Noel Rose was an immunologist, not an endocrinologist, but we are privileged that his pioneering work which led to the discovery of autoimmune diseases was focused on the thyroid, giving our specialty a central role in the elucidation of these disorders. Until the 1950s, it was generally believed that the body did not attack itself as it did micro-organisms, a teleological principle first enunciated by Paul Ehrlich as “horror autotoxicus.” The manner of Rose’s momentous revelation tells you much about his qualities of genuine curiosity, challenging dogma, and brilliant experimentation.
Following a PhD in microbiology at the University of Pennsylvania, he was accepted into medical school at the University of Buffalo in 1951 where he joined the laboratory of Ernest Witebsky and began to study thyroglobulin as an example of an organ-specific antigen. Asked to make pure thyroglobulin, Rose tested his preparations for any denaturation by injecting them into rabbits, as an antibody response would imply a denatured protein according to convention. Intravenous injection showed, as expected, no antibody response, but subsequent experiments using an adjuvant to stimulate the immune system and injection into the animal’s footpad led to the entirely unexpected formation of antibodies. Witebsky initially doubted the findings – after all, he had worked with a former pupil of Ehrlich’s – and made Rose test again and again. Although he revered Witebsky, Rose later said that "he almost killed the whole story!” Finally Rose demonstrated that thyroglobulin injected back into the very same rabbit produced an antibody response, and then in a moment of true inspiration examined the thyroid. There was severe inflammation, demonstrating the response was no serological anomaly. When the slides were shown to a surgeon, he was told “Kid, you’ve made Hashimoto’s thyroiditis.” Rose had to look this up because it was rarely diagnosed at the time (and he had deferred the completion of his MD until 1964 to undertake his demanding experiments).
Inevitably, the seminal paper describing this work was rejected before finally appearing in the Journal of Immunology in June 1956. Deborah Doniach, who was working on Hashimoto’s thyroiditis in London, recalled Ivan Roitt coming across the paper in the “very slim, obscure journal at that time” and then “everything fell into place” – within days they had demonstrated thyroglobulin antibodies in patients and published this in The Lancet in October 1956. Rose himself was trying to do the same but only managed to collect sufficient samples to replicate the findings the following year.
Rose made many other fundamental observations in experimental autoimmune thyroiditis which have translated into the human equivalent. These include the recognition of genetic susceptibility, determined by both MHC and non-MHC genes, and the existence of autoreactive lymphocytes in healthy animals and hence active mechanisms for maintaining tolerance. Witebsky and Rose established the fundamental criteria by which a disease can be judged autoimmune in 1957; with revision, these criteria still apply today, and autoimmunity is now known to cause over 80 conditions.
Rose moved to Wayne State University in 1973 and to Johns Hopkins University in 1982. The second half of his long career was concentrated on another animal model, experimental autoimmune myocarditis, which allowed him to study the additional contribution of environmental factors. Remarkably, he held continuous funding from the NIH for 60 years, which he attributed to his persistence in studying up-to-date questions in the models he had become very familiar with. Aged 87, he “retired” from active research to teach immunology at Brigham and Women’s Hospital, as well as Harvard. He said “I didn’t want to cut myself off from science – it’s what I love.” Science loved him back.
Anthony Weetman, Sheffield
