(upbeat music) - Welcome to Science Pub, a monthly series exploring the dynamic and exciting scientific world around us.

I'm your host Nancy Coddington, director of science content for WSKG Public Media.

This season of Science Pub, we have a great lineup of speakers and topics ranging from emerging research on autism to exploring ecology through podcasts.

Tonight's talk is a Fresh Look at Autism: Science, Social Media, and the Search for Clues.

Autism spectrum disorder, or ASD, is a neurodevelopmental disorder with a strong genetic basis.

We will delve into some of the genetic risk factors, examining the precise mechanisms by which they affect brain function and produce changes in social behavior.

We'll learn how one poorly understood risk factor evolved into the discovery of a potential new treatment for ASD, epilepsy, and other conditions.

I'd like to welcome our guest Dr. Ben Rein, who is a postdoctoral fellow in the lab of Dr. Robert Malenka at Stanford University studying the neural basis of social behavior.

Outside of the lab, Ben is a passionate science communicator sharing educational videos with an audience of over 800,000 subscribers on TikTok, Instagram, and other platforms.

He'll share tonight the joys and pitfalls of using social media to educate and entertain curious minds.

Before we begin, I want to acknowledge that autism is not seen as a disease and that the way scientists classify and categorize things is always changing.

We're here to learn about cutting-edge research focused on cellular science and cannot speak to particular individuals or cases.

We welcome audience questions but ask that everyone be respectful of our presenter and each other.

Welcome, Dr.

Rein.

- Hello.

Thank you so much for having me.

It's my pleasure to be here.

- We are very glad you're here with us tonight, and you're joining us from the west coast.

- That's right, yes.

So I'm now at Stanford University, but fun fact for those interested, I did grow up in Buffalo, New York, and did my PhD there as well.

The research I'll be presenting on was done at SUNY Buffalo, and I feel like I'm back in New York State.

- Well, you are for just a moment so thank you for being with us.

Before we get started tonight, what first attracted you towards genetics and autism and this work?

- I've always been interested generally in why there are natural differences in social behavior from one individual to the next, and, yeah, just sort of I became interested in autism spectrum disorder for that reason.

I'm broadly interested in the neural mechanisms which regulate social behavior on a broad level.

And so studying autism was a very relevant and important and valuable way for me to get at that deep interest of mine.

- Well, I can't wait to hear what you have to share with us tonight, so why don't you go ahead and get started?

- All right.

Just let me know that we can see my slides.

- We are good.

We can see your slides.

- Okay, good.

All right, so let's just go ahead and get started with an introduction to autism spectrum disorder.

I will say my dog is in the room.

You may have just heard her stretch and moan.

She's sleeping so hopefully it will continue that way, but if you hear any noise, I apologize.

So autism spectrum disorder is a neurodevelopmental disorder and there's a four-to-one male-to-female ratio in those who are diagnosed.

So here on the right, you can see, (dog barks) there she is on cue, one in 42 males diagnosed with autism spectrum disorder versus about one in 165 females.

(dog barks) I'm sorry.

Of course my dog happened to wake up right now.

Zoey, be quiet.

So autism spectrum disorder is very unique in that you often see high comorbidity with other diagnoses, and meaning that there are overlapping diagnoses within a given individual.

And so there's about 31% overlap with intellectual disability, 25% epilepsy, we also see a high prevalence of insomnia and sleep issues, gastrointestinal symptoms, and motor difficulties.

So as far as autism spectrum disorder itself, the diagnostic criteria, and this is purely clinical information for how specialists diagnose autism, is these two criteria, persistent deficits in social communication, and also, restricted or repetitive patterns of behavior, interests, or activities.

As far as the diagnostic process, the average age of diagnosis is around four years old.

There are regular screenings performed throughout development, around 12, 18, and 24 months, and this is done through something called the Autism Diagnostic Observation Schedule, and so it's actually an observational exam where, for example, whoever's being tested is asked to look at these images, for example, and identify which emotion is being expressed in each face.

So I will say I can't really talk too much about this component of this.

I am not a clinician, I am a researcher.

Again, I'm studying the basic science, the neurobiology of autism spectrum disorder, and so if you do have questions about this, unfortunately, I probably won't be able to answer them very effectively.

So what my research was really looking at is predispositions for autism, specifically genetic predispositions.

So it's estimated that genetic risk factors account for something like 60% of all of cases of autism.

And so there are what's called de novo single gene mutations.

De novo means occurring spontaneously.

So if, let's say, I do not carry a gene mutation that predisposes for autism and I have a child who does carry that mutation, they did not inherit that from me.

That occurred naturally spontaneously so that would be de novo.

And these are single gene mutations, and so we have, like, 25,000 genes and about 100 genes have been identified to be associated with autism spectrum disorder.

So here's just a figure from a paper where there have been a lot of studies seeking to identify which genes are associated with autism, which genes, sorry, mutations in which genes are associated with autism spectrum disorder.

And as you can see here, there's some overlap with genes that are related to things like intellectual disability, metabolic disorders, epilepsy.

And so maybe this can sort of start to explain a little bit of why, like I showed in the previous slide, there's high comorbidity with other conditions like epilepsies, there's a genetic overlap in some cases.

In addition to that, there are also copy number variations.

So this is gonna get a little bit confusing.

What you're seeing on the screen, these 16p11.2, 15q11.13, these are sections of chromosomes.

So in this case, this is chromosome 16, position 11.2.

And the chromosomes contain hundreds, thousands of genes, and they can be broken down into little subsections with a few genes or a number of genes.

And what we see is these sections can be either duplicated or deleted, so this results in a variation in the number of copies of that section, so that's what a copy number variation is.

And so I'm gonna explain this more in detail in the next slide, but I want to emphasize that this right here, 16p11.2, is the genetic risk factor that I was studying and will talk a lot about here.

