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Looking Back and Looking to the Future

December 13, 2022

Dr. Timothy J. Ley and Dr. Robert Montgomery Receive 2022 Henry M. Stratton Medal

The 2022 Henry M. Stratton Medal has been awarded to Timothy J. Ley, MD, and Robert Montgomery, MD, for their outstanding clinical and research accomplishments in the field of hematology. The Henry M. Stratton Medal is named after the late Henry Maurice Stratton, the cofounder of Grune & Stratton, a medical publishi#ng house that first published ASH’s flagship journal, Blood. Dr. Ley, a leading researcher and co-director of the physician-scientist training program in the Department of Medicine at Washington University, focuses his studies on the molecular mutations and altered gene expression patterns responsible for the initiation, progression, and relapse of acute myeloid leukemia (AML). Dr. Montgomery is a renowned researcher in hemophilia and von Willebrand disease (VWD) and a professor of pediatrics at the Medical College of Wisconsin. He has developed a major National Institutes of Health (NIH) –supported Program Project Grant (PPG) collaboration within the United States, Canada, Ireland, and the United Kingdom.

Dr. Ley’s team at Washington University was the first to sequence cancer genomes from patients with AML, leading The Cancer Genome Atlas Study, which identified almost every common mutation associated with AML, improving risk classification and planning patient therapy care. Their study has been essential to the improvement of understanding how AML functions, as developing a clear idea of how the mutations occur and the clonal heterogeneity of cancer helps transform and ground our efficiency in creating targeted therapies for patients. “The development of CRISPR-mediated gene editing approaches and the ability to use modified mRNAs to restore or alter the function of genes are among the most exciting things on the therapeutic horizon in my view,” he stated.

For Dr. Ley, the beginnings of his fruitful studies in hematology coincided with the pivotal, early stages of molecular biology. He was at NIH when they were one of the first centers developing the foundations of modern disease-oriented genetics. It was through this training and his background in human genetics that gave him the opportunity to better understand genomic data. Beyond being in the right place at the right time, Dr. Ley also gives glowing credit and appreciation to a handful of figures who have been present throughout his career. “Dr. Stuart Kornfeld was a major influence in medical school (and continues to be, to this day), and [he] encouraged me to learn molecular biology and apply it to hematologic diseases,” he told us. Dr. Art Nienhuis, Dr. Ley’s postdoctoral mentor and a previous winner of the Stratton Medal, also encouraged him to expand his perspective within hematology research, utilizing experiences in molecular biology. According to Dr. Ley, the work of the hematologist is fruitful no matter how difficult because it ultimately will “help alleviate suffering and improve the quality of our patients’ lives. These are worthy goals, and prioritizing them when the chips are down can help you get through the hard times.”

While the Stratton Medal recognizes his outstanding contributions thus far, Dr. Ley believes there is much more to accomplish. “One of the great unsolved mysteries is how AML-initiating events ‘reprogram’ hematopoietic stem/progenitor cells to make them more fit for transformation,” he said. “This is still a ‘black box’; solving these mechanisms will have a profound impact on our understanding of the roots of hematopoietic malignancies and how we can reverse them.” Dr. Ley is a firm believer that continuous efforts are a necessary challenge and process within hematology. He looks to the future of the field and understands the time and persistence it takes to produce effective patient therapy practices based on the pathophysiological truths they discover today.

“With the ability to directly modify the outputs of genes that are relevant for each disease,” Dr. Ley began, “the effectiveness of therapies will increase, and toxicities will decrease. Decades of additional work will be required to make this a reality, but it will be well worth it.”

Dr. Montgomery is recognized for his studies into the relationship of the two plasma proteins von Willebrand factor (VWF) and factor VIII (FVIII) in endothelial cells and platelets, identifying clinical dysfunctions of VWF through initial VWF gene sequencing. He and his team’s PPG collaboration developed and improved an assay — now named the VWF:GPibM assay — to measure VWF function. This effort is crucial as it avoids the poor reproducibility of the VWF:RCo assay that is due to common polymorphisms in VWF. According to Dr. Montgomery, these polymorphisms are present in 60 percent of Black patients and 17 percent of white patients and give erroneous results owing to the abnormal interaction of VWF with ristocetin. “Normally, VWF is produced in endothelial cells and platelets, but FVIII is produced in just endothelial cells,” Dr. Montgomery stated. “If the FVIII gene is put into bone marrow stems cells under the control of a platelet-specific promoter (αIIb-promoter), FVII is synthesized to megakaryocytes and platelets where it binds to and follows VWF into storage granules.” He went on to explain that if a patient with hemophilia A patient develops inhibitory antibodies, that FVIII is protected from those antibodies until the platelet adheres to the site of blood vessel injury, where the FVIII is then released at that injury site and is able to support normal clotting before there is time for the antibody to inhibit FVIII activity.

Likewise, to Dr. Ley, Dr. Montgomery’s journey into hematology was deeply rooted in academic mentorship. During his internship at the Children’s Hospital of Philadelphia under the guidance of Dr. Frank Oski, and his residency at Johns Hopkins under Dr. Bill Zinkham, Dr. Montgomery realized that pediatric hematologists “were exciting clinicians” and he was intrigued by the field of pediatric hematology. It was during his fellowship training with mentor Dr. Bill Hathaway at University of Colorado and Dr. Ted Zimmerman at Scripps Clinic where he solidified his interest in researching hemophilia and VWD. He was especially concerned about the existing research that may not have been adequately or thoroughly researched at a basic level. Dr. Montgomery commends Drs. Hathaway and Zimmerman, as well as Dr. Dick Aster for showing him how to learn new approaches from new investigation strategies carried out by others, how to balance clinical and research interests, and how to use the bedside as an opportunity to study basic pathways. Lessons and guidance come handy, as Dr. Montgomery shares with other hopeful hematologists: “Every patient has a research lesson to be considered, and every research study has an ultimate benefit to patient care even though the fulcrum between these two may be different.”

Regarding the future of hematology as a field, Dr. Montgomery provides insight into the road ahead. “While many of the diseases we deal with today will be diseases cured through molecular correction of the abnormal gene or genes, others will be solved using structural mimetics that reproduce the physical structure without necessarily being the normal protein,” he said. “We also will deal with the ‘thorny’ issues around germline cures, not just the therapeutic cures that we do today.”

Both Dr. Ley and Dr. Montgomery will be recognized with the Stratton Medal on Tuesday, December 13, 2022, at 8:45 a.m. Central time during the Announcement of Awards session (Ernest N. Morial Convention Center, Hall E).

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