Hyman, Steven E.

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Scientific Life: TrendsTalkSpecial Issue: Cognition in Neuropsychiatric DisordersInterview with Steven E. HymanSteven E. HymanBroad Institute of Harvard and MIT, 7 Cambridge Center 5015, Cambridge, MA 02142, USACorresponding author: Hyman, S.E. (seh@harvard.edu).Steven E. Hyman holds a BA from Yale University, a BAandMA from theUniversity of Cambridge, and anMD fromHarvard Medical School, where he became Professor ofPsychiatry in 1998. He served as Director of the US Nation-al Institute ofMental Health (NIMH) from 1996 to 2001 andProvost of Harvard University from 2001 to 2011. He iscurrently HarvardUniversity Distinguished Service Profes-sor, Professor of Stem Cell and Regenerative Biology, andScholar in Residence at the Broad Institute of Harvard andMIT. He is Editor of the Annual Review of Neuroscience,Founding President of the International Neuroethics Socie-ty, a fellow of the American Academy of Arts and Sciences,and a member of the Institute of Medicine of the USNational Academies. He chairs the International AdvisoryGroup for the revision of the International Classification ofDiseases (ICD-11) Mental Disorders Chapter and is a mem-ber of the Task Force for the Diagnostic and StatisticalManual of Mental Disorders, 5th edition (DSM-5).What turned you on to science in the first place?My infatuation with science started with the naturalworld. According to my parents, I was relentlessly curiousand ever skeptical. One of my earliest personal memoriesof doubting – memorable, perhaps, because I was so wrong– followed my hearing an authoritative voice at a planetar-ium intone that in times past people navigated by the stars.From my childhood perch on the West Side of Manhattan,the assertion seemed preposterous – starswere not reliablyvisible. My view was corrected by a visit to suburbanhinterlands.By my later school years, motivated by bemused obser-vations of my family and my classmates, and my self-reflection, the most compelling questions in science in-volved the workings of the brain and its relationship tolived experience. It was not at all obvious how I could makea satisfying career of such stuff, although academia seemedto be part of the solution. My parents, however, the chil-dren of striving immigrants, hoped that I would forget allthis nonsense and become a private practitioner of somerespectable branch of medicine (i.e. not psychiatry).What steered you towards psychiatry in particular?I did get trained in psychiatry, but arrived by a tortuouspath. There was not much to be learned about higher brainfunction in undergraduate courses of the early 1970s. Thiswas not the fault of the excellent faculty that taught me atYale, but reflected the dominant approaches to psychologyand the early state of neuroscience. I therefore focused onphilosophy. While rigorous and enjoyable, however, myundergraduate experience, followed by 2 years studyingthe history and philosophy of science at the University ofCambridge, convinced me that more penetrating explana-tions of brain function would lie in biology and psychologyafter all. Given my intellectual trajectory, however, I wascertain that I could not convince the few neurobiology PhDprograms that had begun by 1975 that I was either pre-pared or serious. I therefore decided to enter science viamedical school, which in the USA seemed agnostic aboutprior fields of study.I found my first-year psychiatry course at HarvardMedical School repellant. The psychoanalysts and psycho-pharmacologists who taught us proffered, with sereneconfidence, absolutely incompatible views of the causesof mental illness. What they shared was simplistic deter-minism. One apparently revered senior psychoanalystnoted the benefits of ‘putting schizophrenics and manicdepressives’ on the psychoanalytic couch, and conceptual-ized their symptoms as reactions to a ‘crazy world’. Mean-while, the champions of biology ascribed psychopathologyto ‘levels’ of a few monoamine neurotransmitters, all thewhile ignoring emerging understandings of brain circuitryand experience-based plasticity that were coming fromright across the street. Indeed, future Nobel laureatesTorsten Weisel and David Hubel were, in the very samesemester, teaching in a magnificent course that introducedme to neurobiology.By now the reader might wonder why I became apsychiatrist rather than heading right to the laboratoryor perhaps entering neurology. It was not to fight withcolleagues (although for many years that had a certaincharm): it was the patients. In my third year of medicalschool, I was fortunate to observe people with remarkableand moving conditions, including acute mania, deep mel-ancholic depression and florid psychosis. These illnessesstruck me as extraordinarily worthy scientific challenges,an understanding