In the Spotlight talked with Dr. Sweet in 2016 about his career, keeping up on the latest scientific findings, and his interests outside of the clinic and laboratory.
It can be challenging when it comes to balancing his clinical, educational and research activities, but Dr. Robert Sweet wouldn’t have it any other way. He’s excited about extending findings from post mortem studies conducted in his lab to create novel molecular mouse and primary neuronal culture models that will enable him to test aspects of causation. His passion for teaching and mentoring is evident as he discusses how mentoring students, postdocs and junior faculty has enriched his own career and research activities. Outside of the laboratory and classroom, Dr. Sweet demonstrates that same passion when talking about issues that he cares deeply about, such as the inequality experienced by racial and sexual minorities.
Dr. Sweet joined the Department of Psychiatry faculty at the University of Pittsburgh in 1990, and is currently UPMC Professor of Psychiatric Neuroscience and Professor of Neurology. His clinical work as a geriatric psychiatrist has played an important role in his formation as a translational scientist. Over the course of his career, he has established and led an extremely successful and cutting edge research program investigating the genetic liabilities for, and the neurobiological underpinnings of, psychosis in two main disorders – Alzheimer disease (AD) and schizophrenia. Despite his significant research responsibilities, he continues to see patients as part of his role as the director of the clinical core of the Alzheimer Disease Research Center at the University of Pittsburgh. Dr. Sweet has also earned a much deserved reputation as a thoughtful teacher and mentor, and an excellent administrator and academic citizen.
What new projects you are excited to be working on? My work has focused on identifying the structural and molecular changes in cerebral cortex circuitry present in postmortem tissue from individuals with two of the most common psychotic disorders, schizophrenia and psychosis in Alzheimer disease. Although I view these studies as essential to accurately identifying the brain phenotypes of psychosis, they suffer from a fundamental limitation of postmortem studies- we cannot assert whether the changes we observe may cause psychosis, or are alternatively consequences or confounds of the psychotic state. The two new projects I have been most excited about, one in schizophrenia and one in Alzheimer disease, have been taking our postmortem findings that next step further, creating novel molecular mouse and primary neuronal culture models that allow us to test aspects of causation. We use a multistep approach. First, we identify proteins whose levels are altered in the cortex of our subjects with disease. Second, from among these proteins we select for further studies ones that have been linked genetically to psychosis risk, as these have a high probability of contributing causally to disease. Finally, we evaluate the effect of altering these genes in our model systems, to determine if they generate the structural and molecular changes we have observed in the cerebral cortex from human. In mouse models we can also assess whether they generate psychosis-associated behaviors. In the past we have had to rely on existing transgenic or knockout models, or overexpression systems, to create these models. Now, with the advent of CRISPR/CAS9 gene editing, custom models can be created quickly, reliably, and inexpensively. We just generated our first (and perhaps the first) point mutation model of schizophrenia, and hope to be characterizing these animals soon. During the past year we have been behaviorally and pathologically characterizing a molecular model of psychosis in Alzheimer disease that we developed. In the coming year we have plans to test a novel pharmacologic approach to reversing the impairments we have observed in this model.
Have you ever doubted yourself regarding your ability as a researcher? If so, how did you overcome that self-doubt? What helped you to continue to pursue a career in research? I don’t know how someone in this field could not doubt themselves periodically. I am sure I have not fully overcome it- every time I try to move into a new area, or use a new technique, it rears up again- often aided by manuscript and grant rejection. Early in my career, however, I was faced with my most serious doubts as I struggled to obtain my first R01 after my initial K award. Like many other early researchers, I substantially misjudged a number of factors regarding developing my “innovative” research pursuits to the point where others would view them as worth investing in. What ultimately allowed me to sustain my career was the support and guidance of several mentors. My Chairman, Dr. Kupfer, arranged clinical and administrative duties that were not overwhelming to support a portion of my salary while still leaving time for research. The Director of the Alzheimer’s Disease Research Center (the research program I was most closely affiliated with at the time), Dr. DeKosky, found a way to provide support for my effort in the center and helped me to secure funding for a project grant within that center that ultimately developed into an R01. I developed a relationship with a new mentor, Dr. Lewis, who provided access to resources and convinced me to train in new techniques outside of my current interests. Perhaps most importantly, he put a lot of effort into teaching me the difference between writing a good grant and an outstanding one. At the end of the day, it was the “village” of mentors I had that made all the difference.
How do you stay informed of new, very high impact publications outside your immediate interests but that might benefit your research? Every researcher needs to figure out how to identify the important developments that may influence the questions they ask and the approaches they use to answer them. I have several methods that I use. First, I have a number of interdisciplinary collaborations. I routinely draw my collaborators out on what is new in areas they know about, but which I don’t follow actively. In addition, my collaborators’ and I forward to each other articles of interest in our areas. Second, although I am not a subscriber to Science, or Nature, I make a point of cruising their websites regularly to look for interesting new research. Year-end issues are particularly helpful to find lists of the most important recent developments. Third, my lab reads articles of interest together every other lab meeting. I ask all of my trainees to nominate papers for review, which allows them to expand my view of relevant science. Fourth, I make a point of learning about big ideas which are new to me from plenary sessions at major conferences. While this can be informative at major psychiatric conferences such as Society of Biological Psychiatry or the American College of Neuropsychopharmacology, I find I often learn of more useful developments in plenary sessions at what for me is the major basic science meeting for my work, the Society for Neuroscience. Finally, I should point out that we are fortunate to have a stream of nationally renowned speakers at WPIC and at Pitt almost every week. Going to talks given by accomplished scientists, especially those outside your expertise, is always a good idea.
As a mentor or mentee, what do you think are the top 2-3 elements in successful mentoring? To me what is exciting about the mentoring relationship is the creative interplay of ideas between the mentor and mentee. This interplay also generates some of the challenges in the relationship. There will always be some unclear boundaries regarding intellectual contributions and ownership of data or products that arise from this shared effort. As a consequence, my experience has been that the most important attributes of the mentor and mentee are those that allow useful work to flourish in the face of this uncertainty. There needs to be a generosity of spirit in the mentor- a willingness to promote and offer opportunities to the mentee, and to give of his time and effort. For the mentee an ability to sustain trust in the face of the uncertainties and vulnerabilities inherent in the situation is critical. Finally, as a dyad they need the ability to communicate openly so they can creatively problem-solve together. In particular, they need to view their primary goal as an effort to generate win-win outcomes whenever possible, ahead of outcomes only beneficial for one of them.
Are there political or social issues you feel passionately about? Through my experiences as an adoptive parent, I entered a community of inter-racial and transgender families. That experience has led me to be profoundly concerned about inequality experienced by racial and sexual minorities. I am a strong supporter of equal rights in all aspects of life for the LGBT community, but especially around the right to marriage and parenthood. I similarly feel deeply around issues of racism in America. Not just the obvious extremist forms, but more importantly the subtle (actually only subtle to those with white privilege), institutionalized racism that is present in our country. It is perhaps most visible within the courts and police departments of the criminal justice system, but also present in industry, the arts (the Motion Picture Academy has recently come under scrutiny again), and academia. In particular I am horrified by our failure to vigorously pursue a solution to the epidemic of deaths of young black men in the inner city from gun violence. To me this issue calls out for the same national effort used to reduce fatalities due to other medical and social causes, from polio to drunk driving.