Thymopoietin

1966-1968

The Mystery in the Thymus

1966: Goldstein begins studying thymic germinal centres in myasthenia gravis patients

In 1966, a young Australian physician named Gideon Goldstein became obsessed with a puzzle. He was studying the thymus—a small organ tucked behind the breastbone—in patients with myasthenia gravis, a strange disease where muscles grew weak because the immune system attacked nerve-muscle connections. Goldstein noticed something odd: these patients had abnormal thymus tissue.

Why would a thymic problem cause someone's immune system to attack their own nerves? Goldstein suspected the answer lay hidden within the thymus itself. Perhaps the thymus made something—some kind of chemical message—that told the immune system what to do. Perhaps that message had gone wrong in myasthenia gravis patients.

Goldstein decided to find out. He traveled to the National Institutes of Health in Bethesda, Maryland, where he worked as a visiting scientist from 1967 to 1968. There, surrounded by some of the world's best immunologists, he began one of the most ambitious searches in thymic biology: finding the thymus's secret message.

He would spend the next several years hunting for a substance—any substance—that the thymus made. It would have to be small enough to travel through the bloodstream, powerful enough to control immune cells, and clever enough to explain both the immune system's normal job and its failures in disease.

What Goldstein didn't know yet was that he would find something even more remarkable: a five-amino-acid snippet with the power of a forty-nine-amino-acid protein, and a molecule that spoke two completely different biological languages at the same time.

1968-1975

The Extraction from Calf

1968-1974: Years of tissue extraction and purification work at NYU Medical Center

From 1968 onward, Goldstein moved to New York University Medical Center as a Research Associate Professor. His mission was clear: isolate whatever the thymus was making. The problem? The thymus made hundreds of different substances, and finding one specific immune hormone was like finding a single grain of sand on a beach.

Goldstein and his team began with calf thymus tissue—the same tissue that myasthenia gravis patients had in abnormal amounts. They ground it up, dissolved it, and ran it through filter after filter, column after column, trying to separate and purify the thymic materials. The work was tedious and frustrating.

By the mid-1970s, years of this painstaking work paid off. In 1974-1975, Goldstein finally isolated a pure substance. It was a protein made of 49 amino acids, weighing about 5,562 Daltons. They named it thymopoietin—the thymus's hormone that makes T cells. In 1975, they published their discovery in the Annals of the New York Academy of Sciences under the title 'The Isolation of Thymopoietin (Thymin)'.

But Goldstein's discovery had only begun. The real shock came when he and his team tested what this 49-amino-acid protein actually did. It didn't just affect T cells in one simple way. It had complex, elegant, and sometimes contradictory effects on the immune system.

Most surprising of all: when they tested smaller pieces of thymopoietin, they found that a five-amino-acid fragment—just amino acids 32 through 36—could do almost everything the whole 49-amino-acid protein could do. This small piece, which they called thymopentin or TP-5, seemed to hold the secret code of the entire molecule.

1975-1985

The Five-Amino-Acid Revolution

1974-1977: Goldstein becomes Professor at Sloan-Kettering Institute

In 1977, something remarkable happened. Goldstein moved to the prestigious Sloan-Kettering Institute for Cancer Research in New York. There, with improved chemical techniques, he and his team synthesized the five-amino-acid active fragment of thymopoietin: arginine, lysine, aspartate, valine, and tyrosine (Arg-Lys-Asp-Val-Tyr). They called it TP-5.

When they tested TP-5, they made a stunning discovery: this tiny five-amino-acid peptide could do everything the full 49-amino-acid protein could do. It induced T-cell differentiation. It enhanced suppressor T-cell function. It boosted natural killer cell activity. It even showed the same strange neuromuscular blocking effect.

This was revolutionary. In medicine and biology, scientists expected that you needed the whole protein to get the full effect. But thymopoietin proved this wrong. The active site was incredibly tiny—just two percent of the full protein's size—yet it contained nearly all of the biological power. This meant scientists could now manufacture TP-5 synthetically, which was much cheaper and easier than extracting it from cow thymus tissue.

