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Director’s Blog: The Top Ten Research Advances of 2012

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As in past years, once again I venture to suggest a “top 10” list for NIMH based on the most notable discoveries and events of the past 12 months. This year several of the major breakthroughs were not funded by NIMH and not directly focused on mental disorders, but they suggested new vistas for biology that will almost certainly change the way we understand serious mental illness and neurodevelopmental disorders. There is, of course, no way to do justice to the richness or the diversity of this year’s research by citing only 10 findings or events. But a list of 50 would be too long, and a list of 5 or fewer would be far too short.

10. Manipulating the epigenome to treat brain disorders
The epigenome – the collection of chemical compounds that transcribes our genome, telling it what, where, and when to do something – provides a link between nature and nurture. In previous years we have seen the effects of early stress or medication on the epigenome. This year marked some of the first studies manipulating the epigenome, revealing a new frontier for treating mental disorders. In an extraordinary study from Li-Huei Tsai’s laboratory, an increase in histone deacetylase 2 (HDAC2) – a protein that plays an important role in regulating the transcription of genes – was found to reduce memory in mice (and was associated with Alzheimer’s Disease in humans). Reducing HDAC2 improved memory in mice, suggesting a new target for developing treatments.1

9. The end of the AIDS epidemic?
The International AIDS meeting is an annual global event reporting on progress in behavioral and biomedical research on the epidemic. The meeting had not been held in the US since 1991 due to a ban on issuing visas to HIV-infected foreigners. With the lifting of this ban, the meeting was held in Washington DC in July 2012. Beyond the historic hosting of this meeting in the U.S., attendees heard for the first time a vision for an “AIDS free generation” with a combined prevention and treatment strategy that could end the epidemic.2

8. Neurodevelopmental genomics
The search for genetic variation associated with autism spectrum disorder, schizophrenia, and bipolar disorder seemed to move at light speed this year, with every month revealing new findings.3,4 The importance of de novo, or spontaneous mutations, often single base changes, became more apparent in 2012. And the role of paternal age, which shows a linear increase with de novo changes, demonstrated a mechanism by which environment and genes may interact.5 The current state of the field was summed up by State and Sestan as “one to many” (each genetic finding appears to be a risk factor for several different neurodevelopmental disorders) and “many to one” (disorders like autism appear to have scores, perhaps hundreds, of genetic factors contributing risk).4

7. Global mental health
If 2011 was the year to establish a vision for research in global mental health, 2012 was the year to initiate bold efforts to realize that vision. Grand Challenges Canada announced nearly $20 million in support of 15 innovative projects designed to improve mental health diagnosis and care in developing countries. The Centre for Global Mental Health, a collaboration based in London, increased its investment to over 30 projects across 20 countries. And NIMH launched the Collaborative Hubs for International Research in Mental Health in low- and middle-income countries – a network of 5 centers focused on research and research capacity-building in this field. The research agenda is designed not only to reduce the mental health treatment gap in low- and middle-income countries, but is actively learning and gaining insight from the innovations developed in these countries.

6. Optogenetics and oscillations in the brain
The holy grail of neuroscience has been finding the engram, the neural representation of memory (or thought or emotion). In 2012, we saw new evidence of the importance of synchronized waves of activity in the cortex - so called oscillations of coherent activity between distant regions - for supporting visual memory.6 Using optogenetics, which can turn activity on and off with light, scientists were able to manipulate gamma oscillations, the class of oscillations thought to be most relevant for schizophrenia 7,8 In one of the most remarkable demonstrations of the power of optogenetics, symptoms associated with depression in a mouse were turned on and off by regulating only the serotonergic input to the frontal cortex.9

5. Mapping the human brain at the molecular level
Ribonucleic acid (RNA) is a fascinating and frequently surprising family of molecules responsible for the coding, translation, expression, and regulation of genes. Building on the first maps of RNA expression of the developing human brain in 2011, this year saw the first comprehensive maps of RNA expression in adult humans, the first epigenomic map across human development and the first description of human specific patterns of gene expression.10,11,12,13,14

4. Mapping the human connectome
The wiring diagram of the human brain is extremely complex and traditionally has been considered too difficult to untangle in full. Using a new approach for visualizing white matter (the “cables” that connect brain regions), Wedeen and his colleagues at Massachusetts General Hospital discovered an inherent grid pattern in the human brain.15 While there is still discussion about the validity of this grid, the human connectome – the comprehensive map of all neural connections in the brain – promises to reveal important aspects of human variation, just as is the case with the human genome. Adding to this new picture of the structural connectome, brain imaging scientists from around the world have combined functional magnetic resonance imaging (fMRI) data to describe a functional connectome.16 Even at “rest,” distant brain areas appear highly active and synchronized, promising a new picture of individual differences in functional connectivity.

3. Unexpected variation
2012 may be considered as the year of genomic weirdness. Who knew that there would be genomic variation in the brain that was not apparent in blood cells? The possibility that somatic mutations – alterations that occur in DNA after conception – could contribute to neurodevelopmental disorders suggests that cancer may be a useful model for understanding autism or schizophrenia.17,18 Who knew that women could carry cells in their brains with DNA from their offspring? Microchimerism – in this case, the presence of male cells in a woman’s cortex – gives an entirely new meaning to the biology of motherhood.19 And who knew that microDNA segments could be transmitted independently of chromosomes? There appear to be thousands of short (200 – 400 bases long) circular DNA elements that function free of the well-known structured bundles of DNA called chromosomes in mammalian cells.20

