The Man Who Found a Hormone in a Gland Everyone Ignored

In 1974 the US Food and Drug Administration allowed an extract of calf thymus to be given to children. The children had primary immunodeficiencies — immune systems that had failed from birth — and the study, a first-phase trial at the University of California, San Francisco, was run under the first investigational new drug application ever granted for a thymic hormone preparation 3. The extract was called thymosin fraction 5. The biochemist whose group had learned to make it in quantity was Allan Goldstein, then at the University of Texas Medical Branch in Galveston, and within three years his laboratory would pull the first defined peptide out of it.

That peptide was thymosin alpha 1. Goldstein and his colleagues isolated it from fraction 5 and reported its full sequence in 1977: twenty-eight amino acids, heat-stable and strongly acidic, one of several peptides in the fraction thought to help regulate the maturation and function of T cells 2. Its synthetic form, under the name thymalfasin, became a medicine — first approved in China in 1996 and, by 2014, approved in some thirty countries 5 — but never in the United States, where it was found. How a thymus extract came to be called thymosin at all is told in a companion piece on this site; this is the story of the man behind it and of the long road from a gland to a pharmacy shelf abroad.

A young biochemist and an unfashionable organ

Goldstein came to the thymus in the early 1960s, at Albert Einstein College of Medicine in New York, in the laboratory of the biochemist Abraham White 3. The timing matters. In 1961 experiments had shown that removing the thymus from newborn animals devastated their capacity to mount immune responses 4. An organ long treated as a vestige was suddenly implicated in the central machinery of immunity, and nobody knew how it did its work.

White's group bet on a hormone. In a 1966 paper in the Proceedings of the National Academy of Sciences, with Goldstein among the authors, they described the preparation and partial purification of a thymic factor that stimulated lymphocytes, and proposed a name for it: thymosin 1. The trouble with that name is a story of its own. What concerns us here is the bet, and the man who spent the next half-century trying to make it pay.

Galveston, and an extract that could be made to order

By 1972 the team had moved to the University of Texas Medical Branch in Galveston, and it was there that they developed thymosin fraction 5 — a partially purified preparation suitable for clinical application 3. That phrase carries more weight than it seems to. A research extract only has to work once, in one laboratory, on one afternoon. A clinical material has to be made the same way every time, in amounts large enough to treat patients, from a starting tissue that varies from animal to animal. A later review by Goldstein's collaborators describes fraction 5 in exactly those terms: a preparation that could be made in large amounts and was suitable for clinical use 4.

It was still a mixture. Goldstein's own history of the programme describes fraction 5 as holding at least forty acidic polypeptides, spread across a wide range of molecular sizes 3. But it was a reproducible mixture, and in the 1970s reproducibility was what separated a laboratory curiosity from something a regulator would consider.

Children first

The first people to receive it were children with primary immunodeficiency disorders, under that 1974 investigational new drug application 3. It is easy to see why they were chosen. If the thymus issued signals that instructed lymphocytes, children whose immune systems had failed from birth were the population in which replacing those signals ought to show most clearly. It was also a population with few alternatives.

A report in the New England Journal of Medicine in 1975 documented what Goldstein's history calls the immunorestorative capabilities of fraction 5 in this setting 3. It is worth being exact about what a study of that era and size could establish. A first-phase trial in a small group of seriously ill children, with no randomised comparison, can show that a treatment is tolerated and that laboratory measures of immunity move. It cannot show that the treatment changes the course of disease. That distinction would follow the thymosins for the next fifty years.

Taking the mixture apart

Goldstein's decisive scientific contribution came next. If fraction 5 contained dozens of peptides, then the useful question was not whether the mixture worked but which of its components did what. In 1977 his group reported the isolation and sequence of the first of them, from the alpha region of the fraction's separation profile: thymosin alpha 1, twenty-eight amino acids long, heat-stable and highly acidic 2. It carries an acetyl group at its front end, and its molecular weight is a little over three thousand daltons 4.

Here a naming confusion began that has never been cleared up. The peptides of fraction 5 were labelled by where they ran in an electric field — an alpha series and a beta series — and numbered within each. Thymosin alpha 1 and thymosin beta 4, the peptide sold today under research names such as TB-500, share the word thymosin, a fraction of origin and nothing else of substance. They are different molecules, with different sequences and different jobs. A reader meeting the single word thymosin on a label, or in a headline, cannot tell which is meant.

A medicine, somewhere else

A defined sequence of twenty-eight residues could be made by chemistry rather than extracted from calves, and it was. Synthetic thymosin alpha 1, given the non-proprietary name thymalfasin, was commercialised by SciClone Pharmaceuticals under the brand Zadaxin. By 2014 it was approved in thirty countries, but almost all of its sales — ninety-seven per cent, by the company's figures as reported that year — came from China, where it had first been approved in 1996. The indications described included hepatitis B and C, liver cancer and other cancers, and use as a vaccine adjuvant 5.

At the end of the 1970s Goldstein had moved to George Washington University in Washington, where he chaired the department of biochemistry and later became professor emeritus 6. So the arc of his career ran from New York to Galveston to Washington, while the molecule he isolated found its largest market on the other side of the world.

Why the road ran east is partly a matter of regulatory systems and partly of disease burden, and it deserves care rather than a slogan. A regulator approves a medicine on the evidence submitted to it, against the standard it applies and the alternatives available to its patients. Chronic hepatitis B was, and remains, a heavy burden in China; a well-tolerated immune modulator had an obvious clinical case there that it lacked where other options were stronger. Nothing in that implies the Chinese approval was wrong or the American absence was right. It means that the same molecule, reviewed in different places, can reach different conclusions for defensible reasons.

The long afterlife of a molecule

Goldstein never let the subject go. With the Italian scientist Enrico Garaci he helped build an international symposium on the thymosins, alternating between Washington and Rome 6. In 2017 his university announced laboratory work suggesting that thymosin alpha 1 corrected genetic and tissue defects in models of cystic fibrosis and reduced inflammation, with a small first-phase trial planned in Naples 6. The molecule kept being brought to new diseases, which is what happens to a peptide that is well tolerated, cheap to make and approved somewhere.

Not every return visit has gone well, and the record should show that. When COVID-19 arrived, thymosin alpha 1 was used in China and studied. A retrospective analysis of 275 patients, 126 of whom received it, found no significant difference in the recovery of CD4 and CD8 T-cell counts between treated and untreated patients, and an association with slower viral clearance; the authors concluded it may not help restore those cells or speed clearance of the virus 7. A retrospective study cannot settle the question either way. It is, though, a useful corrective to the assumption that a molecule with a long history has a long record of proof.

What one career bought

Measured against the hypothesis that started it, the career is complicated. The thymus does instruct the immune system, but largely by educating T cells as they pass through it, not chiefly by secreting a hormone into the blood, and the single thymic hormone of the 1960s imagination was never found. Measured against what it produced, the career is plain. A crude extract became a reproducible clinical material; the material yielded a defined, sequenced peptide; the peptide became a synthetic medicine used in dozens of countries for three decades.

The questions it leaves are the ones a technical article has to take up. What thymosin alpha 1 actually binds; how an acidic peptide of that length is thought to act on the innate immune system's pattern-recognition receptors and on dendritic cells; why effects on immune markers so often fail to become effects on disease. Those belong to the immunopharmacology of the molecule — and that is where a technical account of it begins.