Post by Former NIMH Director Thomas Insel: Best of 2014
No question: this year’s big biomedical story was Ebola. Headlines, Sunday news shows, multiple Congressional hearings, a Presidential visit to NIH—autumn seemed to be all Ebola all the time. Thus far, the death count from Ebola has been one in the U.S. and over 6,000 in Africa. Less noticed, deaths from suicide in 2014 will probably surpass 40,000 in the U.S., roughly one every 13 minutes. According to a recent World Health Organization report, there are 800,000 suicides globally each year, with 75 percent of those deaths in low and middle income countries. For the week after the suicide of Robin Williams, the nation focused on this issue, but for 51 weeks this year, suicide remained the silent epidemic.
What were the mental health stories of note in 2014? As always, finding the top ten is both unfair and unsatisfying. But that will not keep me from trying.
10. Mental Health Philanthropy - The ecosystem for supporting research has changed markedly. After 10 years of nearly flat budgets, federal purchasing power is below the 1999 level when the doubling of the NIH budget began. The pharmaceutical industry investment in R&D is traditionally twice the NIH budget. But in the top 11 companies, projects on brain disorders have dropped from 29 to 12 since 2009. Yet the news is not all gloomy. In contrast to these traditional funders, philanthropy has become a major source of support. Adding to established, large research programs like the Lieber Institute for Brain Development and the Allen Institute for BRAIN Science, this year marked the largest gift yet, with $650 million donated to the Stanley Center for Psychiatric Research at the Broad Institute. Also 2014 marked the creation of the $100 million Allen Institute for Cell Science and the Simons Foundation's $50 million brain initiative. And in the UK, a new charity, called MQ, has made their first awards to support research on psychological treatments.
9. Circuit Breakers - Precise tools to modulate circuit activity in the brain have transformed neuroscience over the past five years by moving studies of brain function increasingly from correlation to causation.1 Optogenetics, which uses pulses of light to turn on circuit activity, advanced this year with the development of a light regulated chloride channel that can turn off activity2 and the use of light pulses to study the dynamic properties of neural pathways.3 An alternate method, with the clunky but descriptive name “designer receptors exclusively activated by designer drugs” (DREADDs), uses synthetic biology to modulate cells on a slower time scale with pharmacological methods rather than light.4 While neither optogenetics or DREADDs have been used in humans, optogenetics has been used to answer critical questions about circuits in the primate brain5 and this year DREADDs made the jump to studies in non-human primates.6,7
8. Tweaking the Engram - Learning and memory have been the Holy Grail of brain research for over 60 years, since Karl Lashley searched for the engram, the neural representation of a memory. This year, several groups tweaked the engram by using optogenetics, the light-based system for activating or inactivating specific cells in a circuit. Two studies induced and erased memories by stimulating activity that increased the strength of synapses, a process called long term potentiation, in a key memory circuit.8,9 Another study was able to use the same technique not only to turn on and turn off memories but to convert negative memories to positive ones.10 All of these studies in mice demonstrate the importance of circuit activity for memory, reminding us that the engram is really a network. In a remarkable study in humans, circuits that link hippocampus and cortex were activated non-invasively with electromagnetic stimulation. Multiple sessions of this stimulation not only increased the functional connectivity of the network but improved memory performance.11
7. Reproducibility and Data Sharing - This year started with a lot of attention to reports that more than 70 percent of the preclinical research from academic labs could not be replicated.12 Misconduct or fraud is not the source of most problems with reproducibility. Lack of rigor in experimental design or data analysis appears to be a much more important factor, along with the complexity of behavioral and biological research. New standards for experimental design have been recommended as has increased attention to reducing bias in data analysis.13 Of course, in many of the areas of NIMH interest, variation between experiments is an opportunity as much as a challenge. With improved rigor and increased data sharing, studies of variation can reveal important mechanisms. How appropriate that a year that started with a focus on lack of reproducibility ended with a focus on data standards and data sharing! Over the past few weeks, NIMH established its first Common Data Elements for PTSD and suicide prevention with Common Data Elements for eating disorders and early psychosis expected in early 2015. The Institute set new expectations for data sharing. And the RDoC database and the National Database for Clinical Trials were launched recently to deposit and share data from NIMH research.
