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What would you give for a Nobel Prize?

For more than a century, the Nobel has been science’s highest honor. The prize is awarded to only a few researchers per year for achievements in physics, chemistry, and “physiology or medicine.”¹ Nobel laureates hold immense prestige and wield influence not only within their fields but also within the broader public sphere. Nearly every scientist, at some point in their career, dreams of winning a Nobel, even if just as an overconfident undergraduate student. But for some, the prize is more than merely a dream: it’s an obsession.

Published in 1981, Nicholas Wade’s The Nobel Duel recounts how endocrinologists Andrew Schally and Roger Guillemin discovered peptide hormones produced by the hypothalamus, earning each of them a 1/4 share of the 1977 Nobel Prize in Physiology or Medicine.²

But more than this, Wade’s book details an intensely bitter rivalry, shaped not only by the personalities of the characters involved but by the incentives of the system in which they worked. More than forty years later, The Nobel Duel remains a valuable cautionary tale about the competitive pressures that shape scientific discoveries.

Hypothetical Hormones

Before diving into Schally and Guillemin, it’s helpful to learn a bit about the hypothalamus, the subject of their scientific struggles. The hypothalamus is a small lump of brain tissue, about the size of a hazelnut, that sits about seven centimeters behind the nose.³

Despite its small size, the hypothalamus serves an important role as a regulatory center for hormonal signaling. It controls the pituitary gland, for example, another small tissue nodule located directly underneath it. The hypothalamus responds to nerve signals from the brain and stimulates the pituitary to release hormones that act on the rest of the body. This pathway controls a wide variety of critical processes, including growth, metabolism, reproduction, and stress response. The hypothalamus plays an integral role in reproductive biology, too, controlling everything from the production of sex hormones to ovulation and the menstrual cycle.

In rabbits, where ovulation is triggered by sexual intercourse, the hypothalamus converts the neural signal (female orgasm) into a hormonal signal (luteinizing hormone release by the pituitary) causing the ovaries to release eggs. This was discovered in a set of groundbreaking experiments in the 1930s,⁴ but the mechanism remained unclear for decades. How, exactly, does the hypothalamus communicate between the brain and the pituitary?

An obvious hypothesis would be that the hypothalamus controls the pituitary via nerve signals. However, although the hypothalamus sits immediately adjacent to the pituitary, anatomists were unable to identify any nerves that could plausibly be responsible.⁵ In the 1940s and 50s, the English physiologist Geoffrey Harris conducted a set of experiments to test an alternative hypothesis: namely, that a small molecule, rather than a physical neural connection, might be responsible.

Working in rats, Harris carefully severed a set of tiny blood vessels connecting the hypothalamus and pituitary and showed that the rats stopped reproducing. Harris proposed that the hypothalamus sends its own hormones through these blood vessels, triggering the pituitary to release its own set of hormones. But until such hormones could be directly identified, many scientists met this idea with skepticism. In order to explain the regulation of all the different hormones of the anterior pituitary, Harris had to hypothesize not just one hypothalamic hormone, but a whole set of them. And after all, Occam’s Razor states that “entities are not to be multiplied without necessity.” Even for Harris, this hypothesis was a leap into the unknown.

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Stress and Strife

Roger Guillemin and Andrew Schally were no strangers to stress, even early in their lives. And in an ironic coincidence, it was stress itself that sparked their acrimonious race to discover the hormones of the hypothalamus.

Guillemin, born in 1924, grew up in the French town of Dijon. The Nazi occupation interrupted his medical studies, but after the war, he found a position in Montreal, where he completed his PhD under professor Hans Selye, studying the stress response mediated by the pituitary and adrenal glands.

Unfortunately, Guillemin clashed with his advisor. As another of Selye’s students, Claude Fortier, put it, the two men were occasionally “in complete and total disagreement in our intellectual approach to research.”⁶ Although Guillemin finished his PhD in Selye’s lab, he was eager to search for a job elsewhere. In 1953, he secured an assistant professorship at Baylor College of Medicine and began setting up his own lab.

When a colleague at Baylor, professor Charles Pomerat, complained to Guillemin that pituitary cells did not produce hormones when cultured in vitro, Guillemin saw an opportunity to test Harris’ hypothesis. With the help of one of Pomerat’s students, Barry Rosenberg, Guillemin repeated the experiment. As before, the cells did not produce hormones in culture. But Guillemin took the experiment a step further, adding a piece of tissue from the hypothalamus to the culture dish with the pituitary cells. If Harris’ hypothesis was correct, the hypothalamus hormones would cause the pituitary cells to resume their own hormone production.

In particular, Guillemin noticed that ACTH, a pituitary hormone that mediates the response of the adrenal glands to stress, was only produced in the presence of hypothalamus tissue. Since no nerves were formed between the hypothalamus and pituitary cells in the cell culture, this interaction had to be hormonal. Guillemin immediately published his work, but to his consternation, he soon saw that he wasn’t the only one who had made this groundbreaking observation. As The Nobel Duel describes it, “The experience was like planting a flag at the top of Everest only to see, as the mist cleared, that another flag was being erected by somebody else.”

