The hypothalamus synthesizes and releases hormones to act on the pituitary gland, which has long been a cornerstone of secondary school biology textbooks. But until scientists actually extract and synthesize peptide hormones from the hypothalamus, the neuroendocrine hypothesis that the hypothalamus controls pituitary gland function has been a deviant theory. Those who changed this perception eventually won the Nobel Prize, namely the French-American neurophysiologist Roger Guilleman and his formidable rival Andrew Sully. In February 2024, just after his 100th birthday, Guilleman passed away, and his scientific career from small-town doctor to Nobel laureate was legendary.
Written by | Guo Xiaoqiang (Hebei University of Physical Education)
French-American neurophysiologist Roger Guillemin was awarded the Nobel Prize for his discovery of several hypothalamus-releasing hormones, which led to the neuroendocrine hypothesis that the hypothalamus controls pituitary gland function, as well as endorphins involved in pain perception and fibroblast growth factor for the treatment of eye disease and diabetic blindness. What's more, his scientific career is legendary.
罗歇·吉耶曼(Roger Guillemin,1924.1.11—2024.2.21)
01 Early Experience
On January 11, 1924, Gilleman was born into a wealthy middle-class family in Dijon, the capital of Burgundy, France. Although the parents are not highly educated, they attach great importance to the education of their children. From an early age, Gilleman was interested in science, collecting plant specimens and being able to distinguish hundreds of plant species, observing and dissecting frogs with a microscope, and making simple equipment such as radios. Guilleman completed his primary education at the local public school in Dijon and graduated from the University of Burgundy in 1942 with two degrees in general education and science. After graduating, Gilleman faced an important choice, on the one hand, he was interested in medicine and was preparing to enter medical school, and on the other hand, he liked to be hands-on and wanted to go to engineering school. He chose Dijon Medical School because medicine also requires strong hands-on skills. Unfortunately, this idea was not fully realized, and the medical school at the time had relatively rudimentary experimental facilities and few instruments other than gross anatomy (which only observed the external structure of the human body), so it was impossible to use his talent in this area. Luckily, Geyemann met two clinical medicine teachers who taught endocrinology, and the knowledge he learned laid the foundation for his future career in scientific research.
In 1940, Germany invaded France and Dijon was occupied. German's studies were temporarily suspended, and he subsequently joined an underground group of rebels against Germany. At school, Guilleman took German at the suggestion of his mother, which played an important role during World War II. It was with his fluent German with a local accent that Guilleman "got through" many times in the process of German interrogation and search, and finally saved the day. He helped French refugees and Allied pilots navigate the blockade and reach Switzerland safely. For these outstanding contributions, Guillemán was awarded the Order of Merit of France in 1973.
02 Noble people help each other
In 1947, after graduating from medical school, Gilleman came to work as a general practitioner in a small town north of Dijon. His dedication to providing medical care to the residents has earned him universal praise (two of the most respected people in the area are doctors and pastors). Giljemann felt happy and frustrating at work: first, the helplessness of the patients strengthened the motivation to change the status quo, and second, Gyeyemann always wanted to do scientific research because he liked to explore the unknown. According to the French academic system at that time, in order to obtain a medical doctorate, you had to complete a research thesis and pass a defense, and the post-war France was in ruins, which made the already weak research system even worse, so Guilleman came up with the idea of going abroad.
By chance, Gyemann learned that Hans Selye, a well-known Hungarian-Canadian endocrinologist, would be coming to Paris to give a lecture. He had already been familiar with Shayer's name from his textbooks, and now that he was lucky enough to meet him, it was a once-in-a-lifetime opportunity. Guilleman came to Paris alone with his brother's patronage.
Sheyer arranged three presentations in Paris to focus on new developments in the impact of stress, such as life stress and illness stress, on body physiology and health. This was a great shock to Gillémann, who was impressed by the beautiful slides, the passionate presentations and the depth of knowledge. Shayer's point of mentioning that stress stimulates the body to produce adrenocorticosteroids is a fascinating story that Guillemann doesn't know much about, but finds it a fascinating story that sets the stage for his future research. After Sheyer's second presentation, Geyeman eagerly stepped forward to talk, introducing himself as a young doctor and talking about the idea of going to his lab to do some research to get an MD. Shayer, who completed his education in Europe, had a deep understanding of Giljeman's situation and eventually agreed to Gyeyeman's request.
