The Hormone Harvested From the Dead

In the spring of 1985, clinicians in San Francisco were caring for a young man dying of Creutzfeldt-Jakob disease, a degenerative brain illness that almost always strikes people in their sixties and seventies. As a child he had received growth hormone, and the hormone had been extracted from human pituitary glands removed at autopsy and pooled in batches 3. The report they wrote that year raised the possibility that the two facts were connected. By the end of the year the programme that supplied the hormone in the United States had been halted, and a replacement made in bacteria had been approved.

How a medical programme that collected glands from the dead came to exist, why it was ended in a matter of weeks, and what it left behind in the way peptides and proteins are made, is one of the central cautionary stories of twentieth-century pharmacology. It is told here as history only: of an institution, a disease and a manufacturing choice.

1958: a hormone that only worked if it was human

Growth hormone was one of the first pituitary hormones to be purified. By the 1940s it had been prepared from cattle, and it could be shown to make young laboratory animals grow. But the animal hormone did nothing in a child. Growth hormone is strongly species-specific, and with the exception of primates, hormone from another animal is not recognised by human receptors. If a child's own pituitary failed to make it, the only hormone that could stand in was human.

In 1958 Maurice Raben, an endocrinologist in Boston, reported the first treatment of a patient with hypopituitary dwarfism using human pituitary growth hormone prepared from glands removed at autopsy 1. Nothing in that report was industrial. The material came from a small number of glands, by an extraction method adapted from Choh Hao Li's laboratory in California. But it demonstrated the principle, and the principle created a problem: a single patient used the hormone from many glands, and the glands could only come from the dead.

The glands: a national collection effort

What followed in the United States was a public programme, financed by the federal government and known as the National Hormone and Pituitary Program, or NHPP. Glands were collected from autopsies, processed into purified hormone, and distributed through physicians to children whose growth had failed for want of it 2.

The logistics were considerable and the arithmetic unforgiving. Each gland is the size of a pea and yields a very small amount of hormone. Supply was limited by how many glands pathologists could collect, and for years the limit was the number of children who could be treated. Because the pituitary produces many hormones, the glands were also a source for other preparations, and the programme served researchers as well as clinicians.

A programme for 7,700 children

From 1963 to 1985 the programme distributed pituitary growth hormone to nearly 7,700 people in the United States, and by the time it ended the Department of Health and Human Services still held names and addresses for 6,272 of them 2. The patients were overwhelmingly children, and the people who ran the programme thought of it, with reason, as a success of public medicine: a scarce material fairly allocated.

One feature of the process matters for what came next. The hormone was extracted from large pools of glands, because it would have been impractical to process each person's gland separately. That is efficient. It also means that one unrecognised problem in one gland could reach every vial made from the pool. The NIDDK notes that before 1977 glands were often processed repeatedly to wring out as much hormone as possible 2; a further purification step was introduced that year.

Three deaths in 1985

Creutzfeldt-Jakob disease is caused by a misfolded form of a normal brain protein, called a prion, which can convert its normal counterpart into the same abnormal shape. It is rare, fatal and, in its usual form, a disease of old age. A person in their twenties dying of it would be remarkable. Three of them, all of whom had received pituitary growth hormone, was a signal that could not be explained by chance.

The New England Journal of Medicine carried the first detailed case report, of a young adult with childhood hypopituitarism, that spring, and raised the possibility that cadaveric hormone was the route of infection 3. The Centers for Disease Control reported the finding in its weekly surveillance bulletin, describing fatal degenerative neurological disease in patients who had received pituitary-derived hormone 4. According to the NIDDK, health officials learned that three young men treated with the hormone had died of the disease, and they stopped distribution at once 2. The pooled-source problem explained how the contaminant reached young recipients: it required only one affected donor in a pool of thousands.

October 1985: the first recombinant hormone

The reason the halt did not leave a generation of patients without a hormone is that there was already a replacement in advanced development. Through the early 1980s, Genentech and others had been working out how to make human growth hormone in bacteria by inserting the human gene, an approach that had already delivered recombinant insulin. In October 1985, months after the deaths were recognised, the US Food and Drug Administration approved Genentech's recombinant product.

The significance for the history of peptide and protein manufacture was immediate. A product made in a fermenter, from a defined genetic sequence, has no human tissue in it and so cannot carry an agent from a donor. The story of that shift, and what it required, belongs to the article on the cell that makes the peptide instead. What is relevant here is that the cadaver programme and its replacement overlapped by only a few months, and that the replacement had been in development before the deaths were recognised.

The long tail

The deaths did not stop in 1985. Creutzfeldt-Jakob disease acquired from contaminated hormone can have an incubation period measured in decades, so recipients exposed as children continued to fall ill into adulthood. The NIDDK reports 36 cases among the US recipients of the NHPP hormone 2. Other countries that had run their own collection programmes saw cohorts of their own affected, and the number of cases varied with the size of the programme, the sources of the glands and the purification methods in use.

In 2015 a group at University College London reported an unexpected finding in the brains of eight people who had died of the disease in the United Kingdom after childhood treatment with cadaveric hormone. Several showed deposits of amyloid-β, the protein associated with Alzheimer's disease, in a pattern unusual for their age. The authors suggested that amyloid-β seeds, as well as the prion, might have been present in the preparations 5. They were careful to say that the finding did not show that Alzheimer's disease is transmissible in any ordinary setting, and that no such conclusion should be drawn for current treatments. It is a finding about a particular historical exposure and a small group of patients.

What the episode changed

The lessons were not about growth hormone as a molecule. They were about sources. Any product extracted from human or animal tissue carries the possible burden of whatever was in the tissue, and pooling multiplies the risk. After 1985 the field accelerated its move away from extraction towards recombinant and, for short sequences, chemical synthesis, where the product is assembled from defined starting materials and where the manufacturing record can account for every step.

The same reasoning shapes how regulators now treat biological source materials, and why documentation of origin is a routine requirement for any peptide or protein medicine. It also explains a quieter feature of the modern literature: the insistence, when a peptide is described, on how it was made and from what. The cadaver programme is, in this sense, the reason the question is asked.

Where the chemistry articles begin

Growth hormone is a protein of 191 amino acids, much longer than anything that can be made efficiently by chemical synthesis, which is why the replacement had to be a recombinant one. The companion articles on this site pick up at that boundary: what a cell can make that a synthesiser cannot, how a peptide is built when the sequence is short enough to assemble chemically, and how purity is established in both cases. They begin where this one ends, with a hormone made from a sequence rather than from a donor.