That somebody else was Andrzej (Andrew) Schally. Born in Wilno, Poland⁷ in 1926, Schally was the son of Kazimierz Schally, a general in the Polish Army. When Germany and Russia invaded and occupied Poland in 1939, many Polish soldiers escaped to Romania, Schally’s family among them. Andrew Schally survived the Nazi and Soviet occupations and then moved to the United Kingdom after the war, where he studied chemistry. By that time, he already displayed “a sort of manic persistence” for scientific research, his old supervisor recalled. In 1952, Schally moved to McGill University in Montreal, where he would eventually earn his PhD. Together with his advisor, professor Murray Saffran, Schally showed that samples of rat pituitary tissue cultured in vitro would produce ACTH only in the presence of a substance, which Saffran named “corticotropin-releasing factor (CRF),” found in the hypothalamus.⁸

Schally’s study was published in the journal Endocrinology in October 1955. Guillemin’s paper was published in the following issue of the same journal. Now, suddenly, both scientists were aware of the other’s work; their race began in earnest.

Both scientists, importantly, viewed CRF as “their discovery,” and each aimed to make it the central focus of an illustrious academic career. While both had shown that a hypothalamus hormone exists, neither knew what that hormone actually was. The next step was to isolate the hormone, purify it, and determine its structure. With the molecular biology tools available in 1955, however, such a feat was much easier said than done.

Thus began a 26-year marathon.

Brains, Brains, Brains

There were three main challenges in determining the structure of CRF: the hormones are made only in minute concentrations, the hypothalamus is small, and the analytical techniques of the time were not very sensitive. Instead of developing new analytical methods, Guillemin and Schally instead mounted a straightforward, brute-force attack on CRF.

At first, the two scientists worked together, embarking on their research using “state-of-the-art” technology available to biochemists in 1955. But to describe these methods as “old-school” would be extremely charitable. The duo began by using chemical methods such as salt precipitation to try to purify CRF from puréed hypothalamus. This was similar to Edwin Cohn’s successful fractionation of blood into albumin and other proteins during World War II (a story previously told in Asimov Press). However, albumin is the most abundant protein in blood plasma, whereas CRF is present in the hypothalamus in only trace amounts.

In a biochemistry lab class as an undergraduate, I got a small taste of the difficulties these researchers faced as I labored to purify lactate dehydrogenase from beef heart using salt precipitation and Sephadex ion-exchange chromatography.⁹ Grinding up a beef heart in a blender was not a pleasant experience, and even then, I was only able to isolate less than a milligram of lactate dehydrogenase — one of the most abundant proteins in the heart. These days, it’s much easier to produce proteins by recombinant expression in bacteria, but that technology did not become available until the 1970s. So instead, Schally and Guillemin were forced to grind up literally millions of animal hypothalami, dissected from hundreds of tons of brains, and carefully separate them into their constituent molecules. Each fraction had to be assayed for hormone activity, and at first, the only way to measure this was by injecting it into animals and waiting multiple days to monitor a response.¹⁰

From 1957 to 1962, Schally performed his research in Guillemin’s lab at Houston. Since Guillemin specialized in physiology and Schally in biochemistry, they formed a complementary pair. However, their search for the structure of CRF bore little fruit, and resentment began to grow between them. Guillemin was the lab head, which meant that he was able to pursue more productive avenues of research, even setting up a second lab in France and splitting his time between Paris and Houston. By contrast, Schally toiled for up to 18 hours per day on the CRF project, tediously isolating fractions without much success. As Schally saw it, “[Guillemin] wanted me to take the blame when things went wrong and to take the credit for himself when things went right … An equal partner I could be with him, but he wanted me to be his slave.”

The tipping point came at a conference in late 1961 organized by the NIH Endocrinology Study Section, a major funder of Schally and Guillemin. The endocrinologist tasked with summarizing the presentations, Roy Greep, was clearly unimpressed by the lack of progress in actually isolating and characterizing CRF, writing: “never before to my knowledge, except for the monster of Loch Ness and the Abominable Snowman of the Himalayas, has the existence of hypothetical objects been indicated by so much imposing circumstantial evidence.”

Having CRF likened to the Loch Ness Monster struck a nerve. Nearly five years had been spent, and although Schally and Guillemin had made a small amount of progress, they still had not achieved their primary aim of determining the hormone’s structure. In private letters, Schally accused Guillemin of supplying him with inadequate materials, and Guillemin responded by suggesting Schally’s poor biochemical work was to blame. Not long after, Schally began looking for other positions, eventually obtaining a job at Tulane University in New Orleans. By the end of 1962, Guillemin and Schally had publicly fallen out, and Schally started setting up his own lab.

To compete with Guillemin, Schally needed a lot of brains — and not just metaphorically. Each experiment required tens of thousands of hypothalami to isolate minute quantities of hormones. Guillemin favored sheep hypothalami¹¹ and purchased well over two million of them from slaughterhouses in France over the course of his lab’s work. Schally instead opted to use pig hypothalami, for two reasons: First, by using pigs instead of sheep, if Guillemin beat him to the discovery of a hormone, Schally’s work would not be completely wasted since hormones in different species are not necessarily the same. More importantly, Schally established a plentiful source of pig brains through a connection with Oscar Mayer, the meat-packing company that slaughtered ten thousand pigs per day. In the end, Schally’s work on the hypothalamic hormones would consume more than one million pig hypothalami, provided by Oscar Mayer free of charge.

Troubles with TRF

With Guillemin and Schally now leading separate laboratories, a vicious competition began. In the beginning, both men had focused on CRF, since it was the only hypothalamic hormone for which a good measurement assay was known. However, five years of unsuccessful attempts to determine the structure of CRF had convinced both to seek an easier target. Shortly after Schally left his lab, Guillemin made an important advance by developing an accurate assay for thyrotropin releasing factor (TRF), a hormone that coaxes the pituitary to release thyroid stimulating hormone (TSH).¹² The new assay opened up TRF as a target for isolation, starting a race to characterize its structure in addition to CRF.

