This year, ASH has awarded the prestigious Ernest Beutler Lecture and Prize to Stuart Orkin, MD, and John Tisdale, MD. Their significant contributions to gene therapy have transformed the lives of individuals battling sickle cell disease (SCD), a painful and debilitating blood disorder affecting millions globally. This honor celebrates their combined efforts in translating bench discoveries into life-changing clinical solutions.
Patients undergoing ex vivo gene editing have experienced significant improvements in their quality of life, with many achieving long-term remission from debilitating symptoms. This gene editing approach has reduced the frequency of hospitalizations and the need for chronic pain management, allowing individuals to lead more active and fulfilling lives. As a result, patients have gained hope for a future free from the constraints of SCD, empowering them to pursue their personal and professional aspirations.
Charting the Genetic Blueprint: Dr. Orkin
Dr. Orkin, the David G. Nathan Distinguished Professor of Pediatrics at Harvard Medical School and an investigator at Boston Children’s Hospital, identified the genetic underpinnings of the thalassemias and SCD.
Central to his work was the discovery of B-cell lymphoma/leukemia 11A (BCL11A), a critical repressor of fetal hemoglobin. By uncovering how BCL11A silences fetal hemoglobin production in adults with sickle cell anemia, Dr. Orkin opened the door to a therapeutic strategy that reactivates fetal hemoglobin to compensate for the defective adult form. This discovery was not just a molecular triumph; it became the foundation for gene-editing therapies that are now offering a functional cure to SCD patients. Having seen development of these therapies move from concept genesis to U.S. Food and Drug Administration approval and clinical implementation, Dr. Orkin said he is assured that “sustainability of this treatment is robust.” To the question of risks known and unknown, Dr. Orkin said, “There is a long history of safety in transplant and gene modification, and risk of treatment is less risky than suffering from the disease itself.”
Dr. Orkin’s pioneering work has earned him numerous accolades, from the Warren Alpert Foundation Prize to the Canadian Gairdner International Award. Yet, his most profound legacy lies in the lives touched by these therapies — children and adults alike who are experiencing freedom from the unrelenting burden of sickle cell crises.
Evolution and execution of “functionally curative” gene therapies will need a lot more support on the ground. Getting stakeholders to buy in and centers to be fully equipped to handle the nuances of cell therapy, as well as addressing the knowledge gap and unmet needs of caregivers and patients, has to happen in parallel with improving the method itself. Dr. Orkin is hopeful that the “science exists” but the question of “economic viability” concerns him. “The historic under-investment in the disease ... is tied into profitability,” he said, adding that the financial aspects will play a key role in how these therapies evolve over time, both in the U.S. and globally.
Building the Bridge to Patients: Dr. Tisdale
After Dr. Orkin's discoveries illuminated the path, Dr. Tisdale, a senior investigator at the National Institutes of Health, brought these innovations directly to patients. A hematologist and cell therapist with a focus on curing hemoglobinopathies, Dr. Tisdale has spearheaded clinical trials that translate genetic insights into curative therapies.
Dr. Tisdale's work in bone marrow transplantation and gene therapy has turned the theoretical into the tangible. By refining myeloablative chemotherapy regimens and integrating gene-editing tools such as CRISPR, he enabled the implementation of gene therapy for patients with SCD. Under his leadership, clinical trials have reported unprecedented success rates, transforming what was once a lifelong affliction into a highly treatable condition.
Dr. Tisdale offered the following advice to the next generation of clinician-scientists and gene therapists: “Follow your passion. Everything we decide to do in medicine takes some considerable effort, but we have to focus on the problem that drives us to do something.” He added that it’s important to also consider, “What can I do where I am?”
A Legacy of Innovation
The Ernest Beutler Lecture and Prize underscores the power of science and collaboration. The work of Drs. Orkin and Tisdale exemplifies hematology at its best: an alliance of scientific curiosity and compassionate care. Their work not only advances the field but also provides a model for addressing other genetic disorders through precision medicine. Dr. Tisdale said he is humbled by the honor: "It’s extraordinary that the Beutler prize is being given for sickle cell disease research and is being recognized at this level.”
Despite challenges such as affordability, fertility preservation, and equitable access — especially in low- and middle-income countries — the advent of ex vivo gene editing as a commercial therapy is a marvel once confined to science fiction. This transformative breakthrough rewrites the trajectory of monogenic disorders, showcasing human ingenuity and commitment to reshaping the course of the lives of many. This year’s award not only honors these achievements but also serves as a beacon of hope for patients with SCD, celebrating the roles of Drs. Orkin and Tisdale in redefining care and transforming a painful diagnosis into a story of resilience and recovery.
