Top 10 selections for 2013 by NIMH director

15 12 2013

By Thomas Insel on December 13, 2013

It’s time again for the year’s ten best from NIMH. A year that included a 16-day government shutdown and a 5.2 percent sequester also saw some outstanding scientific breakthroughs and historic changes in policy. Befitting the complexity of the problems, many of the breakthroughs were not individually reported findings but the cumulative results of several groups contributing different pieces of the puzzle. And some of the most historic policy changes are just launching so their impact is unclear. Paring a lengthy list down to “ten best” is both difficult and unsatisfying, but here goes.

Illustration of neurotransmitters10. Nobel Prize—This year’s Nobel Prize in Physiology or Medicine (and Lasker Award) recognized NIMH grantee Thomas Südhof for his discoveries of how neurotransmitters are released from the pre-synaptic terminal. Südhof and his colleagues described the molecular machines that allow vesicles to empty their contents into the synapse and then re-form to collect more neurotransmitters. This process is critical for neurons to communicate efficiently. Recently, Südhof’s work on the post-synaptic compartment has revealed a new world of molecules important for translating these biochemical messages. The genes for many of these protein families (i.e., shanks, neuroligins, neurexins, etc.) are emerging as leading risk candidates for autism and schizophrenia, giving us a new vocabulary for the molecular basis of mental disorders.1

brain three-quarters view9. Beyond Magic Bullets—Several important new trends emerged this year in non-pharmacological treatments, sometimes from pharmaceutical companies. In April, a Nature commentary that included authors from the pharmaceutical giant GSK described “electroceuticals,” heralding a new era in treatment development focusing on devices to deliver electric signals rather than drugs to alter the activity of neurotransmitters in the brain. Neuromodulation, arguably a better term than electroceuticals, had already been gaining traction with treatment of depression using deep brain stimulation and direct current stimulation. This year neuromodulation was introduced for anorexia nervosa. But neuromodulation was also extended to include approaches beyond electrical stimulation. In September, the cover headline of Nature—“Game Changer”—referred to a study by Adam Gazzaley and colleagues on the impact of cognitive training with NeuroRacer, a video game for enhancement of cognitive control. Not only did older adults (60 – 85 years old) trained on this game surpass performance of untrained 20-year-olds, cognitive enhancement generalized to working memory and other forms of cognitive control, with improvements persisting 6 months later. Cognitive training changed local brain activity as well. The key concept: if mental disorders are brain circuit disorders, then successful treatments need to tune circuits with precision. Chemicals may be less precise than electrical or cognitive interventions that target specific circuits.2,3,4

8. Organoids—It’s been 6 years since the first report of induced pluripotent stem cells (iPSCs). These are cells derived from mature skin cells, induced to become undifferentiated stem cells in a dish, and then differentiated to form mature cells like neurons or heart muscle cells. It’s been a year since this work was awarded the 2012 Nobel Prize in Physiology or Medicine. The excitement of this new technique was the potential to take cells from an individual with a disorder and either regenerate new cells in vitro (imagine new dopamine cells for someone with Parkinson’s disease) or recapitulate the disorder in vitro to define its development and screen for new treatments. This year there were some remarkable reports of using iPSCs to explore the altered development of neurons in children with rare forms of autism. But if autism and mental illnesses are circuit disorders or “connectopathies,” how can individual cells teach us about the altered connections? Amazingly, according to a team from the Austrian Academy of Sciences in Vienna, when neurons are grown in a dish, they self-assemble into circuits that resemble the normal cortex. These “organoids” are not “mini-brains” capable of consciousness but they are functional enough to permit the study of connections. It now appears that iPSCs could be a powerful tool to study circuit disorders.5,6,7

