Collaboration Is Key to Breaking New Ground in Genomics
Daniel L. Kastner, MD, PhD, Scientific Director for the Intramural Research Program at the National Human Genome Research Institute (NHGRI), received the 2019 Ross Prize in Molecular Medicine — an honor established by The Feinstein Institutes for Medical Research and the Springer Nature journal Molecular Medicine — for his pioneering work on the genomics of auto-inflammatory diseases. “The Ross Prize is the most memorable, exciting, rewarding prize that I have ever received,” declared Kastner.
In the 1990s, Dr. Kastner led an international consortium that identified the gene responsible for familial Mediterranean fever (FMF), a rare inherited disorder characterized by recurrent fevers and severe inflammation.
What makes Dr. Kastner unique is that he is a master in bringing people together, helping them to leverage complementary strengths and achieve a common goal. This manifested in the international FMF consortium, comprising six groups with a total of 46 collaborators located in Israel, Australia and four centers around the United States. “Ideal collaborations are win-win propositions,” said Kastner, and “trust is the currency of the realm.”
The endeavor was a resounding success. It also laid the groundwork for the identification of the tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a second periodic fever syndrome beside FMF, which led to the novel concept of an emerging family of autoinflammatory diseases.
Inflammation is now thought to play an important role in a number of rare monogenic diseases akin to FMF and TRAPS, as well in more common and genetically complex diseases like gout.
Colleagues of Dr. Kastner, like Dr. Luke O’Neil from Trinity College Dublin, take the bold position that addressing inflammation could impact any number of ailments. Certainly it is the case that inflammation plays an important role in several common diseases such as atherosclerosis and cancer. However, “the inflammatory process is a double-edged sword” warned Kastner. Indeed, dampening patients’ autoinflammatory diseases with anti-inflammatory agents brings them to a normal, base-level of immunity — and may even be protective against other inflammation-mediated disorders. But in most individuals, a blanket prescription of anti-inflammatories could prevent their immune systems from performing its most basic and necessary function: fighting off microbial infections.
Looking ahead, Dr. Kastner developed a clinical infrastructure at the National Institutes of Health (NIH) to examine patients with undiagnosed inflammatory diseases, using genetics to identify the cause of rare diseases and autoinflammatory disorders. As of 2019, the inflammatory diseases section has seen over 2,000 patients, referred from around the world. This prolific program led to the identification of more than 15 new diseases, and over half of them now have effective therapies.
Treatments for these diseases, such as cytokine inhibitors or JAK-kinase inhibitors, target the molecular pathways involved, but are only effective for as long as patients take them. Thus, curative measures such as bone-marrow transplants, or potentially gene therapy, are attractive to patients and their families. But these are not without risk, advised Kastner. For inflammatory diseases caused by mutations in white blood cells, bone marrow transplants are appealing and logical in lieu of a lifetime of treatment. However, depending on the clinical circumstances, this measure may come with a significant mortality rate, he explained. It is difficult to justify such risk if patients are responding to effective drugs such as colchicine (for the control of FMF), with no reported long-term side effects in the last 50 years. Dr. Kastner is constantly working to weigh these risk-benefits with his patients.
Dr. Kastner shared that he owes a debt of gratitude to Dr. Robert Rich, his first research mentor at Baylor College of Medicine, who not only allowed him, but also expected him to follow his interests independently as a young scientist. Dr. Rich also urged him to go back to medical school after his PhD, to apply his new knowledge to the care of patients. Kastner continues this tradition, constantly moving between the bench and the bedside in his continued quest to understand inflammatory disease.