Additionally, aside from genetic, there are also environmental predispositions, so various things that can occur in utero.

So if pregnant mother is exposed to pathogen or toxin or pollution exposure, there's a lot of research going into understanding what those risk factors are and, of course, why those exposures can lead to or predispose to autism.

Maternal stress, infection during pregnancy.

There are also drug induced cases, so valproic acid, if taken during pregnancy, may predispose for increased risk for autism spectrum disorder.

Idiopathic, meaning we don't know, it's inexplicable.

And not actually, but (chuckles) vaccines.

I wanted to caution because I didn't want people to see that and think, "Wait a minute, he's actually saying that."

No, vaccines do not predispose for autism.

Of course, I could dive into this and talk for a while, but yes, there was a research paper published in 1998 which suggested that the MMR vaccine was associated with autism.

Turns out it was falsified, it was retracted, it's not true, but many people have continued to believe that that vaccines do cause autism, they do not.

Many studies have been performed to confirm that that link does not exist, so wanted to take the opportunity to clarify that here.

So as a neuroscientist interested in studying the neurobiology of autism and really getting at the molecular cellular changes which are occurring in the brain, we actually have to use animal models of autism spectrum disorder.

And so there are mouse models, which are what we call transgenic, and they actually carry the same gene mutations which are associated with autism in humans.

So for example, these are some of the most common, like SHANK3, CNTNAP2, FMR1, these are three genes that, if a mutation occurs, it may predispose, or may increase the likelihood of developing autism in humans, and when we induce these same gene mutations in mice, the mice also show measurable changes in social behavior.

And so using these mouse models, we can start to understand why a mutation in the SHANK3 gene, for example, may lead to changes in social behavior by better understanding the exact cellular changes which link those two things.

There are also other mouse models involving, again, copy number variations, 16p11.2.

I'll get back to this.

There are environmental models in mice so if you expose, or if you induce an immune reaction in a pregnant mouse, that seems to be more likely to induce autism, well, sorry, that's not, that it may be more likely to induce social deficits, measurable social deficits in the mouse offspring.

And then, like I said, valproic acid exposure in pregnant mothers may predispose for autism.

Similarly valproic acid exposure in pregnant mice also is likely induce offspring with social deficits in some measurable way.

So the 16p11.2 duplication, so what the heck am I talking about?

I keep bringing this up.

Let me explain exactly what this means.

So, as I said, chromosome 16, position 11.2, it contains about 27 genes, about 600 kilobases, that's 600,000 base pairs of DNA.

You can picture, like, a DNA twisting and the little links, the ladder links, 600,000 of those, and it's 27 genes.

So let's say here's chromosome 16 and this is my section 16p11.2.

So what can happen, as I described earlier, is you can either have a spontaneous deletion, in which case that section of the chromosome is actually lost and it's just shortened, or you can have duplication, in which case you have an extra copy.

And this changes the overall amount of these genes that are present in all brain cells, and this can lead to changes in all sorts of thing.

Deletions and duplications are both broadly associated with a range of conditions that are all neurodevelopmental, so autism spectrum disorder, of course, that's why I'm gonna talk about this, but also intellectual disability, epilepsy.

And like I said in the previous slide, we can develop mouse models of this, and another lab had actually developed a mouse that was carrying this 16p duplication.

And at the time when I began my PhD, there was very little understood about what exactly is occurring.

There's an estimated 1 million or so people across the globe who carry this 16p duplication, and there's very, very little understood about how this is occurring, about what this genetic change leads to in the brain that may cause things like epilepsy and intellectual disability and autism, so by studying a mouse model, the goal was to identify what those changes were.

So yes, we can measure social behavior in mice.

And one of the tests that we do is we have this open chamber, a rectangle, you know, not sure how big, if you can really see, but it's about this big in real life.

And on one side, there's a mouse under a cup.

They're not in jail, it's not super distressing for them, they're only under the cup so that they can't move because we are in interested in seeing what this mouse is going to do.

Is it gonna interact with the mouse under the cup, or is it gonna interact with an object?

And so typically, when you put a mouse in here, they'll run around and they'll interact with the mouse and they'll spend more time over here with the other mouse.

But what we found is that when we put the 16p mice in here, they actually preferred spending time with the object.

And so this test is called the three-chamber, there are three chambers, social preference test, because mice typically will prefer the social cue versus the object.

But like I said here, so here's a heat map, you can actually, this is a true heat map of a mouse's behavior.

So if you see WT, that's wild type.

Those are mice that do not contain the 16p duplication, that genetic change.

And what we saw is that these mice spent a lot of time, you can see the red is increased time, surrounding the cup with the mouse and not so much with the cup containing the object.

Whereas the 16p duplication mice, they still spent time hanging out with the other mouse, but you can see it's almost a little bit more even here, so you can't necessarily say that they preferred the object, but there was a reduction in their social preference.

Another test that we can do is- - Dr.

Rein, that is really interesting.

I do have a quick question that I wanna ask you before we get much further into this.

- Please.

- John was asking, "Is dyslexia connected to ASD?"

- Not that I know of.

As far as those comorbidities and overlapping genetic sort of Venn diagrams I was showing, I don't believe dyslexia is at least strongly related.

There may be some link but not that I know of.

- Okay, thank you so much.

- Sure thing.

And yes, please feel free to interrupt me at any time.

So another test is a simple social approach test where we're taking all the complexities out of this.

Now there's just a mouse in the middle of the chamber and we just wanna know how much time do they spend.

Do they interact with them?

Or do they sit over here in the corner and sort of avoid them?

And again, what we find, here you can see the heat map, the wild type mouse shows a lot of time, they're almost exclusively spending time around the other mouse.

But the 16p duplication mouse is not so much compelled to interact with the other mouse.

Instead, they sit in the corners, which is a very standard thing for a mouse to do because if they're scared or they're just bored, they will go into the corner where it's safe.

