Profile written by Robert S Rust, MD, MA
Donna Ferriero attended Rutgers University, achieving BA in Zoology in 1971 and MS in Immunology in 1973. Frank Margolis proved an influential mentor; under his tutelage she studied neurotransmission, biochemical and morphological aspects of olfaction transmission, work that resulted in several publications. Further attraction to the neurosciences was experienced during the preclinical phase of her medical education at UC San Francisco. Although this interest might initially have led her in the direction of “adult” neurology, it became apparent to her that child neurology was a better fit. As has been the case with many others, Bruce Berg played an instrumental role model in this decision and served as a role model, as would Suzanne Wilson-Davis. Awarded the MD degree in 1979, Dr. Ferriero’s Pediatrics residency years at Tufts and the Massachusetts General Hospital were followed by training in Neurology and Child Neurology and a two year fellowship in Developmental Neurobiology, both at UCSF. Additional important influences on her career development were fellow-residents Tom Koch, Jim Barkovich (who provided her with solid grounding in neuroimaging), and Susan Cummings (with regard to the epidemiology of cerebral palsies). Karin Nelson would also become a role-model for Dr. Ferriero.
Bench investigations quickly prospered in Dr. Ferriero’s hands, initially under the guidance of the protein/peptide neurochemist, Stephen Sagar, and with the foundation in molecular biology provided by Bob Edwards. Six papers were published with Sagar in a four year span, important and fundamental work concerning developmental and functional aspects of neocortical and retinal neurons and Dr. Ferriero’s earliest investigations of response of neurons to hypoxic-ischemic stress. By that point she had achieved clear independence with regard to the direction not only of her basic but also her clinical research, including a remarkable capacity to recruit and direct the efforts of others at various levels of training and to establish important collaborative efforts with numerous peers. The results are characterized in more than 135 peer-reviewed publications in prestigious journals, as well as 49 splendid chapters and reviews. Slightly more than half of the peer-reviewed publications are based on bench research, the remainder are important clinical publications. The bulk of this work was completed within fifteen years, chiefly concentrating on the pathobiology or clinical manifestations of hypoxic-ischemic injury to the developing nervous system. Basic and clinical observations have been closely linked throughout this remarkably productive interval.
Bench investigations directed by Dr. Ferriero have characterized with particular elegance the unique ways in which developing nervous tissues are sensitive to oxidative stress and the manner in which this accounts for cell death after perinatal asphyxia. She has greatly advanced the understanding of variations in regional vulnerability to injury at various stages of early nervous system development. She has enlarged understanding of oligodendrocyte vulnerability as a basis for periventricular white matter injury of the premature newborn, but has also drawn attention to the importance of subplate neuron vulnerability in this form of injury. One fundamental concept that Dr. Ferriero and her colleagues have provided is the role that relentless signaling by nitrous oxide synthase-expressing neurons, spared during the acute phase of hypoxic-ischemic injury, may play in producing excitatoxic injury via their connections neurons in deep gray nuclei. Other aspects of post-hypoxic ischemic cell death remote from initial areas of injury at varying times have also been investigated. These observations have provided a more rational and sensitive basis upon which investigations of the potential neuroprotective effects during this post-stress “window of opportunity” may be carried out employing selective NO-synthase inhibitors and other potentially neuroprotective agents. Many such investigations have been completed or are currently underway in the Ferriero laboratory.
Dr. Ferriero and her colleagues have systematically characterized other ways in which approaches to europrotection in developing brain differ from approaches that may be pertinent to mature brain. Thus, superoxide dismutase overexpression has been shown to increase rather than attenuate injury to developing brain, due to the lower antioxidant reserve of the latter. On the other hand, demonstration by Dr. Ferriero and colleagues of the protective effects of overexpression of glutathione peroxidase in an animal model of hypoxic-ischemic injury has provided an alternative avenue of possible intervention. To her model of asphyxial brain injury Dr. Ferriero has added a model of vascular territory infarction which has provided new information of fundamental importance in understanding this form of injury, including the participation of inflammatory mechanisms and demonstration that, contrary to widely held belief, blood-brain barrier is far more intact after stroke than has been believed. Other studies have characterized the post-stroke migration of subventricular stem cells to areas of infarction.
