Solomon Berson (1919-1972) and Rosalind Yalow (1921-2011) invented the principle of radioimmunoassay which revolutionised endocrinology. Berson was raised in New York City and in 1950, when most hospitals were scrambling to set up radioisotope services, was appointed to the staff at the Veterans Administration Hospital in the Bronx where he joined Yalow who had a PhD. He was so clever that he gave everyone else in the lab, except Yalow, an inferiority complex. What is extraordinary is that Berson's research skills were essentially self taught since he entered research directly from clinical medicine. He was an accomplished violinist and chess player as well as being a top flight mathematician. When he went on holiday he took four or five books on higher mathematics with him. He would undoubtedly have shared the Nobel Prize with Yalow, probably before 1977, had he not died suddenly shortly before his 55th birthday.
Solomon BersonThe first of 200 papers by Berson and Yalow appeared in Science in 1951 and was entitled “The use of K42 -tagged erythrocytes in blood volume determinations”. This was followed by work on thyroid physiology. Berson did not have any training in endocrinology and why they became interested in diabetes and insulin is not clear. One possibility is because Yalow’s husband Aaron had been an insulin dependent diabetic since 1932, although Yalow’s biographer, Eugene Strauss suggests that the stimulus was a 1952 paper in which Arthur Mirsky (1907-1974) hypothesised that type 2 diabetes was due to abnormally rapid degradation of insulin by insulinase. If this was right, disappearance of insulin from the circulation would be faster in type 2 diabetes than in type 1 or normal subjects. Berson and Yalow labelled insulin with I131 and injected it into normal subjects, hospital patients with diabetes and a schizophrenic who had had insulin shock treatment for 6 weeks.
Contrary to Mirsky’s hypothesis, they found that insulin disappeared rapidly in normal subjects and diabetic patients who had not been treated with insulin. In diabetics on insulin for more than a few weeks and in the schizophrenic it disappeared much more slowly. To approach this problem they invented a new method of electrophoresis which separated molecules of different sizes, in this case plasma proteins. Insulin in the serum of insulin treated diabetics migrated with the gamma globulin fraction and Berson and Yalow deduced that this was because it was bound to antibodies. This was contrary to received wisdom that only large proteins could be antigenic. Their findings were eventually published in a 1956 paper in the Journal of Clinical Investigation (JCI) entitled ‘Insulin I131 metabolism in human subjects: demonstration of insulin-binding globulin in the circulation of insulin-treated subjects.’  The editors were so offended by the idea that insulin might be antigenic that they only agreed to publish the paper on the condition that the word ‘antibody’ was removed from the title. The editor in chief wrote to the authors:
“I regret that the revision of your paper entitled “Insulin I131 metabolism in Human Subjects: Demonstration of Insulin Transporting Antibody in the Circulation of Insulin Treated Subjects” is not acceptable for publication in the Journal of Clinical Investigation….The experts in this field have been particularly emphatic in rejecting your positive statement that the “conclusion that the globulin responsible for insulin binding is an acquired antibody appears to be inescapable.”
Within a few months their observations were confirmed by others and the JCI published their next paper entitled “Ethanol Fractionation of Plasma and Electrophoretic Identification of Insulin Binding Antibodies” without a whimper. During the next few years Berson and Yalow studied the reaction of various species of insulin and, inter alia, found that guinea pig antibodies to pork insulin reacted very strongly with human insulin. This led them to devise the radio-immunoassay in which they used guinea pig antiporcine insulin serum and I131 labelled porcine insulin. Immunoassay uses the principle of competitive inhibition in which the ability of unlabelled insulin to compete with Insulin I131 for antibody is measured. This is based on the fact that insulin antibodies at very low concentration can be detected in the absence of precipitation by their ability to react with Insulin I131. This labelled antigen-antibody complex formation is decreased on the addition of unlabelled insulin.
They first used their assay to measure the concentration of endogenous insulin in human plasma. This paper holds the record as one of the most cited articles in the JCI – 2,341 times as of 2004. Among their early important findings was that diabetics with moderate glucose intolerance were hyperinsulinaemic whereas more severe glucose intolerance was associated with insulin deficiency. They also showed how measurements of plasma insulin made it possible to distinguish between insulinomas and other forms of fasting hyperglycaemia. After insulin, the radio immunoassay was extended to virtually all other peptide hormones and resulted in a revolution in endocrinology.
^ Berson SA, Yalow RS, Baumann A, Rothschild, Newerly K. Insulin –I131 metabolism in human subjects: Demonstration of insulin binding globulin in the circulation of insulin treated subjects. J Clin Invest 1956; 35: 170-190.
^ Yalow RS, Berson SA. Immunoassay of endogenous plasma insulin in man. J Clin Invest 1960; 39: 1157-75.