7. DSM-5 and RDoC—For NIMH, probably the year’s most oft-quoted statement was my April blog post about transforming diagnosis. Referring to the pending release of the DSM-5, I said, “Patients with mental disorders deserve better.” To many, this was interpreted as a critique of mainstream psychiatry. In truth, I was complaining that we in the research community have failed to provide the objective measures for diagnosis present in every other area of medicine. The Research Domain Criteria (RDoC) project aims to do just that, by using biological, cognitive, and social information to build more precise classifiers for each patient. RDoC is not a diagnostic system. At this point it is simply a framework for organizing the data. But it is a promise from the NIMH to get beyond diagnostic categories based only on symptoms. Why is this important? For brain disorders, symptoms are generally a late manifestation of a years-long brain process. In medicine, early detection and early intervention have often been the best ways to improve outcomes. RDoC is a first step towards achieving these goals with mental disorders.8,9

6. EP3—A year that began with concerns about school shootings and mental illness saw more mass shootings, many of them connected to serious mental illness (SMI). For this unfortunate reason, there was more media attention on mental illness this year than any time in recent memory. The number of articles about “mental illness” in theNew York Times in 2013 were more than double the average of the previous five years. Among the many recurring themes—access to weapons, access to treatment, incarceration—one prominent one was the need for earlier detection and treatment for SMI. The Early Prediction and Prevention of Psychosis (EP3) program, launched this year at NIMH, is an example of efforts to answer that need. Building on the success of the Recovery After Initial Schizophrenia Episode (RAISE) project, which was implemented this year in New York and Maryland, EP3 will focus on tools for the prodrome, that period prior to psychosis when symptoms are just beginning to emerge and may be most treatable. New studies will build on results from the North American Prodrome Longitudinal Study (NAPLS), just completing 10 years of critical research to develop ways to identify individuals who are at risk for an initial psychotic episode. With a series of new funding announcements and with the success of RAISE and NAPLS, NIMH made EP3 its signature program this year.10,11

chromosones and double helix5. Psychiatric Genetics—In 2003,Science magazine named the identification of genes for mental illness as its #2 breakthrough of the year (just behind confirmation of the existence of dark energy in the cosmos). It has taken another decade to deliver results that are statistically significant and clearly reproducible. For schizophrenia there are now 128 genetic associations, all common variants found across the genome. None of these alone accounts for much of the risk, but groups of these “hits” point to specific biological pathways. For autism, there are many rare variants emerging, many of these “de novo” or spontaneous mutations not found in other family members. These mutations seem to be most common in children with both autism and intellectual disability. Studies that have looked across disorders find some common genomic associations, with some findings across childhood disorders and others across adult disorders, irrespective of diagnosis. Before concluding anything about the significance of these cross-disorder findings, it will be important to understand the actual variation (which gene is involved) and the functional role, if any, of the variant.12,13

4. Brain Exceptionalism—For me, 2013 will be the year when we began to realize how much the brain differs from other organs. We already knew that cells in the brain express (translate into protein) more of the genome and use more energy than any other organ. But two discoveries this year really made the case for the human brain as not only the most mysterious but the most exceptional of organs. Leveraging new tools for single cell biology, scientists working with Rusty Gage at the Salk Institute and Ira Hall at the University of Virginia reported that the brain has its own genome, with abundant and sometimes profound variation not found in other tissues. In human frontal cortex, they report as many as 41 percent of cells having at least one large mutation, with a million DNA bases either duplicated or deleted. These are mutations not seen in blood cells (which have been the basis for all psychiatric genetic studies) or in neurons elsewhere in the brain. Equally surprising, the brain epigenome also appears unique. The epigenome is a complex of molecules that coat the DNA helix, “silencing” parts of the genome to ensure that certain genes are not translated. The entire DNA strand consists of only four bases: cytosine, guanine, adenine, and thymine. Whereas in most cells in the body silencing occurs where cytosine and guanine are adjacent, brain cells follow a different set of rules with all the base pairs involved. This means that the mechanisms by which experience influence biology are completely different in brain cells compared to blood cells or liver cells. The lesson is that we cannot use peripheral cells to know what is happening in the brain.14,15

