Director’s Blog: NIMH’s Top 10 Research Events and Advances of 2010
The journal Nature began the year by declaring that this decade would be “the decade for psychiatric disorders,” in that the field is “ripe for a revolution.” In this opening year of the decade, the revolution seems well underway. Here are 10 breakthroughs and events of 2010 that are changing the way we approach mental disorders.
- HIV/AIDS: treatment as prevention. Treatment for HIV/AIDS has improved markedly in the last decade, but HIV infection rates continue to be unacceptably high. Globally, treatment cannot keep pace with new infections; in Sub-Saharan Africa, it is estimated that seven are infected for every one person who starts treatment. Behavioral prevention via education about safer sex, male circumcision, and microbicides for women all have an impact in research studies, but barriers to implementation limit population-level impact. This year we discovered that doses of HIV-treatment among HIV-negative persons is the best prevention to date. Pre-exposure prophylaxis (PrEP) reduced infection by nearly 50 percent in the most conservative estimate and, when combined with behavioral interventions to ensure adherence, reduced infection by a stunning 97 percent. For the first time, we have an effective prevention strategy that may be readily taken to scale.1
- The human connectome. Functional magnetic resonance imaging (fMRI) of the brain when it is at rest (sometimes called resting state fMRI) has emerged as a powerful approach for detecting correlations of large, infrequent fluctuations in activity levels across functionally related brain areas. A collaboration across 35 laboratories in 10 countries compared patterns of brain-function connection (called connectomes) in 1,414 volunteers, yielding harmonized brain maps based on age and gender.2 As with the human genome, this functional connectome is important not only for providing a reference wiring map of the human brain, but also demonstrating intriguing, stable individual differences. New projects on the human connectome, supported via the NIH Blueprint for Neuroscience Research , will be exploring individual differences and developing more precise tools for measuring connections in the human brain. http://www.humanconnectome.org/consortia/
- DNA sequencing. The cost of DNA sequencing has dropped by a factor of 10 every year for the past few years. This new capacity to sequence rapidly and inexpensively the full genome (or candidate gene regions) is transforming psychiatric genetics. In previous years, costs have constrained full genome sequencing efforts, and investigators have compensated by using strategies to search for hints of variation in certain regions of the genome. This year, however, whole genome sequencing in multiple individuals finally became a reality. The result was the discovery of enormous genomic variation across healthy subjects, with hundreds of thousands of rare gene variants identified and, on average, each child showing 50 – 100 new mutations not present in his or her parents.3 We have also learned that autism, schizophrenia, and other neurodevelopmental disorders are associated with rare “structural” variations in the genome, sometimes involving millions of bases of DNA.4 Only through full genome sequencing efforts will we be able to understand the scope of these rare variations and their contribution to the causes of mental disorders.
- Parental imprinting. We have long known that certain diseases and disorders can be inherited via genetic mutation. For certain genes, it makes a big difference whether you inherit a copy from your mother or your father. For instance, inheriting a mutation on maternal chromosome 15 confers a disorder called Angelman’s syndrome. The same mutation inherited from the father results in a completely different disorder, Prader-Willi syndrome. This phenomenon is known as “parental imprinting,” a process through which the gene inherited from one parent is either always silenced or always expressed. Parental imprinting was once thought to be a rare event, influencing only a few genes. This year, however, Dulac and colleagues discovered that in the mouse, parent of origin matters for over 1300 genes involved in shaping the brain’s structure and function.5 Paternally-inherited genes were most evident in the hypothalamus, while maternally-inherited genes exerted their effects on the brain’s cortex. While these findings have yet to be demonstrated in humans, observations from these studies in mice suggest that the rules for gene expression in the brain may be far more complex than we ever considered.
- The human epigenome. Although every cell in your body has identical DNA, different parts of the code are expressed in neurons, blood cells, and muscle cells. The epigenome describes all of the proteins that bind to DNA that lead to different patterns of gene expression – accounting for differences in cell type, differences in identical twins, and presumably how experience influences development or, fundamentally, how nurture affects nature. In this year, epigenomics became a discovery science, as new techniques allowed the interrogation of epigenetic marks across the entire human genome. 6 Stable, individual differences in the human epigenome suggest a powerful new approach to study the long-term effects of early experience.
