Featured Researcher

Larry Luchsinger, PhD

Q What is your background, education, awards and title(s)?

A I grew up in Manitowoc, Wisconsin along the shore of Lake Michigan and always knew I wanted to be a scientist but had no idea how to go about choosing a career at 18. I knew I didn’t want to go to a Big-10 university like UW-Madison, so I chose Marquette University in Milwaukee, a Jesuit institution which is famous for the diversity of its curricula. The required coursework of theology and philosophy were a bit more provocative than those I received in public high school and I was reasonably sure these classes were superfluous. Nonetheless, upon reflection over the years I really enjoyed my time there and what I had learned and, most importantly, that chemistry was what I wanted to pursue as a career.

Immediately after undergrad, I entered the chemistry Ph.D. program at Boston University but realized fairly quickly that small molecule synthesis wasn’t the chemistry that I was interested in after all. I received an M.A. in Chemistry and entered the Biochemistry Ph.D. program at the BU School of Medicine. I chose the laboratory of Dr. Barbara Smith who researched the regulation of collagen expression models of disease, including atherosclerosis and lung fibrosis. Here I gained an extensive set of molecular biology skills and solidified my interests in studying transcription factors in cells but realized that I was very interested in the therapeutic potential of stem cells. Networking with collaborators at BU, I was referred to a stem cell biologist at Mount Sinai, Hans Snoeck, that might be in the market for a Biochemistry postdoc and the rest is history.

Q What is your main interest in immunology and medicine?

A A major goal of medicine that interests me is the application of stem cells as a therapy to treat disease. Hematopoietic stem cell (HSC) have the potential to give rise to all the cell types in the blood. Although HSCs are relative easy to access and may be the best characterized type of adult stem cell in the body, the processes that control maintenance and self-renewal of these cells is still largely unknown. More practically, the ability to expand these cells in vitro is not possible and represents a major obstacle in achieving the overall goal of application as a therapy.

Q What is your goal as a researcher?

A My broad research goal is to fulfill the practice of performing “bench-side” basic research and oversee those findings translate into “bedside” utilities in the form of new diagnostics or therapeutics to treat disease. For years now, stem cells have inspired the imagination of many as a radical transformation in medicine. Yet, it has taken science a long time to understand the origin and course of any particular disease let alone how to use these newly defined cells as a therapy. We still have a long way to go, but I think there are fields are at a stage where we know enough in some areas to begin realizing the anticipation of stem cells as a therapy.

Q How are you currently reaching for that goal, i.e. what is the scope of your current research and experiments?

A We are using mouse models of hematopoiesis and investigating the consequence of genetic deletion of the gene Prdm16 which results in a severe defect in the renewal of hematopoietic stem cells (HSCs). We believe that understating the function of Prdm16 may allow us to discover the mechanism by which HSCs self-renew and bring us a step closer to artificially expanding these cells in culture. Such a breakthrough would potentially offer an unlimited source patient-specific, or autologous, HSCs to treat many diseases, for instance leukemia, and avoid the complications of graft-versus-host disease (GVHD) that can occur when patient and donor cells are not compatible.

Q What have some of your successes as of late been?

A Our results show that Prdm16, which is specifically expressed in HSCs, regulates mitochondrial morphology and calcium signaling, which can modulate the activity of the transcription factor NFAT and results in enhanced HSC function and, unexpectedly, biases HSC differentiation towards lymphoid cell types. These findings will be the first characterization of a molecular process directly regulated by Prdm16 in hematopoietic stem cells to date. Furthermore, our progress suggests the first demonstration of a role for Ca2+ signaling in the homeostasis of HSCs, the first rigorous assessment of the role of NFAT in HSC function, and, most importantly, the first identification of a molecular mechanism regulating lineage bias in HSCs.

Q How do you see these successes helping patients/people?

A This novel and fundamental insight into the regulation of HSCs will broad implications including aging and the age-associated reduction of lymphopoiesis and the origin and development of myeloid malignancies that develop with age. Additionally, our findings may lead to the discovery of novel molecular targets for genetic therapy of HSCs. For example, in the case of immunodeficiency lymphoid biased HSCs would be beneficial. Conversely, after bone marrow transplantation, myeloid biased HSCs reconstitution of myeloid and erythroid cell production is critical for survival. Much more work is to be done before these findings impact anyone directly, but these “bench-side” discoveries have given us new insight and a previously unconsidered path to follow to make an impact on patients and the community.

Q Finally, what has impressed you about the CCTI and what do you hope the center can contribute to the scientific community?

A The CCTI has brought together basic scientists and clinicians and has provided me with many unique perspectives on aspects of my research while at the same time has greatly expanded my knowledge of important issues in immunology. As such, the CCTI fosters a multidisciplinary approach to the research aims of its members. I believe this strategy guarantees the best chance of translating our findings into clinically relevant advances and making significant contributions on the scientific community.