So we showed here that these mice actually showed changes, measurable changes in the way they behave towards other mice, in their social behaviors.

And in the lab that I was working in, we had a focus on a brain region called the prefrontal cortex.

This brain area is involved in higher level executive functions, and it has a lot of different things that it really does and that it helps you do.

It's a very, very important and very human brain area in that it allows for things like personality expression, focus and attention and impulse control, and, of course, social behavior.

So your prefrontal cortex is very much involved in guiding your decisions and helping you navigate social situations, and really, social cognition and sort of thinking about how should I behave?

How does this person interpret what I'm doing?

So we're interested in the prefrontal cortex and we decided to investigate how the cells were functioning in these mice.

But before I get into that, I wanna just give an overview so that you can understand a bit more about what I present.

So if we were to zoom into the prefrontal cortex, we would see two primary cell types.

Pyramidal neurons, which release glutamate, and I'm not sure if you can see behind me, I have a beautiful pyramidal neuron on the wall behind me here.

These are the main type of neuron.

Again, they release a glutamate, so they have this neurotransmitter called glutamate, which is this chemical that they kinda just deliver to one another.

And when they release that chemical, it makes the other cells activate.

So we can't just have a city, if you like to think about the brain like a city, we can't just have a city with all green lights everywhere.

We need to have red lights as well, or else, just like if we had a city with all green lights, it would be disaster.

There would be traffic and accidents, it would be chaos, so the brain has red lights as well.

There are cells called interneurons, which release a chemical called GABA, and this is an inhibitory neurotransmitter.

So while glutamate, when it's passed between cells, makes cells become more active, GABA makes cells become less active.

So there's this nice balance in the brain of these signals.

And I'm actually gonna go one level further to really explain this.

So I'm so sorry if this is extremely boring.

I hope that this is at least somewhat interesting.

- [Nancy] It was fascinating.

- [Ben] But it's an opportunity to at least learn about or understand how brain cells work literally on a single-cell level.

So let's pretend that this sphere is a brain cell.

So on the membrane, and okay, over here, we have a continuum of membrane potential, which really means the electrical activity of the cell.

So right now, the cell is hanging out, it's right here in the middle.

It's at its baseline.

This is where it likes to be.

And let's say the cell expresses receptors.

I'm gonna skip over the details here.

There are glutamate receptors.

So remember I said, glutamate is excitatory.

It makes cells activate.

If glutamate is present, so this plus logo represents glutamate, these channels are gonna open these receptors and calcium is going to flow into the cell.

And calcium is positively charged so this will cause the membrane potential over here...

Sorry, one more thing.

There's also another receptor called AMPA, and if glutamate's there, it will cause another positively charged ion called sodium.

This should be a 1, I'm sorry, this is a singly positive-charged ion.

So when glutamate's around, these receptors open, positively charged ions flow into the cell, and the membrane potential of the cell will increase, so the cell becomes temporarily hyperactive.

And if the cell stays too active like this, it will be unhappy.

And in fact, if there's way too much hyperactivity of cells, this can lead to seizures and could lead to epilepsy.

So on the other hand, we also have GABA receptors.

Remember, I said GABA is a neurotransmitter that inhibits cells.

So when GABA is present, GABA, again, is the neurotransmitter that's being passed between cells, it will cause these receptors to open and flow and allow chloride, a negatively charged ion, to flow into the cells.

So when these GABA receptors are active, it'll allow the membrane potential to swing back to the homeostatic level.

So this is where the cell wants to maintain its activity, right here in the middle.

This is called excitation/inhibition balance.

But if there are too many GABA receptors, sorry, or too much GABA, then there's a chance that the cell can become, or sorry, or if there's not enough of these glutamine receptors, there's a chance that the cell can become hypernegative, it can become too not active, and this is also bad.

And so any variance from this baseline can cause a lot of issues in the cell function, and this imbalance between excitation and inhibition in cells is thought to be associated with autism spectrum disorder.

So if you look this up on Google Scholar, there's 10,000 results on this.

So what we wanted to do is measure whether there was too much activity or too little activity in these brain cells, and we did that using a technique called electrophysiology where we can actually...

I know this is a complicated graph.

Let's just focus on this one on the right.

So this is literally a brain cell looked at through a microscope, and this right here is a little glass pipette that's touching it.

And what we can do with that pipette is we can actually measure the signals that are being triggered when GABA or glutamate are being released onto this neuron.

So we did that in the brain cells in the prefrontal cortex, again, the region we're interested in, in these mice with the 16p11.2 duplication.

And when we look at glutamate signals, so this is actually a real-life trace of the response in a brain cell when glutamate is released, and you can see that if you compare the peak here, they're about the same between the wild type and the 16p duplication mice.

So there's no change in glutamate.

It appears to be entirely normal.

On the other hand...

So it's even, that's what that is supposed to show.

On the other hand, we found that GABA signals were reduced.

So if you look at, and again, these are just three different traces from the same brain cell, three different traces from a 16p duplication brain cell.

And you can see, it's most dramatic here, that this trace goes all the way down here, but in comparison, the 16p trace is much smaller.

Along with that, we saw that there was an increase in the frequency of action potentials.

And overall, this means that the brain cells were more active.

So we have a loss or a reduction in the inhibition to these cells and an increase in their activity, which seems to make sense going together.

But we really didn't know why.

Why are these brain cells more active?

Why aren't these GABA synapses working the way they are properly designed to?

And so to figure that out, we decided to do some sequencing where we looked at all the genes in the entire cell and to see what was changed.

And when we did that, we found that a molecule or a gene called Npas4 was reduced.

The role of Npas4 is to cause GABA synapses to be built.

And so it made sense that if we have a loss of Npas4, then it's likely we may have a loss of GABA synapses, which could be explaining this right here, why GABA causes less of a response in these brain cells.