6. Autism Rare Variants - Studies this year revealed a large number of rare genomic variants in children with autism from simplex families (with only one family member affected).14 The current estimate is that 30 percent of simplex cases have a rare mutation, most of which are “de novo,” meaning that they are found in the person with autism but are not apparent in anyone else in the family. The most recent tally shows 22 loss of function mutations that appear to be causal, including 17 that have been found more than once.15 Many of these genes influence synaptic function or chromatin (the protein tags that modify DNA), providing insights into possible mechanisms for the development of autism. Will rare mutations lead to new treatments? Studies of Fragile X, Rett, and Phelan-McDermott syndromes all show promise in mice. But reports in 2014 also reminded us that efficacy in mice may not predict efficacy in men or women.16
5. Schizophrenia Common Variants - In contrast to the large number of rare mutations found in autism, the story for schizophrenia in 2014 was a large number of common variants. The Psychiatric Genomics Consortium reported 108 loci associated with risk for schizophrenia. While none of these 108 regions alone contributed substantial risk, a combined polygenic risk score was able to identify as much as a 20-fold increase in risk for schizophrenia.17 A related study demonstrated that some of the genetic risk for schizophrenia may be non-specific, as similar genomic associations can be found across mental disorders.
4. BRAIN Launch - After a year of planning, in 2014 we had lift off for the NIH BRAIN initiative, which the President has called “the next great American project.” Guided by the BRAIN 2025 report, NIH funded over 100 investigators in 58 projects with $46 million. A first meeting of investigators in November revealed how engineers, physicists, computational scientists, and neurobiologists will tackle the complex questions about how the brain works. Together they are developing tools for the next generation of neuroscience. From a first cell census to mapping the activity of thousands of neurons to entirely novel approaches to imaging the human brain, BRAIN is taking on some big challenges. But BRAIN is just at the beginning of what should be a 10-year project. And this year, the “next great American project” began to look more global. Japan announced and China is about to announce their brain initiatives; the EU Human Brain Project continues amid some controversy, and the NIH BRAIN Initiative has a new collaboration with Australia.
3. Exosomes - Each year seems to bring a completely novel insight about biology with eureka potential for understanding normal and abnormal behavior. This was the year of the exosome.18 Who would have imagined that fragments of RNA are being released from cells? These fragments, which are bound into vesicles called exosomes, may function as messengers between cells, an unexpected sort of endocrine system. Early evidence suggests exosomes influence synaptic activity and behavior, as well as transmitting pathogenic elements between cells. Perhaps most remarkable, exosomes may retain bar codes of their origin. Could exosomes from brain be detected and isolated in blood as a future source of biomarkers of brain disorders? The field of extracellular RNA is still emerging, but already the potential seems extraordinary, reminding us that there are still vast frontiers of human biology to be explored.
2. Convergence - One of the most important developments of 2014 was not a technique or discovery or policy, but a conceptual trend. In a Science editorial published in 2011, Sharp and Langer promoted convergence as the “third revolution” in biomedical science, following molecular biology and genomics.19 Noting that complex problems were simply beyond the capability of current disciplines, they recommended the convergence or merger of multiple disciplines including engineering, computational, and physical sciences with biology and cognitive science. Beyond traditional inter-disciplinary scholarship, convergence calls for creating new disciplines as a pathway to innovation. Convergent science provides the ability to cross levels of analysis from genomics to behavior and to consider the dimension of time. Recently, the convergence of neuroscience and physical science created innovations such as CLARITY and new applications of fluorescent microscopy (recognized with the Nobel Prize this year).20 This year convergence was driving the BRAIN Initiative to bring engineers, physicists, and neurobiologists together; helping RDoC to include informatics and computational science; and transforming imaging with concepts like the “chronnectome” to understand temporal dynamics of fMRI signals.21
1. RAISE Research to Practice - The gap between research and practice has been a serious challenge to every field of medicine. In the treatment of mental disorders, that gap looks more like a canyon. But this year we saw a spectacular example of how to move research into practice in months instead of years. The Recovery After an Initial Schizophrenia Episode (RAISE) project developed a patient-centered, multi-element treatment approach for optimizing outcomes after a first episode of psychosis. Although results from the 34-site comparative effectiveness trial are not yet available, initial feasibility data from the parallel RAISE implementation study convinced Congress to move ahead with program dissemination in 2014. Congress set aside funds from the Community Mental Health Block Grant program administered by the Substance Abuse and Mental Health Services Administration (SAMHSA) to support dissemination of evidence-based interventions for first episode psychosis similar to those tested in RAISE. This set in motion an unprecedented collaboration between NIMH and SAMHSA to move research into practice in a timely and efficient manner. We estimate that RAISE-like programs, called Collaborative Specialty Care, will be available in at least 29 states by October of 2015. While NIMH has been focused on moving practice into research via large health care systems, like the Mental Health Research Network, this experience with RAISE reminds us how research can be moved into practice when agencies, Congress, and states are aligned.