of which would help to illuminate highercognitive function and emotion. At the same time it seemedthat research, if successful, could have enormous benefitsby relieving terrible human suffering and disability.How has the landscape of psychiatric research chan-ged in the past 30 years?Optimism reigned when I began psychiatry residency in1981. Despite the daunting complexity of the brain, therewas reason to believe that important clues to pathogenesisand treatment of severe disorders might be at hand.The serendipitous discovery of lithium, chlorpromazine3Scientific Life: TrendsTalk Trends in Cognitive Sciences January 2012, Vol. 16, No. 1(the first antipsychotic drug) and several antidepressantsin the 1950s and of their initial targets in the brain in the1960s and 1970s promised both therapeutic progress andsignificant probes of brain function. Looking back, the pic-ture is painfully different. The efficacy of psychotherapeuticdrugs plateaued by 1955. Subsequent progress has beenlimited largely to tolerability. Strikingly, we still do notknow how psychotherapeutics exert their desired effects.Genetics also promised important clues to pathogenesis.Serious mental illnesses were long known to run in fami-lies. Twin and adoption studies demonstrated that genesplayed major roles in schizophrenia, bipolar disorder, al-coholism and other disorders. With the dawn of molecularbiology (the field in which I did a 5-year post-doctoralfellowship after psychiatry residency) it seemed that wemight soon identify causal mutations. There were concernsthat risk could be polygenic and thus very difficult toanalyze, but such worries were generally suppressed asthe field focused on families in which schizophrenia orbipolar disorder seemed to be transmitted with tragiccertainty. Only later were the striking phenotype differ-ences even within such ‘high-density’ families recognizedas significant harbingers of genetic complexity, along witha plethora of other disconcerting observations.How have your views evolved with respect to theDiagnostic and Statistical Manual of Mental Disor-ders (DSM)DSM-III was published in 1980, the year before I beganmypsychiatric residency. For all its flaws, most seriously thelack of validation, it was an exciting advance central to theoptimism of the field. Without the inter-rater reliability(promised by the operationalized, field-tested diagnosticcriteria of the DSM), validity could never be achieved. Ibelieved that DSM-III represented a first draft of a moderndisease classification that would evolve as science pro-gressed. More than three decades later, this promise hasnot been realized, partly because the brain, in its complex-ity, gives up its secrets slowly and grudgingly, and partlybecause the DSM system quickly became so central topsychiatric research and practice that its diagnoses havegone unquestioned to a striking degree.Nonetheless, as the DSM approach was applied to clini-cal practice and research, fundamental flaws began tosurface. These flaws were not the sort to be repaired byrefining of criteria. As one major example, the authors ofDSM-III conceptualized mental disorders as discrete cate-gories, discontinuous from health and from other disor-ders. Except for mental retardation, they rejectedapproaches in which disorders might represent a quanti-tative deviation from health on relevant dimensions (inanalogy to hypertension or type 2 diabetes). Much subse-quent research demonstrates that dimensional approacheswould better represent depression, attention deficit hyper-activity disorder (ADHD), autism, anxiety disorders, per-sonality disorders and many others. This error contributesto much of the disutility of the DSM for research and forsetting of defensible treatment thresholds.Another salient example: Psychopathology is not trans-mitted in families in the form predicted by the DSM.Symptoms do not segregate across generations in the4groupings that define a single disorder. Rather familiesmight exhibit schizophrenia, mood disorders and interme-diate states or else multiple different putative anxietydisorders and depression. This observation reflects the factthat the genetic, epigenetic, and other environmental risksof psychopathology are etiologically complex and heteroge-neous. For example, the many risk genes that mightcontribute to schizophrenia are not transmitted togetheracross generations. The categorical DSM approach as-sumed far simpler causality, in analogy with a single gene(Mendelian) disorder or a disease caused by a single mi-croorganism.What was your thinking concerning the DSM systemas director of NIMH?When I became director of NIMH in 1996, I was aware of‘DSM troubles’, but given a scientific career focused onregulation of gene expression, I had not given these pro-blems deep thought. Indeed, I thought classification a dulltopic