So we double checked and we confirmed that, yes, comparing wild type versus 16p prefrontal cortex, we did see a significant reduction in the level of this Npas4 protein.

And what's interesting is that we actually also had brain tissue from human ASD patients, and we also found that in the prefrontal cortex of those patients, there was a similar reduction in this same molecule, Npas4.

So what we wanted to do was see if we increase the level of Npas4, can we cause more of these GABA synapses to be built?

Because we presumed that there was a loss of GABA synapses.

So what this is showing here, and I know this is a lot and I'm sorry, and I'm kind of speeding through this so I apologize for any lack in clarity or understanding, but just focus over here on these images on the right.

So this right here, these blue dots are the nuclei of brain cells.

And all of these red dots that you see throughout here are actually these tiny little synapses, like this right here, where the brain cells communicate.

These are specifically GABA synapses, so these are opportunities for cells to release GABA to each other and reduce each other's activity.

But looking at the 16p, you see there are plenty of cells still, but there's a severe scarcity of these GABA synapses.

You can see very, very few of them.

But what we found was that when we increased the level of Npas4, it's not a dramatic increase, it doesn't go all the way back to here, but you can see that there are more GABA synapses that exist.

So by increasing Npas4, we allowed it to do its function in cells, which is to build GABA synapses.

After we established that it was building more GABA synapses, or at least it appeared to be, we went back and we measured those signals again.

And we found that, again, so let's just look at here, for instance, this top row, here's the wild type, the GABA signal is about yea big.

Here is the 16p, it is much smaller.

But what we found is that when we treated them, we increased the Npas4 level, it made the signals a bit bigger.

And, of course, we have quantification of this, we ran statistics.

For simplicity for the presentation, I felt it was best to simply show the traces here 'cause it's the most clear.

Again, here, you can see that there is a bigger signal.

And again, this signal represents how shut off the cell becomes in response to GABA being released onto it.

Additionally, this may not be as clear, this is very clear, we can say, okay, this is definitely smaller than this.

These are a bit harder to read where this is actually each individual line is a spike that is an action potential where the neuron spikes and becomes active very temporarily and then comes back down.

And what you can see is that, initially, so this is at the lowest, I guess don't even worry about the amplitudes and all this.

This is a, there we go, sorry about that.

This is from wild type cells and this is from 16p cells.

So you can actually see, in this time period here, the wild type cell only fires two action potentials versus the 16p cells fires six, so the cells are a lot more active.

But what we found is that when we restored these GABA synapses, thereby decreasing the activity of the cells, hopefully, it did reduce the action potential firing frequency.

So this is a readout indicating that we did effectively make the cells less active, which, again, they were hyperactive so we were restoring them back to a healthy homeostatic level, which makes them more comfortable and more capable of performing the functions of the cell.

Now- - [Nancy] So Dr.

Rein.

- [Ben] Yes.

- Bringing this all back around for, you know, a lot of us are hanging on to minimal of some of the things that you're understanding.

So can you give us, what does this all mean?

- Yes, okay, so overall summary, in the mice with the 16p gene mutation that's associated with autism and other things like epilepsy and intellectual disability, there was a decrease in the overall presence of these synapses where GABA is released.

And GABA turns cells off so there was a loss of what I like to call red lights in the brain, which is the simplest way, much simpler to explain and takes a lot of the jargon out.

So yeah, if you really think about green lights and red lights existing in the brain between brain cells, we found that there were fewer red lights, which resulted in the cells being overall much more active.

And that's actually, like I showed earlier, not a good thing and that can result in things like epilepsy.

What we found here and what we're showing here is that increasing the level of Npas4 in these cells restored the number of green light, or sorry, restored the number of red lights and also made the cells less active.

So if you picture a city with no red lights, right, it's gonna be traffic and accidents and chaos.

That's sort of like what the cells were experiencing.

By building more red lights, we brought them back down to a baseline level that is healthy for a cell of this type.

So I hope that that explains a bit better.

- That does, and then I do have a couple questions I would like to ask.

Michael says, "It looks like the Npas4 was also added to WT.

Is that true?"

- That's right, yeah.

So that was our control experiment.

So we wanted to see, you know, we're adding Npas4, like he said, into the 16p brain cells, we just wanna see, you know, as the control, what occurs when we add them to the wild type samples.

This is sort of a, it doesn't really mean a whole lot, it's really not super important, but in science, we always have to have every control.

So it probably would've been best for me to just completely remove this because I didn't even mention it, so sorry about that confusion, but yes, you're right, it was added there as well.

- Okay, thank you.

And then, "What type of genetic testing is recommended to know these benign CNV?"

- That's a great question, so- - So there's a follow-up to that so I'm gonna add that in there 'cause that might help.

"Is a chromosomal microarray test, such as a ClariSure Oligo-SNP, good enough?"

And I'm sure I'm not saying those correctly.

- Okay.

I do not believe so.

So that type of microarray will, like you said, SNP, SNP is a single-nucleotide polymorphism, so that's a single gene mutation where the sequence of the gene, the DNA, is actually changed and that can change the function of the gene.

This would not be detectable by that because this is actually a change, in this case, a duplication of 27 genes.

So this doesn't actually affect the sequence of the gene.

This affects what we call expression of the gene, meaning that the genes are more prevalent in the cells, so they're being used more and, therefore, whatever job it is that they do is sort of overactive, there's too much of the gene.

So it's a really good question, actually.

I'm not entirely sure of what type of genetic screening would be done to detect a copy number variation, but I will say that these are very rare.

Something like a SNP would be a lot more common.

And so for anyone interested or curious whether they might be carrying a copy number variation, the likelihood is quite small.

But that's definitely a question for, like, a clinical geneticist rather than me, unfortunately.

- Well, thank you.

- Sure thing.

Okay, so let me wrap this all together.

So the brain cells were hyperactive because there were fewer red lights.

We built more red lights.

