By Prashant Sharma, MD, FACP, and Peter Forsberg, MD
The origins of blood cells intrigued scientists for centuries, but it was the development of atomic weaponry in the first half of the 20th century that kindled research interest in the field of hematopoietic stem cells (HSCs). Researchers attempted to understand how ionizing radiation damaged hematopoiesis and whether the damage caused could be reversed by medical intervention. In the 1950s, seminal discoveries showed that intravenously injected bone marrow cells could rescue lethally irradiated mice by re-establishing blood cell production leading to recognition of the presence of HSCs. These initial findings were of course followed by the groundbreaking work of Dr. E. Donnall Thomas and others to elucidate the capacity for HSCs to be transplanted for therapeutic purposes in dogs and humans.
Recognizing her extraordinary contribution to the field of hematopoietic and leukemic stem cell research, Connie J. Eaves, PhD, of BC Cancer Agency and University of British Columbia was awarded the 2018 E. Donnall Thomas Lecture and Prize on December 3, 2018. It is hard to imagine a more fitting recipient of Dr. Thomas’ eponymous honor. Dr. Eaves’ lecture focused on the historical background of the discovery of HSCs and progress made in advancing our knowledge in the field. Highlighting seminal work in the field, she also discussed research done by her laboratory on HSC biology. One emphasis of her talk was that HSCs are not one thing. She summarized that “HSCs are biologically and molecularly heterogenous throughout development and at any given time.” This heterogeneity has profound effects on how you study stem cells and how you may utilize them in different clinical situations that require different cellular properties. As she described, “For Dr. Thomas, it was important to get a cell that would transplant,” while what is needed for gene therapy may be very different.
Dr. Eaves mentioned that when the self-renewal property of HSCs was recognized, “detection and characterization of these cells were attempted by growing the HSCs in suitable tissue cultures or in transplanted immunodeficient mice. This process needed development of protocols that were sensitive (able to detect every stem cell), specific (able to detect only stem cells), and quantitative (able to measure the progeny of individual stem cells).” Dr. Eaves’ group pioneered such methods capable of developing primitive human hematopoietic cells in vitro and used these to investigate some of the factors that controlled the maintenance and differentiation of both normal and leukemic human cells. The results revealed important similarities and key differences that helped distinguish primitive normal cells and leukemic human cells, thereby providing new evidence of a hierarchical structure in leukemic populations.
In the 1980s, while studying chronic myeloid leukemia (CML) cells in her laboratory, Dr Eaves’ team discovered that leukemic stem cells in culture rapidly died off and were replaced by normal cells. “This finding of stem cell exhaustion was unexpected because the prevailing thinking at that time was that patients with CML no longer had any normal blood cell precursors,” she explained. Dr. Eaves further noted that this discovery was significant because it indicated that most CML patients might be cured “if a way of selectively killing CML cells could be found, with reliance on this residual normal stem cell population to restore normal blood cell production.” This eventually prompted studies to evaluate leukemic stem cell exhaustion in the setting of exposure to imatinib and other BCR-ABL–targeting tyrosine kinase inhibitors and findings identifying a potential functional cure in some patients following targeted therapy alone.
Dr. Eaves’ team is also credited for having first demonstrated clonal hematopoiesis. In 1989, her group published a study performed in patients who had undergone bone marrow transplantation, that was the first to show that most of the blood cells produced in a person could be derived from a single transplanted cell from a normal donor. This provided the first formal evidence of the growth potential of normal human blood stem cells and spurred the thinking that gene therapy approaches could work even with suboptimal gene transfer efficiencies. Dr. Eaves’ lecture ended with a focus on future directions for research on HSCs and its potential to continue influencing the care of patients with a variety of conditions. She could not have concluded with a more inclusive message to empower researchers than how she described the collaborative nature of her work and the future of research: “The rock star era is over. We are a symphony orchestra.”
Drs. Sharma and Forsberg indicated no relevant conflicts of interest.