David G. Schatz, PhD, chair of Yale School of Medicine’s immunobiology department, can explain mind-bendingly complex processes of the human body’s immune system in relatable terms. For instance, here is his description of a process that produces antibodies to fight viruses and bacteria as follows: “This immune system reaction treats the chromosome like a big long string. It comes in with molecular scissors, cuts the string, and then different enzymes come in and tie the string back together in a new configuration.”
What Schatz just described is called the variable, diversity, and joining, or V(D)J recombination process, and it allows T cells and B cells to randomly assemble different gene segments. As a graduate student at MIT in the lab of David Baltimore, a virologist who shared the 1975 Nobel Prize in Physiology or Medicine, Schatz established an assay to detect V(D)J recombination activity. Then, in collaboration with another doctoral student, he used this assay to isolate and discover two key enzymes in this process called RAG1 and RAG2. That groundbreaking contribution to the field happened almost 30 years ago. Schatz never slowed his pace.
Earlier this year, Schatz, the Waldemar Von Zedtwitz Professor of Immunobiology and professor of molecular biophysics and biochemistry, was elected to the National Academy of Sciences in recognition of his biochemical insights into RAG function and evolutionary origins. He was also a Howard Hughes Medical Institute investigator between 1991 and 2017; has been elected to the American Academy of Arts and Sciences; and is a fellow of the American Association for the Advancement of Science.
Yale Medicine Magazine caught up with Schatz, who earned his BS and MS degrees in molecular biophysics and biochemistry from Yale University in 1980, to learn more about the intricate processes of the immune system and what he values most in colleagues.
Has public awareness about the immune system and immunology changed during your career? Yes. The central driving trend for growing awareness has been a recognition that the immune system is involved—often quite directly—in almost every human disease. That’s particularly true for what we call the “diseases of modern society,” like obesity, diabetes, and heart disease. There’s also growing recognition of the process of inflammation and the role it plays in initiating or exacerbating diseases. Another major trend in awareness is within cancer immunology. Immunotherapy has revolutionized our thinking about cancer and how it can be treated.
How would you summarize your research focus now? I’ve gotten very interested in the question of how recombination processes evolved. They are so unusual that it immediately raises the questions: Where did they come from? How did the human body come to have these processes? We think we can trace the V(D)J recombination process to a piece of DNA known as a transposon. This is an autonomous, mobile piece of DNA that encodes an enzyme that’s able to bind to an element, snip it out of one location, float, and place it into another one. We believe that’s how the immune system can make hundreds of millions of different antibodies. Our antibody genes are broken up into discontinuous bits and fragments of DNA, and the enzyme comes along and allows those fragments to join in new configurations. So, we owe our adaptive immune system to this mobile DNA element that gave us the capacity to snip and cut and rearrange our DNA.
What comes to mind when you think about the microbiome and immunology? The microbiome has come onto the stage with incredible speed. Much like the immune system itself, which influences almost every process in the body, the microbiome—we are learning—affects so many different processes. There is incredibly sophisticated intercommunication going on between the immune system and the microbiome. In our own department, Noah Palm, PhD, assistant professor, is studying how the microbiome affects health and disease states in an area that few people think about, which is the metabolites that bacteria produce. These are small organic molecules that bacteria either have on their surface or secrete. We know virtually nothing about what these tens of thousands of chemicals tell our body, what they signal our body to do or to think. Noah is just beginning to explore the diversity of those chemicals and their effects.
What message do you have for today’s future scientists? Once, during a conversation with David Baltimore, I asked him what made a great leader. His answer was one word. “Generosity.” That succinctly captures much of what I admire in the great leaders I’ve known. I would like to convey the message that respect and a humble eagerness to learn from one another are incredibly important parts of doing science and being a scientist. Acts of kindness, sharing, cooperation, collegiality—all of these have an enormous impact on atmosphere, and ultimately, the productivity of the whole scientific endeavor. The brilliant ideas that drive science forward can happen at any time from any one, so you just need to make people as free as possible from stresses and pressures. The other point I would like to convey is the excitement that comes from learning something or discovering something no one else has ever known before. I would love to pass on that deep love of making new discoveries.