CLARITY 3D brain image3. CLARITY—It may be an inelegant acronym but the results are utterly beautiful. CLARITY = Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue hYdrogel. By replacing the brain’s fat with a clear gel, CLARITY turns the opaque and impermeable brain into a transparent and porous structure. Most important, the hydrogel holds the brain’s anatomy intact. And because the hydrogel is permeable, the brain can be stained to localize proteins, neurotransmitters, and genes at a high resolution. Unlike other recent breakthroughs in neuroanatomy, this one can be used in human brains. And unlike virtually all neuroanatomy of the past century, CLARITY is 3-dimensional. Flying through the tissue in 3-D allows the first comprehensive view of how cells and processes are arrayed across the entire brain. Karl Deisseroth earlier developed optogenetics as a revolutionary tool for studying brain circuits in behaving animals. This time his lab has revolutionized how we will look at the brain post-mortem.16

full color brain scan2. BRAIN—On April 2nd, President Obama in the East Room announced the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative. The speech should be read by everyone with a stake in brain research or brain disorders. Calling BRAIN the “next great American project,” he challenged a broad scientific community to explore the brain as we had once explored space. BRAIN will involve several government research agencies as well as several private sector partners. And it complements a large brain project underway in the European Union and projects being developed in Israel, Japan, China, and elsewhere. This global interest in neuroscience reflects both the growing awareness of the cost of brain disorders and the growing recognition that success in the 21st century will depend on a “brain economy” rather than a “brawn economy.” The U.S. BRAIN initiative will launch in 2014 with $110M, of which $40M will be from NIH. Funding announcements for the first wave of NIH projects will be released this month.17

Woman at NIMH Clinic1. Parity—My guess is that in terms of mental health issues, history will remember 2013 not for a scientific finding but for a long overdue policy change: mental health parity. While the Mental Health Parity and Addiction Equity Act was signed into law in October 2008, the final rule providing the guidance to implement this law was only released in November 2013. Most important, the Affordable Care Act, signed into law in 2010, affirmed mental health care as an “essential benefit.” As a result, mental health care must be provided in all health care plans and the provision of care for mental disorders must be on a par with other medical disorders (i.e., same co-pays, deductibles, certification requirements). When you add to these changes the removal of exclusions for pre-existing conditions, the extension of coverage to offspring until age 26, and in some states the expansion of Medicaid, you can see that this is really the most far-reaching change in mental health care since the Community Mental Health Act 50 years ago. And this is coming at an important time. Over the summer, the Global Burden of Disease project reported out on 291 medical disorders, updating its 1990 report with 2010 data. The new report finds mental illness and substance abuse disorders to be the leading source of years lost to disability, with the burden of illness from this group of disorders increasing 37 percent since 1990. Depression and anxiety were the largest contributors among the 20 mental and substance abuse disorders, accounting for 55 percent of the DALYs (disability adjusted life years—a composite measure of disability and premature mortality).

There are many questions about how parity will reduce DALYs: Who will provide the care? What will it cost? Where will mental health care be delivered? What is the dose and duration of psychosocial treatments that will be covered? None of these questions will be answered in 2013, but going forward NIMH can ensure that the best science informs this historic change.18,19

References

1 Südhof TC. A molecular machine for neurotransmitter release: synaptotagmin and beyond. Nat Med. 2013 Oct; 19(10):1227-31. doi: 10.1038nm.3338.

2 Anguera JA et al. Video game training enhances cognitive control in older adults. Nature. 2013 Sep 5;501(7465):97-101. doi: 10.1038/nature12486.

3 Lipsman N et al. Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial. Lancet. 2013 Apr 20;381(9875):1361-70. doi: 10.1016/S0140-6736(12)62188-6. Epub 2013 Mar 7.

4 Famm K et al. Drug discovery: a jump-start for electroceuticals. Nature. 2013 Apr 11;496(7444):159-61. doi: 10.1038/496159a.

5 Shcheglovitov A et al. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients.Nature. 2013 Nov 14;503(7475):267-71. doi: 10.1038/nature12618. Epub 2013 Oct 16.

6 Krev JF et al. Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons.Nat Neurosci. 2013 Feb;16(2):201-9. doi: 10.1038/nn.3307. Epub 2013 Jan 13.

7 Lancaster et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013 Sep 19;501(7467):373-9. doi: 10.1038/nature12517. Epub 2013 Aug 28.

8 Cuthbert BN, Insel TR. Toward the future of psychiatric diagnosis: the seven pillars of RDoC. BMC Med. 2013 May 14;11:126. doi: 10.1186/1741-7015-11-126.