better suited to medieval scholastics. As I viewedprocesses for grant review, however, I began to thinkdifferently. Indeed, I saw a troubling paradox. As a reliableand widely accepted diagnostic system, the DSM under-girded the replication of research results. As a result, butproblematically because the DSM was clearly deeplyflawed, grant reviewers, journal referees, editors and reg-ulatory agencies all required DSM diagnoses for disease-related research. Indeed, they acted as if DSM criteria,mutatis mutandis, picked out real human diseases. Thus,its wide acceptance meant that a conceptual schema basedon the thinking of the 1960s and 1970s exerted control overthe scientific questions that could be asked.Classification now had my attention, but I could notfigure out how to facilitate a fundamental transformationwithout undercutting the diagnostic agreement crucial forclinical practice as well as research. I rejected the idea ofcommissioning NIMH research diagnoses because theywould split researchers from clinicians. If an imaging studyor clinical trial were conducted using research diagnoses,how would the results be correlated with DSM-basedclinical practice?What is your role in the revisions that will produceDSM-5 and ICD-11?I left NIMH in 2001 thinking that I would return toacademia, having kept my laboratory functioning duringmy years of government service. I could not resist an offerto return to Harvard to be provost (chief academic officer)with a special focus on building cross-disciplinary andcross-school science. I did not realize just how long I wouldstay in post, but that is another story.Despite my day job, I continued to read, muse and writeabout issues in neurobiology and psychiatry. In 2007 Ipublished a possible path forward in DSM reform in Na-ture Neuroscience, with the result that I was invited intothe revision processes for DSM-5 and the World HealthOrganization ICD-11. The idea is simple: diagnostic crite-ria for individual disorders could be left unchanged in theabsence of a compelling scientific reason. However, disor-ders should be clustered according to our best currenthypotheses. For example, high levels of comorbidity andScientific Life: TrendsTalk Trends in Cognitive Sciences January 2012, Vol. 16, No. 1twin studies would suggest clustering of fear-based anxietydisorders and unipolar depression; similar approachessuggest clustering of antisocial personality disorder, sub-stance use and other impulse control disorders. Neuralcircuit hypotheses suggest that obsessive–compulsive andrelated disorders should be a cluster carved out of anxietydisorders. The key to any utility is that scientists, grantmakers and journals should be encouraged to ignore indi-vidual DSM-5 disorders and to work at the level of clustersor even across related clusters to develop and test newbottom-up disease definitions, including dimensional mea-sures that that cut across diagnoses. Happily, NIMH has aprogram that will facilitate this scientific transition.If you knew earlier what you know now, would youhave pursued the same career?I would still pursue much the same career, because I findno other topic as engaging. Despite the heady nature ofleadership roles, I find that I am happier surrounded byscientists as I am during my sabbatical year at the BroadInstitute of Harvard andMIT. Sometimes I wonder wheth-er it would have been better to have followed a straighter,more focused scientific path through life. In truth, I wouldnot give up the breadth that my education and my variousroles have allowed. This is not to say that I would everrecommend my precise path to a young person because itcould just as well have been a recipe for failure. I have beenvery lucky.What is next for you?I decided some years before stepping down after a decadeas Harvard provost that I did not want another high-leveladministrative position, but that I was hungry to returnfull time to science. I am focused on how emerging geneticsresults in autism, schizophrenia and bipolar disorders canyield incisive neurobiological experiments and how wemight as a result accelerate much-needed new therapeu-tics.What advice would you give to young people interest-ed in a research career in psychiatry?By all means enter this exciting field, but make sure thatyou are well grounded in your chosen area of science. Gaintraining in the best possible laboratories, not necessarily inyour clinical department. Progress will be challengingbecause the brain is by far our most complex organ. Thus,only deep and effective scientific training is likely to equipa person to make significant – and much needed – con-tributions.1364-6613/$ – see front matterdoi:10.1016/j.tics.2011.10.007 Trends in Cognitive Sciences, January 2012, Vol. 16, No. 15

Interview with Steven E. Hyman

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