Simon Baron-Cohen: Is autism passed on through genes?

In this edition of The Naked Scientists, Titans of Science continues as Chris Smith chats with autism research pioneer, Simon Baron-Cohen...

Chris - But you were one of the first people, and it was actually in your book, that impressed upon me the difference when one compares the empathic abilities of women and men, for example. You show in your book slices of a person’s face – just the eyes – with a word at each corner of the oblong, and say what emotions are the eyes showing. And I failed all of them. My wife got 100%. She’s very, very empathic. That brought it home to me that women tend to perform much better on this sort of task – that there does appear to be a clear difference empathically between men and women. And you’re arguing that this is a manifestation of that.

Simon - Yes. So we talked about limitations of clinicians, and also masking or camouflaging as a response to social pressures. But I think another factor we haven't talked about yet might be the role of biology. And the biology of sex differences – or gender differences – is, of course, very controversial. But the test you’ve just described – we call it the Eyes Test for short – the long name is the Reading the Mind in the Eyes Test, where you just have to decode someone’s facial expression from photographs of the eye region of the face. Reliably, across cultures, we see gender differences – that women, on average (and those two words are really critical), score higher on this test of empathy than men do. The reason I underline those two words – on average – is, of course, because all we’re really doing is comparing groups of men and groups of women, and you can easily find individuals who are atypical for their gender. But that sex or gender difference, we recently showed in a publication, holds true across cultures. We studied it in 57 different cultures. It suggests that there might be a universality – that it’s not just about how we raise our daughters compared to our sons – that there might be a role for prenatal biology. And that took our research group into looking at the obvious biological mechanism, which is the sex steroid hormones, like testosterone and oestrogen. So we were able to measure these hormones prenatally and then follow up the children. We measured them during pregnancy, waited for the child to be born, and looked to see whether there was any relationship between your exposure to these hormones – partly because these hormones are produced at higher levels in male foetuses than in female foetuses – and that’s exactly what we found: that the higher your prenatal testosterone, for example, the more difficulties you have on these social tests of empathy when you're eight years old. But conversely, we found that if you had higher levels of these prenatal hormones like testosterone, the better your skills at pattern recognition. So this is kind of confirming something that we’ve known from animal research for decades – namely that these sex steroid hormones, the androgens and oestrogens, shape brain development prenatally. And we went on to test the next obvious prediction: do autistic people – so people with a diagnosis – have elevated androgens and oestrogens? And we did that in collaboration with the Danish Biobank, because that was the opportunity. They had thousands – tens of thousands – of samples of amniotic fluid. That’s the fluid that surrounds the baby during pregnancy. And in women who chose to have a procedure called amniocentesis, where some of that fluid is extracted for clinical reasons, we were able to measure the hormone levels in that fluid and look to see whether individuals who have a known diagnosis years later of autism had elevated prenatal sex steroid hormones – and indeed, they do.

Chris - This is the basis really of your argument that autism is a sort of shifting towards a more male brain pattern, in that respect.

Simon - That’s right.

Chris - It’s very difficult to get the language right. You can see I’m struggling slightly, but you know what I’m saying – it’s almost extreme maleness, isn’t it? That’s what you’re arguing.

Simon - Yes. So at various times, I’ve called this the extreme male brain theory, but it’s very open to misunderstanding. Because, in people’s minds, when they hear the word male, and certainly the phrase extreme male, they might have all kinds of connotations that don’t apply. So, for example, some people might think of male characteristics as aggression.

That’s not the relevant dimension here, because we’ve been talking about empathy and also pattern recognition – or what I call systemising – being able to understand a system according to the rules and patterns that govern that system. But either way, if we shift to the level of biology, we’ve known that these hormones masculinise the body and the brain prenatally.

Chris - Can you see that reflected in structure, though? Has anyone done the study where you can do what you’ve done for the steroid exposure – the oestrogens and the testosterone exposure – and then looked at brain structure to see if there is a correlation?

Simon - Mike Lombardo, when he was here in Cambridge, did that very experiment. So, the children whose mothers had had amniocentesis – where we knew their prenatal testosterone levels – when they were eight years old, we invited them in for an MRI scan. And we looked at grey matter volume in different regions of the brain, and found that different brain regions – particularly language areas, and parts of the brain associated with social skills – some of those brain regions were larger, showing a positive correlation with prenatal testosterone.

Chris - We know that there is a familial aspect to autism. It definitely runs in families, in so much as we can say scientifically the word definitely. How does that tie up with this hormone story then? Have you found a link?

Simon - So I'm glad you've mentioned genetics because it's the missing part of our discussion so far. Autism runs in families, that's true. So if you've got one child who's autistic in the family, the chances of the next child also being autistic are higher than the general population. The other clue that autism is genetic is from twin studies. If one twin is autistic and the pair are identical twins, there's a much higher likelihood that the co-twin will also be autistic compared to when you look at non-identical or dizygotic twins. So these are genetic designs, family genetic designs, which give clues to genetics. And since probably the year 2000, there's been a big push to also look at the molecular genetics. And what's been found is that autism is associated with over 100 rare genetic variants. So that just means mutations, for example, that are rare in the general population, but they're more common in autistic people. So we're just kind of beginning to crack our understanding of the genetics of autism. But let's bring this back to your question about how do the hormone findings relate to the genetics? Well, what we know is that when you have identical twins, you can also find discordant twin pairs. So one is autistic and one isn't. So it means that genetics can't explain autism 100%. Otherwise, if one had autism, they should both have autism if autism was 100% genetic. So we think that the hormones are interacting with the genetic predisposition. And to understand the cause of autism, and maybe that gender bias we talked about earlier, we need to factor in genetics, hormone exposure, and then of course, your early experience postnatally.

Chris - When one looks at the structure of the brain, and how different bits of the brain talk to each other and how well they talk to each other, can we see consistent pictures that explain why people with autism have the traits and characteristics that they do? Can we marry those things together yet?

Simon - I think we've still got a long way to go. So some of the evidence is inconsistent. So MRI studies, for example, over the last few decades, have tended to be fairly small scale studies, 30 autistic people compared to 30 non-autistic people, that kind of scale. Whereas these days, as you know, neuroscience is moving towards big data. And I've got a colleague here in Cambridge, Richard Bethlehem, who's put together a huge collection of MRI scans, I think the last count, he's got 200,000 MRI scans, across ages, across development, across gender. I think that's the kind of data set that you need to start looking at how autistic people might differ in their rate of brain development, and then very regionally different parts of the brain. But also, because autism itself is so heterogeneous, we need to start doing studies, which, for example, tease apart autism with intellectual disability and autism without intellectual disability, autism with ADHD, autism without ADHD, the whole sort of range of different manifestations, as you said. So still lots of work to be done.