Dr Steve Scherer - Autism genetics

We're all becoming more aware of autism and related disorders such as Asperger's syndrome, and more than 100,000 children in the UK are currently thought to be living with an autistic spectrum diagnosis. The causes of autism are not fully understood - although any link with childhood vaccines has been ruled out by robust scientific studies - but it's clear that genes play a role.

To find out more about the complex genetic landscape of the autistic spectrum, I spoke to one of the world's leading experts in the field, Dr Steve Scherer at the Hospital for Sick Children in Toronto. I started by asking him to explain what autism actually is.

Steve - Autism is a childhood developmental disorder that actually lasts a lifetime, that involves deficits in learning, repetitive stereotypic behaviours, anxieties, and language communication deficits. So, these are grouped into a so-called triad of symptoms that lead to an autism spectrum disorder diagnosis.

Kat - So, what do we know so far about what causes autism?

Steve - So, there's been many studies over 40 or 50 years in fact, probably the most interesting data came in studying identical twins that have the same genomes. And if one sibling twin was on the autism spectrum, in some of the studies published, over 90% accordance rate or chance that the second twin would also be on the autism spectrum. And then in the last say, 8 years now, but more in the last few years, the ability to scan DNA at a very high resolution using what we call 'genome technologies' and more recently, by doing genome sequencing itself. So, you're decoding all of the chemical bases of information in the genomes of individuals and we've been able to find some of these genes that are in fact causative for autism.

Kat - With a disease that's as complex as autism and there is a wide spectrum so people can have different levels of it, if you like, it seems obvious to me that it's not just one gene. What do we know about the genes for autism so far and how they interact?

Steve - So, what's really come out in the last few years is the fact that we now know for sure there's dozens and dozens, and dozens, and we estimate perhaps a few hundred genes that can be involved in this very complex clinical disorder that we were calling autism spectrum disorder. If you look at the clinical expression of the disorder in identical twins that have the same genome, in some cases, you could have one child who's very mildly affected with say, Asperger's syndrome and another identical twin who's severely autistic. So, this gives kind of information that there is this underlying clinical complexity and we also now know the genetic complexity. There are certainly at least a dozen or so bona fide genes that have been identified that if you have only one copy of that particular gene instead of the typical two, there's a very high probability that you'll be on the autism spectrum.

Kat - And what sort of things, certainly of the genes that we know about already, what sort of things do they do in the body?

Steve - So, there were a lot of hypotheses before about what genes might be involved and they were completely wrong to be honest. But in retrospect, the genes that have been identified, it makes sense. It's just that people were kind of chasing the wrong ideas. So, the genes that have been identified are encoding proteins that are involved in how the brain nerve cells or the neurons develop and communicate with each other. They're so-called synaptic genes. They work at the synapse or the area where the neurons come together to exchange information. And what's very interesting is, most of the autism, what we call 'susceptibility genes' found now, encode molecules that are working together in what we call a genetic pathway or a biological network at the synapse in the brain. And that becomes really important because if you have a very genetically heterogeneous disorder like we know now in autism, we'd like to try to use that genetic information to help us guide development of therapeutics - medicines, drugs. But if each one of these variants only accounts for 0.5% or less, it's pretty hard to develop hundreds of different drugs. But you might imagine, if they're all working in the same pathway, different components of pathways, you might be able to group together or stratify patients into certain groupings that may - say, drug A may have an impact on them, or drug B may impact another group of patients. And that's kind of the underlying idea going forward.

Kat - Because that's a very exciting concept and it's certainly for families that are affected by this condition because there could actually be drugs that will be effective in the future.

Steve - Yes, so right now, there is no effective drug in any individuals as far as we know for the core deficits that are involved in autism. Some of the medically associated observations like anxiety, we see in a very high percentage ADHD for example, you can take some drugs. In some cases they work, in some cases, they don't. Some cases, they have adverse effects, but not for the core symptoms for autism. So, that's precisely the approach. What typically happens is when a gene is identified, we can then go and generate the equivalent of genetic change or mutation in an animal model - we usually use mice for this - check to see if the mice have characteristics like autism. We'd look to see how they groom themselves, how they interact with their littermates, things like this.

And then you can test drugs on these mice and in many cases, some drugs have been developed for different things that are known to work on these proteins that we know now are involved - genes or proteins involved in autism. So, we can test those or we can develop new ones. There's been quite a bit of progress. There's at least 6 or so different drugs that have been developed, in particular for other medical genetic disorders like Fragile X syndrome and Rett syndrome, of which a high proportion of patients actually have autistic-like characteristics too.

Those genes were identified 20 years ago and they've gone through this whole route of looking at animal models and generate drugs. It turns out, those drugs can also be tested in autism populations. If you look at that group of the population, it has mutations in genes that are involved in the Fragile X and the Rett syndrome pathways, and that's exactly what's happening. And then for some of the newer genes that are involved in different types of synaptic proteins, there are some other off the shelf drugs that have been developed in other studies, for example in ADHD, that can now be tested in the population of autistic individuals that have their alterations in that genetic pathway. So, that's exactly what's happening.

Kat - It sounds like the next couple of years are going to be an incredibly exciting time in this area.

Steve - It is. It's kind of opened up the black box now and we've shed light on what the real problem was and the biological challenges so we can do experiments that are informed and design things in a right way. So, we're seeing incredible progress, but the key will be to turn that information to benefit individuals involved and the families so that they can have a better life.

That was Dr Steve Scherer at the Hospital for Sick Children, known as Sick Kids, in Toronto, Canada.