Although Guillemin had a head start in this race, he was unable to maintain his early lead. Solving the structure of TRF was basically a biochemical problem, and since Guillemin was not a biochemist himself, he relied on others to perform the experiments. Despite their help, though, Guillemin looked down on the biochemists he worked with, neglecting to properly credit them for their work. This “inability to work with others on an equal basis” was what drove away not only Andrew Schally but also a succession of biochemists — first Marian Jutisz (who performed much of the initial work on TRF) and, later, Wylie Vale and Roger Burgus, two of Guillemin’s star proteges. Guillemin also clashed with administrators at the Collège de France, which led him to move all his work back to Houston. Meanwhile, in New Orleans, Schally was busy grinding up pig hypothalami. His goal was simple: to prepare a sufficient quantity of pure TRF for structural determination. But in practice, this was deceptively complex.

After four years of painstaking work, Schally and Guillemin had both nearly succeeded, but astonishingly, both made the same wrong turn, erroneously concluding that TRF is not a peptide due to faulty experiments.

Guillemin’s laboratory, for example, extracted TRF molecules from 500,000 sheep, but found that it only contained 8 percent amino acids by mass. Unaware of his mistake, Guillemin trumpeted this result as a breakthrough. Schally came closer but still missed the mark. He found three amino acids in his hypothalami — histidine, glutamic acid, and proline — but was unable to determine the sequence in which they were linked, and worse, falsely concluded that they made up only 30 percent of the TRF molecule. With the remaining 70 percent unknown, Schally could only guess at the molecule’s identity.¹³ (It’s now known that TRF is a peptide, meaning it is made entirely of amino acids.)

Throughout this time, both labs were not only busy with science but also with undermining each other. They would slight each other at conferences, downplay each other’s contributions in review articles, refuse to share materials, and send passive-aggressive letters. After a conference at which Guillemin had allegedly disparaged Schally, Schally wrote: “Your somewhat derogatory and deprecating remarks . . . surprised me as the attack on Pearl Harbor surprised the U.S. Navy”.

Guillemin replied with a calculated riposte: “I have no comments except to say that I am neither your conscience nor your psychiatrist.”

Overall, it appears that Guillemin took up a strategy of subtly provoking Schally, whose angry reactions made him look like the aggressor. Guillemin would alternate between public attacks and private reconciliations. Writing to Schally, he claimed “there have never been any bad feelings on my part toward your laboratory, your group of collaborators, or yourself.” But a few months later, he was back on the attack, ridiculing Schally in a review article. As a junior scientist in Guillemin’s lab observed, “Neither one could stand the other’s guts. Every time a letter was sent from one lab to the other there was usually some kind of terse reply. But Schally usually ended up looking like the heavy because he was not as clever as Guillemin.”

Besides the winner-takes-all nature of their race, another major driver of conflict was the fact that Guillemin viewed Schally as his junior.¹⁴ As Nicholas Wade writes, Guillemin “could never bring himself to accept that Schally was not a child but a scientific colleague of approximately equal, if different, abilities.” After Schally left Guillemin’s lab and started out on his own, the prospect of Schally succeeding as an independent researcher was a threat to Guillemin’s psyche. Meanwhile, Schally was fed up with Guillemin’s attempts to belittle him. He could not accept anything less than an equal standing with Guillemin, and was determined to prove himself superior to his former supervisor, even if this required ungentlemanly tactics.¹⁵

Within their own labs, both Schally and Guillemin played up the growing rivalry in an attempt to motivate their subordinates: if the other lab scooped them, it would mean disaster for their careers.¹⁶ However, on the rare occasions they faced a common threat, such as a third researcher calling into question their prior work on CRF, the two labs did move to defend each other. Still, the overall attitude was one of steadily escalating hostility.

By 1968, the structure of TRF was still unsolved, and the broader endocrinology community was losing patience. As Nicholas Wade summarizes:

Guillemin and Schally had achieved nothing. Noisy claims and mutual abuse could not forever substitute for real progress. Indeed, the lack of progress, the skeptics argued, raised pointedly the question of whether the releasing factors really existed.

While Schally and Guillemin traded inimical letters and slighted each other in review articles, the NIH, which funded both labs, was coming close to withdrawing its support. According to Murray Saffran, who at that time was a member of the NIH Endocrinology Study Section, “Their support was on the brink because they were chasing each other rather than the real problem.” In January 1969, the Endocrinology Study Section held a conference in Tucson, Arizona, at which both labs were expected to showcase their results. If their progress was found unsatisfactory, it would surely mean the end of the scientific careers of both Guillemin and Schally.

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Showdown at Tucson

Unbeknownst to the Endocrinology Study Section, Guillemin’s student Roger Burgus had in fact made progress towards deciphering the structure of TRF. Using newly developed analytical methods (including NMR and mass spectrometry) over a three-year span, Burgus had amassed enough data to conclude that TRF was in fact a peptide, and that histidine, glutamic acid, and proline made up at least 80 percent of it. Finally, the research was back on track.

But at the conference, Guillemin was faced with a dilemma. Should he announce his lab’s progress, or wait to reveal it until his lab had completely solved the puzzle? Making an announcement would help prove to the NIH that his funding was worthwhile. But it would also tip Schally off, and risk Guillemin’s getting scooped.