We made the cells no longer hyperactive.

The final question that remains is, does that change, in this activity of these cells, alter the behavior of the mice?

Does it alter their social behavior specifically?

And this is a very scientific graph, I'm very sorry, but the answer is yes, actually.

So there's a lot going on here so let's just focus on the bar graph.

So this is a quantification of the way the mice behave in that three-chamber test.

So again, here's the social cue on one side and they're spending a lot of time, the wild type mice, don't worry about GFP, are spending a lot of time over here with the mouse and not so much time with the object.

So we can calculate an index that represents their social preference, meaning how much they preferred the social cue over the object.

And so for the wild type mice, it was around 55%, but the 16p mice, it was closer to, I don't know, 8%, and that was significantly lower than the wild type mice.

But if you look at this, this is actually navy but it looks black, this black bar, this was after we increased the level of Npas4 in these mice and, as you can see, they show a significant increase in the amount of time that they spent interacting with the social cue, the other mouse, relative to the object.

So this suggests that by increasing the number of red lights and thereby decreasing the overall activity of these brain cells in the prefrontal cortex, it increases the mouse's level of interest interacting with another mouse preferentially compared to an object, which is very interesting because as a scientist who's interested in social behavior, both in and outside of the context of autism, we are interested in what systems in the brain regulate sociability.

And so this is a really interesting finding that points to the fact that the prefrontal cortex is in some way regulating social preference or the drive to interact with a social cue versus an object.

So I have a whole bunch of mechanistic slides here that I'm gonna skip right past.

There's a lot of stuff that happens here on these slides, which is sort of an explanation, but I don't think that the cellular stuff is entirely necessary.

I'm sure there's probably a lot of questions that we could preferentially cover.

So with all that said, I would like to, of course, acknowledge the funding, the National Institutes of Health and Nancy Lurie Marks Foundation, many of the people here listed for their help and training, and Michael Greenberg for providing a reagent for that experiment, or for that study.

So these are all the people, these are acknowledgements for the research that I just shared.

Of course, there's also a science communication component to this presentation.

Nancy, would it be good to break and answer some questions, or you want me to dive right into that?

- [Nancy] You can keep going.

- [Ben] Okay, cool, so as Nancy mentioned, I am a science communicator on social media, and so I wanna talk a little bit about this.

So I got my start on TikTok and this is my profile.

Here, I make videos about neuroscience and, you know, cool discoveries that occur in science broadly, and I try to just make people interested in science in general.

I also have an Instagram account where I also share things.

Intriguingly, I have a Bilibili account.

This is sort of like Chinese YouTube.

As you can see, it's all in Chinese.

So these are my main three platforms where I share these educational video.

I've also done some academic science communication where I competed in something called the Three Minute Thesis where you present your research in just three minutes, big challenge.

Also, something called the Mind Science Foundation, which is a private foundation I applied to and won this pitch competition where they run, where I explained some neuroscience research related to what I just presented and won a $30,000 research grant, which is awesome.

They are fantastic people over there.

And what's interesting is, I wanna point out, you see here, I'm on TikTok, I'm on Instagram, to most people, TikTok might be a symbol for, like, teenagers dancing, and it's very strange to be a scientist on this platform, but there are a lot of scientists on the platform and there is a lot of educational value in being on these social medias.

When I first started, I was really nervous that my colleagues in science would laugh at what I was doing and think it was silly, because it is kind of silly, you know?

And especially by typical academic standards.

But the more I did it, the more I discovered that people were actually very open and interested in the stuff that I was doing, even if it was silly 60-second videos.

You know, my goal, and I hope it's clear by watching my videos, is to educate the public about science.

And this all sort of came to a head recently, this discovery that science is a field that actually cares about this stuff, when an organization called the American Association for the Advancement of Science, this is a very prestigious scientific organization, they publish the "Journal of Science," which is arguably the number one journal in the world, they recognized me as a finalist for this award called the Early Career Award for Public Engagement with Science.

And that was really amazing for me, where I realized that, holy cow, this foundation, which is super, super legitimate, actually is acknowledging that the videos I'm posting on TikTok are helping scientists, you know, the field of science, engage with the public, and so that was really awesome.

And I've really had a great experience in general, and I'm happy to answer questions, of course.

There are many pros and cons, which I wanna go over, so- - Dr.

Rein, before you jump into that, I do have one question I wanna ask before we move too far into your science communication, which I find really fascinating.

Sophie wants to know, "How does the research that you have done, how does this tie into autism in humans?"

- Yeah, so great question.

Okay, I'm just gonna leave this slide up 'cause I don't wanna go back too much.

So of course, mice are very different from humans.

Mice interact with each other differently than humans do.

And there's automatically a question, you know, does a system in the brain that regulates sociability in mice have any relevance in humans?

Because, you know, mice may sniff each other's butts and that might be a sign of, "Hey, we're hanging out," where, of course, humans don't do that.

It's a big question.

We don't really know.

The only evidence that we have as far as to say whether or not this might have some translational value for humans is that, again, I showed it many slides ago, that this molecule Npas4 was not only reduced in the prefrontal cortex of the mice, but it was also reduced in the prefrontal cortex of human autism patients.

And so that might signify that there is some relationship, some direct relationship, not only in mice but also in humans between that molecule and social behavior.

As far as whether Npas4 can be targeted as a potential treatment for autism, what was done in the mice is not at all feasible in humans because it involves a surgery and of course that's not gonna happen at all in children and nobody would ever agree to that.

So there's a big gap still in trying to translate this, but I also want to just point out that my goal with this research was never actually to identify a treatment for autism.

Being on social media and speaking about autism has put me contact with a variety of people and a variety of members of the autism community and representatives, and I have heard a diverse range of responses, some of which have included sentiments like, you know, "It's wrong of you to assert that autism is a condition that should be treated."

Others saying that, "Please, if you are going to help develop this into a treatment, I would love to be the first person to get it.

