Michael Beaven received his B.Pharm. with first class honors from the Chelsea School of Pharmacy, University of London in 1959 and his Ph.D. in medicinal chemistry from the University of London in 1962. He then came to the NHLBI as a visiting fellow and began a long and successful tenure at the NIH. In 1966, he was appointed a pharmacologist in the NHLBI Laboratory of Chemical Pharmacology, and later in 1977 he became Chief of the Section of Cellular Pharmacology in the Laboratory of Cellular Metabolism. In 1982, Dr. Beaven became Deputy Chief of the Laboratory of Chemical Pharmacology, and in 1994 Deputy Chief of the newly formed Laboratory of Molecular Immunology. Dr. Beaven became a Scientist Emeritus in 2010. He has authored over 180 original scientific articles, as well as over 60 reviews, book chapters, and monographs. He has served on numerous editorial boards, and is currently on the editorial board of the European Journal of Immunology. He is a member of the American Society for Pharmacology and Experimental Therapeutics, American Association of Immunologists, and American Society of Cell Biology.
Fifty years ago, very little was known about the biological characteristics of mast cells, which are the major source of histamine in the body. Since Dr. Beaven first came to the NHLBI in 1962, his laboratory’s research has helped elucidate scientific understanding of the signaling mechanisms and physiological function of these important inflammatory cells. His early studies involved developing a series of radiochemical micro-assays for histamine and other compounds that were widely adopted for clinical and biochemical research. His group’s own use of these assays resulted in several seminal discoveries, including defining the maturation of mast cells and their role in idiopathic urticarial diseases. He was also the first investigator to recognize the anti-tumor effects of non-steroidal anti-inflammatory drugs (NSAIDS) in vivo and in vitro.
Subsequent work in Dr. Beaven’s laboratory focused on the process of mast cell activation and subsequent release of inflammatory mediators, beginning with research that showed for the first time that phosphoinositide hydrolysis, calcium homeostasis, and degranulation were closely linked and that an increase in cytosolic calcium was an essential signal for degranulation. Similar relationships between the phosphoinositides and calcium were demonstrated in B cells and smooth muscle cells. His group next showed that activation of protein kinase C was also essential for degranulation and that a calcium signal along with activation of MAP kinase was necessary for activation of phospholipase A2 and production of inflammatory eicosanoids.
Several themes that emerged from these previous studies are the basis of Dr. Beaven’s most recent and ongoing work. His group has uncovered that glucocorticoids act not only by suppressing cytokine gene transcription but also by suppressing key mast cell signaling pathways, revealing an additional layer of regulation in mast cells with potential therapeutic implications. The second is the prominent role of phospholipase D (PLD) in regulating degranulation, with each of the two protein isoforms having a distinct function; PLD1 is essential for migration of granules to the cell periphery whereas PLD2 is essential for fusion of granule with the plasma membrane. The third theme is that responsiveness of mast cells to antigen is markedly enhanced by pathogenic factors. Some agonists such as adenosine enhance degranulation, whereas other molecules like the inflammatory mediator IL-33 augment cytokine production in mast cells by up to 50-fold by recruitment of additional transcription factors that act in synergy with those recruited by antigen; such interactions may account for the exacerbation of allergic disease by infection. Dr. Beaven’s lab has also revisited older work related to calcium signaling in mast cells following the discovery of the Ca2+-selective Orai/CRAC-channel protein thought to be the exclusive Ca2+-channel in many cell types. He found instead that Ca2+-influx in mast cells is dependent on the less selective TRPC5 channel protein as well as Orai1 and the Ca2+-sensor STIM1. This combination accounts for the ability of Sr2+ and Ba2+ to substitute for Ca2+ in supporting mast cell degranulation that had been described some decades ago.
Overall, Dr. Beaven’s research has helped lay out in broad strokes the linkage between various signaling pathways and the major functional responses of mast cells to antigen, increasing our understanding of inflammation and the allergic response.