9 Casey BJ et al. DSM-5 and RDoC: progress in psychiatry research?;
Nat Rev Neurosci. 2013 Oct 18;14(11):810-4. doi: 10.1038/nrn3621.

10 Fusar-Poli P et al. The psychosis high-risk state: a comprehensive state-of-the-art review. JAMA Psychiatry. 2013 Jan;70(1):107-20. doi: 10.1001/jamapsychiatry.2013.269.

11 Carrion RE et al. Prediction of functional outcome in individuals at clinical high risk for psychosis. JAMA Psychiatry. 2013 Nov 1;70(11):1133-42. doi: 10.1001/jamapsychiatry.2013.1909.

12 Cross-Disorder Group of the Psychiatric Genomics Consortium: Genetic Risk Outcome of Psychosis (GROUP) Consortium.Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013 Apr 20;381(9875):1371-9. doi: 10.1016/S0140-6736(12)62129-1. Epub 2013 Feb 28.

13 Ripke S et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia.Nat Genet. 2013 Oct;45(10):1150-9. doi: 10.1038/ng.2742. Epub 2013 Aug 25.

14 McConnell MJ et al. Mosaic copy number variation in human neurons. Science. 2013 Nov 1;342(6158):632-7. doi: 10.1126/science.1243472.

15 Lister R et al. Global epigenomic reconfiguration during mammalian brain development. Science. 2013 Aug 9;341(6146):1237905. doi: 10.1126/science.1237905. Epub 2013 Jul 4.

16 Chung K et al. Structural and molecular interrogation of intact biological systems. Nature. 2013 May 16;497(7449):332-7. doi: 10.1038/nature12107. Epub 2013 Apr 10.

17 Insel TR et al. Research priorities. The NIH BRAIN Initiative.Science. 2013 May 10;340(6133):687-8. doi: 10.1126/science.1239276.

18 US Burden of Disease Collaborators. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors.JAMA. 2013 Aug 14;310(6):591-608. doi: 10.1001/jama.2013.13805.

19 Whiteford HA et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013 Nov 9;382(9904):1575-86. doi: 10.1016/S0140-6736(13)61611-6. Epub 2013 Aug 29.





“With so many roads not yet taken, who would want to follow the herd?”

28 11 2012

Today I wish to present a new post of NIMH’s director Dr. Thomas Insel, that talks about the importance of research that explores the frontiers of science and funding efforts to encourage innovative research:

Julius Axelrod was one of NIMH’s greatest scientists and mentors for five decades until his death in 2004 at age 92. In addition to his many discoveries – which led to his 1970 Nobel Prize – Julie, as he was known, was famous for his aphorisms. One was his saying that “98 percent of the discoveries are made by 2 percent of the scientists.” While this might sound arrogant or elitist to some, data emerging over the past few years support the notion that much of our scientific endeavor involves following the herd and, importantly, that the herd grazes on not much more than 2 percent of the available land.

In a paper published last year in Nature entitled “Too many roads not taken,” Aled Edwards and his colleagues provide a nice example of this instinct.1 The class of enzymes called kinases are critical biological gatekeepers, and many are potentially involved in diseases of the brain. Although there are over 500 protein kinases known from the human genome, about 65 percent of the 20,000 kinase papers published in 2009 focused on the same 50 that were being studied in the early 1990’s. This narrow focus has persisted after many of the unexplored kinases showed up in unbiased genomic screens as potentially related to diseases.

The narrow focus of our science is even more conspicuous in this age of “-omics” – when we can study all of the genes, all of the transcripts, or all of the proteins without a hypothesis. Although we thought the fields of genomics, transcriptomics, and proteomics had defined the universe of roads not taken, recent publications from the ENCODE project reveal a dramatic expansion of this universe.2 ENCODE is a landmark effort that is mapping the working parts of the human genome and exposing just how limited our exploration has been to date. Researchers have focused mostly on the 2 percent of the genome that belongs to genes, but we now know that 80 percent of the genome is translated. In fact, the genome codes for a range of important biological signaling molecules, many of which are still being identified.