Guillemin decided to make the announcement, which, while saving his scientific career, set off a furious sprint to nail down the structure of TRF. Building upon Burgus’s results, Guillemin ordered the Swiss chemical company Hoffmann-La Roche to synthesize all six possible tripeptides containing histidine, glutamic acid, and proline, as well as versions of these peptides with an acetyl group attached to the N-terminus. In early 1969, Burgus tested these candidates for TRF activity, seeing if they could stimulate the pituitary to release thyroid-stimulating hormone. Excitingly, he found that his sample of acetyl-glu-his-pro behaved like a weaker form of TRF. Guillemin quickly published this result in the French journal Comptes Rendus, and also submitted it to Science — which rejected the manuscript because a French-speaking reviewer noticed that it had already been published elsewhere!

Meanwhile, Schally was also getting close, finding that the sequence of amino acids in TRF was glu-his-pro, and that the peptide lacked a free N-terminal amino group and C-terminal carboxyl group, which meant that there were chemical modifications at these sites. At that point, the nature of these modifications was still unknown, but Schally guessed that the N-terminus had a fatty acid attached,¹⁷ and the C-terminus had an amide group attached. Schally instructed his collaborator, Franz Enzmann, to add these chemical modifications to the glu-his-pro peptide. Schally was delighted to find that three different modified versions of glu-his-pro all had TRF-like activity.

Remarkably, both research groups had been saved by the same unexpected side reaction. Under the conditions used to synthesize the modified peptides, glutamic acid present at the N-terminus will spontaneously cyclize to form pyroglutamic acid. By June 1969, both labs had realized that the TRF activity in their samples was due to a side product, pyro-glu-his-pro-amide. But was this compound actually the same as TRF?

Here, Schally and Guillemin drew different conclusions. Guillemin equivocated, writing that although pyro-glu-his-pro-amide behaved very similarly to TRF, the actual structure of TRF was still “an open question.” By contrast, Schally’s collaborators Karl Folkers and Franz Enzmann had painstakingly compared the properties of synthetic pyro-glu-his-pro-amide and natural TRF in seventeen different assays, leading them to the correct conclusion: the compounds were identical. Although Guillemin’s lab soon reached the same result, Schally’s team had won the seven-year race — by a margin of just thirty-seven days.

In determining the structure of TRF, Schally had scored a victory over Guillemin. But to the wider community, it looked more like a draw — an interpretation also espoused by Guillemin in several review articles. The main result of the race was that the theory of hypothalamic releasing factors was no longer in doubt. But TRF was only one of the many releasing factors thought to exist. So with CRF and other hormones still left to identify, Guillemin and Schally continued their work in an attempt to achieve a clear-cut victory.

LRF: the Second Lap

Luteinizing hormone releasing factor, or LRF,¹⁸ had long been a target of researchers due to its crucial role in reproduction. As far back as the 1930s, animal breeding experiments had revealed that the hypothalamus controls the release of reproductive hormones from the pituitary. In fact, these results were what first led British neuroendocrinologist, Geoffrey Harris, to propose the existence of hypothalamus-derived hormones. So unlike TRF, which was mainly of niche interest, LRF had attracted much more attention. Determining its structure would be an advance with important applications in reproductive medicine.

After finally succeeding with TRF, both Schally and Guillemin were eager to be first to make this discovery. However, this time the field was crowded, as several other researchers, including Harris himself, were already hard at work on the same problem.

Those other researchers, however, lacked two crucial things: a fanatical obsession to be first, and an industrial-scale source of hypothalamus tissue. Only Guillemin and Schally would go “all-in,” and labs that did not devote 100 percent of their effort to solving the structure of LRF quickly fell behind. By virtue of having a decade-long head start, Geoffrey Harris came close, but he was hindered by his reliance on an LRF assay which was highly accurate yet slow to perform. Schally and Guillemin used assays that were less accurate but much more rapid, allowing them to optimize their procedures for isolating LRF.

Just as the race for LRF began to heat up, Schally was handicapped by a previous problem stemming from the last stages of the battle for TRF. To come out ahead of Guillemin, Schally had collaborated with the chemists Folkers and Enzmann, and the physiologist Dr. Cyril Bowers. However, Schally was reluctant to give them the credit they deserved, leading to a breakdown in the collaboration. When Folkers and Enzmann filed their own patent on synthetic TRF, Schally was outraged. And worse, Folkers approached Oscar Mayer, asking for a cut of the cheap hypothalami that had thus far been going solely to Schally. Thus, Folkers and Bowers went from being collaborators to competitors.

Fortunately for Schally, Guillemin was also delayed due to moving his lab from Houston to a better-funded position at the Salk Institute in San Diego. When his research resumed in 1970, Guillemin’s student Roger Burgus quickly identified that LRF contained nine amino acids, but lacked enough material to determine the order in which they were arranged. Extracting and purifying more LRF would take time.

Then came a shock. In February 1971, Guillemin was organizing the Endocrine Society’s annual conference and received a list of abstracts of conference applicants. Among these was one from Schally, which reported that LRF contained the same nine amino acids. Clearly, Schally had progressed at least as far as Guillemin’s team had. Seeing the abstract also placed Guillemin in considerable political danger: he was now vulnerable to accusations of obtaining an unfair advantage from seeing Schally’s unpublished work. Deciding to clear up the matter, Guillemin wrote a letter to Schally explaining that Burgus had independently discovered the same thing. Schally countered: if Guillemin knew the nine amino acids of LRF, then why hadn’t he submitted his own conference abstract?

