By ZEYNEP YILMAZ
Published: December 5, 2013
Dr. Thomas Insel, the Director of the National Institute of Mental Health (NIMH), visited UNC on November 13, 2013 and gave a presentation entitled “Psychiatry in 2023” as a part of the Annual Psychiatry Research Day. His presentation was geared toward providing researchers with a roadmap of NIMH’s funding priorities and information on the prominent areas of psychiatric research that are likely to contribute to our knowledge of psychiatric disorders and their treatments in the next decade. In line with the recently announced BRAIN Initiative by the U.S. government, Dr. Insel’s talk focused on the following three emerging areas: (1) brain circuitry; (2) genetics; and (3) neurodevelopment.
In the first part of his presentation, Dr. Insel emphasized how little we know about the brain compared to the other organs, and especially since evidence clearly suggests that psychiatric disorders are brain disorders, there is a dire need to develop innovative methods to explore the human brain and its processes. For example, up-and-coming neuroanatomical tools such as Brainbow (which allows the exploration of the “connectome”—the map of neural network connections in the entire brain—by using fluorescent proteins) and CLARITY (which works by filling the postmortem brain with hydrogen, making it transparent and eliminating the need to dissect the brain) could have serious impact on how scientists study the networks within the brain and explore molecular markers of interest in 3D. The Human Connectome Project is an international collaboration geared toward exploring white matter tracts, disentangling them and potentially counting the number of fibers between various brain regions. All these exciting developments will hopefully lead to gaining a more in-depth understanding of specific circuitry and functional domains within the brain and their contributions to individual psychiatric disorders.
Considering that biological factors have only been recently considered in the case of eating disorders, we know very little about the brain circuitry underlying their development and maintenance. Although the new neuroanatomical tools Dr. Insel mentioned in his talk sound promising, practical application of these methods is currently limited; moreover, some of them require brain tissue from deceased individuals with psychiatric disorders, and there is currently no such collection available for eating disorders. That being said, the glass is definitely more than half full for the potential that brain research holds for examining eating disorders: for instance, animal studies using innovative technology —such as the project Dr. Bulik wrote about in her recent blog post “New Research A Game Changer for Understanding Binge Eating” are moving us closer to uncovering the brain circuitry of overeating behaviors. Many lines of sophisticated imaging studies and brain-based exploratory treatment studies are being carried out in individuals with eating disorders, and these studies are bound to be increasingly informative as the technology becomes more precise and affordable to boost sample size. Study of the brain circuitry in psychiatry has indeed made leaps and bounds in the last few years, but a word of caution also merits consideration in this exploratory phase: Dr. Insel emphasized the variable and dynamic nature of the brain; in other words, currently we can only take a snapshot of the brain at a single point in time, which depends on many factors and may be difficult to generalize. As a result of this, it is important to practice caution before making overly general comments about a specific disorder and instead focus on brain activity and/or connectivity patterns for individuals based on their personal baselines.
The second part of Dr. Insel’s presentation covered the genetic advances in psychiatry. Indeed, under the leadership of Dr. Patrick Sullivan at UNC the Psychiatric Genomics Consortium has enjoyed tremendous success in the last few years, with genome-wide association studies having identified over a hundred significant hits for schizophrenia and promising findings being reported with other major psychiatric disorders as the sample sizes exceed ten of thousands. In particular, with the historical low cost of DNA sequencing, researchers can afford to include many more individuals in genetic studies, bringing us one step closer to identifying genes conferring risk for psychiatric illness. With numerous significant genome-wide results in psychiatric genetics, the next step should consist of following up on these findings and gaining insight into their biological roles and function, as well as investigating beyond the traditional gene boundaries as a part of many new lines of research in this quest.
Compared to other psychiatric disorders, eating disorders have only recently entered the genomic era. Although the potential contribution of genetic factors to the development of disorders such as schizophrenia and autism have been widely accepted for the last few decades, eating disorders have been viewed as predominantly sociocultural and psychological conditions until recently. So far, most eating disorder genetic studies have focused on a small number of genes selected for their biological role. However, due to small sample sizes and other methodological issues, these studies have led to variable findings that have not been consistently replicated. As genome-wide association studies conducted in very large samples have brought us much closer to discovering the genetic underpinnings of psychiatric illness, it became clear that eating disorder researchers worldwide also needed to combine forces and form international consortia to boost sample size. Under the leadership of Dr. Bulik, the Genetic Consortium of Anorexia Nervosa (GCAN) was formed in 2007 and included more than 5,000 anorexia nervosa DNA samples collected across 15 countries, and the results of this study will be presented in Molecular Psychiatry in an upcoming issue. So far, no targets that meet genome-wide significance have been identified in anorexia nervosa, but if there is anything we have learned from other disorders, it is that significant findings are a function of attaining adequate sample sizes. As impressive as 5,000 DNA samples sounds, GCAN is only the beginning. With the launch of Anorexia Nervosa Genetics Initiative (ANGI), which will collect 8,000 more samples, and Charlotte’s Helix which will collect thousands more in the UK, our new goal is to reach at least 25,000 anorexia nervosa samples worldwide by 2015. Once the initial genetic discoveries are made, we will be able to supplement genomic results with more preclinical research to shed light on the biological significance of the findings in anorexia nervosa.
