David Baltimore (1938–2025): architect of the modern molecular approach to conquer leukemia

1. A LEGACY THAT TRANSCENDS TIME The world of science mourns the passing of David Baltimore, Nobel laureate and pioneering biologist, who died on September 6, 2025, at the age of 87. While Baltimore’s innovative discoveries fundamentally reshaped virology, oncology, immunology, and modern molecular biology, and his revolutionary work on reverse transcriptase earned him the highest honor in science, his laboratory’s contributions to understanding and conquering leukemia represent an equally profound aspect of his scientific legacy. As we reflect on his monumental career, the blood cancer research community expresses deep gratitude for his fundamental discoveries that provided the essential molecular toolkit for understanding leukemogenesis, ultimately paving the way for targeted therapies that have saved countless lives. Baltimore’s journey in science was characterized by extraordinary insight and relentless curiosity. His research not only altered our fundamental understanding of biological processes but also generated the precise knowledge necessary for therapeutic interventions in hematologic malignancies. This editorial pays tribute to his specific, foundational contributions to leukemia research, which continue to resonate in laboratories and clinics worldwide. 2. LAYING THE GROUNDWORK: FROM VIRAL ONCOGENES TO CELLULAR PROTOTYPES Baltimore’s groundbreaking Nobel Prize-winning work in 1970 demonstrated that genetic information could flow from RNA to DNA, contrary to the previously unidirectional central dogma of molecular biology.1 This discovery of reverse transcriptase fundamentally changed how scientists approached cancer research, particularly regarding retroviral involvement in oncogenesis. It was within this context that Baltimore’s lab made its first decisive contributions to oncology. His laboratory isolated and cloned the v-abl oncogene from the Abelson murine leukemia virus, which caused leukemia in mice.2,3 This critical work directly led to the identification and cloning of its cellular counterpart, the proto-oncogene c-abl4 (later renamed as ABL1). In a seminal achievement, Baltimore’s team was the first to demonstrate that the Abl protein possessed tyrosine kinase activity.5 This discovery was revolutionary; it identified Abl as one of the earliest known tyrosine kinases and established a direct mechanistic link between enzymatic activity and the dysregulated cell growth that characterizes cancer. 3. CONNECTING THE DOTS: FROM ABL1 TO THE PHILADELPHIA CHROMOSOME The profound importance of this foundational work became clear when other laboratories discovered that the Philadelphia chromosome, the hallmark of chronic myeloid leukemia (CML), was formed by a translocation between chromosomes 9 and 22. This translocation resulted in the creation of a novel fusion gene, BCR/ABL1. Because Baltimore’s lab had already characterized the normal ABL1 gene and its kinase function, the scientific community was immediately equipped to understand the sinister nature of this fusion. The BCR/ABL1 oncoprotein was quickly recognized as a constitutively active tyrosine kinase that perpetually signals cells to proliferate, effectively hijacking the normal regulatory mechanisms of blood cell production. Baltimore’s prior work provided the essential reference point that allowed researchers to decipher this oncogenic mechanism with remarkable speed. 4. DEEPENING THE UNDERSTANDING: PATHOGENESIS, SIGNALING, AND NEW DOMAINS Rather than resting on these foundational contributions, Baltimore’s laboratory actively switched to studying the BCR/ABL1 pathogenesis itself. His group developed critical experimental models, including mouse models for CML,6 which allowed researchers to study the disease’s progression and test new therapeutic strategies in a living system. This deep dive into the mechanics of the oncoprotein led to further landmark discoveries. Through meticulous study of how BCR/ABL1 transmits signals, Baltimore’s lab made two pivotal contributions to all of cell signaling: the discovery of the SH3 domain binding site7 and the PH domain.8 These domains are crucial for protein–protein interactions and membrane targeting, respectively. Their identification in the context of ABL1 research provided fundamental insights into how signaling networks are organized within cells, insights that have resonated far beyond cancer biology into immunology, neurobiology, and developmental biology. 5. FROM FUNDAMENTAL DISCOVERY TO THERAPEUTIC REVOLUTION The direct line from Baltimore’s basic science to the clinic is one of the most compelling stories in modern medicine. The characterization of ABL1 as a tyrosine kinase made it a “druggable” target. The understanding that BCR/ABL1 was an active version of this kinase directly spurred the development of imatinib (Gleevec), the paradigm-shifting targeted therapy that revolutionized CML treatment. Baltimore’s laboratory did not develop imatinib, but their work created the intellectual framework that made its conception possible. Furthermore, their subsequent research into BCR/ABL1 signaling pathways and resistance mechanisms provided critical knowledge that helped inform the development of second- and third-generation tyrosine kinase inhibitors (TKIs) when resistance emerged. 6. ENDURING LEGACY: THE BALTIMORE IMPRINT ON HEMATOLOGY David Baltimore’s contributions to conquering leukemia exemplify how profound, curiosity-driven basic research provides the essential foundation for clinical revolutions. He embodied a mode of scientific inquiry that connected fundamental biological mechanisms to human disease. His study on the ABL1 gene did not just describe a molecule; it provided the language and the tools to understand, target, and defeat a specific cancer. The development of tyrosine kinase inhibitors—which turned CML from a fatal disease into a manageable condition for many patients—stands as a tribute to this approach. This achievement rests squarely on the foundational work carried out in Baltimore’s laboratory. 7. CONCLUSION: HONORING A VISIONARY David Baltimore’s passing represents the loss of a singular figure in modern science. For the hematology community, his legacy is both specific and profound: the meticulous cloning and biochemical characterization of ABL1 created the cornerstone upon which our understanding of CML was built. His later work unraveling the pathogenesis and signaling of BCR/ABL1 continued to illuminate the path forward. As we reflect on Baltimore’s monumental contributions, we recognize that the best way to honor his memory is to champion the same spirit of rigorous, fundamental, and creative science that he exemplified throughout his career. His study is a permanent reminder that investing in basic biological inquiry, pursued with excellence and vision, yields the most practical of human benefits: the alleviation of suffering and the extension of life. “We must be willing to challenge dogma, to take risks, and to recognize that scientific understanding is a journey rather than a destination.”—David Baltimore. The editorial board of Blood Science joins the global scientific community in mourning David Baltimore’s passing while celebrating his extraordinary contributions to hematology and to the conquest of leukemia.