In 1948, Guillemann came to the newly established Institute of Experimental Medicine and Surgery at the University of Montreal, where Sheyer was located. Over the next year, Gilleman produced a model of hypertension by removing both nephrities in rats, and then using peritoneal dialysis to keep the rats alive for several weeks while observing the effects of adrenocorticosteroids on the heart. In 1949, Guillemán received his MD from the University of Lyon for these studies. At the same time, Geyemann became truly fascinated by scientific research and gave up the idea of continuing to practice medicine and decided to pursue a doctorate in science. Dissatisfied with the academic atmosphere in France at the time, and the ease with which work was going well here in Canada, he decided to stay in the lab to continue his research, and Shayer agreed to the idea once again. Over the next four years, Gillmann completed a joint endocrinology program at McGill University and the University of Montreal, culminating in a PhD in physiology in 1953.
03 Mysterious hypothalamus
The word hormone comes from the Greek word transliteration hormone, which originally means "excitement", and excitability is one of the basic characteristics of life. There are many hormones in the body that are involved in many of the most basic life processes, such as regulating metabolism, influencing growth and development, and controlling the reproductive process. Hormones are usually synthesized and released by specific endocrine glands, such as insulin secreted by the pancreas, and the more familiar endocrine glands include thyroid, adrenal and gonads. The brain also has an endocrine gland called the pituitary gland. As early as Galen's time, it was discovered that the pituitary gland has a secretory function, but it was mistakenly believed that it was a channel for the brain to excrete nasal discharge, and in fact, the ancient Greek word for pituitary (ἀδήν) originally meant phlegm. With extensive research, it has been found that the pituitary gland plays an extraordinary role and can be regarded as the "chief conductor of endocrine glands", because it controls the growth, development and function of multiple endocrine glands such as the thyroid gland, adrenal glands and gonads. The question now is, who controls the pituitary gland?
At the end of the 19th century, researchers discovered that nerve fibers can extend from the hypothalamus (part of the brain) to the posterior pituitary, affecting the posterior pituitary to secrete vasopressin and oxytocin, but no nerve reaches the anterior pituitary, which is more important. Argentine physiologist Bernardo Houssay shared half of the 1947 Nobel Prize in Physiology or Medicine for finding that removal of the anterior pituitary lobe can cause hypoglycemia in animals, and that injecting these animals with anterior pituitary extract can raise blood sugar, indicating that the anterior pituitary has a role in regulating glucose metabolism.
杰弗里·哈里斯（Geoffrey Harris，1913–1971）
When Gilleman was at the institute, in order to carry out academic exchanges and expand students' knowledge, the institute invited world-class physiologists to give academic lectures every month, including the British physiologist Geoffrey Harris. Harris was so interested in pituitary regulation that he conducted a series of experiments in the lab. He found that the activation of hypothalamic activity or the disruption of hypothalamic structure can affect the secretion of pituitary hormones, suggesting that the hypothalamus controls the pituitary gland, and that the hypothalamus to the anterior pituitary lobe lacks nerve fibers, but the two are connected by blood vessels that flow from the hypothalamus to the pituitary gland, and severing these blood vessels can disrupt the hypothalamus' control of the pituitary gland. Harris proposed the hypothesis that the hypothalamus affects the activity of the pituitary gland by secreting hormones, but this hypothesis was not universally accepted by the academic community, and the idea of endowing hormone-producing functions to the brain as a thinking organ was too radical at the time (it was considered to be a bit of a "Guan Gong vs. Qin Qiong" flavor, that is, two unrelated organs were inexplicably integrated). The biggest flaw of such a deviant theory is the lack of direct evidence that the hypothalamus has hormonal secretion.
Hypothalamus and pituitary gland
After listening to the Harris report and learning about it, Gilleman readily accepted Harris's hypothesis, and at the same time was keenly aware that finding the hypothalamus secreting hormone was the key to solving the problem. Because Sheyer is biased towards physiological research, is better at describing physiological phenomena, and does not pay much attention to mechanistic exploration, Geyeman decided to leave Canada after graduating from his PhD to start independent research.
