Endocrinology · 1960
Radioimmunoassay (RIA)
Through the 1950s, measuring hormone concentrations in blood was a laborious and insensitive undertaking. Bioassays required injecting plasma fractions into experimental animals and observing physiological responses, a process that needed substantial hormone quantities, took days, and could not be automated. For insulin specifically, the minimum detectable concentration by bioassay was well above the levels circulating in fasting healthy subjects, which meant that normal physiology was largely invisible to the available technology. Rosalyn Yalow, a medical physicist, and Solomon Berson, an internist, were working together at the Bronx Veterans Administration Hospital when they began investigating whether antibodies could serve as a more sensitive detection tool.
Their initial discovery was itself controversial. In 1956, studying diabetic patients who had received bovine insulin, they found that these patients developed circulating antibodies against the exogenous insulin, a phenomenon the scientific community was reluctant to accept because it implied that a small molecule could be immunogenic. The Journal of Clinical Investigation initially rejected that paper as implausible. Yalow and Berson persisted, and by 1959 they had worked out the competitive binding principle that became radioimmunoassay: labeled (radioactive) antigen and unlabeled antigen from an unknown sample compete for a fixed quantity of antibody, and the ratio of bound to free labeled antigen reveals the concentration of unlabeled antigen in the sample.
Their formal RIA paper, published in the Journal of Clinical Investigation in 1960, reported insulin detection at concentrations as low as a few picograms per milliliter, orders of magnitude more sensitive than any prior method. The assay required only a small volume of plasma, could be run in parallel on many samples, and produced quantitative results within hours. The immediate clinical implication was that fasting insulin levels in healthy and diabetic subjects could now be directly compared, which revealed that many type 2 diabetic patients had normal or elevated, not deficient, insulin levels, pointing toward resistance rather than deficiency as the primary mechanism.
Other investigators recognized almost immediately that the same competitive binding principle applied to any hormone for which an antibody could be raised. Within a decade RIA had been adapted to measure thyroid-stimulating hormone, cortisol, aldosterone, human growth hormone, parathyroid hormone, and dozens of other analytes. It also extended to non-hormonal molecules of clinical interest, including digoxin levels and, critically, hepatitis B surface antigen, which Baruch Blumberg identified using RIA techniques and for which he received the 1976 Nobel Prize.
Yalow received the Nobel Prize in Physiology or Medicine in 1977 for the development of RIA. Berson had died in 1972 and was therefore ineligible, since the prize is not awarded posthumously. Yalow consistently and publicly credited Berson throughout her career and named her laboratory at the Bronx VA after him. The technique itself has since been largely supplanted in routine clinical laboratories by enzyme-linked immunosorbent assays and automated chemiluminescent immunoassays, which avoid the handling of radioactive materials, but the competitive binding principle Yalow and Berson defined remains the conceptual architecture underlying all of them.
Key People
- Rosalyn Yalow — Medical physicist who co-developed RIA; Nobel laureate 1977
- Solomon Berson — Physician who co-developed RIA with Yalow at the Bronx VA
- Baruch Blumberg — Used RIA-derived techniques to identify hepatitis B antigen; Nobel 1976.
J Clin Invest. 1960;39:1157-1175.
Related landmarks
- 1971 · Schally and Guillemin: Hypothalamic Releasing Hormones (Endocrinology)
- 1982 · Recombinant Human Insulin (Humulin) Approval (Endocrinology)
- 1993 · DCCT (Diabetes Control and Complications Trial) (Endocrinology)
- 1994 · Discovery of Leptin (Endocrinology)