For the past 50 years, NIMH researchers have focused on a few pages of this vast text, assuming that dopamine and serotonin were most of what we needed to know about the biology of mental disorders. Where we have been is akin to colonial North America where the overwhelming majority of the population remained on a small fraction of the continent and the Midwest and West were frontiers explored by very few.

How do we encourage exploration of the vast frontiers of biology? How do we nudge the scientific field toward the unknown? In truth, much of what we currently do reinforces herd behavior. NIMH funding is guided largely by a system of peer review, and peer review tends to reward the familiar or, at best, small steps. But the problem is much more fundamental than this. Scientific training is based on an apprenticeship model, with the focus placed on following a mentor, not on breaking for a frontier. Furthermore, academic success requires publishing, which is most easily accomplished by remaining where the tools are good, the field is safe, and the territory is familiar. Not all kinases, for example, are equally easy to study. Successful scientists know to focus on problems that have a good chance of being solved. As the British biologist Sir Peter Medawar noted, “Science is the art of the soluble.” But the targets that are easiest to study are not always the most important. We have created a world of incentives for looking where the light is, even if that is not where the keys were lost.

This would not matter so much if our problems were not so important to solve. We simply cannot afford to have 98 percent of our scientists looking where the light is, staying within the safe zone. Given this, NIH has been working to build incentives to help attract the most intrepid scientists into the frontiers of science. NIH’s Pioneer Awards and New Innovator Awards are grants for innovative ideas that are opening new areas to research and creating new tools. Importantly, these awards are for the person, not the specific project, encouraging these scientists to pursue novel approaches to important problems. For example, a recent NIMH-supported Pioneer Award will allow Feng Zhang of MIT to develop a new approach to manipulating the genome and epigenome.3

NIMH is also trying to encourage innovation among young investigators through the BRAINS (Biobehavioral Research Awards for Innovative New Scientists) initiative. So far, we have awarded 28 early stage investigators with support to pursue an idea deemed high-risk but high-reward, helping to move them into areas not previously studied. Among the 28, Amit Etkin4 of Stanford is studying the neurobiology of psychotherapy, and Zhaolan Zhou5 of the University of Pennsylvania is defining the epigenetic signature of early life stress.

My own sense is that Julie Axelrod was partly right. There is a small group of scientific leaders who seek out new frontiers and set the pace for the vast majority of the field. But I am not convinced that tells the entire story. Each new breakthrough is based on a foundation laid by hundreds of scientists often working in distant fields. Today we find that discoveries are often the products of groups working together, rather than a lone investigator striving to be in the 2 percent club. At the same time, we do need to make more room for scientific pioneers – researchers who have completely new ideas and are willing to take risks to open up a new area of inquiry.

This need is important to consider during this period of austerity for NIMH funding. Tight budgets are not kind to risk takers. But, when budgets are tight, it is more important than ever to shore up support for the innovators who are not following familiar paths. At NIMH we are using the Pioneer and New Innovator initiatives, our own BRAINS awards program, and a policy of supporting grants that are trying new approaches even when the peer review scores are beyond our nominal payline. If there is any lesson to be learned from the many discoveries of this past year, it is that the continent we need to explore is both larger and more complex than we ever imagined. With so many roads not yet taken, who would want to follow the herd?

References

 1 Edwards AM, Isserlin R, Bader GD, Frye SV, Willson TM, Yu FH. Too many roads not taken. Nature. 2011 Feb 10;470(7333):163-5. PMID: 21307913

 2 The September 6, 2012 issue of Nature includes multiple articles pertaining to the ENCODE project. Information about the project and related publications are accessible via Nature’s ENCODE web pages:http://www.nature.com/encode/

 3 Additional information about this project may be accessed at:http://projectreporter.nih.gov/project_description.cfm?projectnumber=1DP1MH100706-01

 4 Additional information about this project may be accessed at:http://projectreporter.nih.gov/project_info_description.cfm?aid=8319594&icde=14517184

 5 Additional information about this project may be accessed at:http://projectreporter.nih.gov/project_info_description.cfm?aid=8299100&icde=14517215