However, although neither lab realized it, both had made the same mistake. LRF actually contains ten amino acids, not nine. The method they were using to break up LRF into its amino acids involved treatment with acid, and this happened to degrade the amino acid tryptophan. Having just a little more LRF available for analysis would enable a full structural determination, but this would require laborious extraction from huge amounts of tissue. By 1971, “the gift of a few millionths of a gram of LRF to either side would have tipped the balance.”

Once again, Schally came out ahead, but was able to do so only through the help of three Japanese researchers, Akira Arimura, Yoshihiko Baba, and Hisayuki Matsuo, who had joined his team to share their biochemical expertise. Initially, despite processing 160,000 hypothalami, Schally had only obtained 250 micrograms of LRF, a quantity too small for traditional peptide analysis. But Matsuo saved the day, devising an ingenious scheme to cleave the LRF into smaller fragments, and then analyze the fragments without first separating them. Although this analysis still left some ambiguity in the hormone’s structure, it narrowed it down to two candidate peptides, which Matsuo synthesized. Arimura, using a new radioimmunoassay he’d developed (based on a previous technique invented by Rosalyn Yalow), found that one of them had the same biological activity as LRF.

Schally had won again, but this time, he was determined to make it an unforgettable victory. The large Endocrine Society conference was due to be held in June 1971, but a smaller conference took place earlier in May. At this earlier conference, Schally instructed his lab members to show data proving that they had made synthetic LRF, but not to reveal the structure unless Guillemin had also solved it. Although Schally’s students — and the conference audience — were bitter about this gag order, the purpose was clear: to provoke Guillemin.

At the Endocrine Society conference, Schally personally delivered the coup de grace. Guillemin was moderating a session on releasing factors, and all of the major players in the field were in attendance. First, Roger Burgus presented the work he had performed for Guillemin, and crucially, he still claimed that LRF had only nine amino acids. When Schally presented the true structure of LRF, the crowd went wild. As Karl Folkers, who was in attendance, described it, “That must have been perhaps the worst thing that ever happened to Guillemin.”¹⁹

Somatostatin: Schally Stumbles

Guillemin, however, would soon score a victory of his own with the discovery of somatostatin. One of the many roles of the pituitary is to produce growth hormone. By analogy with the other releasing factors, it was thought that this process was regulated by a growth hormone releasing factor (GRF) from the hypothalamus. Throughout the 1960s and early 1970s, Schally’s lab worked to isolate GRF from pig hypothalami. Although this project was paused several times due to the races for other factors, by 1971, Schally had found a ten amino acid peptide which he tentatively identified as GRF.

However, Schally had made a massive mistake. In isolating GRF, he relied on a simple yet inaccurate assay, based on measuring rat bone growth. In the race for LRF, choosing a simple assay instead of a more accurate yet more complicated one had been crucial for success. But now the opposite was true. Schally had neglected to validate his results using a more accurate assay. As it turned out, the peptide that he thought was GRF was actually just a degradation product of pig hemoglobin that happened to give positive results in the rat bone growth assay.

Meanwhile, another scientist, Ladislav Krulich, was also hard at work studying the hypothalamic regulation of growth hormone. But instead of a releasing factor, he noticed that the hypothalamus produced a molecule (which he termed GIF) that inhibited the release of growth hormone. Although Roger Guillemin, like Schally, had initially been chasing GRF, a chance discovery by his student Paul Brazeau led him to reconsider. In early 1972, Brazeau tested hypothalamic extracts for their ability to promote growth hormone release but found that they inhibited the release instead. At first, Guillemin was incredulous, but then he remembered Krulich’s reports of GIF. Soon, Roger Burgus had isolated a large amount of GIF from hypothalamic extracts which were left over from the race for LRF. Within a year, Guillemin’s team had determined the structure: a cyclic peptide of fourteen amino acids.

Finally, Guillemin was victorious. And like Schally before him, he was determined to make his victory count. First, he renamed GIF to somatostatin, a name which is still in use to this day. In changing the name, he also diminished the contributions of Krulich who had been the first to propose the existence of GIF. Furthermore, Guillemin downplayed the role of his own students in carrying out the GIF project. In a 1974 editorial he wrote for the New England Journal of Medicine, he extolled the medical potential of somatostatin but left out Burgus and Vale from the author list, and failed to cite Krulich even once. By contrast, Guillemin took care to cite the barely related work of Rolf Luft, a Swedish endocrinologist who just happened to be on the Nobel Prize committee.

The Prize and Its Price

After Schally’s discovery of LRF and Guillemin’s discovery of somatostatin, each knew they were in the running for a Nobel Prize. Starting from their first experiments in 1955, they both had made major contributions to endocrinology and validated Harris’ theory of hypothalamic releasing factors. Harris had died in 1971, so he was ineligible for the Nobel (the award is not given posthumously). Schally and Guillemin were considered to be front-runners in the field and had shared a Lasker award in 1975. However, their chance at a Nobel was not assured. After all, the prize committee could only honor one area of research per year, which meant that endocrinology was competing with exciting new advances, such as recombinant DNA.²⁰ To boost their chances for a Nobel, both Guillemin and Schally cultivated relationships with prominent Swedish scientists.

In October 1977, the call from Stockholm came. Guillemin and Schally would each receive a 1/4 share of the Nobel. The remaining half would go to Rosalyn Yalow, a biochemist who had developed an extremely sensitive assay for hormones that made Schally’s and Guillemin’s work possible.²¹ Guillemin, feigning humility, proclaimed that his research goal had been to treat the sick, not to win the Nobel. Schally was more forthright, admitting that “pride and ambition have a lot to do with whatever I have achieved.” Pride and ambition, yes, but also a singular obsession. As Nicholas Wade observes:

No brilliant scientific insights, no high exercise of intellect or imagination was required in their endeavor, just years of extreme determination and the tenacity to grind up tons of brain tissue.

