Melissa Harris-Perry: You're back with The Takeaway. I'm Melissa Harris-Perry.

Michael Thomas: A lot of people our age aren't interested in commitment. They're only interested in intercourse.

Speaker 3: [unintelligible 00:00:09] it's true.

Michael Thomas: What I've also noticed with a lot of girls your age [unintelligible 00:00:13] when they're still in high school, they only want a boyfriend for intercourse. Not just for intercourse, but also as a bodyguard and as a sugar daddy.

Speaker 3: I think every family needs a Michael. It just adds something different.

Melissa Harris-Perry: That is just a little bit of wisdom from Michael Thomas, one of the young adults featured on the Netflix reality series Love On The Spectrum. The series, out of Australia, features young adults living with autism, who are navigating the challenges of love and dating for the first time. Unlike many reality dating shows, this one does not thrive on conflict and competition, it's disarming in its sincerity and humanity. It's a show that makes viewers root for every single person involved and in that way, Love On The Spectrum is at least a little bit like real-life parenting on the spectrum for families with autistic children.

One in every 54 American children is affected by autism spectrum disorder. It's a complex, lifelong condition that manifests quite differently for the millions of people who live on the spectrum, but for nearly everyone with autism, the condition impacts communication, interpersonal relationships, and social interactions. For some with autism, there's no possibility of engaging with a reality TV show because the effects of the autism are severe.

Researchers at Washington University are using stem cells to study a rare form of autism linked to a gene mutation. It's a form of autism affecting 16-year-old Jake Litvag, and WashU researchers bred mice that mimic Jake's exact gene mutation in order to better understand the disorder. Dr. Joseph Dougherty is a professor of genetics and psychiatry at Washington University in St. Louis. Welcome to The Takeaway.

Dr. Joseph Dougherty: Thank you so much for having me. I'm very happy to be here.

Melissa Harris-Perry: Thank you. Dr. Dougherty, let's just start with how this research project got started. Talk to us a little bit about Jake and his family.

Dr. Joseph Dougherty: Yes, this whole story really starts with that family, it's very family-centric. 16 years ago, the Litvag family had a child who was later diagnosed with autism. He developed more slowly than his peers. He was late to a lot of developmental milestones. Like a lot of families, initially it was quite a challenge to understand what was going on and why it happened, but as time went on, they connected with a good clinical colleague of mine, John Constantino, who's one of the preeminent autism clinicians here in St. Louis and nationwide.

As they met him and came to know him, he talked to them about the possibility of doing genetic testing to try and understand what the causes were for Jake's autism. Autism, it turns out, is very strongly genetic. If you look at twins, identical twins who have autism, if one has autism, it's very likely that the other one will also have autism. This means that genes play a strong influence in the disease, but the question is, which genes and how? With their family, as sequencing costs have dropped in the last 10 years, they, like many others, have been able to get their child's genome or at least the protein portion of the genome, the exome sequenced and they found that he had this rare mutation in a gene called MIT1L.

Melissa Harris-Perry: For those of us who are not genetic researchers, remind us what it means to say that one could have your gene sequenced.

Dr. Joseph Dougherty: Oh, since the [unintelligible 00:03:49] genome project 20 years ago, scientists have been developing technology to read out base by base every letter of your genome. The genome is a 3 billion base pair string, so 3 billion letters of A, T, C, or G and the sequence of that is what provides the instructions for different proteins that build your body. Now that sequencing costs have dropped, you can look through each of everyone's 3 billion bases and try and identify those where they might differ from the general population. With Jacob, this is relatively painless these days, you can swish some saliva and pick up some cheek cells and extract DNA from those, which is a painless procedure, and then sequence that in a laboratory and identify places where your sequence might differ from the general population.

Melissa Harris-Perry: Okay, so it doesn't surprise me to learn, especially when we're talking about billions, right, that there are genes and particularly sequences that would be associated particularly across a broad spectrum like the autism spectrum. I'm wondering, what have you discovered in terms of which genes or which genes sequences are most likely to be associated with autism?

