Noel R. Rose, MD, PhD, is currently a member of the Department of Pathology at Brigham and Women’s Hospital, a position he refers to fondly as his “retirement job.” Over a career spanning more than 60 years, Rose has made seminal contributions to the field of immunology and the understanding of autoimmune disease. Rose has published more than 880 articles in peer-reviewed journals and has edited or co-edited 22 books, including the classic textbook The Autoimmune Diseases. In this Q&A with Brigham Clinical & Research News, Rose shares his insights, memories and reflections on a remarkable career in science.
Q: What brought you to the Brigham and what makes this place special to you?
NR: I retired from Johns Hopkins in 2015 after 60 years of uninterrupted grant support from the National Institutes of Health (NIH). I was determined not to start another lab — with so many young people competing for grants, that didn’t seem like the correct thing to do. But I didn’t want to cut myself off from science — that’s what I do, and it’s what I love. I had several interesting opportunities to consider, but when I met the Brigham’s chair of the Department of Pathology, Jeffrey Golden, MD, the decision was made. I came to the Brigham; it was such a welcoming place.
I co-teach a course each spring in clinical immunology at HMS and I treasure the opportunity to work with students, to talk with them about their research, to go to poster sessions and to hear them present. It’s a joy to work here. To consult, to teach, to do everything except run a lab.
Q: Do you see similarities or connections between the Brigham and Johns Hopkins?
NR: There is a deep historic connection between the two institutions. I was recently over at the Hale Building for Transformative Medicine and noticed a new exhibit featuring large paintings of three people: the first Brigham chairs of Pathology, Surgery and Medicine. All three were originally from Johns Hopkins.
The connections between the Brigham and Johns Hopkins are not accidental. Johns Hopkins University School of Medicine (JHUSM) was the first modern medical school, the first fully academic medical school, requiring a bachelor’s degree when it was established about 1893. The dean was William Henry Welsh, the chair of pathology. Having built the school, he had a lot to do with spreading the doctrine of academic medical education — most medical schools began to emulate the basic model of JHUSM. Harvard didn’t have a university hospital. The Peter Bent Brigham Hospital served that role and its dedication was given by Dr. Welch.
The Brigham is a Hopkins-like institution. Big universities can be huge and hard to grasp, but the Brigham is human sized. You feel part of a family here. People’s friendliness to a newcomer like me is very reassuring.
Q: Can you take us back to your time at University of Buffalo School of Medicine and your pioneering studies on autoimmune thyroiditis in the 1950s? What was the conventional wisdom about immunity at that time?
NR: After I graduated from Penn with a PhD, I moved to the University of Buffalo School of Medicine to complete medical school and joined the lab of Ernest Witebsky, MD, who was quite famous in those days. His research had led to better understanding of major blood types — A, B, AB and O — and he was also interested in antigens that were organ specific, those associated only with a certain organ in the body. He set me to work on an antigen that was specific to the thyroid and asked me to prepare this antigen, known as thyroglobulin, so that it was not denatured. With the pride of youth, I thought, “Of course I can do this,” I worked very hard to develop a method to make it in a pure form. A lot of benchwork went into this. I found that rabbits responded to thyroglobulins of all of the species that I tested.
In those days, we all believed in Paul Ehrlich’s theory (he was the greatest immunologist of the day) of ‘horror autotoxicus’: Animals won’t respond to the self because disease may result. Blood groups are an example where horror autotoxicus is true, so Dr. Witebsky’s life’s work depended on it.
Based on Ehrlich’s theory, if I made the thyroglobulin correctly, the rabbit won’t respond. So, when I got a response, Dr. Witebsky told me I must have mixed up the materials or denatured the protein. He suggested trying to inject thyroglobulin back into the very same rabbit; I still got a response.
Then I had an inspiration that changed the whole picture. If I inject a true auto-antigen, what would happen to the rabbit’s thyroid? It turned out that the thyroid became grossly inflamed or even destroyed. I was convinced: this was a real auto-antibody.
Q: What did you do to convince others?
NR: We did follow-up experiments, all showing damage to the thyroid gland and only the thyroid gland. It did exactly what an auto-antibody should do. At that point, even Dr. Witebsky said, ‘My boy, you’ve done it. You’ve demolished the dogma.’ We published the findings together. And we took our findings to a surgeon who performed many thyroid surgeries and he looked at me and said, ‘Kid, you’ve made Hashimoto thyroiditis.’ I had to look up what that meant. [Hashimoto thyroiditis is an autoimmune disorder that causes inflammation of the thyroid.] We then worked with endocrinologists to obtain serum samples from patients, which took a year to get — at that time, it was thought to be a very rare disease — and I tested them. They had the same kind of antibody to thyroglobulin.
Autoimmunization was a general phenomenon. Over the years, we reproduced it in other animal models and found that it occurs in many humans. We now know that autoimmune diseases affecting various organs are very common. Over 20 million Americans have an autoimmune disease.
Q: How were your findings received?
NR: I spent about 10 years expanding the work based on the thyroiditis story. I spent a second 10 years mostly looking at the genetics. At first, the immunologic world was suspicious of this whole business. To take one of the basic dogmas of immunology — horror autotoxicus — and turn it on its head, well…but eventually people bought into it. And the pendulum began to swing the other way, where people began to think that every unknown disease must be due to autoimmunity. We then had to push back and say, you must do the hard work and show that you can produce this disease by serum transfer or by experimental immunization.
Q: What advice would you give to the next generation of researchers and clinicians?
NR: I found it was advantageous to focus on a model I was very comfortable with. It was the thyroid for the first 30 years and the heart for the next 30 years. Use this model to ask up-to-date questions. You can only go so far with a model and then it loses its charm and you need to be very well informed and current on what the real questions in immunology or another field of biology are. If you can answer those questions using a model you’re very familiar with, that’s a good way to stay at the top of the field. You know your model better than anyone else knows it, but you’re asking novel questions that study sections [who review grant applications for the NIH] are interested in. That to me was the system for staying funded for all those years.