- Next Gen antidepressants. Antidepressant medications or cognitive behavioral therapy generally require six to eight weeks to have an effect. In the past five years, ketamine and scopolamine have been shown to reduce depression experimentally, including thoughts of suicide, within six hours. This year saw the first identification of biological indicators of how the brain responds to ketamine7 and the first demonstration of the molecular mechanism for this rapid response—the rapid activation of an enzyme, mTOR, which regulates cell growth, proliferation, and survival.8 In addition, new targets for intervention have emerged, including MKP-1, a protein involved in the resiliency of brain cells to stress.9 While several pharmaceutical companies moved away from psychiatric medication development this year, the scientific opportunities for new targets and new approaches have never been better.
- The autistic brain. Autism spectrum disorder (ASD) has been recognized as a disorder of brain development, but there have been few clues to what is different in the brain of someone with ASD. Several papers this year described differences in structure of brain regions; patterns and strength of connections between brain regions; and function of brain circuits.10-13 One intriguing brain imaging study looked at brain activity in response to social information in children with ASD, their unaffected siblings, and controls. Compared to controls, both children with ASD and their unaffected siblings showed different brain activity patterns in some regions. Remarkably, the brains of unaffected siblings appeared to compensate for the difference with additional brain activity in other regions.14
- Disease-in-a-dish. History may judge one of the most important discoveries in the past decade to be the creation of induced pluripotent stem cells (iPSCs): cells taken from adults, de-differentiated into a pluripotent state (in which they have the potential of becoming any cell type), and then differentiated into a mature cell type. For example, a skin cell taken from an adult can be made pluripotent and then differentiated into a neuron. This year, we saw this revolutionary technology begin to shed light on Rett Syndrome, a genetic disorder that causes autism. Marchetto et al. (Cell, Nov, 2010) derived iPSCs from patients with Rett Syndrome and then differentiated them into neurons in vitro (e.g. “in-a-dish”), with a range of abnormalities corresponding to observed neuronal abnormalities seen in Rett Syndrome patients.15 These cells were useful not only for identifying the process of developing Rett pathology but also allowed testing of potential treatments.
- High throughput screening. High throughput screening of small molecules, previously the domain of pharmaceutical companies, has been developed as a tool for academic scientists with the Molecular Libraries Program , an NIH Common Fund effort led by NIMH and the National Human Genome Research Institute . The Molecular Libraries Program Comprehensive Screening Centers provide academic scientists with the means of quickly screening over 350,000 small molecules to identify those that interact with biological targets. Using this technology, researchers have identified over 120 molecules with biological activity that may one day lead to the development of new medications. In one extraordinary effort, independent of the Screening Centers, Andrew Pieper and his colleagues at University of Texas Southwestern Medical Center identified a series of novel molecules with antidepressant and neuroprotective effects.16
- Nature focuses on schizophrenia. Nature, regarded by many as the world’s premier science journal, rarely features a disease as a special topic. In November, Nature dedicated a special issue to schizophrenia, with articles spanning the biology, psychology, and social implications of the disorder.17
Image courtesy of Rodger Casier and NARSAD Artworks, featured on cover of Nature Nov. 11, 2010
1. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, Goicochea P, Casapía M, Guanira-Carranza JV, Ramirez-Cardich ME, Montoya-Herrera O, Fernández T, Veloso VG, Buchbinder SP, Chariyalertsak S, Schechter M, Bekker LG, Mayer KH, Kallás EG, Amico KR, Mulligan K, Bushman LR, Hance RJ, Ganoza C, Defechereux P, Postle B, Wang F, McConnell JJ, Zheng JH, Lee J, Rooney JF, Jaffe HS, Martinez AI, Burns DN, Glidden DV; the iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Nov 23. [Epub ahead of print] PMID: 21091279
2. Biswal BB, Mennes M, Zuo XN, Gohel S, Kelly C, Smith SM, Beckmann CF, Adelstein JS, Buckner RL, Colcombe S, Dogonowski AM, Ernst M, Fair D, Hampson M, Hoptman MJ, Hyde JS, Kiviniemi VJ, Kötter R, Li SJ, Lin CP, Lowe MJ, Mackay C, Madden DJ, Madsen KH, Margulies DS, Mayberg HS, McMahon K, Monk CS, Mostofsky SH, Nagel BJ, Pekar JJ, Peltier SJ, Petersen SE, Riedl V, Rombouts SA, Rypma B, Schlaggar BL, Schmidt S, Seidler RD, Siegle GJ, Sorg C, Teng GJ, Veijola J, Villringer A, Walter M, Wang L, Weng XC, Whitfield-Gabrieli S, Williamson P, Windischberger C, Zang YF, Zhang HY, Castellanos FX, Milham MP. Toward discovery of human brain function. Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4734-9. Epub 2010 Feb 22.
