William Eaton, MD, PhD, of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH), and Richard A. Larson, MD, of University of Chicago, are being presented with the Henry M. Stratton Medal. This award recognizes contributions to both basic and clinical or translational hematology research. Dr. Eaton has dedicated his career to the study of the genetic basis of leukemia and translating this knowledge into more effective therapies for patients. He took a special interest in therapy-related myeloid leukemias, which are those that occur several years after exposure to cytotoxic chemotherapy, usually given for a prior cancer. Dr. Larson, on the other hand, started working on the physics and physical chemistry of hemoglobin allostery and sickle cell hemoglobin (HbS) polymerization in the early 1970s, took a 25-year break in 1990 to work primarily on protein folding, and has now returned to researching sickle cell disease (SCD) full time.
Dr. William Eaton was among the first MD/PhD students at Penn Medical School. He transferred to NIH in 1968 to fulfill his military obligation as a medical officer in the U.S. Public Health Service. There, he constructed a microspectrophotometer to study the optical properties of single crystals of hemoglobin in polarized light. He then investigated the optical absorption of elongated sickled cells in polarized light. These studies sparked his interest in understanding how sickle fibers form This is turn led to the discovery of the basic equilibrium properties of HbS gels and the highly unusual kinetics of HbS polymerization, characterized by a delay period prior to fiber formation. Dr. Eaton’s group has developed a sensitive high-throughput kinetic assay for measuring sickling times to screen compound libraries to find a drug to treat SCD.
He expressed enthusiasm regarding several major breakthroughs in SCD, including gene editing of hematopoietic stem cells, currently being developed by John Tisdale, MD, and others. Dr. Eaton sees a major challenge in this area as well. “The vast majority of patients with SCD live in developing countries and do not have access to advanced medical facilities for such treatments. This is my motivation to use high-throughput screening to try to discover an inexpensive oral drug that can be used worldwide,” he explained. For this purpose, his lab is currently screening the ReFRAME library of the Scripps Institute, which includes 12,000 compounds that have been tested in clinical trials, in search of a compound that inhibits polymerization at concentrations that are therapeutic, according to their assay, and nontoxic. If they find success with these compounds, investigators expect to quickly start clinical trials with volunteers who have sickle cell trait. Dr. Eaton’s passion for finding a solution to these issues is inspired partly by his mentors. Dr. Eaton’s PhD mentor, Robin M. Hochstrasser, MD, PhD, advised him to perform experiments that no one else was doing and to search for important questions and answer them before anyone was even aware of such questions. His mentor in SCD research, H. Franklin Bunn, MD, helped him with red cell biochemistry, physiology, hematology, and how to best apply physical chemistry research to understanding the molecular pathogenesis of therapy for SCD.
As a medical student, Dr. Richard Larson recalled being intrigued by the fact that a hematologist could make a diagnosis with a microscope and actually see the disease that was ailing the patient. He learned that chromosomal rearrangements were partly responsible for the abnormal behavior of malignant blood cells and that cytogenetic analysis provided independent prognostic information for treatment outcomes, allowing hematologists to perform risk assessments to assign the best individualized therapy. He began his research under the mentorship of Janet Rowley, MD, Michelle Le Beau, PhD, and James Vardiman, MD, at the University of Chicago; they were working on identifying important clinicopathologic and cytogenetic correlations within subsets of acute leukemia.
Dr. Larson led the Leukemia Committee of the Cancer and Leukemia Group B (CALGB; now called the Alliance) at a time when great progress was being made in identifying recurrent genetic mutations across multiple different types of acute and chronic leukemias. He recognizes clinical trials as the most powerful tool used to develop better therapies for patients. Along with investigators such as Charles Schiffer, MD, Clara Bloomfield, MD, Richard Stone, MD, Kanti Rai, MD, John Byrd, MD, and Wendy Stock, MD, among others, he continues to pursue innovative trials that incorporate novel agents and treatment strategies. However, Dr. Larson commented on challenges in accruing enough patients with the same homogenous disorders for large clinical trials, owing to leukemia being recognized as a syndrome of many genetically distinct diseases. He is excited about the many novel agents recently approved to target defined vulnerabilities in leukemia cells, and he finds that they spark hope that more highly effective therapies can be developed for other genetic subsets of leukemia. “Nevertheless, it remains to be proven whether novel, highly specific, targeted agents would be best used in combination with cytotoxic chemotherapy, which may have greater impact across a spectrum of multiple subclones,” he said. Dr. Larson is inspired every day by his colleagues, including Dr. Stock, Toyosi Odenike, MD, Andy Artz, MD, Hongtao Liu, MD, PhD, Jane Churpek, MD, Lucy Godley, MD, PhD, and Dr. Le Beau, to continue looking for answers to these challenges.
Dr. Larson remarked that these are exciting times across the spectrum of hematologic disorders. “Hematology offers tremendous opportunities that overlap with vascular biology, transplantation, immunology, infectious diseases, and many other important areas such as global health,” he stressed. His advice therefore is to learn as much as possible about the biology of a specific disease, assemble a collaborative team, and think creatively about how to test treatment strategies to improve outcomes for patients. Meanwhile, Dr. Eaton left us with three highly important words of wisdom: “Follow your passion.”