04 Look for direct evidence
As he first approached and offered a faculty position at a professor in Yale's Department of Physiology, he met another nobleman, Hebbel Hoff. Hove had just been appointed chair of the Department of Physiology at Baylor College of Medicine, and he admired Giljeman so much that even though he had learned that Gilman had been offered a job at Yale University, he invited him to visit beautiful Houston and ordered him a plane ticket to try to change Giljeman's mind. The Houston delegation left a deep impression on Giljeman, who finally changed his decision due to the spacious experimental space, sufficient scientific research funds, free academic atmosphere and livable living environment. Soon after, he became a young assistant professor in the Department of Physiology at Baylor College of Medicine, where he began independent research to explore the mechanisms of hypothalamic regulatory function.
Soon after his arrival in Houston, Gilleman visited Charles Pomerat's laboratory. Pomerat is culturing anterior pituitary cells, which are normal but do not secrete any hormones. Geyeman realized that this could be due to a lack of hypothalamic stimulation and suggested co-culturing with the hypothalamus. Pomerat eventually detected adrenocorticotropic hormone (ACTH) – a hormone secreted by the anterior pituitary gland – in the culture medium. This result provides important evidence for the Harris hypothesis, and more importantly, they have established an in vitro system to detect hypothalamic secretory activity, which greatly simplifies the operation.
In the summer of 1955, Gilleman went to the Harris Laboratory in London for academic exchanges, and presented his results in vitro experiments to prove the secretory function of the hypothalamus. This exchange broadened Guillerman's horizons, provided him with more ideal scientific research ideas for further experimental design, and convinced him of the correctness of Harris's hypothesis, so that he persevered without hesitation no matter how difficult it was, and did not question his original choice and gave up.
Determined to speed up his research, Gilleman was able to recruit young biochemist Walter Hearn at a symposium on hypothalamic function at medical school. They discussed and agreed that hypothalamic secretion should be done in the most direct way, that is, to isolate hormones, but they were inexperienced in this area. Luckily, the opportunity presented itself again and they were helped by Vincent du Vigneaud.
文森特·迪维尼奥(Vincent du Vigneaud, 1901—1978)
Divigno was a well-known biochemist who was awarded the 1955 Nobel Prize in Chemistry for his identification of the structures of the posterior pituitary hormones vasopressin and oxytocin. He was invited to speak in various places, including Houston, where Gilgriman met Diviño and invited him to his home. Guilleman introduced his approach to hypothalamus research to Divigno and asked him what kind of separation system was best to use, as there were many separation methods such as paper chromatography and column chromatography at that time. Based on his own research experience, Diviño gave advice: first of all, it is not to choose which advanced isolation method, but to consider obtaining sufficient experimental materials from animals, which is a hurdle that cannot be bypassed, such as the study of vasopressin and oxytocin, which first requires the pituitary gland of cattle.
Inspired by this suggestion, Gilleman decided to solve the problem of sourcing materials first. Since the nature of the activation of the hypothalamus is not well understood, a large amount of hypothalamus needs to be collected to prove in vivo results. Initially, he chose cattle as donors, but unfortunately it was too difficult to obtain the materials and he gave up. After many comparisons, he finally found that the acquisition of sheep hypothalamus is easy to operate and suitable as a material. Just as he was preparing for the big deal, a new problem arose: Hearn joined Iowa State University, and his departure made further research difficult. For this reason, Gyeman had to post job postings in anticipation of new recruits. It wasn't long before Gilman received a cover letter from Andrew Schally.
05 Cooperation and competition
安德鲁·沙利（Andrew Schally，1926—）
Born into a military family in Wilno, Poland (present-day Vilnius, Lithuania), Shali came to England to study after World War II, and because of his love of medicine, he joined the National Institute of Medical Research in the United Kingdom after graduation, where he came into contact with many famous scientists (some of whom would later win Nobel Prizes). This experience has led him to master many emerging technologies and, like Gillémann, to develop an interest in academic research.
