Translational medicine in rheumatology has benefitted from unsung but successful bridge-building efforts that facilitate mutually beneficial research relationships between basic scientists and clinicians working toward a common goal, and lately the fruits of such efforts have led to ground-breaking drug discoveries and therapeutic advances.
For rheumatology in particular, because the discipline encompasses multiple organ systems and diverse pathology, such translational research is critical for gaining an understanding of the complexities of the immune system and disease mechanisms and developing and testing treatment strategies, according to Dr. Iain McInnes, professor of experimental medicine and rheumatology at the University of Glasgow (Scotland). "It’s a simple concept, really. It’s the idea that we might understand more about the basic science pathways if we look at them operating in the real world. And it’s a two-way street. Basic science can in turn be informed by the clinical pathologic entity that people come to study."
Dr. Iain McInnes
Examples of "good translation stories," said Dr. McInnes, a clinician/scientist himself, include the tumor necrosis factor (TNF) blocking story and the interleukin-1 (IL-1) story. The development of the TNF blocking therapies, which have had a major impact on the treatment of rheumatoid arthritis and other inflammatory diseases, followed "a series of basic science and clinical medicine iterations, initially in the infectious diseases world and eventually in immunology and rheumatology," he said.
"The evolution of the IL-1 biology is an especially interesting translational story," Dr. McInnes acknowledged. Since it was first cloned in the 1980s, the cytokine family (IL-1a and IL-1b) was identified as a key player in regulating inflammatory processes. This led to the development of IL-1 inhibitors, which were tested primarily in rheumatoid arthritis, but with only modest success, he said. "But this helped investigators understand how IL-1 was synthesized and how its biology was regulated." Such insights eventually led to the development and testing of IL-1 directed agents such as anakinra and rilonacept in patients with hereditary autoinflammatory conditions and in nonhereditary inflammatory diseases associated with aberrant IL-1 signaling, including Mediterranean fever, Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease, and gout. In turn, the efficacy of IL-1 blockade in the treatment of many of these conditions "has changed the understanding of these disorders," he said, and has led to investigation IL-1’s role in other diseases, including adult-onset Still’s disease and systemic juvenile idiopathic arthritis.
The IL-1 story is "elegant science" with respect to the back and forth between the lap and clinical correlates, Dr. McInnes explained. "Although it ultimately did not lead to a good rheumatoid arthritis treatment, the continual cross talk allowed relevance to be maintained and clinical pathology to direct the lab focus over time."
Despite the successes, the bench-to-bedside lag is real and sometimes inevitable given the actual and perceived separation between basic science and clinical research. One of the fundamental reasons for the schism, according to Dr. McInnes, is that scientists and clinicians often don’t share the same philosophy. "We have to be careful about generalizations but, from an academic point of view, a basic scientist is driven by trying to answer a legitimate scientific question: Why is the sky blue? Why are daffodils yellow? How does this chemical activate this target cell?" he said. "So in our area of autoimmune research, a basic scientist’s approach to cytokine research would be, ‘I’m just going to keep chasing down this molecule and its biological effects until I get the answer.’ "
The clinical investigator, on the other hand, "is trying to understand the complex matrix of events that lead to the pathology or disease state, so he or she may well rely on a basic scientific pathway for a certain period of time, but if it turns out that the pathway is really not involved in the disease pathogenesis after a period of investigation, the clinician will part company with that scientist." So while the scientist presses ahead trying to answer the basic scientific question, the clinician investigators will be driven by where the disease takes them, he said.
The separation between basic science and clinical investigation is not deliberate as much as it is circumstantial, according to rheumatologist Dr. Bruce Cronstein, director of the Clinical and Translational Science Institute at New York University. "Many bench researchers are not aware of whom to contact among their clinical colleagues to best obtain relevant collaboration, and clinicians are also unaware of whom to contact among their bench research colleagues," he said. Further, in the United States, "rewards for collaboration have not aligned well with the clinic requirements. Increasing pressure to maximize income [both personal and institutional] by seeing more patients has diminished the time for clinicians to collaborate by gathering extensive data about patients or biosamples," he said.