Science is full of ideas that have been proven wrong. Up until the 1950s, one prevailing view among scientists was that the body could not produce antibodies against itself. This concept, known as horror autotoxicus, or the fear of self-toxicity, was coined in the 19th century by Paul Ehrlich, a German physician-scientist who was awarded a Nobel Prize for his contributions to immunology.
Nearly half a century later, horror autotoxicus was overturned by Ernest Witebsky, a protégé of one of Ehrlich’s trainees, with the help of Witebsky’s student, Noel Rose.
When Rose joined Witebsky’s lab at the University at Buffalo in 1951, Witebsky was studying organ-specific antigens—molecules that make different cell types functionally distinct. Witebsky was particularly interested in thyroglobulin, a large protein found exclusively in cells of the thyroid gland, and he gave Rose the task of identifying the properties that made this molecule unique to the endocrine organ. Rose extracted and purified the protein from various animals—including horses, pigs, and humans—and mixed each with Freund’s adjuvant, a solution containing dead bacteria that helps stimulate an immune response, before injecting it into rabbits. In response, the rabbits generated antibodies against the thyroglobulin as their immune systems reacted to the foreign substance.
“It really struck me that all of these very different animals would generate an immune response in the rabbit,” Rose says. Careful analysis of the thyroglobulin revealed that the protein was indistinguishable no matter which species it came from, raising a question for Rose: How was the rabbit able to distinguish its native thyroglobulin from the injected protein? He decided to repeat his experiment using thyroglobulin from a rabbit. Presuming the protein to be identical across all rabbits, Rose extracted it from one animal and injected it, along with Freund’s adjuvant, into another. Lo and behold, the rabbit that received the injection produced antibodies against the thyroglobulin derived from the donor rabbit.
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When Rose first showed the results to his advisor, Witebsky was in disbelief. “He said, ‘This is crazy. No one will believe this. How could this be?’” Rose recalls. Witebsky suspected that there must have been a mistake—that the thyroglobulin must have been denatured, for example. The young scientist went back to the bench and repeated the experiment, this time, using a more cautious method to ensure the protein was preserved. The results were the same. Following that, Witebsky told him to repeat the experiment once more, this time extracting thyroglobulin from a rabbit and injecting that protein back into the same animal. Even then, the animals developed antibodies against the protein when it was taken from the thyroid and introduced to another part of the body. “That was enough for Witebsky,” Rose says.
Some other scientists—including journal editors—refused to accept the findings at first. It took six years to publish the work, but when it finally appeared in print, the results shook the foundations of immunology. Rose had proved horror autotoxicus was wrong. And he wasn't alone. Another team, the UK scientists Deborah Doniach and Ivan Roitt, reported findings on autoimmunity around the same time.
“In every aspect, [Rose] is the father of autoimmunity,” says George Tsokos, a professor of rheumatology at Harvard Medical School. “The man opened a whole chapter in the book of medicine.”
Rose is more cautious about saying his work completely overturned Ehrlich’s on autoimmunity, explaining that Ehrlich’s original quote on horror autotoxicus may actually have been misconstrued. “If you read the whole paragraph in which he proposed this idea, he really never said that you couldn’t produce autoimmunity,” Rose says. “He said that if you produce it, it may be dangerous. So in many ways, Ehrlich may have been right.”
Rose grew up in Stamford, Connecticut, and caught his first glimpse into the hidden world of microorganisms in seventh grade. One of the science teachers at his school would bring in a personal microscope—and some of the students, including Rose, spent their spare time peering through it. The tiny creatures they saw captivated their young minds. “I became enraptured with the idea that there is another world around us that we don’t see,” Rose says. “It was something that raised my curiosity from the beginning and has been the theme of most of my career.”
I became enraptured with the idea that there is another world around us that we don’t see.It was something that raised my curiosity from the beginning and has been the theme of most of my career.—Noel Rose, Brigham and Women’s Hospital
After high school, Rose was accepted into a bachelor’s program at Yale University. It was the mid-1940s, and his father, a physician who had just returned home after serving as a medical officer during World War II, was reestablishing his clinic. This meant the family had little money to spare—but Rose was able to obtain a scholarship to help cover the cost of his education. “Without that, I certainly would not have been able to attend,” Rose says. “Those were very hard days.”
When Rose began his undergraduate studies, he wanted to pursue microbiology. But it was not yet a well-developed discipline, and there weren’t many courses on the subject, so Rose majored in zoology and took the microbiology classes as electives. Those classes were taught by researchers in the botany department, because bacteria were largely regarded as members of the plant kingdom at the time. It was in that department Rose met his first mentor: a doctoral student named Joshua Lederberg who would later go on to win a Nobel Prize for his discoveries in bacterial genetics. In those days, Lederberg let Rose and his classmates spend time in the lab where he worked, learning about his research. “He taught us how to think as scientists,” Rose says.
After completing his undergraduate degree, Rose was torn between going to medical school or to graduate school to focus on basic research. Rose had developed a strong interest in medicine due to the influence of his father. But the microscopic world still fascinated him and tugged at his desire to do research. MD/PhD programs weren’t an option back then, so Rose took the advice of a member of the medical school admissions committee at Yale, who suggested he obtain a PhD and then teach while working on a medical degree.
Rose started his PhD in microbiology at the University of Pennsylvania in 1948. At Penn, he joined the lab of the microbiologist Harry Morton and studied the bacterium Treponema pallidum, which causes syphilis. Culturing the organism and examining it under an electron microscope, Rose discovered that the microbe had flagella-like structures on its surface that drove it to whirl in a corkscrew motion.