Dr. Joseph Dougherty: There are these 3 billion bases in the genome, but only 1% of that actually codes for the instructions to make proteins. I often think of it-- my kids love Legos. So the genome is the instruction for every Lego that the manufacturer might make. 20,000 different little possible pieces that could be made, but a particular cell in the body only uses a little fraction of those. If you're buying the pirate ship Lego kit, you get the little cannons, you get the little sails, the hatches, those kinds of things, and some of those little square blocks that are in everything.

When you get the spaceship kit, you have little laser blasters, jet thrusters, and pilot seats, but also still some of those same little blocks. Of these 20,000 genes, different ones are differently used in different parts of the body. What we do when we're sequencing is we look at the instructions for each block and try and see how are those different from one to the next. The challenge is there's 20,000 different genes and it turns out that copying all 3 billion bases, especially that very first time, they need to do it right after the egg is fertilized, biology sometimes makes some mistakes and sometimes miscopies one of those bases.

A lot of times it doesn't matter. There's 3 billion bases. There's a lot of surrounding material. Only 1% of it is really coding for those blocks, but once in a while, strike of lightning event, you hit something important. To sequence the genome, we try to look for those events where we see a certain base has been mutated as a field. Then what we try and do is sequence large collections of children with autism or intellectual disability.

We look for the times that we're seeing the same block hit over and over again. We're fortunate, there's two copies of every gene in your body. You get one from your mom and one from your dad, so sometimes taking one hit doesn't really matter. The other one can compensate for it, but there are some genes where that appears not to be the case and just getting one mutation can disrupt you. The way we tell is we just look and try and look for those mutations we're seeing more in kids in autism than in uninfected children, often we're using their siblings as controls because we know those kids grew up in the same environment, on the same genetic background and ancestry yet they're not showing traits of autism.

If we see mutations in those kids, then we know that those are ones that happened by chance that probably aren't damaging compared to the ones with the siblings with autism.

Melissa Harris-Perry: Dr. Dougherty, you've been talking with us through genes, through gene sequencing and understanding how these genetic expressions, I love the Lego visual there, can help us to understand which genes are related to autism. Talk to me about the mice.

Dr. Joseph Dougherty: Sure, Jake has a really rare form of autism. As sequencing became cheap enough to sequence lots of different kids with autism, initially we thought-- we'd always known autism was a genetic disease, but the field thought that maybe there'd be a few dozen autism genes, but as they started doing these experiments, what they found was that there are probably hundreds of different genes that can cause autism, but each one of these is hitting a very small fraction of kids.

If you add them all up, on the whole, there's maybe 10% or 20% of autism is caused by these strike of lightning events, but each type is maybe, initially in the initial discovery studies might have been two or five kids and now maybe worldwide at this point that sequencing's gone on, we found about a hundred with Jake's mutation as an example. The challenge there is really understanding what that gene does. We can look at it and look at similar genes and try and guess what it might be involved in but there's so many genes in the genome and many of them have not been that well studied before.

With looking at the kids, one thing that clinicians will do is they look at a series of kids and try and find the commonalities across all of them. With Jake's gene mutation in MIT1L, you very often see that the kids have developmental delay, a slow motor development, a lack of coordination, some intellectual disability, sometimes autism, sometimes slightly smaller brains, and maybe a tendency towards hyperactivity and obesity, but we don't know which of those traits really come from the gene and which might have been coincidence.

There's plenty of kids that get hyperactivity that don't have autism and don't have this gene, for example, so would Jake have gotten that diagnosis even without this mutation? The advantage of trying to make a mouse that models that mutation is it lets us really figure out what traits in biological traits are a consequence of that gene mutation and do it in a well-controlled and well-powered way. Each kid with this mutation also grows up in a different environment. They're all different ages by the time the clinician sees them, but with mice, we can generate a lot of individual animals that have an identical mutation, live in the same environment and really study in a very controlled way the biological consequences.