But even our standard approaches to genetics revealed unexpected variation. The 1000 Genomes Project, an audacious project to sequence the genomes of 1000 typical humans, has forever put to bed the concept of “normal.” Based on data from the first 185 volunteers, the range of variation found has been, by any standards, stunning. Imagine that each of us has 100 genetic variants causing some loss of function, with 20 of these being variants that totally inactivate the gene. That means that each of us, on average, has a “knockout” of 20 genes. Overall, the team found more than 1000 different genes knocked out within the sample, apparently without consequences since all of their participants were selected because they were “healthy.”21 This suggests that a tremendous amount of unexpected redundancy is built into our genome. In another recent report, the 1000 Genomes Project demonstrates much of this variation is related to ancestry, with large differences observed across 14 different human populations.22

2. The human microbiome
This NIH Common Fund project  delivered much of its payload in 2012 with some 17 papers published in June describing the findings from a consortium of 200 investigators mapping the microbial world of 18 different body sites.23 The results have altered how we think about what it means to be human, as our bodies are more of a complex ecosystem in which human cells represent a paltry 10% of the population. But beyond the sheer numbers, we now know about the profound diversity of this ecosystem and striking individual differences. How these differences in our microbial world influence the development of brain and behavior will be one of the great frontiers of clinical neuroscience in the next decade.

1. ENCODE
For sheer scientific shock value this year, nothing beat the prosaically-named ENCyclopedia Of DNA Elements (ENCODE) project. ENCODE, funded by the National Human Genome Research Institute , set out to map the active parts of the human genome where the prevailing belief had been that 2 percent was genes and 98 percent was “junk DNA” or, at best, the dark matter of the genome. In September, 30 papers in Nature, Science, and other journals reported that 80 percent, not 2 percent, of the genome was transcribed with over 20,000 non-coding RNA sequences serving as active biological elements of the genome.24 The biggest finding of the year is also the most humbling: we are still in the earliest stages of understanding the blueprints that make us human.

References

 1 Gräff J, Rei D, Guan JS, Wang WY, et al. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature. 2012 Feb 29;483(7388):222-6. PMID: 22388814 

 2 More information about the conference is available at its website: http://www.aids2012.org/ 

 3 Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012 Apr 4;485(7397):237-41. PMID: 22495306 

 4 State MW, Šestan N. Neuroscience. The emerging biology of autism spectrum disorders. Science. 2012 Sep 14;337(6100):1301-3. PMID: 22984058 

 5 Kong A, Frigge ML, Masson G, et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature. 2012 Aug 23;488(7412):471-5. PMID: 22914163 

 6 Salazar RF, Dotson NM, Bressler SL, Gray CM. Content-specific fronto-parietal synchronization during visual working memory. Science. 2012 Nov 23;338(6110):1097-100. PMID: 23118014 

 7 Deisseroth K. Optogenetics and psychiatry: applications, challenges, and opportunities. Biol Psychiatry. 2012 Jun 15;71(12):1030-2. PMID: 22503111 

 8 Sohal VS. Insights into cortical oscillations arising from optogenetic studies. Biol Psychiatry. 2012 Jun 15;71(12):1039-45. PMID: 22381731 

 9 Warden MR, Selimbeyoglu A, Mirzabekov JJ, et al. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature. 2012 Nov 18. Epub ahead of print. PMID: 23160494 

 10 Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 2012 Sep 20;489(7416):391-9. PMID: 22996553 

 11 Zeng H, Shen EH, Hohmann JG, et al. Large-scale cellular-resolution gene profiling in human neocortex reveals species-specific molecular signatures. Cell. 2012 Apr 13;149(2):483-96. PMID: 22500809 

 12 Numata S, Ye T, Hyde TM, et al. DNA methylation signatures in development and aging of the human prefrontal cortex. Am J Hum Genet. 2012 Feb 10;90(2):260-72. PMID: 22305529 

 13 Shulha HP, Crisci JL, Reshetov D, et al. Human-specific histone methylation signatures at transcription start sites in prefrontal neurons. PLoS Biol. 2012 Nov;10(11): Epub ahead of print. PMID: 23185133 

 14 Konopka G, Friedrich T, Davis-Turak J, et al. Human-specific transcriptional networks in the brain. Neuron. 2012 Aug 23;75(4):601-17. PMID: 22920253 

 15 Wedeen, V. J., D. L. Rosene, et al. The geometric structure of the brain fiber pathways. Science. 2012; 335(6076): 1628-1634. PMID: 22461612 

 16 Milham MP. Open neuroscience solutions for the connectome-wide association era. Neuron. 2012 Jan 26;73(2):214-8. PMID: 22284177 

 17 Poduri A, Evrony GD, Cai X, et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron. 2012 Apr 12;74(1):41-8. PMID: 22500628 

 18 Evrony GD, Cai X, Lee E, et al. Single-neuron sequencing analysis of l1 retrotransposition and somatic mutation in the human brain. Cell. 2012 Oct 26;151(3):483-96. PMID: 23101622 

 19 Chan W.F, Gurnot C, Montine TJ, et al. Male microchimerism in the human female brain.
PloS One. 2012; 7(9): e45592. PMID: 23049819 

 20 Shibata Y, Kumar P, Layer R, et al. Extrachromosomal microDNAs and chromosomal
microdeletions in normal tissues. Science. 2012; 336(6077): 82-86. PMID: 22403181 

 21 MacArthur DG, Balasubramanian S, Frankish A, et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science. 2012 Feb 17;335(6070):823-8. PMID: 22344438 

 22 1000 Genomes Project Consortium, Abecasis GR, Auton A, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012 Nov 1;491(7422):56-65. PMID: 23128226 

 23 More information on these and other articles in the journal PLoS may be accessed here: http://www.ploscollections.org/hmp 

 24 Additional information on ENCODE publications may be accessed here: http://www.genome.gov/10005107#al-2