Ironically, the Nobel that Schally and Guillemin shared was for “Physiology or Medicine,” yet the key to their work had been chemistry. Both laureates had relied heavily on chemists in their lab. For Guillemin, Roger Burgus served as the key player in the purification and structural determination of TRF, LRF, and somatostatin. Without Burgus, Guillemin would have had no chance of a Nobel. Schally, unlike Guillemin, had expertise in chemistry and performed his own peptide purification. But he still relied heavily on other chemists for structure determination — Enzmann and Folkers for TRF, and Matsuo for LRF. However, both then and now, scientific credit goes to the lab chief, not to his subordinates.

And many of Guillemin’s subordinates resented the way their chief treated them. The New England Journal of Medicine editorial on somatostatin marked the starting point of a breakup of Guillemin’s lab. Burgus and Vale, who had been left off the author list, realized that Guillemin had gone too far in arrogating credit to himself. Worse, Guillemin began playing Vale and Burgus against one another.²² Both ended up leaving the lab. Vale’s departure in December 1977 was particularly remarkable since he and several other trainees left and set up a new lab just a few hundred yards away in the same institute!

The true price of the Nobel Prize is best expressed in the words of the researchers who actually accomplished the work. As Vale put it:

[Guillemin] has given too much control to the people who are giving him the prizes … I think he has always had difficulty in working with people as equals. I care for him, but several of us have learned what hell it can sometimes be for people who get caught up in the meat-grinder, churning out more and more gloire for Guillemin, especially if you are the meat.

Whither the Nobel?

Guillemin and Schally took competition to pathological levels in the race for the Nobel. Their desire for fame pushed them to do nearly everything (short of outright sabotage) to hinder the progress of their perceived enemies, and in the process, they even drove away their own allies. Their comportment was unacceptable even in light of their genius.

However, the blame does not fall entirely on them. The terms of their race were set by the academic system in which they operated: the first to characterize a hormone would receive prestige and awards, while any runners-up would be largely ignored. Furthermore, this prestige would accrue to the lab chief, even if he had not been responsible for the critical contributions. Thus, Schally could not bear to work for Guillemin, because if he made a discovery while in Guillemin’s lab, the credit would go to Guillemin. The fact that the Nobel Prize is only awarded to a maximum of three people means that worthy researchers are inevitably passed over and the prize inevitably “distorts and simplifies the true pattern of achievement.” To win, one must not only be good, but better than everyone else. (Or at least, live longer than them.)

If this weren’t dispiriting enough, after receiving a Nobel Prize, a researcher’s productivity often drops. This effect was noted as far back as 1967 and is also mentioned in The Nobel Duel. A recent analysis compared citations to papers published by Nobel laureates in the 3-year period prior to the award, and the 3-year period after the award, and found the post-award papers to be significantly less cited on average. Although this might be explained by regression to the mean,²³ in many cases, researchers who win Nobels feel like they can only work on “big problems.” In the field of biology, one example is Jack Szostak, who pivoted his laboratory to studying the origin of life after winning a Nobel.²⁴ It’s a very interesting problem, and his lab has made some progress, but I don’t think they are close to solving it.²⁵ In other cases, researchers begin spreading fringe or discredited ideas after winning a Nobel — Kary Mullis and Luc Montagnier being the best-known examples.²⁶

The toxic effects of the Nobel prizes could lead one to conclude that scientific prizes should be abolished altogether. But this conclusion is too simplistic. In science, competition is just like stress hormones: although harmful in excess, moderate levels prove beneficial. Competition encourages researchers to perform to their fullest ability and helps allocate resources to people and projects who can make more impactful contributions.

What, then, would a better system look like?

One example of a scientific prize done right is the Vesuvius Grand Challenge, which aimed to decipher text on burnt papyrus scrolls from ancient Rome. Instead of rewarding scientists for work that was important in retrospect, the Challenge set a series of clearly defined goals. Furthermore, the prizes were not awarded on a “winner-take-all” basis, which encouraged researcher collaboration. After all, for challenging scientific problems, the default case is that nobody solves them, so it makes sense for researchers to collaborate to increase the chances that the prize will be awarded.

To promote scientific progress, a small change in the granting of Nobel Prizes would make a big difference. Instead of focusing the awards on particular people, they should be given for particular discoveries, and each prize should be shared among everyone who made a meaningful contribution to that discovery. This includes lab chiefs, but also the researchers who actually carry out the work. Today, few people remember the names of Matsuo and Burgus, but without them, there would have been no Nobel for Schally and Guillemin. Although it may be difficult to set the threshold for “meaningful contribution,” this would certainly be better than the current system.

This call for reform may be wishful thinking. After all, Alfred Nobel’s will specified that prizes should be granted:

to those who, during the preceding year, have conferred the greatest benefit to humankind … one part to the person who made the most important discovery or invention in the field of physics; one part to the person who made the most important chemical discovery or improvement; one part to the person who made the most important discovery within the domain of physiology or medicine; one part to the person who, in the field of literature, produced the most outstanding work in an idealistic direction; and one part to the person who has done the most or best to advance fellowship among nations.

