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Director’s Blog: The Long Paths to Breakthroughs


In a recent blog post describing discussions that occurred at our last Advisory Council meeting, I posed the problem of choosing between funding basic science studies with long-term transformative potential versus funding clinical studies with the promise of reducing the urgent unmet need we have for mental health services. At NIMH we strive to support both. But I appreciate the frustration: for many, it appears our investments in basic science are an endless promissory note, while they watch the suicide rate and early mortality show no signs of decreasing.

I thought two examples of scientific advances on neurodevelopmental disorders might show where the unpredictable paths of gradual, incremental advances in brain science can lead. In both of these cases, NIMH-supported research on fundamental questions about how genes shape brain function and behaviors led to clinical trials that could alter outcomes for conditions that currently lack effective treatment.

Fragile X syndrome is the most commonly inherited cause of intellectual disability. About 1 in 5,000 malesi are born with the disease, and tend to have more severe symptoms than females. People with Fragile X syndrome show physical abnormalities and mild to moderate intellectual deficits, which worsen with age. NIMH-supported work provided the basis for early clinical trials of a compound that may correct a central neurochemical defect underlying Fragile X syndrome. The journey to these trials has been a long one and could be said to have begun with early research on genetics and how cells in the brain communicate using chemical signals. In 1991, the first breakthrough was the identification of a gene called FMR1 (Fragile X mental retardation 1) that was disrupted in individuals with Fragile X syndrome.ii This discovery allowed scientists to generate mice, flies, and fish in which the gene was inactivated, making it possible to observe changes in brain and behavior, and understand the molecular function of the gene.iii At this point, researchers were able to provide an increasingly detailed picture of how the deficit of the FMR1 gene led to disruptions in synapses, the connections between brain cells that underlie learning and memory. A disrupted FMR1 gene altered signaling by glutamate, a major signaling molecule in the brain. With this information, scientists identified a class of compounds that corrected both neuronal function and behavior in mice with a disrupted FMR1 gene.iv This mouse study set the stage for the current clinical trials in humans, for which NIMH has also provided support, carried out by Seaside Therapeutics, in Cambridge, Massachusetts. While we all wish that the work of identifying molecular targets could go faster, this process opened the possibility for targeted drug design and testing. As slow as it may seem, this approach allows us to understand the root cause of a disease, and then take a “surgical” approach in trying to correct it.

The second example is a series of advances that has led to preclinical testing of a compound identified for its ability to correct the genetic defect underlying a rare neurodevelopmental disorder, called Angelman syndrome. Infants with Angelman syndrome appear normal at birth, but begin to show developmental delays by 6 to 12 months. The difficulties associated with this disorder include seizures and movement disorders; these children require continual assistance. Early research showed that children with Angelman syndrome had deletions of part of chromosome 15; moreover, the deletions were always in the copy of the chromosome inherited from the mother. Identification of the gene whose loss causes Angelman followed. The paternal copy of this gene is normally silenced in neurons, an example of a phenomenon called genetic imprinting, in which the expression of a gene depends on whether it is inherited from the mother or father. With the paternal gene silenced and the maternal gene lost, none of the protein that this gene codes for is produced, the result being the symptoms associated with Angelman syndrome.v

NIMH-supported scientists at the University of North Carolina School of Medicine used this information as the starting point for searching for a treatment. Their strategy was to use neurons from genetically engineered mice to screen for compounds that would activate the normally silenced paternal gene, which could come to the rescue of the defective copy of the gene; they found a class of compounds that could do so and have chosen one for continued NIMH is now supporting studies in mice to investigate the best means of administering this potential treatment, determine optimal dosage levels, and understand side effects.

Identification of active compounds depended not only on decades of advances in genetics, but also on automation and cell biology, capabilities made available to scientists through NIMH’s Psychoactive Drug Screening Program. The program offered investigators access to “libraries” of molecules for testing and expertise in screening of candidate compounds. As research moves from basic studies and identification of candidate molecules to medication testing, pharmaceutical companies can take this work forward.

The work described here has implications beyond Fragile X and Angelman syndrome. Knowledge of the genes involved is likely to offer insight into the causes of autism and other neurodevelopmental disorders. This is the kind of information that will set the stage for the precision medicine of the future; testing young people with developmental delays, and treating them when appropriate with targeted, neuroscience-based treatments like those being tested. Advances in genetics and neuroscience, achieved in what seem to be very small steps, are making it possible to trace the path between genes and illness and on that basis to identify and test compounds that have real potential to change lives.


 iCoffee, B. et al. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet. 2009 Oct;85(4):503-14.
iiVerkerk, A. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991 May 31;65(5):905-14.
iiiHuber, K.Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7746-50.
ivDölen, G. et al. Correction of fragile X syndrome in mice. Neuron. 2007 Dec 20;56(6):955-62.
vAlbrecht, U. et al. Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat Genet. 1997 Sep;17(1):75-8.
viHuang, H.-S. et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature. 2011 Dec 21;481(7380):185-9. doi: 10.1038/nature10726.