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Gregory Holmes, MD

Gregory Holmes, MD

Born in Toledo, Ohio in 1948, Greg Holmes’ initial interest in epilepsy was prompted during high school, observing the seizures of young lady and the fear and shunning that these engendered in classmates and teachers. Dr. Holmes attended Washington & Lee University. He was awarded Bachelor of Science with a double major in biology and psychology in 1970. Holmes obtained his medical degree from the University of Virginia in 1974. Encounters with neurologists Jim Miller, Fritz Dreifuss, Bill Logan, and T.R. Johns shaped his decision to become a neurologist. He admired their emphasis on observation and analytical thinking referenced to the neurobiological basis of disease. He was struck by the remarkable energy and productivity of Dr. Dreifuss. Logan and Dreifuss would remain particularly influential clinical role models. Encounters with Ben Shaywitz and Peter Huttenlocher at Yale, where Holmes completed two years of pediatrics training, further confirmed his career decision. Another fateful encounter at Yale was Holmes meeting a nurse who would become Mrs. Colleen Holmes upon the completion of his training in neurology/child neurology at the University of Virginia In 1979 Holmes assumed his first faculty position, at the University of Connecticut.

A remarkable pattern of achievement was established during these years. Dr. Holmes was first author of four papers based upon his two pediatrics years and five based on his three years of neurology. His seven years of Connecticut experiences resulted in 39 papers. These were not inconsequential case reports. Virtually all were substantial contributions. His very first paper on Strmpell’s paraplegia has been cited 62 times. Nine of these papers have been cited more than 50 times. Of particular note was his work on pseudoseizures, Landau-Kleffner, childhood absence, and the prognostic value of EEG in neonates. A Connecticut paper published in 1984 was a watershed event – Holmes’s consideration of the effects of a single brief seizure on threshold for seizure recurrence in rat pups. Dr. Holmes credits the CNS in general and Dr. Nico Moshé in particular for his decision during this stage of his career to become a bench scientist. A Moshé CNS abstract prompted a letter from Holmes to Moshé and a return invitation to come to Einstein and learn the technique. In addition to a skill, Holmes acquired Moshé’s fascination for what might be learned from the brain of a rat pup and found in Moshé – one of the smartest and most insightful colleagues that he was ever to encounter – a role model.

Another person Holmes regards as having been critical to his bent toward basic science in addition to a clinical one was his Division Chief, Barry Russman. The bench techniques were learned during fleeting trips to New York. Russman not only skillfully advised Holmes, he carefully protected his time during the critical early phase of career development; at least, he did so as best he could in the face of Holmes’s strong work ethic and capacity to get many things done at once. The Moshé and Russman lessons were not wasted on Holmes, who has subsequently provided the same sort of support for his own large cadre of trainees and faculty colleagues. Associate Professor Holmes continued successfully and essentially seamlessly to organize and carry out research as he moved in 1986 to the Medical College of Georgia as Director of Pediatric Epilepsy and then, in1988, to Boston Children’s as Director of neurophysiology, epilepsy, and the Center for Research in Pediatric Epilepsy. He rose to the rank of Professor in 1996. There appears to have been no interruption in the pace of work and productivity in 2002 when he moved to Dartmouth, initially as Chief of the Section of Neurology (Internal Medicine), and subsequently in 2009 when he became the first Chair of a newly established Department of Neurology. As his administrative responsibilities widened, Holmes credits the example of Joseph Volpe as the best possible model for effectively and productively carrying out a complex set of duties, balancing research, a continued commitment to excellence of clinical care, and mentoring for the maximal benefit of all concerned.

Very early in his bench career Holmes became adept at the adaptation of experimental methods and paradigms to the accomplishment of hypothesis- driven investigations of both the physiology and pathophysiology of developing brain, particularly as regards developmental changes in vulnerability to the development of epilepsy. With his colleagues, Holmes has characterized physiological changes with or without evidence of cellular injury as the result of seizures generated in the hippocampus and has documented the evolution of the kindled state with relation to receptors as well as local or distant changes in neural network function. His initial 1984 paper was the first of what has to date included 136 full-length original papers, the substantial nature of which is reflected in the fact that these papers have been cited more than 3750 times. Only a few highlights of this technically sophisticated work of three decades can be considered here. One most important element has been his decision to center many considerations on the effect of seizures on hippocampal place cells and their connections, employing their function in relation to orientation to study explorational learning, memory, adaptation, sensorimotor development, and even emotion in his rat pups. His end-points have involved disarmingly clever and revealing rat behavioral paradigms.

