The Ernest Beutler Lecture and Prize is named after Dr. Ernest Beutler, a past ASH president and physician- scientist with a remarkable career that spanned 50 years. This year, the award is being presented to Sriram Krishnaswamy, PhD, of the Children’s Hospital of Philadelphia (CHOP) and Perelman School of Medicine at the University of Pennsylvania, and Jeffrey I. Weitz, MD, of McMaster University. Dr. Krishnaswamy is being recognized for basic science and Dr. Weitz for clinical science/translational research. Early on, both serendipitously found themselves studying hematology, which led to extraordinary careers.
Dr. Krishnaswamy said of his decision to study hematology, “It was accidental in my search for a laboratory to pursue postdoctoral training.” He was finishing his PhD, studying the biochemistry of a plant enzyme, and looking to broaden his horizons when blood coagulation caught his eye. He landed a postdoctoral position with Ken Mann, PhD. “… Accidents happen, and good fortune favors the prepared mind,” remarked Dr. Krishnaswamy.
Dr. Weitz’s interest in hematology began during his internship at the Toronto General Hospital where, for every patient admitted, he had to perform a urinalysis, measure the hematocrit, and examine a blood film. The Chief of Hematology there, John Crookston, MD, showed him how the seamless connection between the patient and laboratory enabled diagnosis and enhanced clinical care. “This is what drove me to study hematology,” commented Dr. Weitz.
Dr. Sriram Krishnaswamy’s main research focuses on understanding the mechanisms by which protein-protein interactions regulate enzyme function. “It turns out that blood coagulation is an ideal system to study these specific problems in the biochemical and biophysical detail necessary to establish molecular mechanisms,” he said. His laboratory has studied the kinetic and molecular mechanisms that determine how the enzyme complexes of coagulation assemble on membranes, how they specifically recognize and act on their protein substrates, and how protein cofactors regulate enzyme function. These studies combined biophysical approaches with unique probes and, according to him, “good fortune.” They have opened up a comprehensive understanding of the stepwise interactions between proteins and membranes that result in the formation of membrane-bound enzyme complexes of proteinase and cofactors — a major breakthrough he is very excited about. This information is now being combined with structural biology to obtain further insights into the basis for coagulation enzyme function at the atomic level, and has been used to investigate how these interactions among constituents of a typical enzyme complex dictate its specificity and function in slicing the biological substrate.
Dr. Krishnaswamy stressed that the new generation of oral anticoagulants that block the catalytic sites of proteinases interfere with all aspects of enzyme function, and newly developed insights show new ways in which specific surfaces on the interacting proteins can be targeted to modulate coagulation enzyme function in discrete ways. He reflected on the significance of this discovery, saying, “These therapeutics of the next generation are expected to affect enzyme function in tunable ways for the treatment of either thrombosis or bleeding.”
While evoking his early days as a hematologist, Dr. Jeffrey Weitz, whose research focuses on thrombosis, recalled that the only available treatments for the condition were the anticoagulants heparin (injectable) and warfarin (oral). He found that while effective, these drugs required frequent blood testing to ensure that therapeutic levels were achieved, which is inconvenient for patients and physicians, and costly for health care systems. His work prompted the development and licensing of new anticoagulants associated with less bleeding that simplify prevention and treatment of thrombosis by not requiring monitoring, thus providing patients with better quality of life. He finds that direct oral anticoagulants represent the most exciting recent breakthroughs in the field. However, he understands challenges remain, such as bleeding as a major side effect. Therefore, his current work focuses on developing a new class of safer anticoagulants.
Both Drs. Krishnaswamy and Weitz encountered challenges throughout their careers, but they have faced them with perseverance and the help of outstanding mentors. For Dr. Krishnaswamy, Jack Bryan, MD, PhD, and Richard Levy, MD, exemplified the importance of hard work, and Kenn Mann taught him to be fearless, and Peter Lollar, MD, and Billy Church, close colleagues for 35 years, constantly remind him of the importance of having a sense of humor and never backing down from a valid argument, “scientific or otherwise,” he added. He has also been inspired by colleagues at Penn and CHOP, including Charles Abrams, MD, Joel Bennett, MD, Skip Brass, MD, PhD, Rodney Camire, PhD, Mark Kahn, MD, and Morty Poncz, MD.
Dr. Weitz reflected on the significance of past ASH Coulter Award recipient Aaron Marcus, MD, and Sam Silverstein, MD, in his life and career. “They were my saviors in New York; they helped me navigate the complexities of academic research after Hymie Nossel, MB, ChB, DPhil, [my mentor at Columbia University] died suddenly.” During that time of uncertainty, Dr. Weitz sought out new mentors, learned how to secure funding, and built a research program. “It was a hard lesson that prepared me for where I am today,” he said. He learned from Jack Hirsh, CM, MD, FRCP, his mentor at McMaster, to ask important questions and to ensure that his studies are optimally designed to address them.
Dr. Krishnaswamy, who is honored to receive this recognition along with Dr. Weitz, sees a bright future for hematology full of promise regarding the development of new technologies to solve complex biological questions and strategies to treat complex human disease. “Solutions to these big questions will require enthusiastic, creative, and talented investigation into basic and translational science.”
Dr. Weitz agrees with the sentiment. “This is an exciting time for hematology,” he said, noting that hematology is the ideal choice for those who want to bridge laboratory investigation with clinical advances. “No one did this better than Dr. Beutler, who pursued basic and patient-centered research to address the clinical problems he witnessed at the bedside,” Dr. Weitz remarked, while advising early-career professionals to seek training and networking opportunities. He continues to follow in Dr. Beutler’s footsteps and is thrilled to be recognized, stating, “It is not just an honor for me, but for my talented staff, my dedicated learners, and for my wonderful colleagues who made this possible.”
Drs. Krishnaswamy and Weitz will present their lectures Monday at 1:30 p.m. in Hall D of the Orange County Convention Center.