AWARDEES: Noel Rose and Ernest Witebsky
SCIENCE: Autoimmune Diseases
FEDERAL FUNDING AGENCIES: National Institutes of Health
It had to be a mistake – that was the first thought of Dr. Ernest Witebsky, a department chairman at the University of Buffalo known for his work on human blood cells.
Dr. Noel Rose, a new faculty member and part-time medical student, had observed something perplexing: an animal in the lab had developed an immune response to its own tissues. This unexpected finding went against everything that scientists understood at the time … and ultimately led them to the recognition of a new category of disease: the autoimmune diseases.
Rose, now 91, joined Witebsky’s department in Buffalo in 1951. “He was also my mentor, and I revered him,” he said.
Born in Frankfurt, Witebsky had left Nazi Germany in the 1930s and forged a new phase of his career in America, joining the University of Buffalo in 1936. His son, Frank – who became a microbiologist at the National Institutes of Health – recalled how much work in the lab meant to his father. Indeed, Witebsky was a respected investigator who had gained recognition for his pioneering studies on the substances (antigens) that induce an immune response in the body, and that distinguish blood group A from blood group B red blood cells.
When Rose joined the Witebsky lab, the team was working on a National Cancer Institute grant to study organ-specific antigens; that is, molecules that characterize different organs. One example is thyroglobulin, a substance produced by the cells in the thyroid gland, and the source of the thyroid hormone, thyroxine. Witebsky was hoping to figure out the biologic mechanisms behind organ-specific antigens, and perhaps even use them to screen for certain cancers.
As a new member of the faculty, Rose decided to focus on thyroglobulin as an organ-specific antigen that was already known to be mimicked in many different species. He tested thyroglobulins from various species by injecting them into rabbits, the technique designed to induce an immune response. All of the rabbits produced thyroglobulin-specific antibodies, the substance in blood that the body uses to fight off viruses and other outside invaders. Since all foreign thyroglobulins induced antibody production in rabbits, he wondered what would occur if he injected rabbit thyroglobulin into rabbits.
Something unexpected happened: the rabbit produced an antibody response.
This result was surprising because it went against all scientific doctrine at the time. The German scientist Paul Ehrlich, a Nobel Prize winner whose student, Hans Sachs, had mentored Witebsky, developed the concept of “horror autotoxicus” – the idea that the body could never react against itself. Thus, blood group donors of type A will never induce an immune response to type A antigen, although they induce a brisk response to group B antigen.
Again … and again and again
Since Rose hadn’t expected an immune response following immunization of the rabbit with rabbit thyroglobulin, he first thought something had gone wrong in the experiment. Witebsky agreed, and asked him to perform the experiment again … and again and again. He needed to make sure that they were seeing a truly novel phenomenon, termed autoimmunity, and not a mistake in experimental design. “It delayed my graduation from medical school for years,” Rose commented.
In fact, Rose gives great credit to Witebsky for saying no. “He taught me so much and I will always be grateful to him. But to be honest, he almost killed the whole story!” he chuckled. “Sometimes the best mentors are the ones who keep saying no. I learned from him how to do rigorous research.”
To dig further into this unexpected finding, Rose needed to determine if he had actually produced autoimmunity in the rabbit. He removed the rabbit thyroids and examined them microscopically. The glands of the immunized animals were grossly inflamed and, in some cases, virtually destroyed. He realized that he had now produced an autoimmune disease by experimental immunization.
Witebsky suggested one additional experiment before he was completely satisfied. “You must immunize rabbits with their very own thyroglobulin,” he said. That was quite a task. The thyroid of a rabbit is a tiny organ, and the entire organ could not be removed to prepare the thyroglobulin because the goal was to test for thyroiditis, inflammation of the thyroid gland. To do this experiment, Rose had to develop novel methods to immunize rabbits with small amounts of antigen and devise new, more sensitive tests for antibodies. After these methods were at hand, he was able to perform the experiment. He found that the serum, the fluid part of the blood, contained specific antibodies to thyroglobulin, and the thyroid was inflamed.
Subsequently, the team received serum samples from several patients with Hashimoto’s disease and tested their serum. Hashimoto’s disease, a human form of thyroiditis, is a major cause of low thyroid function, especially in women. Using his new test, Rose found antibodies that reacted strongly with human (and other) thyroglobulins. “You have,” Witebsky acknowledged, “fulfilled the postulates and proven that a human disease can be caused by autoimmunity.”
“Father of autoimmunity”
It wasn’t an easy road—“no one believed the results when we first presented them,” Rose recalled—but in a series of papers published between 1955 and 1958, a basic dogma of immunology was turned on its head. In an unexpected way, Rose had created an autoimmune disease in the laboratory and found that it replicated a well characterized human disease. Seizing on this discovery, other investigators showed that many other enigmatic diseases are related to autoimmunization.
Today, medicine recognizes more than 80 autoimmune diseases; some of the more commonly known ones include type 1 diabetes, lupus, multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis. This kind of disease affects more than 20 million patients in the United States alone, Rose estimated, and women account for the majority of known cases. There is still much to learn. We have little understanding of how the body actually distinguishes self from non-self, noted Rose.
Witebsky passed away in 1969 after making autoimmune disease a major focus of his research. He spent the bulk of his career at the University of Buffalo and continues to be recognized for his scientific achievements. The discovery also set the course of Rose’s career. He became an expert in autoimmune disease; in fact, he has been labeled “the father of autoimmunity.” Said former student Joseph Bellanti, who went on to direct the International Center for Interdisciplinary Studies of Immunology at Georgetown University Medical Center, “His iconic description and publication is one of the most important events that ever occurred in the field of autoimmunity, and set the stage for the studies that followed.”
After leaving Buffalo, Rose spent many years at Johns Hopkins, where he directed a large NIH-funded research laboratory and founded and directed the Autoimmune Disease Research Center. In 2015, Rose moved to Harvard Medical School, where he spends his time mentoring the next generation of autoimmune researchers. He is passionate in spreading the word about autoimmune diseases within the medical community, particularly through his book, “The Autoimmune Diseases,” co-edited with Ian Mackay. He also writes articles for public audiences and lectures to patient groups. Said Virginia Ladd, executive director of the American Autoimmune Related Diseases Association, “He travels all over this county to talk to patients for us. It’s amazing that he takes so much time to educate patients, and he does it very well.”
It was a federally funded experiment that seemingly went off track that illuminated a new concept of autoimmunity and autoimmune disease. The opportunity given to Rose as a young investigator by his chairman and mentor, Witebsky, to pursue an unexpected lead has paid dividends in terms of fundamental immunologic science and greater understanding of human disease—illustrating that the chance to follow up an unexpected finding can sometimes lead to a novel major discovery.