A few of many areas to which Holmes and associates have directed their attentions have been the effects of provoked or kindled seizures (including intensity, frequency, and duration, the effects of maternal seizures, hormones, toxins, genetic determinants, starvation, temperature, medications, and the downstream effects on other hippocampal and extrahippocampal locations including mirror foci and cortical connections. In essence the work is filling in the details of the actual functional anatomy not of just one type of seizure, but of several. The stage of brain development has been a particularly important aspect of these studies, including regional developmental changes in the polarity of action GABAergic synapses and the formation of neural networks. This aspect of the work has been particularly influenced by Yezekial Ben-Ari, with whom Holmes spent a Parisian sabbatical year. These studies have provided a window on epileptogenesis and the opportunity to study factors that heighten or reduce risk for such a transformation. They have in addition provided the opportunity to assess or develop preventive or ameliorative approaches to the development of epilepsy in developing brain. They have expanded understanding of normal physiological brain development and function including factors that influence normal or abnormal neurogenesis and the nature of brain plasticity. Even the possible ameliorative effects of enriched environmental stimulation on the developmental outcome of rat pups that have experienced status epilepticus have been studied.

The design and carrying out of so much work is a tribute to Holmes’ prepared mind (he reads and listens as well as he observes), experimental flexibility and cleverness, quiet determination, and his capacity to recruit and retain the best and the brightest of trainees, colleagues, collaborators. Despite such potential disruptions through the course of his career, Dr. Holmes has been the Primary Investigator of seven NIH-sponsored grants and the support of 32 additional grants. He has attracted a total of 32 basic research fellows in his laboratory and 29 fellows to carry out clinical investigations. Thirty-eight of his trainees now hold academic positions.

The clinical work in which Dr. Holmes and his colleagues have engaged is also quite remarkable, covering a breadth of topics that cannot adequately be reflected in this space. This includes 91 full-length original papers to date, concerning a broad spectrum of clinical subjects amongst which epilepsy in particular is richly but not exclusively represented. This work has been cited more than 2670 times – a particular achievement for clinical investigation. Among the more highly cited contributions are reports refining the clinical and electrophysiological descriptions of epileptic and non-epileptic entities, efficacy and side effects of treatments of epilepsy, neurological consequences of asphyxia, neonatal seizures, ECMO, and cardiac bypass surgery, and many other topics.

Particular personal qualities figure importantly in Holmes’ success in organizing collaborative basic and clinical research and exerting leadership in the other aspects of his career. These include impeccable honesty, kindness, an understated and often self – deprecatory sense of humor, and an almost invariably calm and imperturbable bearing. To these are added the remarkable quickness of his prepared mind for perception of the most worthwhile objectives to pursue with swiftness and extraordinary energy and exemplary diligence. In pursuit of such objectives his respect for the contributions of both collaborators and trainees has inspired considerable loyalty.

Dr. Holmes has published 123 intelligent and informative review papers, 62 book reviews, fifty-six excellent chapters, and he has edited more than ten books. As if his publication record were not enough, Dr. Holmes has made the remarkable international contribution of delivering more than 420 invited lectures to audiences on six continents. It has been suggested that these efforts provide him with the opportunity to get some uninterrupted time during flights to get yet more work done. Dr. Holmes talents, wisdom, and insight have been proffered as consultant for the NIH, the March of Dimes, and the medical research councils of Canada, Ireland, Britain, the Netherlands, and Czechoslovakia, as well as 17 drug manufacturers. His service in professional societies is too extensive to review in detail. As a CNS member his services have included membership on the Awards, Long-range planning, Decade of the Brain, Program and Scientific Selection Committees. From 1993 to 1995 he served as Councillor from the East on the CNS Executive Committee. He served with similar distinction on numerous committees with similar responsibilities in the American EEG Society, AAN, Southern EEG Society, Epilepsy Foundation of America, the AES (including Presidency), and the learned societies of other nations. Dr. Holmes has served on 31 NIH committees and study sections, with similar responsibilities on the research institute committees of eight other nations.

Dr. Holmes’s contributions have been recognized in the presentation to him of numerous awards, including the Sidney Farber (UCP), John Horsley (UVA), Segawa (Japan), Michael (Germany), Milken (AES), Pierre Gloor (ACNS), Ambassador for Epilepsy (ILAE), Inspiration for a Cure (WMEAC), and now the Sachs (CNS). It cannot be doubted that Dr. Holmes appreciates the recognition he has achieved, although he tends to assign to credit for much of the work to his associates. There is little doubt, however, that he also cherishes the fact that despite so many and various demands, he and his wife, Colleen have managed to raise two outstanding sons—Marcus, whose studies for a PhD in political science have carried him from the University of Virginia to Georgetown and then Ohio State, and Garrett, whose route to a PhD in philosophy has carried him from Dartmouth to University College London, and now University of Texas, Austin. Greg’s quite remarkable and patient wife Colleen has maintained her own professional career as clinical and research nurse at each of the successive stages of academic moves. The family is rounded out by a pair of Golden Retrievers, the usual company of Dr. and Nurse Holmes when they find quiet time together to hike in each other’s excellent company.