Thomas L. Rothstein, MD, PhD, has always had intense curiosity as to how things work.
Paired with his strong interest in science and medicine, Dr. Rothstein has dedicated his life to the pursuit of alleviating human suffering, practicing internal medicine for nearly two decades while running a research lab at Boston University before migrating to full lab work at the Feinstein Institute for Medical Research and now, Western Michigan University Homer Stryker M.D. School of Medicine (WMed).
“The connection of our research to clinical outcomes is very important to me,” said Dr. Rothstein, who serves as chair of the Department of Investigative Medicine and leads the Center for Immunobiology at WMed. “It's very important for me to find scientific advances that can be translated into therapies for human disease that alleviate suffering.”
Dr. Rothstein earned his MD and PhD degrees through the Medical Scientist Training Program at Duke University, completed advanced clinical training in Internal Medicine and Hematology/Oncology at The George Washington University Hospital in Washington, D.C. and Beth Israel Hospital/Harvard Medical School in Boston, and undertook advanced research training at the National Cancer Institute in Bethesda, Maryland, and the Massachusetts Institute of Technology in Cambridge, Massachusetts.
He was then appointed Assistant Professor of Medicine and Assistant Professor of Microbiology and Immunology at Boston University School of Medicine/Boston Medical Center and rose to the position of full professor, filling roles as Associate Chief for Research in the Section of Hematology/Oncology, as Director of the Immunobiology Unit, and as Director of the T32 Hematology Training Grant. He was subsequently recruited to the Feinstein Institute for Medical Research as Investigator, Professor in the Elmezzi Graduate School of Molecular Medicine, and Head of the Center for Oncology and Cell Biology.
Dr. Rothstein was subsequently recruited to WMed in 2016 with the task of building the medical school’s research arm from the ground up, an extensive project he now views as “one of the major accomplishments in my career.”
“I feel we have been enormously successful in recruiting exceptional investigators here to Kalamazoo,” Dr. Rothstein said. “The work that we're doing is of a very high order and competitive with any work that's going on anywhere else in the country.
“The people that we recruited bought into the idea that we are going to develop a department focused on sharing and collegiality. And this was, to be honest, one of the big attractions for me,” Dr. Rothstein added. “I’ve always dreamed of having a division where people cooperate, where everyone is invested in everyone else's success as well as their own. And we've achieved that. We have a wonderful group of top-notch scientists who all believe that we will all be successful together.”
At WMed, Dr. Rothstein’s lab continues to study B cells and the antibodies they produce, with particular interest in B1 cells, which generate natural antibodies that are especially effective at counteracting infectious pathogens during the time required for development of adaptive immunity. These B1 cells are present in mice, and Dr. Rothstein's lab identified them in humans by determining their surface phenotypic characteristics.
Dr. Rothstein’s lab has also shown that B1 cell numbers and B1 cell function in terms of the level of natural antibodies they produce decline with age.
“What we’ve found is that the B1 cells making antibodies against pneumococci in young people make antibodies that are different than the B cells from older individuals, and this may partially explain why older individuals are more at risk for pneumococcal disease,” Dr. Rothstein said. “The antibodies made by young people are more effective and someday may be a therapeutic option for administration to older patients who develop pneumococcal pneumonia.”
A second project in Dr. Rothstein’s lab involves extracellular vesicles, which are small, membrane-limited particles produced by all cells in the body that can emerge from one cell and enter another cell, acting as a form of intercellular communication. Many cell types generate extracellular vesicles, but their production by B cells has received very little attention to date.
“We’ve found that B cells make these extracellular vesicles and that they contain antibody, and they appear to be an additional or new antibody distribution system, a new way of moving antibody around the body to fight infection, wherever it may occur, in addition to the soluble antibody, which are proteins that float in the bloodstream,” Dr. Rothstein said. “We’re currently studying whether B cell extracellular vesicles are capable of fighting pneumococcal infection in a mouse model.”
A third project in Dr. Rothstein’s lab involves an anti-apoptotic gene that his laboratory group identified and cloned from inducibly Fas-resistant B cells, which they named FAIM, for Fas Apoptosis Inhibitory Molecule. Subsequently, the lab group discovered that FAIM has the unusual property of being able to block protein aggregation, and to disaggregate protein aggregates that have already formed.
“Protein aggregation is thought to be a cause of Alzheimer’s Disease, Parkinson’s Disease, and several other neurodegenerative illnesses,” Dr. Rothstein said. “FAIM is capable of disaggregating those aggregates, and we think that someday, in some form, FAIM or a molecule like it might be a therapeutic option for resolving aggregates that are pathogenic for neurodegenerative diseases.”
Dr. Rothstein said all of this work is advanced by the hard work of the members of his lab group — Hiroaki Kaku, PhD; Naeem Khan, PhD; Michael Gutknecht, PhD; Joshua Mitchell, PhD; Varsha Jawahar, MS; Isabella Trainor, BS, and Jenna Cooper, BA.
The medical school has noted the success of Dr. Rothstein's lab and the Center for Immunobiology and the Department of Investigative Medicine over the past nine years. Since 2016, the center and the academic department, which was established in 2020, has obtained more than $17.5 million in extramural grant support, and additional NIH grant applications are currently pending.
"The success of our lab and our department is due to our secret sauce — our people,” Dr. Rothstein said. “I can’t say enough about the dedication and smarts of everyone in my lab and throughout our department … That’s where creativity and discovery originate.”