At the age of almost 84, I am looking forward to launching a new career – as a fledgling neurobiologist. I stepped aside recently from almost 22 years as the University of Pittsburgh’s senior vice chancellor for the health sciences and medical school dean. For 16 years prior to my arrival at Pitt, I held the position of Scientific Director of the National Institute of Child Health and Human Development (NICHD), one of the National Institutes of Health (NIH). I rose to that role after initially serving, years before, as a Clinical Associate in the National Cancer Institute where, as a young US Public Health Service officer, I satisfied my military obligation during the Viet Nam war. Over almost four decades, these senior roles have defined me as an integrator, synthesizer, and academic leader of medicine and science. Here I have been successful, as assessed by my having built a scientific environment in the NICHD such that it is recognized as one of the world’s leading centers in research on the biology of human development, and by my having recruited a faculty talent base in Pitt that has driven the University’s rise to fifth nationally in NIH funding – the gold standard of research excellence.
My clinical training and experience is as an oncologist, and my scientific training and experience is as a molecular biologist focused on the biology of cancer as it occurs in young people. My research career has run parallel to my leadership one, and I can point to several accomplishments that have led to my interest now in moving from studies on the development of cancer to pursuing some ideas on the development of abnormal brain function – especially what might lead to the neurodegeneration seen in Alzheimer’s disease.
I have had a long-standing interest in how our DNA may be damaged (e.g., by sunlight, chemicals, toxins, normal aging, etc.) and how that damage is recognized and faithfully repaired. A few years ago, my laboratory colleagues and I wondered whether cells that are no longer dividing are able to repair their DNA damage. Such cells are said to be terminally differentiated because they have specialized features and no longer need to divide to evolve into their final state. However, this means that the two DNA strands in each terminally differentiated cell will no longer be copied into another two strands as would happen during cell division, with each of the two resulting cells having two DNA strands. It is during this process of copying the DNA that a damaged strand is repaired, using an intact strand as a template for the faithful repair of the damaged strand. Thus, no DNA copying, no faithful DNA repair. In the fullness of laboratory time, we found – to our surprise and that of our peers – that absent a DNA template strand, terminally differentiated cancer cells use a special form of RNA as the template for high-fidelity DNA repair. With these results safely published in a respected journal, I wondered how neurons – our key brain cells – repair their damaged DNA. After all, they too are terminally differentiated; DNA damage would accumulate as we age and without faithful DNA repair the brain would become dysfunctional. To our even greater surprise, we found that neurons can also repair their DNA damage with high fidelity, using the same special RNA template as a mirror for the error-free repair of the damaged DNA strand.
These novel findings have led me to speculate that defective repair of DNA damage in our brain cells might be the cause – or one of the causes – of neurodegeneration, especially during aging and Alzheimer’s disease. Perhaps after many years of incremental DNA damage, as a consequence of normal metabolism and the damaging effect of oxygen radicals produced in that process, some humans cannot repair the damage faithfully – maybe for genetic reasons. I want to pursue this possibility in the lab, morphing along the way from a trained cancer biologist to an untrained, but enthusiastic, neurobiologist.
While this seems very risky – if not preternatural – l am not unique in considering such a career move. There is, in fact, a tradition of late-career risk takers in science, especially among biologists. It appears that there are two cohorts of neuroscientists: one comprises people who know almost from infancy that they are prepared to tackle the structure and function of the brain (in whatever animal intrigues them), and one that assesses the seeming intractability of this three-pound bag of jelly above our neck and opts for careers that they perceive to be less risky. Late in life, having gained security, achievement, and recognition in the latter, they are prepared to take on the former. Francis Crick comes to mind, as does my own cousin, Donald Glaser (who invented the bubble chamber, making it possible for his fellow physicists to visualize subatomic particles). Crick solved the structure of DNA and felt that once he and his colleagues had begun to understand the fundamental chemistry and biology of life, he could approach even more complex subjects, e.g., the molecular basis of consciousness. My cousin decided on the very day that he received his Nobel prize in physics that he would remain in Stockholm to study biology. Even that was not enough for Don, and in the final years of his career he moved to neurobiology – wanting to understand the molecular basis of perception. I am most certainly not a Nobelist – I am a good but not a great scientist - but I do believe that I am not off base in thinking that I can apply what I have learned about the repair of DNA damage in cancer to the repair of DNA damage in the brain, and hopefully this will lead me and my laboratory colleagues to new insights into the molecular mechanisms of neurodegeneration.
Probably my new lab theme is enough – much more than enough – but the leader in me remains restless. So, I accepted the position of Executive Director of the University’s Brain Institute to share the experience, skill, and judgment that comes from seniority with our 150+ neuroscientists, who in turn can teach me about the brain – the structure and function of cognition, knowledge, memory, behavior, motor and visceral activity, feeling and emotion. In fact, I know of nothing in life – nothing of health nor illness - that does not depend on this structure and function.
With this in mind, never has there been a moment in our species’ history that would not welcome our further understanding of our own and each other’s brains. Witness the fateful errors that we have made as a social, political, economic, and cultural aggregate absent this further understanding. While my own research will be focused on Alzheimer’s disease – especially its molecular roots and its prevention – in fact I hope to offer leadership to my colleagues as they pursue a diversity of critical brain phenomena, e.g., the neurobiology of violence, addiction, stress, conscious and unconscious bias, and how each of us interrogates our life. Wish me luck, please, as I focus both narrowly and broadly on this next maneuver in my professional and personal life.
Arthur S. Levine, M.D.
Executive Director, University of Pittsburgh Brain Institute
Professor of Medicine, Molecular Genetics, and Neurobiology
Senior Vice Chancellor Emeritus, Health Sciences
Dean Emeritus, School of Medicine
University of Pittsburgh
Biomedical Science Tower 3, 10045
3501 Fifth AvenuePittsburgh, PA 15261, USA