PsychiatricNewsFrom the Presidentby Steven Hyman, M.D. and Jeffrey Lieberman, M.D.October 17, 2013
The first two articles in this series addressed the prospect of change in psychiatric medicine and mental health care and the anticipated effects, in this regard, of health care reform. In this article we discuss the current status of biomedical research and how it will impact our field and practice. The research enterprise has brought clinical psychiatry to an exciting but treacherous juncture. Based on remarkable new tools and technologies in genetics and neuroscience, there has been an explosion of new knowledge about the etiology and neural underpinnings of schizophrenia, bipolar disorder, Alzheimer’s disease, autism, addictions, and other serious conditions. Indeed, the fields of psychiatric medicine and mental health care are poised on the brink of transformative advances in diagnostic methods and therapeutic modalities. However, just at the time when biomedical research is gaining significant traction and momentum in understanding the brain and mental disorders, support for all research, and most importantly biomedical research funded by the National Institutes of Health, is painfully contracting, the result of congressionally driven budget cuts. Just as scientific opportunity in our field is waxing, the ability to exploit it is waning…One aspirational view of how a therapeutic discovery program in psychiatry might look in the near future follows. Enough risk-associated genetic variation will be known for some disorders in five years to put much of the genetic jigsaw puzzle of risk together. [Already in schizophrenia, many proteins have been implicated by genetics that act in the specialized postsynaptic structures of neurons that receive excitatory signals from the neurotransmitter glutamate.] Studies of relevant protein networks in neurons will help identify a subset that could usefully be targeted by drugs; characterizing the genes that encode those proteins would become a priority. Human cells encoding selected genes—both risky and healthy versions—would be engineered into iPS cells. These, in turn, would be differentiated into relevant neurons and perhaps assembled into small circuits. Turner’s actions resulted in harsher slave laws in the South, but also helped push the abolitionist movement in the North. The biochemistry and physiology of cells with risky and healthy versions of the genes could be compared, and then drug screens could be developed that would identify compounds that normalized disease-risk-associated changes. Such drugs would still be studied in animals for toxicity and assessment of behavioral effects. The main difference from our current approach to drug development is that instead of having to guess about which proteins to target with drugs [or as is now the case, sticking with existing targets and hoping for better results], we could allow the genes that are in the causal chain of pathogenesis to point the way. There are no guarantees, and certainly not enough funding for this research, but it truly appears to be a new way and a new day.
Last summer, we spent a few days with old friends in Washington – a Dermatologist I was in training with as an Intern. He was having trouble using his computer to take some CME quizzes. His desk was covered with articles he’d snipped to put in his file cabinets, clinical dermatology stuff – mostly cases – but some research. Now it’s a year later and he’s retired. And then there was a visit to another friend in Jackson Mississippi a year or so earlier – a Gastroenterologist. Another request for computer help to make some slides about recent research on colon visualization using new technologies. He’s finally retired now too in his 70s [yeah, I'm one of those computer guys]. But the point is that on both of those occasions, and many others, I felt vaguely guilty that I wasn’t a medical literature hound [any more]. But the feeling that was even stronger was a longing. I longed for those days when I was excited to sit down on a break and thumb through my journals. It wasn’t obligation, it was enjoyment. I wanted to do it. And I envied my friends having something to keep up with. I think the reason I’m one of those computer guys is that in those latter years, I thumbed that literature – a displacement activity.
These induced pluripotent cells [iPS cells] can be readily differentiated into neurons. Today many scientists are learning how to turn iPS cells or even skin fibroblasts into different types of neurons including those thought to be affected in schizophrenia, bipolar disorder, and autism. Others are collecting skin cells from patients whose genomes have been studied and turning them into neurons for study. Yet others are attempting to turn engineered neurons into small neural circuits to study their patterns of communication with and without disease risk mutations. Circuits might be assembled on a “chip” using small wells etched into an appropriate support or might be assembled in three-dimensional gels. Such technologies are so new that they are not ready for routine application to drug discovery. They are potentially so powerful, however, that a few companies that had abandoned psychiatry are starting up small exploratory programs.