While foraying deep into the world of microbiology research, Rose took premed courses with the intention of attending medical school. After obtaining his PhD, he was accepted into medical school at the University at Buffalo (UB) and moved there with his wife, Deborah, to earn his MD while teaching classes on the side for a small salary and waived tuition fees.
Rose arrived at UB in 1951. At the time, Ernest Witebsky, an immunologist who had fled Germany in 1936 to escape the Nazis, was one of the star scientists on campus. Witebsky’s claim to fame was research from his days at the University of Heidelberg, where he had characterized the cellular features that distinguish each blood group and act as antigens if introduced into individuals of differing blood type. Rose was drawn to Witebsky’s work and joined his lab, and it was during his first few years there that he conducted the critical experiments with thyroglobulin and rabbits, overturning the dogma of horror autotoxicus. But this was only the beginning of the story.
Rose went on to investigate the consequence of developing an immune response to substances made by one’s own body. To do so, he removed and studied the thyroid glands of rabbits that had been injected with their own thyroglobulin. Analyzing the tissue showed that the body’s own immune cells, recruited by antibodies, had infiltrated the organ and damaged it—and, in some cases, completely destroyed it. “That was really the major discovery,” Rose says.
Even though Rose and Witebsky knew they had landed on something big, the first journal to which they submitted their results dismissed them as utterly impossible findings—and told the authors they were probably mistaken. So Rose, Witebsky, and their colleagues went back to the lab to do more experiments. This time, their work linked the animal data with a human illness—Hashimoto’s disease, a condition marked by an inflamed thyroid gland (thyroiditis) that, at the time, had no identifiable cause. To make the connection, the team had examined serum samples from patients and tested them against human thyroglobulin and found that the blood developed the same type of antibodies identified in rabbits injected with their own thyroglobulin (JAMA, 164:1439–47, 1957).
“We went ahead and showed that this same destruction applies to humans and that you could induce a disease in an organ by immunizing it with a specific antigen of the same species,” Rose says. “And that was autoimmunity.”
“The findings and the work of Dr. Rose in those early years really set the stage for our understanding of autoimmune disease in the human,” says Joseph Bellanti, a professor emeritus in microbiology and immunology at Georgetown University. Bellanti, who was a medical student at UB when those discoveries were made, says that both Rose and Witebsky, and their work, influenced his own decision to pursue immunology research.
The work influenced many other researchers as well. In labs around the world, researchers began looking into other diseases where inflammation appeared with no apparent cause. In many cases, these turned out to be autoimmune diseases. The discovery also led to the swift rise of Rose’s career. Shortly after publishing the autoimmunity results in JAMA in 1957, he was invited to spend several months in Europe giving lectures about the discovery. “Suddenly, work came out of the walls,” Rose recalls.
Although he had proven himself a keen researcher, Rose did complete his MD in 1964 and remained at UB as a physician-scientist. During this time, he made another, somewhat serendipitous discovery. At a meeting at the Jackson Memorial Laboratory in Bar Harbor, Maine, he met researchers who were using histocompatibility antigens—tissue cell–surface “ID” molecules that, when closely matched, increase the success of organ transplants—to examine the genetic differences in cancer susceptibility in mice.
These antigens intrigued Rose because they seemed to offer a potential explanation for a puzzling finding: while most rabbits would develop an inflamed thyroid gland when immunized with thyroglobulin, some did not. Along with a postdoctoral fellow in his lab, Adrian Vladutiu (who passed away in 2014), Rose used mice to examine whether there was a gene that made the animals more vulnerable to the inflammation. Vladutiu’s experiments revealed that differences within the genes encoding for the murine major histocompatibility complex, H-2, determined how susceptible the mice would be to thyroiditis (Science, 174:1137–39, 1971).
In every aspect, he is the father of autoimmunity. The man opened a whole chapter in the book of medicine.—George Tsokos, Harvard Medical School
As his research progressed, Rose took a professorship at Wayne State University, where he remained for nearly a decade before joining the faculty at Johns Hopkins in 1981. At Hopkins, Rose shifted his focus from nature to nurture, searching for environmental, rather than genetic, triggers of autoimmune diseases. “There was still a big void—that is, even in the best-studied examples of thyroiditis, genetics was always less than half the risk,” Rose says. “We thought something from the environment must be involved.”
The group decided to focus on myocarditis, inflammation in the heart, because clinical evidence showed that patients typically had infections before developing the condition. Myocarditis has remained a primary focus of Rose’s lab for decades, with his team’s relentless work unravelling the causative roles of both genetics and a virus called coxsackie B.
For decades, Rose and his collaborators dug deeper into autoimmunity. In 2016, he became an emeritus professor at Hopkins. He and his wife moved to Boston, where he stayed connected to research, taking a part-time appointment as a senior lecturer at Brigham and Women’s Hospital. Still searching for answers at 92, Rose is passionate about using big data to study autoimmune diseases. He sees great potential in examining large databases of patient data to get at the question of why people develop certain autoimmune diseases and what types of treatment would be best suited for interrupting the development of these conditions.
“What we want to do is avoid the train wreck from the beginning, and I think we can begin to do that,” Rose says. “That’s what I’m excited about.”
Editor's note (June 17): The story was updated to recognize the work of UK scientists Deborah Doniach and Ivan Roitt on autoimmunity and to clarify that in 1951 the University at Buffalo was not yet a State University of New York school. UB became affiliated with SUNY in 1962. The Scientist regrets the oversight and error.