1 Deisseroth K. Circuit dynamics of adaptive and maladaptive behaviour. Nature. 2014 Jan 16;505(7483):309-17. doi: 10.1038/nature12982.
2 Berndt A et al. Structure-guided transformation of channelrhodopsin into a light-activated chloride channel. Science. 2014 Apr 25;344(6182):420-4. doi: 10.1126/science.1252367.
4 Sternson SM, Roth BL. Chemogenetic tools to interrogate brain functions. Annu Rev Neurosc i. 2014;37:387-407. doi: 10.1146/annurev-neuro-071013-014048. Epub 2014 Jun 16.
5 Gerits A, Vanduffel W. Optogenetics in primates: a shining future? Trends Genet. 2013 Jul;29(7):403-11. doi: 10.1016/j.tig.2013.03.004. Epub 2013 Apr 26.
6 Eldridge MA et al. Reversible DREADD inactivation of orbitofrontal cortex neurons in rhesus monkeys with contralateral rhinal cortex removal disrupts cued reward discrimination. I. Behavioral analysis. Society for Neuroscience, Neuroscience 2014 meeting abstracts online.
7 Lerchner W et al. Reversible DREADD inactivation of less than 10% of Orbitofrontal cortex neurons in interconnection with rhinal cortex is sufficient to disrupt cue discrimination in monkeys. Society for Neuroscience, Neuroscience 2014 meeting abstracts online.
8 Nabavi S et al. Engineering a memory with LTD and LTP. Nature. 2014 Jul 17;511(7509):348-52. doi: 10.1038/nature13294. Epub 2014 Jun 1.
9 Johansen JP et al. Hebbian and neuromodulatory mechanisms interact to trigger associative memory formation. Proc Natl Acad Sci U S A. 2014 Dec 8. pii: 201421304. [Epub ahead of print]
10 Redondo RL et al. Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature. 2014 Sep 18;513(7518):426-30. doi: 10.1038/nature13725. Epub 2014 Aug 27.
11 Wang JX et al. Targeted enhancement of cortical-hippocampal brain networks and associative memory. Science. 2014 Aug 29;345(6200):1054-7. doi: 10.1126/science.1252900.
12 Collins FS, Tabak LA. Policy: NIH plans to enhance reproducibility. Nature. 2014 Jan 30;505(7485):612-3.
13 Motulsky HJ. Common misconceptions about data analysis and statistics. J Pharmacol Exp Ther. 2014 Oct;351(1):200-5.
14 Iossifov I et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014 Nov 13;515(7526):216-21. doi: 10.1038/nature13908. Epub 2014 Oct 29.
15 Poultney CS et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014 Nov 13;515(7526):209-15. doi: 10.1038/nature13772. Epub 2014 Oct 29.
16 Perrin S. Preclinical research: Make mouse studies work. Nature. 2014 Mar 27;507(7493):423-5.
17 Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014 Jul 24;511(7510):421-7. doi: 10.1038/nature13595. Epub 2014 Jul 22.
18 Rajendran L et al. Emerging roles of extracellular vesicles in the nervous system. J Neurosci. 2014 Nov 12;34(46):15482-9. doi: 10.1523/JNEUROSCI.3258-14.2014.
19 Sharp PA, Langer R. Research agenda. Promoting convergence in biomedical science. Science. 2011 Jul 29;333(6042):527. doi: 10.1126/science.1205008.
20 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.
21 Calhoun VD et al. The Chronnectome: Time-Varying Connectivity Networks as the Next Frontier in fMRI Data Discovery. Neuron. 2014 Oct 22;84(2):262-274. doi: 10.1016/j.neuron.2014.10.015. Epub 2014 Oct 22.
Source: Andre Berndt, Ph.D., Soo Yeun Lee, Ph.D., Charu Ramakrishnan, and Karl Deisseroth, M.D., Ph.D., Stanford University
Tweaking the Engram
Source: Roberto Malinow, Ph.D., University of California, San Diego
Schizophrenia Common Variants
Source: Psychiatric Genomics Consortium
Source: Cristophe Lenglet, Ph.D., University of Minnesota
Source: Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Lai CP, Breakefield XO. Front Physiol. 2012 Jun 27;3:228. doi: 10.3389/fphys.2012.00228. eCollection 2012. PMID:22754538
Source: Vince Calhoun, Ph.D., University of New Mexico