In May 1952, Sully came to McGill University in Montreal, Canada, to study adrenocorticotropic hormone under Murray Saffran, thus entering the field of endocrinology. At the time, it was known that stress could increase the secretion of corticotropic hormone by the pituitary gland, and in 1955, Shali and Zafran discovered that the hypothalamus produces corticotropin releasing factor (CRF), through which it regulates pituitary function. In May 1957, when he received his Ph.D., Sully was prepared to continue his research on CRF in the laboratory, but Zafran had to find another way because of his academic sabbatical, and he sent a cover letter after learning that Gilleman was also engaged in related research. At first, the two men communicated very smoothly, and their common goal led to a cooperation agreement that soon led to a cooperation agreement, and in September 1957 Sully officially joined the Gilleman laboratory to start the CRF isolation and characterization project. Geyeman was responsible for collecting the sheep hypothalamus, and Shali was responsible for CRF purification. In order to speed up the experiment, Gilleman also arranged for Shali to go to Stockholm, the capital of Sweden, to learn how to use chromatography, a separation technology, and to Uppsala to obtain a new chromatography column resin.
In 1960, Guilleman accepted a job at the Institut Française in Paris, and Hove did everything he could to keep him. Eventually, they reached an agreement to keep the Baylor College of Medicine laboratory for Gilleman under the management of Sully and to secure adequate funding. When Guilleman returned to France, he found that the Paris slaughterhouse could provide a large amount of sheep hypothalamus, which was a good solution to the material problem. Mr. Gilleman shuttled between Paris and Houston, two labs working side by side, but it backfired. Physiological experiments were relatively smooth, providing more evidence for hypothalamic secretory function, but CRF isolation has not been broken through, as if CRF is within reach, but it is out of reach.
The experiment did not go well, causing internal and external difficulties. Many scientists have questioned the direction of their research, arguing that the hypothalamus could not have a secretory function and that these studies are meaningless. The bigger problem is that there is a huge disagreement between Ghieman and Shali, and there are subjective and objective factors that lead to this outcome. Subjectively, the two have a biased understanding of the research project, in Gillman's view, he is the head of the laboratory, and Sally is an assistant, but in Salley's view, he has his own ideas from the beginning, what he lacks is a research platform, Geyeman has a huge advantage in this regard, so they should cooperate on an equal footing rather than an employment relationship, but he is always at a disadvantage at work, and has a certain inferiority complex. This also caused Sully to prefer to be sharp in the subsequent competition, in order to surpass Guilleman in action. In fact, their goal was really difficult to achieve, but of course this is a story for another time - CRF was not finally purified until more than two decades later.
In June 1962, the Veterans Management Hospital in New Orleans prepared to open a laboratory dedicated to the study of the hypothalamus, and Shali was invited to serve as director. Sully left Baylor College of Medicine to set up his own research team and recruited to become a strong competitor to Gilleman .
If cooperation is a harm, separation is not a relief. Their transition from partnership to competition has accelerated the research process, as they both try to prove that the experiment is the fault of the other.
06 Toto Maeyuki
Geyeman retraces the problems of several years. In fact, despite all the setbacks, both Gilleman and Shali are convinced that there was nothing wrong with the initial choice, but that there was a problem with implementation. First, they underestimated the difficulty of the problem, because the hypothalamus secreted hormone levels were extremely low, so it was necessary to collect an excessive amount of experimental material, secondly, they needed to increase the multidisciplinary cross-fusion and intensify the study of protein purification and synthesis (there is a lot of evidence that the hormone produced by the hypothalamus should be protein), and finally a new hormone was selected, and the decision was made to change it to thyrotropin-releasing factor (TRF) based on the research experience and recent advances in the field of the Gilleman laboratory, which was chosen because of the radioimmunoassay of hormones that appeared in the 60s, which can directly detect the hormone contentinstead of the previous indirect method of determining hormone content by physiological activity (one of the reasons for choosing CRF in the first place). After much consideration, Gilleman returned to Houston from Paris in November 1963 to become director of the Neuroendocrinology Laboratory at Baylor College of Medicine, where he devoted himself to the study of hypothalamic hormones.
With the help of the embassy, Gilleman transported a large number of sheep hypothalamus that he had collected in Paris back to Baylor College of Medicine. After returning to Houston, Geyeman visited several large slaughterhouses, eventually collecting 500,000 sheep hypothalamus, and then processing, processing, lyophilizing and extracting more than 50 tons of fresh frozen tissue in the laboratory, and finally obtaining only 1 milligram of hormone for further analysis.
