an unexpected result because it was classically believed that sulfo-conjugation might be a process reserved for detoxification mechanisms (in the liver in particular) of postsecretory steroids. I published my data (in French) in Comptes Rendus, which may well have been the impetus for Lieberman's insistence that I come visit his laboratory. Seymour confirmed the new notion of DHEA sulfo-conjugation in adrenal glands using the tritium labeling technology. He then performed several convincing experiments, which demonstrated the metabolism of sulfo-conjugated steroids, comparing their metabolism with that of free (nonconjugated) steroids. Fairly, he immediately recognized my contribution in his subsequent publications.

The story continued some years later, in 1999, when visiting Lieberman at The College of Physicians and Surgeons, I asked him: “Do you know that we found DHEA and DHEA-S in the brain of rats?” He knew, like me, that DHEA levels are insignificant in rat blood and consequently my new finding could suggest synthesis in the brain of steroidal compounds, which I named “neurosteroids.” Gazing at me intensely, Seymour slowly took a piece of paper from his laboratory coat pocket. Upon it were written the names of those enzymes he intended to study to detect DHEA synthesis in the rat brain, each indicated with the appropriate references, evoking the possibility of local synthesis from cholesterol! Lieberman had envisaged steroid synthesis in the central nervous system, and he was prepared to start work on this possibility. Marvelously, he simply congratulated me, once again systematically citing my work in his lectures for many years and underscoring its potential importance. Furthermore, he continued to work on neurosteroids and made original findings on their biosynthesis and degradation pathways.

Our friendship was on even better terms after this incident: a true gentleman!

Seymour Lieberman was always engrossed by the contributions of endocrinology to medicine. Since 1960, there are traces of his persisting interest up until his final days, when he was concentrated on the hormonal components involved in human arterial hypertension. His views led him to be almost obsessed by the possible role of several steroids (approximately 12) in this pathology. Unfortunately, because the work remains to be completed, the precise and related compounds that he had identified do not yet define a new therapeutic avenue.

Obviously a great endocrinologist, Lieberman was also a visionary hormonologist. In addition to his interest in the regulatory effects of classical hormonal systems, he absolutely insisted on working toward the understanding of novel biosynthetic pathways, largely thanks to his competence as a chemist. For example, his experiments suggested new reactions, leading to hormonal steroid synthesis from cholesterol, including the modification of the classical mode of cholesterol side-chain cleavage by the activity of hydroxylases (involving cytochrome P450_scc), particularly in the central nervous system. He did not believe that 17-hydroxylase–dependent synthesis of the 17α-hydroxyl of glucocorticosteroid occurred in the same fashion as the hydroxylation of the side chain of the cholesterol.

His revolutionary hypothesis contradicted the generally held view that hydroxylations are followed by glycol cleavage. Seymour Lieberman suggested that according to the metabolism of those cells involved, cholesterol-derived reactive species of epoxide and peroxide structures may be important intermediates. He predicted novel therapeutic activities for these unstable intermediary molecules. He recognized that we still lacked precise details on the formation of related molecules; this was also the case for the significance of the metabolism of the unsaturated D-ring in C19 steroids and some pregnane metabolites found in ovaries. The search for their properties justifies his defining himself as a hormonologist, as suggested in the title of the remarkable presentation delivered when he received the Dale Medal.

Finally, he drew attention to the term “hormonads” that he used for designing “factories” or, as indicated to Thoru Pederson, enzymatic ensembles that specifically synthesize (monads) intermediates capable of appropriately leading to active hormones. Hormonads thus permit the production of diverse structures using similar/identical enzymes. Proteins that efficiently facilitate the specific reunions of enzymes into functional units are critical to a novel understanding of differentiated hormonal systems, and they may be future targets for selective therapies.

Seymour Lieberman held an interminable interest in each individual's activities and feelings; he was always attentive to the research of his students, insisting on the use of their established experimental capabilities and helping them to devise a perspicacious pathway for their career. Lieberman insisted that “personality traits determine, whether intelligence and creative capabilities, efficient success in science,” which would not materialize “only because they possess an arcane and impenetrable knowledge and command superhuman powers of logic, concentration and persistence.”

“As University Professors we deal principally with existing knowledge…. We know how to deal with facts…. We do little about intelligence…. It would be a notable accomplishment if we could teach creativity… (but a Professor does little to induce the creative output of individuals taught by him!).” To knowledge, intelligence, and creativity, Lieberman also gave tribute to chance or luck, impossible to control, and to optimism, open mindedness; he was aware of the comedy and spirit of enterprise with the energy to create opportunities rather than simply await them. The whole scientific activity, he liked to say, depends upon “taste”: “Taste is the ability to make proper judgements, to have preferences that are correct. But it is more than just choosing between what is correct and between is incorrect. Many of the choices we make in science seem to be derived from the gut rather than from the brain. The alternatives we choose are those that make us feel good, that give us pleasure, that fit comfortably into our view of ourselves. When we make choices for nonscientific, irrational reasons and when these choices coincide with scientific subjects that are truly important, then it may be said that we have good taste in science.” I also heard him indicate that “esthetics can play a significant role in determining success even in such (scientific) endeavors…. ” He said once that art enters science as “part of the whole enterprise.” He added the role of intuition that he defined simply as “the facility of guessing the future correctly.”

In summary, Professor Lieberman had a broad influence on the entire field of endocrinology. But he favored the term “hormonology” to describe his qualitative and quantitative work exploring hormonal formation and activities, thanks to many new technologies that he developed, which are applicable to human medicine. His chosen themes of studies were original and carefully selected; they led often to great discoveries. His life's work constructed a well-justified legendary prestige still celebrated by legions of collaborators and their own students all over the world. Lucky are those who met him. He insisted that life, especially when consecrated to scientific research, is to be enjoyed and he helped others to be happy. His death deprives biological sciences of an exceptional actor, of outstanding scientific vision and humanistic activity.