Roger Guillemin (1924 to 2024): Discoverer of brain hormones that control physiology

Roger Guillemin, widely recognized as the father of Neuroendocrinology, passed away on February 21, 2024, in La Jolla, California. He had still been able to celebrate his 100th birthday a few weeks earlier in the joyous presence of his family, friends, and many ex-colleagues. His copious scientific contributions, which led to numerous prizes and awards, culminating in the Nobel Prize for Physiology or Medicine in 1977, had opened the way, not only to a new understanding of the mechanisms that control the function of the anterior pituitary gland but also to the development of novel treatments for sex-steroid-dependent cancers, endometriosis, precocious puberty, and pancreatic tumors.

Roger Guillemin silhouetted against one of his computer-generated artworks. Image credit: Jamie Simon (graphic artist).

Born in Dijon (France) on January 11, 1924, Guillemin had developed a keen interest in biology and physiology early on, but at the time, the only way to study these fields was to go to medical school. He therefore obtained his medical degree in 1949 from the University of Lyon, but quickly found the practice of medicine too restrictive. While in Paris, Guillemin attended a seminar given by Hans Selye, the physician who had observed that regardless of their specific illness, hospitalized patients all displayed the same set of “nonspecific” symptoms. Guillemin became fascinated by this concept of “stress” and followed Selye to the University of Montreal in Canada, where he obtained a PhD in experimental endocrinology in 1953. Corticosteroids had just been discovered as a major player in our body’s response to stress, but for Guillemin, it was their anti-inflammatory properties that turned out to be literally lifesaving. He had contracted tubercular meningitis at a time when few treatments were available, so Selye decided to try an untested experimental approach to save his student’s life: injection of these steroids into the spinal fluid. This worked so well, that having recovered, Guillemin was able to marry his nurse! A marriage that lasted 67 years and produced six children.

While in Canada, Guillemin had encountered the British scientist Geoffrey Harris who promoted the then-revolutionary hypothesis that the anterior pituitary was regulated by “humoral” signals transported from the hypothalamus through blood vessels—one of the two portal systems of the human body. This went against the more generally accepted concept that this control was neuronal, and at that time, passionate battles raged between the two camps. However, experimental demonstration that hormonal compounds manufactured by the hypothalamus could reach the anterior pituitary through the portal vessel system as hypothesized by Harris, remained extraordinarily difficult. After leaving Selye’s laboratory, Guillemin was recruited to Baylor College of Medicine in Houston, Texas, where he remained until 1970.

Once at Baylor, Guillemin decided to join the “humoral” vs. “neural” battle and, in order to provide support for Harris’s hypothesis, he tried another approach. In the mid-1950s, he designed a highly original experiment, that while simple in concept, represented a very difficult and novel strategy: He cocultured hypothalamic and pituitary cells and noticed that when the two types of tissues remained in close contact, hypothalamic cells produced a substance which stimulated adrenocorticotropic hormone (ACTH) release by the pituitary cells. However, when the two cell populations were subsequently separated, ACTH release stopped. Guillemin concluded, correctly, that the hypothalamus produced signals that were humoral, and not neuronal, as they could act on pituitary cells through the culture medium. This experiment was further complicated by the fact that, at the time, there was no available assay to measure ACTH. Fortunately, Guillemin had the help of an extremely talented technician who would hypophysectomize rats in the morning to remove the endogenous source of ACTH, and then the next day inject the animals with fluids thought to contain ACTH. If they did, this would induce corticosterone release. As if this surgery and the requirement to maintain the hypophysectomized animals alive was not challenging enough, there was no easy assay to measure corticosterone levels either. A complex extraction method using the dangerous solvent sulfuric acid had to be used. Nevertheless, these experiments demonstrated that indeed, the hypothalamus produced at least one factor, which Guillemin called corticosteroid-releasing factor (CRF), that stimulated pituitary activity. In doing so, Guillemin had joined what turned out to be a very heated, often bitter, and breakneck race for the identification of such hypothalamic “factors,” whose existence had by then been generally accepted, largely due to Guillemin’s incredible persistence and tenacity in the face of widespread skepticism, if not outright mockery, and despite his difficulty in obtaining grant funding for this work. To anybody who was part of this search, that Guillemin was rewarded with the Nobel Prize, was no surprise.

By the time he was convinced that the hypothalamus synthesized and released hormonal signals, Guillemin also realized that, in view of the then-available methodology, very large amounts of hypothalamic tissue would be required to extract and biochemically characterize the hypothesized substances. By the late 1960s, he had collected close to 500,000 sheep hypothalami from many Texan slaughterhouses. Then, a new set of heroic separation and chromatographic techniques had to be devised to process such large amounts of tissues, and novel bioassays developed to follow their identification. Fortunately, a new size-based separation methodology had recently been commercialized, dextran-based gels called Sephadex. Guillemin set up very long columns, which required that technicians in charge of loading hypothalamic extracts or of collecting the effluents, communicate by walkie-talkie! The task was not only daunting, but the lab was periodically thrown into a frenzy by rumors that competitors were successful in their own search. Guillemin’s lab members were working nearly 24/7, and any attempts to take a little time off were quickly thwarted by angry reminders that “we have to win this race!”

In 1969, Guillemin was finally successful in isolating the first of these releasing factors, called TRF because it stimulated thyroid function. Remarkably, TRF [now known as thyrotropin-releasing hormone (TRH)] turned out to be a simple tripeptide generated by processing of a large protein precursor. This success was followed by the characterization of a second peptide called GnRH (which stimulates luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion) after Guillemin’s operation had moved to the Salk Institute in La Jolla, California, in 1970. Unfortunately for Guillemin and his team, his former student, Andrew Schally, just beat them in publishing the correct sequence of GnRH, 10 amino acids long. The consequence was that Guillemin shared the Nobel Prize with Schally. Later, Guillemin’s group characterized somatostatin (which inhibits growth hormone release) and GRF (which stimulates it). However, CRF, the factor that Guillemin had originally proposed as evidence for hormonal control of the anterior pituitary, had remained elusive. Highly unstable and requiring technically difficult assays to monitor its isolation, it was only characterized biochemically some years later by a group of Guillemin’s former students and colleagues, also located at Salk, spearheaded by Wyile Vale.

Guillemin was not only an innovative and highly successful scientist, but was also a talented artist. He used computers to produce beautifully colored prints and was an avid collector of pre-Columbian art. Jonas Salk’s initial concept for the Institute he founded was a place where science, philosophy, and art would merge. Indeed, one can still see blackboards strategically placed on each side of the Institute’s courtyard where Salk had thought academicians would congregate to draw up and share new ideas. But this plan did not work out, and over time, the Salk Institute would evolve into a place primarily known for first-rate biomedical research. Nevertheless, Guillemin decided to revisit Salk’s original idea and encouraged various art exhibits, including paintings by Françoise Gilot, Salk’s second wife.

Having joined the Salk Institute in 1970 to create his Neuroendocrinology Laboratory and launch the field that would earn him the Nobel Prize, toward the end of his career, Guillemin also served as Salk’s interim president, demonstrating once more that he was always ready to be where needed. He was also able to witness the development of clinical studies and new treatments based on the hypothalamic molecules he had discovered, thereby coming back full circle to his original status as a physician always eager to help patients.