On the team building side, Gilleman recruited chemist Roger Burgus and physiologist Wylie Vale. Coincidentally, Burgess was a student of Hearn, Gillmann's first collaborator, so he was familiar with Gilleman and was able to devote himself to it more quickly.
At the same time, Sully's team is working intensively on similar research. Sully's choice of pigs as experimental animals was to avoid duplication with Geyeman. This choice was somewhat gratifying, but it was a bonus. Compared with sheep, although the pig is inconvenient to harvest, it has a large slaughter volume and a richer source, and a steady stream of materials has become a reliable guarantee for experiments. In particular, as a result of Shali's efforts, his team received a major reward from a slaughterhouse who donated the hypothalamus of one million pigs (resulting in 2.8 mg of pure product). In this way, the money that was originally used to purchase experimental materials was saved and used to recruit excellent personnel to join, so that they could catch up.
At the end of 1968, the two teams had been working on TRF for nearly six years, but still had not reached a clear conclusion. Many scientists in the industry have become impatient and have suggested convening a workshop to determine whether further funding is needed based on progress. In January 1969, the seminar was held in Tucson, Arizona. At the meeting, the Sully team first reported that TRF is made up of three amino acids, and then Gyeman also reported the same conclusion, which provided initial confidence to the participants.
Gillemann's team then synthesized the tripeptide according to the sequence, but unfortunately it was not biologically active, and Burgess suggested that there might be an amino acid modification. On this basis, they finally synthesized the biologically active TRF, and these results were published in the Proceedings of the French Academy of Sciences on November 12 of the same year, because the journal was published at a rapid pace, unlike Science and the Proceedings of the National Academy of Sciences, which required a longer review time; The Sully team's paper was published on November 6, 1969, just six days earlier.
07 Honors
The identification of TRF has dispelled suspicions about hypothalamic secretory studies, and more researchers have joined the field, with the team of Gilleman and Shali leading the way, with their next target being luteinizing hormone-releasing hormone (LRF). The excellent foundation laid in the early stage greatly accelerated the follow-up research process, and soon the two teams successively determined that LRF is a polypeptide composed of ten amino acids (Sully is one month ahead). Gilleman next sought out ghrelin-releasing hormone produced by the hypothalamus, but he stumbled upon somatostatin, a tetradecadepeptide that strongly inhibits the secretion of ghrein in the pituitary gland.
The identification of a series of new hormones has been completed, which directly proves the correctness of the Harris hypothesis and also clarifies more functions of the hypothalamus. Guilleman and Sully's reputation in the scientific community grew rapidly, with a series of accolades and awards one after another. In 1974, Gilleman was elected a member of the National Academy of Sciences and shared the Gairdner International Award from Canada with Sully, and later received the Lasker Award for Basic Medical Research (1975, with Sully), the Passano Award in Medical Sciences (1976), and the Dickson Prize in Medicine Medicine, 1977). In addition, Gilleman was awarded the 1976 American Medal of Science. Eventually, Gilleman and Shali shared one-half of the 1977 Nobel Prize in Physiology or Medicine for their "discoveries in the production of peptide hormones in the brain" (the other half was won by the Elodame; editor's note: see "Inventing a hormone measurement method but giving up the patent, and after winning the Nobel Prize, she will become the best in the world").
Geyemann is known as the "father of neuroendocrinology" for his outstanding scientific contributions. There's actually a little bit of controversy here, because Harris also has that title. Harris was a theoretical pioneer and Gilleman was an experimenter, both of whom played an important role in the birth of neuroendocrine. In terms of scientific influence, Gilleman was more recognized (experimentally confirming the hypothesis and winning a series of scientific awards, especially the Nobel Prize), while Harris was not able to gain more recognition from the scientific community due to his death in 1970 (he would have been a serious contender for the Nobel Prize in Physiology or Medicine if he had been alive in 1977).
08 Numerous achievements
In June 1970, Gillermann's team left Baylor College of Medicine to join the newly established Neuroendocrinology Laboratory at the Salk Institute, where he continued to work on hypothalamic release hormone and expanded his research. In 1975, researchers discovered the activity of opioids (such as morphine) in the brain, called endorphins, but did not know the sequence. Gilleman was keenly aware of the importance of the problem and initiated research, eventually identifying the complete sequence, but calling it enkephalin, at the end of 1976. In addition, Gilleman has made important contributions to fibroblast growth factor (FGF) isolation and structure identification, and inhibin and activin activity.
