Autism cure by gene therapy

shank3 - Copy

Nothing short of an autism cure is promised by this hot new research paper.

Among many thousands of proteins that a neuron needs to make in order to function properly there is one called SHANK3 made from the gene shank3. (Note the customary writing: by consensus, a gene’s name is written using small caps and italicized, whereas the protein’s name that results from that gene expression is written with caps).

This protein is important for the correct assembly of synapses and previous work has shown that if you delete its gene in mice they show autistic-like behavior. Similarly, some people with autism, but by far not all, have a deletion on Chromosome 22, where the protein’s gene is located.

The straightforward approach would be to restore the protein production into the adult autistic mouse and see what happens. Well, one problem with that is keeping the concentration of the protein at the optimum level, because if the mouse makes too much of it, then the mouse develops ADHD and bipolar.

So the researchers developed a really neat genetic model in which they managed to turn on and off the shank3 gene at will by giving the mouse a drug called tamoxifen (don’t take this drug for autism! Beside the fact that is not going to work because you’re not a genetically engineered mouse with a Cre-dependent genetic switch on your shank3, it is also very toxic and used only in some form of cancers when is believed that the benefits outweigh the horrible side effects).

In young adult mice, the turning on of the gene resulted in normalization of synapses in the striatum, a brain region heavily involved in autistic behaviors. The synapses were comparable to normal synapses in some aspects (from the looks, i.e. postsynaptic density scaffolding, to the works, i.e. electrophysiological properties) and even more so in others (more dendritic spines than normal, meaning more synapses, presumably). This molecular repair has been mirrored by some behavioral rescue: although these mice still had more anxiety and more coordination problems than the control mice, their social aversion and repetitive behaviors disappeared. And the really really cool part of all this is that this reversal of autistic behaviors was done in ADULT mice.

Now, when the researchers turned the gene on in 20 days old mice (which is, roughly, the equivalent of the entering the toddling stage in humans), all four behaviors were rescued: social aversion, repetitive, coordination, and anxiety. Which tells us two things: first, the younger you intervene, the more improvements you get and, second and equally important, in adult, while some circuits seem to be irreversibly developed in a certain way, some other neural pathways are still plastic enough as to be amenable to change.

Awesome, awesome, awesome. Even if only a very small portion of people with autism have this genetic problem (about 1%), even if autism spectrum disorders encompass such a variety of behavioral abnormalities, this research may spark hope for a whole range of targeted gene therapies.

Reference: Mei Y, Monteiro P, Zhou Y, Kim JA, Gao X, Fu Z, Feng G. (Epub 17 Feb 2016). Adult restoration of Shank3 expression rescues selective autistic-like phenotypes. Nature. doi: 10.1038/nature16971. Article | MIT press release

by Neuronicus, 19 February 2016



As nutty as Dali, as crazy as van Gogh

Left: Portrait of Salvador Dali (taken in Hôtel Meurice, Paris, by Allen Warren, 1972). Right: Self-portrait with bandaged ear and pipe (van Gogh, 1889). Courtesy of Wikipedia.
Left: Portrait of Salvador Dali (taken in Hôtel Meurice, Paris, by Allen Warren, 1972). Right: Self-portrait with bandaged ear and pipe (van Gogh, 1889). Courtesy of Wikipedia.

Having a brain disease means to have different scores on emotion, cognition, and behavior inventories than the population mean. Also different from the population mean is the ability of an artist to create evocative things. Whether is a piece of music or a painting (or in my case a simple straight line), whether we like it or not, most of us agree that we couldn’t have done it. Also, artists show a decrease in practical reasoning, just like the schizophrenics.

Power et al. (2015) sought to find out if there is a link between being creative and having schizophrenia or bipolar disorder. Lucky for them, the north-European countries keep detailed medical and genetic databases of their population: they had access to 5 databases from Iceland, Sweden, and Netherlands, featuring tens to hundreds of thousands of people.

The authors analyzed hundreds of thousands of individual genetic differences (i.e. SNPs = single nucleotide polymorphisms) that had been previously linked with schizophrenia or bipolar disorder. As a side note, some of this data was obtained by inviting citizens to voluntarily fill out a detailed medical questionnaire and donate blood for DNA analysis. A staggering amount of people agreed. I wonder how many would have done so in U.S.A….

Anyway, the authors defined creative individuals (artists) as “those having (or ever having had) positions in the fields of dance, film, music, theater, visual arts or writing” (online supplemental methods), including those teaching these subjects. And they found out that the same genetic makeup that increases the risk of developing schizophrenia or bipolar disorder also underlies creativity. This link was not explained by education, age, sex, or shared environment.

The study also knocked down an evolutionary explanation for the persistence of schizophrenia and bipolar disorders in the genetic pool. The hypothesis posits that we still have these devastating brain disorders because they come with the side effect of creativity that offsets their negative fitness; but that does not hold, as the artists in this study had less children than the average population. Authors did not offer an alternative speculation.

Reference: Power, R. A., Steinberg, S., Bjornsdottir, G., Rietveld, C. A., Abdellaoui, A., Nivard, M. M., Johannesson, M., Galesloot, T.E., Hottenga, J. J., Willemsen, G., Cesarini, D., Benjamin, D. J., Magnusson, P. K., Ullén, F., Tiemeier, H., Hofman, A., van Rooij, F. J., Walters, G. B., Sigurdsson, E., Thorgeirsson, T. E., Ingason, A., Helgason, A., Kong, A., Kiemeney, L. A., Koellinger, P., Boomsma, D. I., Gudbjartsson, D., Stefansson, H., & Stefansson K. (July 2015, Epub 8 June 2015). Polygenic risk scores for schizophrenia and bipolar disorder predict creativity. Nature Neuroscience, 8(7):953-5. doi: 10.1038/nn.4040. Article + Nature comment

By Neuronicus, 7 October 2015