Dr. Insel had a few cautionary notes for genetic researchers. First, genetic predisposition does not guarantee that an individual will develop a disorder; genes confer both risk and resilience, hence they are not necessarily causal. Thanks to the recent developments in the field, we also know that DNA sequence is not the complete story, as Dr. Insel’s presentation also touched on how our understanding of genetic function has significantly changed in the last few years. Until recently, 98% of the human genetic code was thought to be “junk DNA” with no functional value. With the emergence of ENCODE (which stands for ENCyclopedia Of DNA Elements), we now know that about 80% of the genome is transcribed, meaning that a majority of the DNA segments once thought to be junk actually play a crucial role in regulating genes. Furthermore, non-inherited factors—which can also be environmental and lifestyle-driven—can “turn genes on and off.” The study of epigenetics is an exciting new area that investigates these factors beyond DNA sequence, holding tremendous potential for early identification of individuals at risk and prevention in the long run. Although epigenetic studies have been carried out in eating disorders, they have been only exploratory in nature and require replication in much larger cohorts. International collaborations are likely to be the way to go for epigenetics as well, in order to achieve the statistical power required to make significant and meaningful epigenetic discoveries. Finally, not all proteins encoded by a gene are present in all organ tissues in equal amounts, and since psychiatric disorders are brain disorders, gene expression studies in the brain hold the key to providing researchers with much needed information about the biological relevance of any genetic findings in psychiatric conditions, including eating disorders.
In the final part of his presentation, Dr. Insel emphasized the neurodevelopmental aspects of psychiatric disorders. For example, in the case of attention-deficit/hyperactivity disorder (ADHD), recent evidence points to delayed cortical maturation, meaning that specific brain regions of individuals with ADHD may develop at a slower pace compared to individuals without ADHD. These new developmental findings further highlight the need to understand the brain processes and biology in a time-sensitive manner in order to be able to predict in the future who will go on to develop an illness before they actually have it. In particular, the brain of a fetus is significantly different than the brain of an adult, and Dr. Insel gave the striking example of this difference being more drastic than the difference between a brain and a liver. Considering the key role of neurodevelopment, Dr. Insel declared the adolescent brain as the new frontier. He also mentioned that neurodevelopment continues until the mid-20s and is not only limited to childhood, so it is crucial to study the brain in a longitudinal manner across all ages.
Eating disorders often begin during adolescence, and in light of Dr. Insel’s emphasis on neurodevelopment, disordered eating risk needs to be studied across lifespan to gain much-needed insight to its etiology. As a part of the UNC Psychiatry Research Day, Dr. Stephanie Zerwas (Assistant Professor in the Center of Excellence for Eating Disorders) gave a well-received presentation on her longitudinal research on disordered eating risk in girls at different points in development, which is exactly the kind of research that holds the potential for understanding (and hopefully, in the future, predicting) who may be at risk for developing an eating disorder and what protective factors can help reverse risk. In addition to observational studies such as Dr. Zerwas’s promising work, longitudinal biological and neuropsychological studies may also aid with the possible identification of biomarkers for eating disorders.
With all these exciting innovations taking place in biological psychiatry, as a researcher, it is impossible not to feel like a kid in a candy store. But as with every exciting research opportunity that has the potential to make a real change, there is also great responsibility placed on the shoulders of scientists, which is to proceed with caution and avoid jumping to rash conclusions without rigorous replication. That being said, as a genetic researcher, I am excited and optimistic about the scientific opportunities that will present themselves in the next ten years, made possible by sophisticated and affordable genetic and statistical tools, as well as the much needed and newly found collaborative spirit among scientists that will undoubtedly help us achieve our ultimate goal of uncovering the genetic code of eating disorders. Enriching ongoing clinical, epidemiological, and developmental studies with meaningful biological data will bring the eating disorders field closer to a clear understanding of the etiology and risk factors for these serious conditions and guide with the development of biomarkers, diagnostic tools, prevention strategies, and novel treatments in the years to come.