In 1989, after retiring from the Salk Institute, Geyeman moved to the Whittier Institute of Diabetes and Endocrinology. In addition to these tasks, Gilleman manages the Salk Institute and the Endocrine Society, driving the discipline.
09 A happy life
1951 was an important year for Geyeman, who was almost simultaneously infected with tuberculosis by three of his laboratory personnel. At that time, tuberculosis was still a problem, and soon one of them died. Jiyeman's lung infection was accompanied by tuberculous meningitis, which was even worse. Experienced in medicine, Geyeman felt the severity of the problem, and during his internship he saw that all children with tuberculous meningitis were killed. Fortunately, at that time, streptomycin had been successfully developed and put into clinical practice, and Geyeman immediately contacted the manufacturer of streptomycin and used the drug in time, and after three months of full treatment and meticulous care, Geyeman was finally cured. A blessing in disguise, Gilleman fell in love with Lucienne Jeanne Billard, a nurse who cared for him, and soon after he was discharged from the hospital, the two tied the knot and had a total of six children.
Lucianna was at home with her husband and children, and the family was happy, ensuring that Guilleman put all his energy into his work, and the two spent 69 years together. In 2021, at the age of 100, Lucianna left first, and three years later, on February 21, 2024, Gyeman, who had just celebrated her 100th birthday, died at Salk's home.
Gilleman was an art lover with a collection of contemporary American and French paintings, and a gifted abstract artist whose works have been exhibited in the United States and Europe.
吕西安娜·吉耶曼(Lucienne Guillemin,1921—2021)
Guyeman has had a huge impact on the world through his life's scientific contributions. His elucidate on the mechanisms by which the hypothalamus regulates hormone production has opened up new approaches to the treatment of a wide range of diseases, including endocrine disorders and mental health issues, and in particular to provide new insights into the mechanisms by which stress and other environmental factors affect physical and mental health.
Gillemán's career in science is a perfect example of the importance of scientific competition. In an era where collaboration is often emphasized as the key to success, his experience shows that competition can advance science better when it is rooted in a shared pursuit of knowledge. To succeed, you need friends, and to achieve great success, you need a strong "enemy", in this case, the enemy refers to the competitor, to prevent you from slacking off, and to remind you to work against the clock.
Guillemán's influence extends beyond his scientific discoveries. The indomitable spirit of exploration and perseverance that lasted for 14 years before and after the discovery of hypothalamic release hormone have inspired generations of researchers to overcome difficulties with rigor and firmness. As a result, Guilleman left behind not only achievements, but also inspiration, demonstrating the power of curiosity to advance science.
Gillemán's life story is a perfect illustration of what he sees as the three elements of scientific success: being smart, working hard and lucky, and luck is essential.
Featured References
[1] Guillemin R. Peptides in the brain: the new endocrinology of the neuron. Science, 1978, 202(4366):390-402.
[2] Guillemin R. A conversation with Roger Guillemin. Interview by Greg Lemke. Annu Rev Physiol. 2013, 75:1-22.
[3] Wade N. Guillemin and schally: the years in the wilderness. Science,1978, 200(4339):279-782.
[4] Burgus R, Dunn TF, Desiderio D, Guillemin R. [Molecular structure of the hypothalamic hypophysiotropic TRF factor of ovine origin: mass spectrometry demonstration of the PCA-His-Pro-NH2 sequence]. C R Acad Hebd Seances Acad Sci D,1969, 269(19):1870-1873.
[5] Burgus R, Dunn TF, Desiderio D, Ward DN, Vale W, Guillemin R. Characterization of ovine hypothalamic hypophysiotropic TSH-releasing factor. Nature,1970, 226(5243):321-325.
[6] Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science. 1973, 179(4068):77-79.
[7] Guillemin R. Endorphins, brain peptides that act like opiates. N Engl J Med. 1977, 296(4):226-228.
This article is supported by the Science China Star Program
Producer: Science Popularization Department of China Association for Science and Technology
Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd
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