But already, the Nobel committees have expanded the number of laureates per prize from one to three, and waived the requirement that their discoveries were made “during the preceding year.” And the newest Nobel, the Nobel Memorial Prize in Economic Sciences, was first awarded in 1969. It is not too far-fetched to believe that the Nobel prizes could be reformed again. At the very least, a “Nobel Memorial Prize” could be established for other fields, including biology and computer science.²⁷

Looking Ahead

After the Nobel, both Schally and Guillemin continued their work on peptide hormones. Guillemin studied endorphins, and Schally explored potential applications of peptide hormone inhibitors in cancer treatment.²⁸ But in an ironic twist, neither of them identified the structure of CRF, the hormone which both had initially set out to solve.

In 1981, shortly after the publication of The Nobel Duel, Wylie Vale published the structure of CRF, a 41-amino-acid peptide, in the journal Science. As for GRF, the peptide that eluded Schally does in fact exist, and its structure was discovered independently by Vale’s lab and Guillemin’s lab, both in 1982.²⁹ Both Schally and Guillemin continued working into old age. Guillemin died in February 2024 at age 100, outliving his former student, Wylie Vale, by 12 years. Schally lasted a few months longer, dying in October 2024 at age 97.³⁰

In the years since The Nobel Duel was published, modern methods of molecular biology and proteomics have completely overtaken the traditional biochemical methods of hormone isolation and structure determination.³¹ And neither Guillemin nor Schally developed any of those traditional methods, instead using techniques that others (including Yalow) created. It’s safe to say that if Schally and Guillemin had not done any of their work, the structures of all the hormones they studied would have been discovered by 1990 at the very latest.³² Perhaps the development of drugs such as GnRH agonists would have been delayed by a decade or so, but overall, I think scientific progress depended more on the development of general methods rather than the knowledge of a few peptide structures.

Setting aside the history of the hypothalamus, The Nobel Duel is a cautionary tale about the interplay between the personal ambitions of researchers and the scientific system which awards prestige on a winner-takes-all basis. In the years since its publication, competition within science has only increased,³³ largely due to a growing number of researchers competing for a stagnant supply of grant money, as well as the pressures of patents and commercial licensing. With recent Nobel controversies (such as the 2024 Physics prize going to AI researchers, or the 2020 Chemistry prize omitting several worthy CRISPR researchers), the time is ripe for reform. Let’s hope that in the future, scientific success will be defined as lifting humanity up rather than pushing one’s colleagues down.

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This article is accompanied by an Interview with the author. Listen on Spotify or Apple Podcasts.

Metacelsus is a recent PhD graduate whose research focuses on growing human eggs from stem cells. He also writes the blog, De Novo.

Cite: Metacelsus. “The Nobel Duel.” Asimov Press (2025). DOI: 10.62211/32pt-67hj

Lead image by Ella Watkins-Dulaney.

Further Reading:

• Contemporary reviews of The Nobel Duel in JAMA (which thought it was “meticulously researched and brilliantly presented”), in NEJM (which praised the coverage of the science, but concluded that the author had gone too far in criticizing the duelists) and in the New York Times (which called it a “compelling account”).
• The Heart of the Brain (reviewed here) is a guide to the hypothalamus, and aimed at a popular audience.
• Laboratory Life: The Social Construction of Scientific Facts is a sociological study of the Guillemin lab conducted in 1979. I must point out that the sociological conclusions drawn by its authors are much less generalizable to other labs than the authors believed!
• A Conversation with Roger Guillemin (Annual Review of Physiology, 2013)
• Obituary of Roger Guillemin
• Obituary of Andrew Schally

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Footnotes

1. There are also prizes for Peace and Literature, as well as a “Nobel Memorial Prize in Economic Sciences.” Each prize can be shared by at most three people.
2. One-half of the prize was awarded to Rosalyn Yalow, a biochemist who developed ways to quantify peptide hormones using radioactive labeling. Yalow was the second-ever female laureate for the Physiology or Medicine prize; the first was Gerty Cori, who won jointly with her husband in 1947.
3. Notably, the size and morphology differs between males and females. This reflects the hypothalamus’ role in regulating sex hormones.
4. Marshall and Verney, 1936; Harris, 1937
5. Nerves connect to the posterior pituitary, which produces vasopressin and oxytocin. The anterior pituitary, which produces all the other pituitary hormones, lacks a direct nervous connection.
6. Selye’s approach was “essentially intuitive, based on observation and vast screening programs” to study stress response in rats, but Guillemin and Fortier both favored a deductive, rather than inductive, approach to research. Fortier kept the conflict mostly under control, and additionally saved Guillemin’s life by developing a new treatment when Guillemin fell ill with tubercular meningitis.
7. Now Vilnius, Lithuania, after Stalin changed the borders.
8. According to The Nobel Duel, “the invention of the accepted name for the hypothalamic hormones was a matter of such significance to Guillemin and Schally that they were still quarreling over it twenty-four years later.” Guillemin had proposed “hypothalamic hypophysiotrophic principles,” but Saffran’s “releasing factor” name caught on, probably because it was easier to say. For a similar nomenclature battle, see Anti-Mullerian Hormone vs. Mullerian-Inhibiting Substance (two names for the same reproductive hormone – AMH has largely but not completely won out).
9. Interestingly, Sephadex chromatography was mentioned in The Nobel Duel as an exciting new technique that Andrew Schally learned from a visit to Sweden in 1961. Schally and Guillemin withheld publication of their results using Sephadex to purify CRF in order to retain an advantage over competitors.
10. Guillemin described the process in an interview in 2013:
    
    Interviewer: Many young people will not realize you had to do these experiments in animals.
    