In 1977, Goldstein patented thymopentin (TP-5). By 1985, he and his collaborator Tapan Audhya published a comprehensive review titled 'Thymopoietin to Thymopentin: Experimental Studies' that explained everything scientists knew about how these molecules worked.

The scientific world was amazed. Here was proof that sometimes nature hides its most important secrets in the smallest packages. A five-amino-acid peptide could reshape how scientists thought about immune regulation, protein function, and drug development.

1980-1996

Two Languages, One Molecule

1984: Goldstein publishes contrasting activities of thymopoietin vs splenin in PNAS

By the 1980s, researchers had figured out something extraordinary: thymopoietin spoke two completely different biological languages. On one side, it was an immune hormone that helped T cells mature and fight infection. On the other side, it was a neuromuscular blocker that mimicked myasthenia gravis weakness.

In 1988, scientists discovered why. Thymopoietin could bind directly to the nicotinic acetylcholine receptor—the tiny protein machine on muscle cells that receives signals from nerves. When thymopoietin bound to these receptors, it blocked the normal signal and paralyzed the muscle. This explained the original mystery: thymic problems in myasthenia gravis patients weren't just about immune dysregulation—thymopoietin itself had neuromuscular effects.

But here's where it gets even stranger: in 1990, scientists discovered that the thymopoietin gene didn't just encode thymopoietin. It also encoded a completely different set of proteins called LAP2 and TMPO—proteins that help hold the nucleus together as part of the nuclear lamina. One gene, two completely different proteins, made through different cellular mechanisms.

This dual identity fascinated researchers. How could one gene produce both an immune hormone and a nuclear scaffolding protein? How did nature hide two entirely different biological functions in a single stretch of DNA? What was the evolutionary logic behind this remarkable dualism?

Meanwhile, Goldstein was building on his success. After leaving Sloan-Kettering in 1978, he joined Johnson & Johnson and the Ortho Pharmaceutical division, eventually becoming Executive Vice President of the Immunobiology Research Institute. In 1996, he founded Thymon LLC to develop thymopentin further and explore its clinical potential in diseases beyond what had been tested before.

1992-2025

From HIV to Cancer: The Modern Era

1992: Double-blind HIV trial shows TP-5 maintains CD4+ cells in asymptomatic patients

In 1992, Goldstein and his colleagues conducted a landmark clinical trial with thymopentin in HIV-positive patients. Ninety-one men and women, half receiving TP-5 and half receiving placebo, participated in a double-blind study lasting up to 52 weeks. The results were encouraging: asymptomatic HIV patients receiving TP-5 maintained higher CD4+ T-cell counts than the placebo group.

More importantly, asymptomatic patients on TP-5 showed a slower decline in immunity—they took longer to lose 20% of their CD4+ cells. Two placebo-treated patients progressed to AIDS symptoms, while none of the TP-5 patients did during the study period. The drug was well-tolerated with no serious adverse effects. For the first time, a thymic hormone showed it could help preserve immune function in one of the most devastating diseases of the late twentieth century.

Around the same time, thymopentin was being used clinically around the world. In China especially, TP-5 became widely used for rheumatoid arthritis, AIDS, chronic hepatitis B, and cancer-related immunodeficiency. Clinical trials showed mixed but promising results in hepatitis B patients and those trying to prevent cancer recurrence.

By 2019, a new application emerged: thymopentin was shown to calm inflamed colons in mice and humans with colitis. The mechanism was elegant—TP-5 triggered the production of IL-22, a protective immune messenger that heals damaged intestinal tissue. This opened doors to using thymopentin for inflammatory bowel diseases.

In 2025, the newest research shows something even more exciting: thymopentin enhances antitumor immunity by rejuvenating the thymus and reprogramming T cells to be better cancer fighters. From the thymic mystery of myasthenia gravis to modern cancer immunotherapy, thymopoietin has traveled an extraordinary scientific journey. What began as Gideon Goldstein's search for answers in a tiny organ has become a tool for fighting some of humanity's greatest health challenges.