Please send it my way."

And I just wanna clarify and just point out that I am not a person who feels that autism is something that should be treated.

The reason I got into this research was because I was interested in sociability, and it led to this experiment where we wanted to ask, does changing the function of this system change the social behavior in the mice?

That was a mechanistic experiment to help us understand what brain systems regulate sociability in general, and then it happens to have relevance for the potential treatment of autism spectrum disorder.

So, you know, I get this a lot and I just wanted to openly clarify, I am not a person who thinks autism should be treated.

I do think that there are people out there who would like to have a treatment who have autism spectrum disorder and, currently, there are no treatments available, so I feel that it would be potentially helpful to address that need for those who want it.

So that was a very long-winded and convoluted answer, but I hope that I addressed what the person was asking about.

- I think you did.

Thank you.

- Excellent.

Okay, so back to the pros and cons of science communication.

So of course, as you might expect, it can be extremely gratifying and lucrative.

So I'm pursuing a career in academia, I would like to be a professor, and being able to teach millions of people is amazing.

It's very gratifying for me.

I really enjoy it.

And of course, it's also lucrative.

There's a lot of money in social media.

That's not at all why I do it, that's not at all why I started.

But this is actually adapted from a slide I was giving to a group of students interested in social media so think about that in that context.

Cons, it can be very challenging and taxing.

It's a lot of work.

What I really do is take scientific papers that are very complex and read them, strip them down into their most bare components, and then frame that into a 60-second or so video, and that is a very challenging process but I do really enjoy it.

But still, it is taxing, it does tire me out a little bit.

Pro, many neat opportunities like this.

You know, this came about because of a Twitter interaction, so it's really cool to be able to do this.

Also, like what's shown here on the slide here is me, I was invited on "Entertainment Tonight" to talk about Bob Saget's death and what could've happened neurologically.

Cons, it takes a lot of time.

Of course, I didn't just go on "ET" and talk.

I wanted to do a little research and of course I had to do some of that, preparing slides like this takes time, but, again, I enjoy it.

Putting yourself out there is definitely a con, or can be a con.

You're putting your reputation at risk.

You know, if I had gone on "ET" and said something completely wrong about Bob Saget's head injury, I could have lost a lot of credibility in the scientific community and that was a risk that I was taking.

So in general, you know, you use a certain word in your video and all of a sudden your meaning is completely misconveyed or misunderstood and then you look like a bad guy.

That happens too, it's a risk, so I've learned to balance that.

And of course, I'm always very careful in the things that I say when I'm on social media.

The pro, the upside of that is people have a really short memory.

You know, I've had things happen where I'm like, "Oh, my gosh, this is gonna change my life forever.

No one's ever gonna see me the same."

And then people forget within a few days.

Pro, you have the ability to reach a global audience.

Like I showed on the last side, I have about 680,000 followers on TikTok, and those people are from all over the world.

And I actually, through that, started an organization called the Aspiring Scientists Coalition, which provides free guidance to students, to students in science, and helps students sort of find their way through this very bizarre and unconventional career.

And it's amazing, we have students from all over the world, 75-plus countries represented, and it's awesome.

I really hope that the resources that Aspiring Scientists Coalition provides will help some people who may not typically have access to those resources.

But with that said, you have this global audience and the internet is pretty rude.

People are pretty mean and very prone to say mean things under the condition of anonymity so, you know, it can be bad sometimes but, generally, people are really, really nice.

But I have some funny examples of people being mean and then just, like, completely walking it back when I become a real person.

You know, I'm just a person on the internet and then when we actually interact, they're like, "Oh, my gosh, I'm so sorry."

So it's just kind of funny.

There's a whole lot of...

I actually think that this should be investigated formally as a scientific discipline of why people are so mean on social media or on the internet, especially as a person who's interested in social behavior.

I think that sort of removing the humanity and them being a string of text rather than a living, breathing person emotionally behaving in front of you somehow makes people more prone to just being horribly rude.

With all that said- - [Nancy] Can see that as your next research project.

- Yeah, I really do wanna get into that.

I could definitely see myself diving in one day.

So with all that said, and this is actually my last slide, there's a lot of power in social media.

And I'm not sure if anyone here, I'm assuming at least a few people heard some level about this whole story that unfolded, that "The Joe Rogan Experience," the number one podcast in the world published an episode that was all about COVID-19, and a group of 260 or so doctors and scientists and educators penned an open letter to Spotify asking for the platform, Spotify, to publish a misinformation policy because the episode contained a lot of dangerous misinformation.

This not only shows the power of Spotify as a media outlet in that it can reach, I mean, "The Joe Rogan Experience" has about 11 million user, or 11 million listeners per episode, and that can carry a huge amount of influence.

Of course, you know, Joe Rogan, I'm sure everyone recognizes this person on the screen here.

He's a huge celebrity, and not just because of "Fear Factor," but because he's currently the number one show in the world, or at least in the United States, I think in the world.

But at the same time, social media can also be used to sort of fight back against misinformation when it occurs.

And actually, this group that led this effort, which ultimately did result in Spotify publishing a misinformation policy, was actually coordinated and began on social media, and I know that because I was a part of it.

So it's really interesting how, you know, I've watched as groups of random people on the internet making TikTok videos have gone ahead and actually made a major impact on society that will shape digital media and science for years, so it's really, really intriguing to be a part of it all.

Now I will share this Q&A slide, but we, of course, can have a Q&A.

This QR code will take you to all of my links.

If you're interested, you can check out my videos, you can contact me, you can go to my website, whatever you'd like to do.

But with all that said, I think I will end my show and we can go to the Q&A session.

I would be very, very happy to answer some questions.

And thank you so much for all of your attention and for bearing with me through many complex neuroscience boring slides, so thank you.

- Well, it looked complex but it was interesting.

We also have Dr.