3. Pelak K, Shianna KV, Ge D, Maia JM, Zhu M, Smith JP, Cirulli ET, Fellay J, Dickson SP, Gumbs CE, Heinzen EL, Need AC, Ruzzo EK, Singh A, Campbell CR, Hong LK, Lornsen KA, McKenzie AM, Sobreira NL, Hoover-Fong JE, Milner JD, Ottman R, Haynes BF, Goedert JJ, Goldstein DB. The characterization of twenty sequenced human genomes. PLoS Genet. 2010 Sep 9;6(9). pii: e1001111.PMID: 20838461
4. 1000 Genomes Project Consortium, Durbin RM, Abecasis GR, Altshuler DL, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA. A map of human genome variation from population-scale sequencing. Nature. 2010 Oct 28;467(7319):1061-73.PMID: 20981092
5. Gregg C, Zhang J, Weissbourd B, Luo S, Schroth GP, Haig D, Dulac C. High-resolution analysis of parent-of-origin allelic expression in the mouse brain. Science. 2010 Aug 6;329(5992):643-8. Epub 2010 Jul 8.PMID: 20616232
6. Feinberg, AP. Epigenomics reveals a functional genome anatomy and a new approach to common disease. Nature Biotechnology. 2010 Oct; 28(10):1050-1052. PMID: 20944596
7. Phelps LE, Brutsche N, Moral JR, Luckenbaugh DA, Manji HK, Zarate CA Jr. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol Psychiatry. 2009 Jan 15;65(2):181-4. Epub 2008 Nov 8.PMID: 18996507
8. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010 Aug 20;329(5994):959-64.PMID: 20724638
9. Duric V, Banasr M, Licznerski P, Schmidt HD, Stockmeier CA, Simen AA, Newton SS, Duman RS. A negative regulator of MAP kinase causes depressive behavior. Nat Med. 2010 Nov;16(11):1328-32. Epub 2010 Oct 17.PMID: 20953200
10. Stevenson JL, Kellett KA. Can magnetic resonance imaging aid diagnosis of the autism spectrum? J Neurosci. 2010 Dec 15;30(50):16763-5. PMID: 21159947
11. Zikopoulos B, Barbas H. Changes in prefrontal axons may disrupt the network in autism.
J Neurosci. 2010 Nov 3;30(44):14595-609.PMID: 21048117
12. Schumann CM, Bloss CS, Barnes CC, Wideman GM, Carper RA, Akshoomoff N, Pierce K, Hagler D, Schork N, Lord C, Courchesne E. Longitudinal magnetic resonance imaging study of cortical development through early childhood in autism. J Neurosci. 2010 Mar 24;30(12):4419-27.PMID: 20335478
13. Ecker C, Marquand A, Mourão-Miranda J, Johnston P, Daly EM, Brammer MJ, Maltezos S, Murphy CM, Robertson D, Williams SC, Murphy DG. Describing the brain in autism in five dimensions – magnetic resonance imaging-assisted diagnosis of autism spectrum disorder using a multiparameter classification approach. J Neurosci. 2010 Aug 11;30(32):10612-23.PMID: 20702694
14. Kaiser MD, Hudac CM, Shultz S, Lee SM, Cheung C, Berken AM, Deen B, Pitskel NB, Sugrue DR, Voos AC, Saulnier CA, Ventola P, Wolf JM, Klin A, Vander Wyk BC, Pelphrey KA. Neural signatures of autism. Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21223-8. Epub 2010 Nov 15.PMID: 21078973
15. Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell. 2010 Nov 12;143(4):527-39.PMID: 21074045
16. Pieper AA, Xie S, Capota E, Estill SJ, Zhong J, Long JM, Becker GL, Huntington P, Goldman SE, Shen CH, Capota M, Britt JK, Kotti T, Ure K, Brat DJ, Williams NS, MacMillan KS, Naidoo J, Melito L, Hsieh J, De Brabander J, Ready JM, McKnight SL. Discovery of a proneurogenic neuroprotective chemical. Cell. 2010 Jul 9;142(1):39-51. PMID: 20603013
17. Nature. 2010 Nov 11; 468 (7321): 133-340.