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E. Rinderknecht is the first-listed author of primary studies with R. E. Humbel that chemically characterized serum polypeptides with insulin-like and growth-promoting activity. Their 1976 amino-terminal sequencing paper compared two preparations then called NSILA I and II and proposed the designation insulin-like growth factor from their biological properties and resemblance to insulin.^[ref]

Of the first thirty-one residue positions examined, twenty-two were identical between the two polypeptides. That is about $71\%$ identity over the measured segment: substantial similarity, but not identity of the entire molecules. The measured segment and the comparison being made must therefore accompany any percentage. The later complete sequence of insulin-like growth factor 1 supplied a more extensive chemical description.^[ref]

The scientific contribution is a shift from classifying preparations by their effects to distinguishing specific related proteins. Shared biological activity, shared amino-terminal residues and a complete molecular sequence are progressively different kinds of evidence; none should be silently substituted for another.

Growth hormone is a protein hormone synthesized and released by the anterior pituitary. It regulates body growth and metabolism, acting on tissues directly and partly through insulin-like growth factor 1 produced by the liver and other tissues. Its release is controlled by signals from the hypothalamus, including inhibition by somatostatin.^[ref]

This makes “growth” a coordinated physiological response rather than merely a change in one chemical concentration. Growth hormone can initiate signaling in one tissue, while a second circulating signal influences other tissues. Negative feedback connects the resulting signal levels back to their control pathway.^[ref]

A revealing molecular experiment determined the structure of human growth hormone bound to the extracellular portions of the growth hormone receptor. The 2.8-angstrom X-ray crystallography structure contained one hormone molecule and two receptor portions. Two different surfaces of the hormone contacted the receptor partners. This provides a concrete example of a signaling molecule organizing a multi-part complex, rather than simply occupying one isolated pocket. The structure supported a model for receptor association; establishing the full sequence of activation in a living biological cell requires additional functional experiments.^[ref]

Insulin-like growth factor 1 is a peptide hormone and growth mediator associated with growth hormone action. The liver supplies an important circulating source, and IGF-1 signalling helps coordinate growth of tissues including cartilage and bone. The regulatory pathway therefore connects a pituitary signal with growth-related responses in other tissues.^[ref]

The motivating experiment was to look for a measurable activity in blood serum. A 1957 report by W. D. Salmon Jr. and William Daughaday examined a hormonally controlled serum factor through sulfate incorporation by cartilage in vitro.^[ref] In his later account, William Daughaday described cartilage culture and sulfate uptake as the readout that motivated the hypothesis of a serum mediator of growth hormone action.^[ref]

This was a functional assay: it detected what a serum preparation did to a tissue. Identifying the responsible molecules required further biochemical work. In 1978, E. Rinderknecht and R. E. Humbel reported structural homology between serum-derived IGF-I and proinsulin, providing a molecular basis for the insulin-like designation.^[ref]

The historical progression connects three kinds of evidence: pituitary control, a tissue response to blood serum, and molecular identification of a protein. A serum bioactivity measurement and a measurement of one purified hormone answer different experimental questions.

R. E. Humbel coauthored experimental work identifying the chemical structure of human insulin-like growth factors with E. Rinderknecht. Their 1978 study determined the complete sequence of serum-derived insulin-like growth factor 1: a single chain of seventy amino acid residues connected by three disulfide bonds.^[ref]

The comparison with proinsulin connected a biological activity to a molecular relationship. Corresponding regions resembled the insulin chains, while an intervening connecting segment remained in the growth factor. Conserved residues were compatible with a related folded structure; sequence similarity was evidence for that inference, not an atomic structure determination.^[ref]

This research illustrates why a bioassay and sequence analysis complement one another. Two preparations can produce similar responses without containing identical proteins. Establishing residue order and covalent connections provides an independent way to distinguish related signaling molecules.

W. D. Salmon Jr. coauthored the 1957 report A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro by W. D. Salmon Jr. and William Daughaday. The work helped motivate the idea that some effects of growth hormone are mediated by a factor carried in blood serum, rather than being explained solely by direct growth hormone action on every responding tissue.^[ref]

The experimental distinction was between applying growth hormone directly to isolated cartilage and measuring the response to blood serum from an animal exposed to the hormone. Sulfate incorporation provided a measurable tissue response. In William Daughaday's retrospective account, this supported the circulating-mediator interpretation that developed into the somatomedin hypothesis and research on insulin-like growth factor 1. A tissue response establishes biological activity; it does not, on its own, establish the chemical identity or purity of a single molecule.^[ref]

William H. Daughaday was a researcher in endocrinology whose work helped connect growth hormone to circulating growth-promoting factors, including insulin-like growth factor 1. He became the founding chief of Washington University's Metabolism Division in 1951 and later led its diabetes and endocrine research centers. The division's institutional history also credits his work on corticosteroid-binding globulin and early measurements of growth hormone and prolactin.^[ref]

With W. D. Salmon Jr., Daughaday investigated why blood serum could stimulate sulfate incorporation in isolated cartilage. The resulting somatomedin hypothesis made an important conceptual separation: a hormone released by one organ can act through another circulating signal. Daughaday's 2000 retrospective describes the historical experiments behind that interpretation; later identification of insulin-like growth factor 1 gave a molecular identity to an important part of this activity.^[ref]

The distinction remains useful when interpreting experiments: observing a growth hormone-dependent response in a whole animal does not show that growth hormone acts directly on the responding tissue.