Studies of gene regulation in brain development may lead to new treatment of mental disorders
December 4, 2012
Diagram showing the hierarchy of TFs and CGGs networks and the novel strategy of drug design based on hierarchical gene–TF network analysis. The blue squares are schizophrenia-related; the red squares are autism-related CGGs and TFs. Some CGGs and TFs are common for both disorders, while some are unique for each disorder. Drugs can be administered at different levels of hierarchy and delivered either to a set of possible targets or the selected CGG. (Credit: Igor Tsigelny, SDSC/UC San Diego)
A team of researchers at the University of California, San Diego and the Institut Pasteur, Paris has come up with a novel way to describe brain development.
The findings could lead to new drug designs for mental disorders such as autism-spectrum disorders (ASD) and schizophrenia.
In the paper, the researchers identified the hierarchical tree of two types of gene networks that determine the patterns of genes expressed during brain development: coherent–gene-groups (CGGs) and transcription-factors (TFs).
The found that some “master transcription factors” at the top level of the hierarchy regulated the expression of a significant number of gene groups.
Instead of a taking the approach that a single gene creates a single response, researchers used contemporary methods of data analysis, along with the Gordon supercomputer at the university’s San Diego Supercomputer Center (SDSC), to identify CGGs responsible for brain development which can be affected for treatment of mental disorders.
The team found that these groups of genes act in concert to send signals at various levels of the hierarchy to other groups of genes, which control the general and more specific (depending of the level) events in brain structure development.
“We have proposed a novel, though still hypothetical, strategy of drug design based on this hierarchical network of TFs that could pave the way for a new category of pharmacological agents that could be used to block a pathway at a critical time during brain development as an effective way to treat and even prevent mental disorders such as ASD and schizophrenia,” said lead author Igor Tsigelny, a research scientist with SDSC, as well as UC San Diego Moores Cancer Center and Department of Neurosciences. “On a broader scale, these findings have the potential to change the paradigm of drug design.”
Using samples taken from three different regions of the brains of rats, the researchers used Gordon and SDSC’s BiologicalNetworks server to conduct numerous levels of analysis, starting with processing of microarray data and SOM (self-organizing maps) clustering, before determining which gene zones were associated with significant developmental changes and brain disorders.
Researchers then conducted analyses of stages of development and quick comparisons between rat and human brain development, in addition to pathway analyses and functional and hierarchical network analyses. The team then analyzed specific gene–TF interactions, with a focus on neurological disorders, before investigating further directions for drug design based on analysis of the hierarchical networks.
In addition to SDSC and its computational resources, support for the research paper was provided by a National Institutes of Health grant.
Comments (4)
by asiwel
I would certainly agree that “defects” – genetic or otherwise – have tragic repercussions and should be corrected/ameliorated whenever possible. But certain types of troubling conditions, such as autism, even though linked to various genes, alleles, or clusters of genes, also are likely to have developmental and experiential roots as well. These conditions are not well-defined (i.e., DSM 5). The Nov, 2012, edition of Scientific American, for instance, has a full interesting article entitled “Autism and the Technical Mind” by Simon Baron-Cohen who directs the Autism Research Center at the University of Cambridge which is worth reading here.
by asiwel
Correcting a potential genetic “brain disorder” diagnosed in an infant to “prevent” something like autistic behavior in the future as a child and/or adult … is a bit different from correcting a faulty heart valve in the same infant so he or she can live to become a child or an adult and fulfill whatever potential is there to whatever degree. It is also quite different than encountering an individual (child or adult) who has a fully formed personality but exhibits autistic behavior .. and then trying to help alleviate that problem while leaving the psyche intact. Even I would have ethical problems with this. It is one thing to “enhance” the potential of an infant, say, by augmentation. It is quite another to “correct/prevent” a predicted mental/social condition that is ill-defined and often linked to leadership, creativity, etc. by pre- or post-natal genetic reprogramming. This sort of thing does indeed “have the potential to change the paradigm of drug design.”
by Bri
@Asiwel: I must admit you bring up a valid point. An affliction such as schizophrenia has most likely been conserved genetically because it can create aspects of genius( A Beautiful Mind). Autism also is expressed at a wide range of functionalities. Even a malady such as PTSD is responsible for MPD( Multiple Personality Disorder). Often when multiples are reintegrated they lack the range of expressiveness that they exhibited in the multiple state. As I reflect on it, I think the treatments will have to be integrated in a cautious manner. Sever cases should be addressed first, and as a greater understanding of the effects , and ramifications comes about, then the decision as to what level of disfunction should be treated. All these diseases can have tragic repercussions on families. It’s too important to leave unaltered.
by Bri
I’m surprised that this article hasn’t received any posts. This research is a milestone in the understanding of gene expression and brain functionality. It may help answer why autism is do rampant nowadays. In terms of mental disorders and treatment, it opens the door for prenatal testing and treatment of many brain diseases. It also can help give us SN understanding of brain function, and how that evolved. Overall this research is an excellent example of taking genetic code and figuring out how it ultimately is expressed. This coupled with environmental epigenetics will give us insight into a vast amount of brain disorders, end why some people have a predisposition towards curtain behavioral characteristics. Absolutely astonishing.