Melissa Harris-Perry: All right, that's super helpful for me. Obviously as a university researcher, much of your work is what we would call a basic researcher or core science. Trying to understand things in order to understand them but I'm the parent of a child on the autism spectrum, and I'm wondering what the end goal of the research is, because I know that for many of us in autism community, we don't want a cure in the sense of, as much as I want to support my daughter in navigating a neurotypical world, I also don't wish her to be any other kind of way. Talk to me a little bit about what learning this about the genetics of autism and of autism expression, what it does for us as it becomes applied research.

Dr. Joseph Dougherty: I love that question. First I agree with you, the decision of what and how to treat is entirely up to the patients and their families. I think my goal as a basic science researcher is to provide the understanding of what happens so that there's an opportunity to treat for some things if it makes sense for you. I think that's going to vary a lot with each different form of autism.

I think there's few parents that wouldn't want to treat epilepsy for example, or some of those challenges that really make their children's lives hard. What we hope to do is provide a deeper understanding of how this mutation causes this phenotype in the brain. What does it do to brain development that results in this to give people the opportunity to potentially intervene if they want to, but I think that's really a decision for the families.

Melissa Harris-Perry: One of the things that your research seems to have discovered here is that this missing gene does not seem to shorten life, that these mice that are little versions of Jake actually live normal mice lives in terms of longevity. Tell me why that's significant.

Dr. Joseph Dougherty: The amazing thing about this project was it really started from the family and that they supported the early stage of the research. They came from a community that had resources and when they heard from John about the mutation their child had, they asked, "Who's doing research on this?" There were really very few people working on it at that time, but he suggested he knew some people who might be able to do some basic discovery of what the gene does and help out.

The challenge is that while the federal government funds a lot of biomedical research, they're relatively risk averse. They want to make sure that tax dollars are very well spent and so given a suite of different projects to choose from, they're always going to choose the lowest risk one with the highest success rate, which is great, but making a new mouse line for something is a risky proposition.

There's a lot of steps in there that may or may not work on the first try, so the family was able to, with the help of friends and family of theirs, gather enough funding to support both our work and the work of [unintelligible 00:12:44] making some stem cell models to help develop it for this disease. They supported the early stage research to be able to generate the mouse for us to fund our generation and characterization of the mouse.

This has been about a two or three year journey and we were able to do the risky parts with their support and from that, then apply to government foundations to support our work to continue and actually characterize these mice and understand their consequences and test a variety of therapeutics. I was taught by my grandmother to always be polite and write thank you notes, and so as this went along, I was always writing letters through my clinical colleague to them just to update them on how things are going.

Like, "Hey, we got the mouse, it looks like it's working," and, "Oh, hey, we started to evaluate the mice." I was talking about the features of MIT1L, how the kids are often hyperactive and a little obese and have motor difficulties. We took a set of mice and we compared them to their sibling mice that didn't have the mutation. We put them in a little American Ninja Warrior course and had them do little tasks of climbing a pole and running on a ledge, and just like the children, they were a little bit clumsier than their siblings and they were a little more hyperactive.

They even tended to be a little more obese, especially in the early generations. I was going along and updating them with each of these things, but I knew one big question for them was lifespan, because a lot of these rare genetic mutations that affect the brain also affect other organs. They might affect heart development or lungs, like Williams syndrome. Those children often have severe cardiac defects that if not treated can really shorten their lifespan. With our first set of mice, we just let them age out and let them live as long as a mouse can, which is about two or three years.

There was this moment a month ago where for the first time we actually met the family. They came into the lab to meet. Jake came in to meet his mouse and meet his stem cells that have been modeled along with him, and he brought along his brother and his parents. It was really a wonderful chance to tell them at that moment that it seems like as far as we can tell, these mice live a normal lifespan. They really don't seem to have anything that's cutting their life short. I think as an early thing to learn from the mice, that was a great thing to be able to deliver that news to them.

Melissa Harris-Perry: It absolutely is. Dr. Joseph Dougherty is a professor of genetics and psychiatry at Washington University in St. Louis. Dr. Dougherty, thank you so much for this research and for your time today.

Dr. Joseph Dougherty: Thank you so much for the opportunity. I've really enjoyed speaking with you.

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