Rein's information that we are sharing in the chat so that you can connect with him in other ways if you weren't able to capture that QR code.

But let's dive right into some questions.

So Lori asked the question, "Have you heard of the genetic test for CH1C?

I understand this genetic condition is associated with ASD and executive function deficits."

- I'm actually doing a Google search right now.

CH1C is cysteine-rich hydrophobic domain-containing protein.

Okay, so I have not heard of the test specifically for that marker.

I also haven't actually heard of this specific marker, so it may not be an extremely prevalent risk factor for autism.

So each of these genes, like I said, there's about 100 of them, they all have different levels of likelihood.

So you might carry a gene mutation that is associated with autism in 20% of people who have that mutation, but you might be in the 80% who do not.

There are other genes where, instead of 20% of people who carry it are diagnosed with autism, maybe something like 80 or 90% of people who have that mutation are diagnosed with autism.

So there are some genes that are really, really strong risk factors, some that are not so strong.

And so CH1C, I'm not technically, or I'm not super familiar with, but I will offer a resource.

It's by the Simons Foundation for Autism, Simons Foundation Autism Research Initiative, and it's called gene.sfari.

I'm not sure if I can throw it in the chat.

Okay, so it's gene, G-E-N-E.S-F-A-R-I, so it's like safari but the first A is missing, .com.

That is a database of all genes that are associated with autism, and it compiles all the research papers that talk about, like, how the link is there and whether it exists or not.

So I'm actually on this site right now and I'm gonna look up CH1C and it actually does not appear.

So there may not be any published evidence linking CH1C, as long as I typed that in right, with autism.

So I hope that was helpful.

(laughs) - (laughs) Thank you.

Thank you for that resource as well.

Nell wants to know, "So does genetic testing prove that vaccines or birth injuries do not cause human autism but that you are born with it?"

- So prove is a very strong word that scientists don't like to use, but I will say that if someone has autism and they also have one of these autism risk factors, genetic autism risk factors, then it is very likely that that change in that gene is what produced some change in brain development and the expression of autism.

So we can't necessarily say that just because genetic risk factors for autism exist that other causes do not, but we can certainly say that disruptions in the functions of certain genes produce changes in brain development and can lead to autism.

So as far as refuting the link between vaccines, there are many papers out there where huge, huge studies have been conducted to see, like, okay, here's a group of people who got the MMR vaccine, here are people who did not, and was there any difference in the likelihood of either group developing autism spectrum disorder?

And the answer is no.

So that has been carefully and rigorously examined separately.

- Okay.

Thank you.

Is autism much more common now, or are we just learning how to recognize it?

- So it's funny, I'm fairly young, so I haven't been around Earth a whole lot (chuckles) so I wish I could say, you know, "Oh, I was there 20 years ago.

I remember when it was this way."

But I get this question a lot.

My answer is that, basically, the diagnostic criteria for autism have changed a whole lot.

A long time ago, autism didn't even really exist.

It wasn't formally recognized.

And nowadays, most people know what autism is, but you may not know what a rare mitochondrial disease is.

You know, something like multiple sclerosis, you might know what that is, but you might not know what something like Krabbes disease is.

And so, you know, back in the day, autism may have been more like one of those sort of quiet things that exist and that some doctors know about but not all doctors know about, and so it was less likely to be diagnosed.

But also, like I said, the diagnostic criteria have changed over time, which may have affected the rate that it was diagnosed.

But what this question is commonly asked alongside with is, does this indicate, since there's more cases of autism nowadays and it's continuing to increase, does that mean that there is something in the water that we're drinking or something in the food that's leading to autism?

And I think that there are a lot of studies going into this type of stuff.

Like I said, there's the questions about pollution and toxin exposure, but I tend to lean on the answer that it's just more understood and more recognized nowadays.

- Yeah, I mean, that definitely signals.

Virginia said, "While she was a pediatric, it wasn't really recognized at all."

So there is definitely a lot more awareness as we learn things, right, and continue to grow as scientists.

So question on, "Are there places on Earth where autism doesn't seem to exist?"

- That's a really good question.

I don't think so.

I'm fairly certain that it exists everywhere.

There may be differences in the prevalence from, like, certain country to country to country.

But, yeah, and those differences, if they do exist, I'm just assuming that they exist, would likely be, I guess I'm only just speculating, but it would likely be due to genetic changes, I would assume, or genetic variability.

But yeah, that's a really interesting question and I'm very curious now.

Not that I know of, would be my answer.

- So right along that lines, do you know what country leads the world in autism research or discoveries?

- Good question.

I don't know.

I don't know that either.

I'm also not sure if that's something formally quantified, but I mean, I think the United States is really good.

There are a lot of foundations, research foundations, in the United States and many prominent autism research, you know, as a scientist in the field, most of the autism research scientists who I am familiar with are American.

- So Lori wants to know, "What do you think of the statement that ASD is more of a symptom versus diagnosis, from the researcher point of view?"

- Okay, so I'm gonna try my best not to give a very long-winded answer to this.

I think that that can sort of be said about any condition.

You know, when you think about anything, like ADHD or depression or whatever it is, these conditions are really just arbitrarily characterized by a group of people who probably did not have those conditions.

You know, at one point, a group of psychiatrists came together and said, "Okay, what are the symptoms of depression?

And it's, okay, this and this."

And then they start to notice that they also see this symptom with it so they're gonna cluster that in and they're gonna change the DSM, diagnostic manual, and it's just sort of a very arbitrary human thing.

But what's really happening underneath, in the neurobiology, is very diverse because those characteristics, those symptoms are really just expressions of neurological changes.

That's the way I look at it is that it all starts here.

It all starts with the way your brain is functioning and whatever's happening inside there.

And if there are changes, deviations from what's average, then you're gonna see some change in, let's say it's mood or let's say it's attention or maybe it's sociability or maybe it's a repetitive behavior.