    Guillemin: Absolutely. A bioassay can give you a result usually in two days, when it’s very good. Some people used bioassays that would take a month to give a response. The only way we could look for this CRF was by studying the secretion of ACTH, which itself was ascertained by looking at the amount of ascorbic acid in an extract of the adrenal gland of hypophysectomized rats [i.e., rats where the pituitary had been surgically removed]. [It was] expensive because you had to buy hundreds of these hypophysectomized rats, which, by the way, you could buy as such. I knew how to do it, but when you need about 100 for a data point, it was easier to buy them as such.The most revolutionary method came a few years later, when Sol [Solomon] Berson and Rosalyn Yalow published their first result with what they called radioimmunoassays, which were actually an incredibly simple method. On top of that, they were thousands of times more sensitive than our bioassays.
11. Primarily because they can be easily removed from the skull. Other species, such as pigs, have a bone structure less suitable for dissection.
12. Guillemin’s TRF assay was an adaptation of a previously developed assay for TSH, which measured radioactive iodine in thyroid hormones.
13. Peptides are entirely made up of amino acids. Other non-peptide biomolecules (for example phosphatidylserine) can still contain amino acids, but at lower fractions. At the time, Schally wrote: “Purified material [TRF] appears to be not a simple polypeptide since amino acids account for only 30% of its composition”. This turned out to be incorrect.
14. This flaw in Guillemin’s character was not limited to Schally. As discussed in other parts of this review, Guillemin drove away several of his own biochemists by refusing to sufficiently credit their contributions.
15. This is illustrated by an exchange in which Guillemin requested a copy of some data which Schally had presented at a conference (and was thus obligated to provide, according to the conference rules). At first, Schally refused. Next, Guillemin sent another letter, appealing to Schally’s sense of honor as a scientist and asking for his cooperation. Schally replied that if “researchers choose to cooperate in a non-gentlemanly fashion (even though duels and wars in the past have been carried out according to a certain code of ethics), very often I have no choice but to use identical tactics myself.” After a third letter from Guillemin, Schally finally provided the data.
16. The junior researchers were generally less sanguine about the rivalry, and more interested in “getting the science done without acrimony.”
17. Franz Enzmann had noticed traces of a fatty acid in Schally’s sample of TRF. This turned out to be a contaminant, but the idea led Schally down the right path.
18. LRF is today known as gonadotropin-releasing hormone (GnRH) because it regulates the release of both LH and FSH (gonadotropin hormones) from the pituitary.
19. And not only for Guillemin, but for all the other researchers who had invested their efforts into determining the structure of LRF. The Nobel Duel mentions Harris as well as two other researchers, McCann and Fawcett, who fell short due to not having access to massive quantities of brains.
20. Which would win in 1978, a year after Schally and Guillemin.
21. Yalow co-developed her assay with Solomon Berson, who died in 1972 and was thus ineligible for the Nobel Prize.
22. Nicholas Wade interviewed Vale while reporting for the book, and wrote that Guillemin had “hinted plainly in several private discussions [with Vale] that Vale was expected to lead an attack on Burgus, and moreover, that this was a test of loyalty, for which failure would mean Vale’s expulsion from grace. Vale was not about to turn on his colleague Burgus. In what he said he essentially criticized Guillemin instead, knowing that in doing so he had crossed the Rubicon.”
23. I don’t think it’s entirely regression to the mean, though, because typically Nobels are given for work performed 10-20 years before the award, not 0-3 years before the award.
24. Szostak began his origin-of-life work several years before he won the Nobel Prize, in 2009. After the Prize, however, his lab has pretty much exclusively focused on it.
25. This is based on my experience working in the Szostak lab for a month as a rotation student in 2019, as well as following their more recent papers.
26. The Nobel Peace Prize is even more wacky in this respect: several laureates have gone on to commit atrocities.
27. This would certainly please chemists and physicists, who see Nobels in Chemistry and Physics being snatched up by biologists and AI researchers.
28. This has not led to any approved treatments, as far as I know.
29. The discovery was enabled through use of a pancreatic cancer cell line that produced large amounts of GRF (also known as GHRH). Guillemin describes more about how he got the tumor sample in his 2013 interview.
30. I started writing this review in 2022, after hearing about the book from Stephen Hammes at the Frontiers in Reproduction course. At the time, both Schally and Guillemin were still alive. As the saying goes, book review longa, vita brevis.
31. ​​As Guillemin himself reflected in a 2013 interview:
    
    "I never made the jump [to molecular biology] because I was intellectually too lazy to do it. Somebody like Wylie Vale did make the jump, and later on in his career, it became quite important. There’s no doubt in my mind that the type of biology that I did in those days, with all those years of effort, those tons of brain tissue, those millions of sheep brain — any postdoc or graduate student nowadays can do better than that with one pituitary hormone or one hypothalamus, based on the new technology of molecular biology. It’s a totally different world."
32. Structures of complex hormones such as basic FGF were already being discovered by the end of the 1980s.
33. Recent examples of competition I’m familiar with include: the development of synthetic embryo models (labs of Magdalena Żernicka-Goetz, Jacob Hanna, and others), split-pool single cell sequencing methods (labs of Jay Shendure and. Georg Seelig), bacterial genomic recoding (labs of Jason Chin and George Church), and genome editing tools (too many labs to count, really). Of course, scientific competition isn’t new (just look at Newton vs. Leibniz) but increased pressure leads to more of it.