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Creating a career in academic neurology has been “all one gigantic stew, which is thrilling, joyous, and occasionally exasperating!” says Henry L. Paulson, MD, PhD, the Lucile Groff Professor of Neurology in the University of Michigan Health System in Ann Arbor. That unbridled enthusiasm encapsulates the reactions of Paulson and two other midcareer research neurologists when NerveCenter asked them to reflect on their work and careers. In addition to Paulson, we recently spoke with Frances E. Jensen, MD, Chair of the Department of Neurology in the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and Amit Bar-Or, MD, FRCP(C), Professor at McGill University and Director of the Montreal Neurological Institute's Experimental Therapeutics Program.

The Attraction to Neurology

  1. Top of page
  2. The Attraction to Neurology
  3. Mentors and Research Directions
  4. Future Wide Open

Fascination with medical science began early for our three subjects. Physician fathers were strong early mentors for both Paulson and Bar-Or. Paulson's lifelong curiosity about brain function began with his father, a neurologist: “From a young age, I can recall having EEG electrodes put on my head as a test subject. I found it interesting,” he says. The tantalizing mystery of the brain, the merging of molecular techniques with classic neuroscience, and the then-uncharted territory of neuroscience all buttressed Paulson's choice to go into neurology.

Bar-Or credits his father with instilling in him an attraction to academic medicine. “He was a clinician-scientist and I was very taken by his overall work and, in particular, what it was like to be an academic physician interacting with colleagues from all over the world, exchanging knowledge, and creating long-lasting partnerships and friendships. That set me on course of pursuing academic medical training.”

Jensen recalls that her interest in neurological science was galvanized by bookend experiences working with neurodevelopmentally disabled children and adults, the first group while in high school in a well-funded enriched setting and the latter in a state hospital where intellectually disabled patients were “basically warehoused.” The contrast in their functional levels clearly demonstrated, she says, the effects of critical period deprivation or enrichment, a realization that propelled her into neuroscience.

Mentors and Research Directions

  1. Top of page
  2. The Attraction to Neurology
  3. Mentors and Research Directions
  4. Future Wide Open

Following a degree in neuropsychology at Smith, Jensen sought out D. Nico Spinelli, then at the University of Massachusetts, and began her doctoral thesis work on remapping the somatosensory cortex. The work yielded publication in Science in 1978. Jensen's coadvisors during residency and for her National Institutes of Health (NIH) K Grant at Harvard were Dick Sidman and Kristin Harris, who allowed her the “intellectual space” to begin looking at early life brain injury, special repair processes unique to the developing brain. Experiments in animal models with early life stroke and seizures led her to her interests in age-dependent mechanisms of epilepsy. Prior to accepting the position of Chair of the Department of Neurology at “the oldest neurology department” in the country, Jensen had an illustrious teaching and research career at Harvard, where, most recently, as recipient of a five-year Director's Pioneer Award from the NIH, she had been examining the ways in which seizures in early life alter neuronal networks in the developing brain, resulting in cognitive disorders such as learning deficits, neuropsychiatric symptoms and autism. Keeping her feet in both camps of academic research and patient advocacy, Jensen has been active with the American Epilepsy Society (serving as President from 2011–2013), among other organizations.

Huda Y. Zoghbi, MD, and Kenneth H. Fishbeck, MD, were and continue to be critical mentors for Paulson. Both have made seminal contributions to our understanding of brain diseases. Paulson praised them as “phenomenally good scientists with a nose for biological problems, while never losing sight of the patient.” For 10 years at the University of Iowa, Paulson focused on hereditary ataxias and polyglutamine diseases; in 1997, his lab described the abnormal protein aggregates in polyglutamine diseases, which are now recognized as a pathological hallmark in these inherited diseases. Since moving to the University of Michigan, where he oversees the neurodegenerative disease research programs and directs the Michigan Alzheimer Disease Center, he has continued with basic and translational studies to understand the mechanisms of neurodegenerative disease and develop therapeutic strategies to treat them. He is now codirector of a newly established Center for Protein Folding Diseases at Michigan.

Enamored with the biology of behavior, Bar-Or took a double major in biology and psychology as an undergraduate. During his medical school neurology rotation at McGill, he encountered Professors Michael Rasminsky, MD, PhD, and Jack P. Antel, MD. “I was most impressed,” he says, “with the way they distilled complex clinical problems into their elements and, based on careful listening and observing, reconstructing what the problem was likely to be. To them I owe the excitement and passion of going into neurology.” His interest in multiple sclerosis (MS), now a major focus of his research lab at McGill, was fed during neurology residency training and subsequently neuroimmunology fellowship at Harvard, initially by Peter N. Riskind, MD, PhD, and then subsequently by David A. Hafler, MD. “Academically, I realized that this field represented an exciting interface of fast-paced neuroscience and immunology,” recalls Bar- Or of those years. In addition, there was, for him, the “compelling clinical aspect of an illness that was only partially treatable and that afflicted relatively young people throughout their most productive years, substantially impacting family, work, and society.” The convergence of scientific intrigue with the opportunity for developing novel and meaningful therapeutic targets “was something I found very attractive,” he says.

MS continues to be a focus in the cellular and molecular immunology lab that Bar-Or directs. MS is one condition for which animal models have yet to capture all aspects of the human disease pathophysiology. Given this, Bar-Or established an Experimental Therapeutics Program, which develops and applies biological assays in the context of clinical trials to better understand disease mechanisms. “This paradigm has been very rewarding,” he says, “because whether or not the therapy is successful in meeting a desired clinical endpoint, much can be learned about the illness itself through thoughtful incorporation of biological measures. These are important lessons our patients can teach us that we will never be able to learn in any in vitro or animal model system.”

Future Wide Open

  1. Top of page
  2. The Attraction to Neurology
  3. Mentors and Research Directions
  4. Future Wide Open

Bar-Or notes that, despite recent advances in the field of MS, important unmet needs remain. However, he points to several opportunities, including collaborations that cut across different disciplines. For example, “several classic neurodegenerative diseases —such as Alzheimer, Parkinson, and [amyotrophic lateral sclerosis]—have had a resurgence of interest in inflammatory mechanisms of disease. Coordinated studies will allow us to learn a great deal about one condition through insights gained from another,” he says.

Jensen points to collaboratives such as One Mind and the NIH's BRAIN Initiative as evidence that this is “a transforming time for neurology. There is a surge of basic science investigating synaptic plasticity, neural function, and signaling pathways, and at the same time we have the computational wherewithal to accelerate our discoveries.”

Paulson, describing himself as “an eternal optimist,” agrees that the future of academic neurology is bright. “We have all these tools available that allow us to query how the brain works in normal and disease states; President Obama and NIH Director Francis Collins have identified the importance of understanding brain function and dysfunction as a key initiative. At the same time that our understanding has grown, the identification of effective therapies has lagged. That's why we need new minds to push the agenda forward.”