By Naseema Gangat, MBBS
At his decennial anniversary we fondly reminisce on Ernest Beutler, MD’s, illustrious scientific career spanning more than five decades. A “pine tree of lights” comes to mind as we stroll down the memory lane to his copious seminal contributions involving several facets of hematologic science; inherited and acquired anemias, notably glucose-6-phosphate dehydrogenase deficiency, iron deficiency, hemochromatosis, Gaucher disease, and several types of leukemia. Additionally, he reached out beyond hematology and invented the software “Reference Manager.”
On this occasion we honor Alan D. D’Andrea, MD, of Dana-Farber Cancer Institute and Neal S. Young, MD, of the National Heart, Lung, and Blood Institute at the National Institutes of Health, with the Ernest Beutler Lecture and Prize for their momentous offerings in the sphere of bone marrow failure (BMF) syndromes. Their two-part lecture focused on pivotal work that has revamped our laboratory and clinical understanding of the esoteric inherited and acquired BMF syndromes.
Bone marrow has been well-defined as the “seedbed” of our blood since the time of William Osler, MD. Just a few decades ago BMF was felt to be uniformly fatal due to limited insights regarding its etiology resulting in a dearth of effective therapies. Among the inherited BMF syndromes, Fanconi anemia (FA) is the most prevalent. We have come a long way since its very first clinical description by pediatrician Guido Fanconi in 1927, explained Dr. D’Andrea. The journey commenced with laboratory observations of chromosomal instability in the early 1960s and continues with the discovery of 23 FA pathway genes throughout the past two-and-a-half decades. He walked us through the contemporary understanding of the molecular pathogenesis of FA resulting from increased P53 expression and hyperactive TGF-β signaling. Furthermore, he described a genome-wide shRNA screen that identified enhanced TGF-β as a mediator of BMF in FA. In both murine and human studies, blocking TGF-β signaling rescued the proliferative and functional defects. We eagerly anticipate the development of novel non-transplant therapies for FA in the form of gene therapy and TGF-β inhibitors – an unmet need for decades – in the foreseeable future. Lastly, in his laboratory work he demonstrated an important molecular interaction between FA and BRCA pathway genes frequently occurring in solid tumors (breast, ovarian, and prostate cancer) in the general (non-FA) population. Therefore, biomarkers of the above pathway may be used to predict cisplatin or PARP-inhibitor sensitivity of nonhematologic cancers.
In the second act, Dr. Young eloquently detailed the pathophysiological mechanisms (chemical exposure such as benzene, physical damage, viruses, namely parvovirus B19, and immune destruction) leading to the “acquired” BMF syndrome, aplastic anemia. His laboratory studies not only characterized the role of parvovirus B19 and the immune system, but also pioneered the clinical development of several effective non-transplant therapies. The latter include immunotherapies, antithymocyte globulin and cyclosporine, the stem-cell stimulating agent eltrombopag, and the androgen danazol, which form the backbone of our current treatment paradigm.
Dr. Young attributes his scientific accomplishments to “perseverance, curiosity, and good fortune.” He is excited to dive deeper into the pathogenesis of aplastic anemia, explore new drugs, and ensure therapies are readily available throughout the world to make a global impact. He believes his systematic approach and discoveries in the field of aplastic anemia might be applicable to other immune diseases as well. “It is a terrific honor to be recognized for my scientific endeavors and is a ‘pick-me-up’ during times of local difficulties,” Dr. Young commented.
The above-mentioned bench-to-bedside stories are a quintessential element of the late Dr. Beutler’s timeless work. Congratulations to Drs. D’Andrea and Young on this extremely well-deserved and prestigious award!
Dr. Gangat indicated no relevant conflicts of interest.