So I tend to think that there are a variety of neurobiological changes which underlie the behaviors, the symptoms that we see, and they have just sort of been like arbitrarily clustered.

And I'm more interested in, like, what are those changes, and why does this change, for example, seem to associate with not only social changes but also repetitive behaviors or also other things.

And so, yeah, I think that the thing we should all be interested in, or at least the thing I'm really interested in, is the neurobiology underneath it all.

- So this might be a little bit out of your realm, but autism, it shows up and varies in different people, right?

Like, the symptoms that are expressed might be different from me versus you.

So can you speak to some of the treatments that are currently being used?

- So with the clinical stuff, I will say I'm sorry but I can't answer it because I know a little bit but I'm definitely the wrong person to ask, (chuckles) and I'm not up to date on what the current procedures are.

So what I can say is that I know for sure there are zero treatments available for the social symptoms of autism, and the only, like, pharmacological pill-based medicines that you would take are related to, like, aggression, and I don't know, I guess I shouldn't really comment.

I have some thoughts on that but maybe they're a little controversial.

I don't really get that prescription personally, or understand it.

- So are stem cells used in autism research?

- So stem cells are really cool.

They're used in all research, I suppose, but I don't believe so.

So stem cells are used generally in neuroscience because what we can do is we can take my skin on my face and swab it, have those cells in a dish, and then we can turn them into stem cells so that they can become anything.

From there, we can turn them into brain cells and we can then study those brain cells.

And those brain cells in that dish will carry the same genetic material that my brain cells have because all my cells in my body have the same genes, the same genome, and they were taken from my skin, now I have brain cells in a dish that have my genes.

So pretty much we get a little glimpse into my brain and my brain cells and how they function.

So the only way that stem cells are being used in autism research, as far as I'm aware, is that you might do that, you might take a swab of a group of 100 people who are not diagnosed with autism and a group of 100 people who are, and then you might compare how those brain cells in the dish are functioning, which can help us understand, you know, instead of looking at mouse models of autism, we can look at actual human brain cells and compare, for example, through electrophysiology, the thing I showed, how they are functioning actually.

But as far as stem cell, like, treatments or therapies or some of the stuff that's being done for things like Parkinson's, I'm fairly certain that that is not happening.

- Okay, thank you.

And I think this might be along the same lines.

Do you see a role in gene replacement therapy or support to mitochondrial function as potential future therapy or treatments?

- Mitochondrial function is interesting.

I'm not familiar with the research on mitochondrial function in autism.

It could be really interesting.

It could be helpful, who knows?

It's possible but I don't really know.

As far as, let's see, what was the other one?

It's right here, gene therapy, is that what I said?

Or genetic therapy?

- [Nancy] Yes, gene therapy.

- That gets into a much more convoluted sort of ethical discussion and that discussion that the entire world is sort of gonna have soon with things, there's technologies being developed like CRISPR, which allows you to change genes in human embryos.

You know, if let's say you are having a child and a genetic screening is done in utero and they determine that there's a gene mutation which is gonna predispose them to something like progeria, which is very likely to be fatal before the age of 20 or so.

I would argue, I would think, that it would make sense in that case to potentially reverse that gene mutation through some sort of gene therapy to prevent that because you're essentially saving a life or at least extending a life a lot.

In the case of, let's say, there's a gene mutation that's detected that predisposes to autism.

That gets into a very, very complex and nuanced debate where, for what it's worth, personally, I would argue that it might be unethical to alter that gene, you know?

But I'm really interested in societally what happens as these technologies become available because those are gonna be big ethical conversations.

- Yeah, absolutely, completely.

Michael had a couple comments on different forms of therapy and applied behavior analysis.

So those really being not really medical treatments but a variety of methods to learn particular skills, so thank you for those comments as well.

So, Dr.

Rein, if we wanna find out more information about this, where can we go?

- About this research specifically?

- About the research and the work that you do?

- So probably the best place to go would be directly to my website, which is my name, benrein.com.

And on there, there's a description of my research interests.

You can find all of my research papers.

Typically, academic, scientific published papers are hidden behind paywalls and you have to pay for them, but I have downloaded all of them and uploaded them directly to my site, so if you're at all interested in reading my papers, you may download them for free right on my website.

There's also information about my science communication, you can find all my stuff there, and there are also free resources on there.

So if anyone here is a student in science and is interested, I have uploaded a handful of resources on there, things like a example CV, which is like a resume, a research poster template that you can use if you have to present a research at a, or a research poster at a conference, and you can also find the Aspiring Scientists Coalition on there if you're interested.

So that's a hub for everything related to me and the things that I do.

And please, if you have any questions, you can also reach out to me on there.

- That's great.

Thank you.

And that is in the chat so you can follow that link.

I would like to thank our guest, Dr. Ben Rein.

Thank you so much.

It has been a very fascinating, interesting talk tonight.

You can also follow him on social media and watch his science communication videos there.

And again, those are shared in the chat for you to follow.

- Excellent.

Well, thank you so much for having me.

I really appreciate it.

- Thank you.

Our next Science Pub is on Tuesday, May 10th, Going Wild with Dr. Rae Wynn-Grant.

She hosts a popular podcast on PBS Nature that transports listeners to animal kingdoms, hidden worlds, and through action-packed adventures of the wildlife conservationists who track them.

The link to RSVP is in the chat.

That's on May 10th at 7:00 p.m.

If you enjoyed tonight's show and you enjoy Science Pub, please consider a financial gift to support science.

Follow the link and support at any level that works for you, and we greatly appreciate it, thank you.

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I wanna thank our WSKG team tonight, our director, Andy Pioch, Alyssa Micha, our chat moderator, Kristine Kieswer.

Support for Science Pub is provided by the Robert F. Schumann Foundation and from viewers like you.

I'm your host Nancy Coddington.

Thank you for joining us.

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