Hundreds of Thousands of Sheep Brains: The Nobel Duel That Gave Us Growth Hormone-Releasing Hormone

Some scientific races are polite. This one was not. In the 1960s and 70s, two laboratories, one in Houston and one in New Orleans, raced to identify the chemical messengers by which the brain controls the pituitary gland. The hunt consumed sheep, pigs, years, and a rivalry so intense that a journalist later wrote a book about it. The prize was a Nobel Prize, and the result was a set of molecules that remain central to endocrinology, including the family to which tesamorelin belongs.

The theory before the molecules

By the 1950s, the neurohumoral hypothesis proposed by Geoffrey Harris held that the hypothalamus, a small region at the base of the brain, secretes chemical signals into a tiny network of blood vessels that carries them directly to the pituitary gland. These signals, releasing factors, would tell the pituitary when to secrete its own hormones. It was an elegant theory with one problem: nobody had ever isolated one of the factors. They existed only as biological activity in crude extracts.

The brute-force era

The problem was one of quantity. The releasing factors are made in minuscule amounts. A single hypothalamus contains a vanishingly small fraction of a milligram of any given factor, and to determine a chemical structure by the methods of the time, you needed milligrams of pure material.

Roger Guillemin, a French-born physician and physiologist then at Baylor College of Medicine in Houston, and Andrew Schally, a Polish-born biochemist then at Tulane University in New Orleans, each concluded that the only path was to collect hypothalamic tissue by the ton. Guillemin’s laboratory processed enormous numbers of sheep hypothalami, obtained from slaughterhouses. Schally’s laboratory used pig hypothalami. Accounts of the project describe hundreds of thousands of fragments passing through a sequence of extraction and purification steps, each tracked using a bioassay that told the chemists which fraction still contained activity.

It was an industrial operation with a scientific purpose. Frozen tissue arrived at the laboratory in bulk. The reward for each stage of purification was a smaller volume containing a larger share of the activity, and eventually a tiny amount of pure material.

The first structure

The first prize was thyrotropin-releasing hormone, TRH, which signals the pituitary to release thyroid-stimulating hormone. When its structure emerged around 1969, it was a shock. TRH turned out to be a tripeptide, just three amino acids: pyroglutamic acid, histidine and proline, with the C-terminus amidated. The surprise was that a molecule so simple could be a hormone at all. Both laboratories reached the structure at about the same time, which fed the rivalry.

Next came gonadotropin-releasing hormone, GnRH, a decapeptide, with the structure published in 1971, and somatostatin, which inhibits growth hormone release, described by Guillemin’s group in 1973. In 1977, Guillemin and Schally shared the Nobel Prize in Physiology or Medicine for these discoveries, together with Rosalyn Yalow, who was recognized for the radioimmunoassay.

The one that would not yield

The factor everyone expected to find next was the one that stimulates growth hormone: GHRH, or GRF. Somatostatin had been found, and its antagonist, the releasing hormone, was assumed to be close behind. Yet it kept slipping away. Hypothalamic extracts showed GHRH activity, but the quantities were small, the molecule was sticky and unstable, and purification repeatedly failed. For roughly a decade after somatostatin, the search had no result.

A tumor provides the answer

The breakthrough came from an unexpected source. Physicians treating patients with acromegaly, a condition of excess growth hormone, found that a few of them had tumors not of the pituitary but of the pancreas, and that these tumors seemed to secrete something that drove the pituitary into overproduction. The inference was striking: the pancreatic tumors were making GHRH ectopically.

Tumor tissue removed at surgery was a far richer starting material than hypothalamus, because the tumor was producing the factor in bulk. In 1982, research groups working with tumor tissue from patients with acromegaly, including Guillemin’s group at the Salk Institute, extracted and sequenced the peptide. Related work from a second Salk group (Wylie Vale, Jean Rivier and colleagues) and from clinical collaborators who supplied the tumors reported the same molecule around the same time. The result was a 44-amino-acid peptide, GHRH(1–44), with shorter fragments retaining the activity. The race that had begun with sheep brains ended with a human pancreatic tumor.

From structure to analog

Once the sequence was known, chemists could do what they do: modify it. Native GHRH is rapidly degraded in blood, in part by an enzyme called dipeptidyl peptidase IV (DPP-IV) that clips two residues from the amino-terminus. A series of analogs were designed to resist this attack. Tesamorelin is a modified form of GHRH(1–44) in which a small trans-3-hexenoyl group is attached to the first amino acid, a chemical cap that shields the N-terminus. The goal was a more stable GHRH-receptor agonist for research and later pharmaceutical development.

What the story teaches

• Bioassay-guided purification works, but it is expensive. The sheer volume of tissue required explains why recombinant and synthetic production were revolutionary.
• Look for natural experiments. The ectopic-hormone tumor was a nature-made enrichment of the target.
• Competition drives science and distorts it. The Guillemin-Schally rivalry accelerated discovery and also produced bitter disputes over credit. Reading both laboratories’ papers side by side is a useful exercise in understanding how priority and independent confirmation interact.
• Design follows structure. Once a sequence is known, rational modifications become possible.

For researchers working with this GHRH analog, specifications and batch documentation are on the Tesamorelin 10mg product page.

All Lucid Aminos products are sold strictly for laboratory research use. They are not drugs, dietary supplements or food, and they are not for human or veterinary use. This article is a historical and educational account and is not medical advice.