Research Q-and-A with Christopher Thom, MD, PhD

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Christopher S. Thom, MD, PhD, is an attending physician and principal investigator in the Division of Neonatology at Children’s Hospital of Philadelphia (CHOP). Here, we delve into Dr. Thom’s drive to understand the differences between adult and infant platelets, his goal to advance blood transfusion practices for babies, and how the Hartwell grant he was recently awarded will help these efforts.  

Q: How long have you been at CHOP?

A: My career at CHOP began in 2008 as a trainee in the University of Pennsylvania MD/PhD program, and continued through the CHOP Pediatrics residency and later the CHOP Neonatal-Perinatal Medicine fellowship. I finished clinical training and started my lab in July 2021. We have been interested in research questions at the intersection of genetics, blood biology and cellular therapeutics.

Q: How would you describe your research specialty?

A: Many translational research projects would benefit from being able to produce large quantities of blood cells in a tissue culture dish. Many regions in the human genome are known to impact blood traits and blood cell development, but it can be difficult to identify which genes are important for the biology behind those variations. My lab uses computational and cellular methods to identify biologically important genes, attempting to leverage knowledge of those genes and mechanisms to coax human stem cells to make more blood cells in culture.

Q: Why did you choose to focus on that specialty?

A: My interests evolved throughout my training. During my PhD, I became interested in genes and molecular mechanisms that impact blood traits. I developed computational and machine learning approaches during residency and fellowship to enhance discovery from human genetic studies. And throughout my clinical training, I’ve seen limitations and problems from current transfusion practices. So, my research focus naturally gravitated to these issues and topics. It turns out there are plenty of related questions that we try to answer in my lab.

Q: Is there a recent research project you are particularly excited about?

A: We have been interested in a gene called Tropomyosin 1 (abbreviated as Tpm1) that normally constrains blood cell formation in human stem cell cultures and in an animal model. The ways Tpm1 biologically constrains blood cell generation are novel, so lifting Tpm1-related repression is a new way to boost blood cell production that is complementary to other methods currently in use.

Q: What long-term research questions do you hope to answer?

A: One of my major goals is to make blood cell transfusions and clinical transfusion practices safer for the babies I care for in the neonatal intensive care nursery. Infant blood cells are different than platelets and other blood cells that exist in older children and adults. Because of this, transfusions of adult platelets can cause problems in babies. If we can engineer and produce more appropriate blood cells for infants, we can help a lot of babies avoid complications.

More broadly, my lab aims to harness human genetics to better understand blood cell formation and function. We hope to paint a more complete picture of the genes and biology that determine our blood traits, and use those insights to improve blood cell production in vitro. Induced pluripotent stem cell (iPSC)-derived blood cells may one day replace donated blood products, but cell yields are currently inefficient. We use genetically manipulated iPSC models to test how novel genes and loci impact blood cell formation and function, with an eye toward genetic changes that enhance cell yields. In fact, many therapeutic modalities, clinical tests, and regenerative medicine applications rely on blood progenitor cells. Enhanced in vitro production of blood progenitors are needed to support these applications.

The lab uses genomics techniques to find non-coding regions, novel genes, and mechanisms that impact hematopoiesis. Recent projects have applied machine learning, genetic colocalization, and Mendelian randomization strategies to human genome-wide association studies and epigenetic data for this purpose. We are excited to incorporate additional cutting-edge techniques in future projects designed to further increase blood cell production in culture.

Q: What is the Hartwell Foundation Award, and how will it help advance your research?

A: The Hartwell Foundation Individual Biomedical Research Award supports innovative and cutting-edge biomedical applied research. It is funding our new project — titled “Comprehensive Platelet Proteomics to Improve Neonatal Transfusion Practices” — which promises to change how we approach platelet transfusions in babies. Platelets do not have a nucleus, and while relatively simple cells, they are packed full of proteins. Until recently, no studies have analyzed platelets on a protein level to understand how and why cell signaling and protein content differs between infant and adult platelets.

We’re looking at the proteins that make infant platelets different than adult platelets and evaluating how well human stem cell-derived platelet products match platelets that normally exist in infants. The process of making blood cells from stem cells recapitulates fetal development, which means manufactured platelets could mimic fetal and neonatal platelets. Through this project, we’re going to learn a lot about infant platelet biology and aim to develop a better platelet transfusion product for babies. This project will also help us inform other neonatologists about why we should probably be more restrictive with the platelets we give babies.