Thirteen papers have provided results from the prospective study of factors that determine outcome of perinatal asphyxia, including detailed imaging studies of more than 150 preterm and more than 200 term infants, employing a wide array of sensitive imaging techniques. Of critical importance are clinical MR spectroscopy studies that have placed in question the wisdom of regarding neonatal seizure as inconsequential to the outcome of infantile hypoxic-ischemic stress. The unreliability of ultrasonography as a predictor of poor outcome of the premature infants has been characterized by Dr. Ferriero and her colleagues. Collaboration with the California cerebral palsy project has shown robust correlation between risk for cerebral and expression of inflammatory cytokines in neonatal blood spots. Blood spots are also being employed to investigate risk factors for perinatal stroke, including more than 100 genetic mutations that may be pertinent. Other elegant clinical investigations by Dr. Ferriero’s group, also based in considerable part upon the insights provided by their bench research, have characterized overlooked aspects of the clinical manifestations of injury to deep gray nuclei after hypoxic- ischemic stress in the term infant. She and her colleagues have similarly applied sensitive imaging techniques to demonstrating that experimental findings concerning limited abrogation of blood- brain barrier after stroke are also true of the human newborn.
The extraordinarily robust network of collaborative efforts within which Dr. Ferriero occupies a central role is in the midst of a broad program of ambitious ongoing investigation. It cannot be doubted that this group will achieve remarkable insights further characterizing selective cellular vulnerability as a function of developmental stage and type of stress, providing additional opportunities for investigation of potentially effective interventions. The proven excellence of this group in carrying these basic findings to the bedside with imaging and other forms of investigation will quickly provide such validation as may be found concerning observations and interventions. Among other techniques, these will include highly sensitive mapping of corticospinal tracts and (returning to an early interest of Dr. Ferriero) the visual system. Genomic and proteomic studies are to be applied to the study of various potentially vulnerable signaling pathways, another preserved thread of the earliest interests of Dr. Ferriero’s remarkably well integrated career. The broad spectrum of other important clinical observations that she has made include not only imaging of particular developmental disorders, but the effects of toxins such as cocaine and alcohol in the developing nervous system. She has mentored the productive early basic or clinical research careers of more than thirty-nine individuals.
Dr. Ferriero has not been sequestered in the laboratory. Her local activities have included particular attention to outreach to the medically underserved and services on behalf of equal opportunities for women and minorities. She has been concerned about the quality of life of all medical professionals. She has served on numerous committees, often as chair, for UCSF, CNS, PCN, AUPN, SPR, APS, ANA, United Cerebral Palsy, American Heart Association, and Society for Neuroscience. She is a very active grant reviewer and member of numerous review sections. She has served on eleven editorial boards and is Associate Editor of Annals of Neurology. She is ad hoc reviewer for 27 journals. Dr. Ferriero has received five teaching awards, representing efforts applied at all levels from medical students through post-doctoral trainees to colleagues throughout the world. Her efforts have included 21 international, 50 national, and even more numerous local lectures, many named and visiting professorships. She rose from assistant to full professor in eleven years, became Director of Child Neurology at San Francisco General in 1987 and at UCSF in 1998. She became Vice-Chair of Neurology at UCSF in 2000 and Associate (2004) and Vice (2005) Dean of Academic Affairs at UCSF. She was recipient of the Sydney Carter Award of the AAN in 2000. She was named to the Institute of Medicine/National Academy of Sciences in 2005.
Dr. Ferriero’s personal qualities are hardly limited to her extraordinary intellectual abilities, powers of analysis and observation, and capacity to get quickly to the heart of a subject. Nor do her remarkable dedication to hard work and exemplary efficiency complete her catalogue of virtues. There are also qualities of honesty, reliability, supportiveness and appreciativeness of others, sociability, and a sense of humor to consider. While it is hard to imagine when she finds time for her avocations, she apparently does and they include music, gardening, swimming, and traveling.