(whimsical music)
- I am gonna talk today about identifying
the genetic underpinning of autism spectrum disorders
and then really wanna talk about that as really
the foundation for beginning to understand not only
the biology of these disorders but also something about
this complex interplay of environment and biology
that you've been hearing about throughout much
of the day today.
I'm gonna start by just showing a video
of a child with autism.
Don't worry about the sound.
In fact, it's very hard to hear but not having the sound,
hopefully, also makes a point.
You don't need clinical training I don't think
to be able to identify really what is the sine qua non
of the diagnosis of autism which is a fundamental impairment
in reciprocal social communication.
So I think you can tell that this is a young man
who is certainly not typically developed in that regard.
In a moment, he'll sit down and start using
a picture board to communicate
and has very little useful language which is also a hallmark
of those social communication deficits
that is particularly prevalent
in more severe cases of autism.
Also, at the beginning you saw I believe that he flapped
his hands in the second domain for the diagnoses.
Those kinds of repetitive behaviors
are highly restricted interest.
So understanding the genetics of this syndrome,
despite the fact that we've known for several decades
that autism does run in families,
has been extremely difficult.
We spent much of the early part of my career
spending more time arguing about why we couldn't get
the same answer than we did in being able to lay
a strong foundation for understanding
the neurobiology of the disorder.
Want to talk to you about the strategy that my lab chose
to pursue, a number of other labs as well,
which was understanding that there was this very complex set
of levels of analysis potentially to try to address
from molecule all the way to complex behavior,
that our thought was that if there was a possibility
that we could go from the complex behavior directly
to the molecule, meaning to get us directly to DNA,
that that could be valuable in laying sort of the foundation
then to pull on that thread to be able to get to more
and more complex levels of analysis
and really the whole idea behind this,
I don't think I could've had a day that had better set up
for sort of laying out why this was a hypothesis
but the notion that if we could understand
the detailed biology of autism
and other neurodevelopmental disorders,
this could give us the kind of opportunities
that you've heard about today with regard to amblyopia
and neurodegenerative disorders, et cetera.
So, there are many reasons why we thought that this might
be a reasonable strategy.
Among them is that in some ways,
we had the sense that this was really the simplest approach
to try to begin to understand something
as complex as autism.
Not a trivial undertaking to try to find
which individual changes among three billion bases
in the human genome present in every cell that has a nucleus
in the nucleus but orders of magnitude less complex,
in my view when I was starting my lab,
than the 100 billion neurons that make up
the human central nervous system
and orders of magnitude still less complex than trying
to understand the hundred trillion connections
and you've heard a lot about synapses today.
So we decided to take this approach.
You could call it really a reductionist approach
to trying to, as I said,
get at the simplest part of the problem
and then move forward.
We did that starting about 10 years ago by focusing
on something called De Novo mutation.
So when people think about genetics,
they often sort of think about that as synonymous
with the transmission of genetic risk
from one generation to the other,
from grandparents to parents to children,
but it's also the case as the small amount
of genetic variation is introduced into the genome
in each generation.
So there is quite a bit of variation in the human genome.
If you turn to your left or your right,
you are 99% identical to the person sitting next to you,
level of your genome.
So I hope you got a good seat.
I enjoyed (laughs),
(audience laughs)
I enjoyed mine
but within that, even though it's about 1%,
that's still 30 million differences that you have
between you and the person sitting next to you.
We were interested in de novo mutation for several reasons.
So the first is that, if a de novo,
if a new mutation which is introduced at a low rate
into the genome in every generation is connected
with something like a neurodevelopmental disorder
to the extent that it has a significant effect,
over time it will be eliminated from the genome
by natural selection.
But for de novo mutation,
natural selection has very little time to act.
So unless the mutation is lethal in the generation
in which it's present,
you can have genetic variations, mutations,
that have very large biological effects and still,
if you can find the de novo mutation,
you're able then to be able to use that as a starting point
and if you're interested in genetics,
as a way to understand neurobiology starting
with something that has many, many fold increase in risk
versus a small percentage increase in risk.
Seemed like a smart strategy.
This also comported with a clinical observation
for many years that many families come
to clinical attention,
I'm a child psychiatrist and can tell you
that it was observations in our clinic as well,
that a substantial portion come in where there doesn't
appear to be any strong family history,
suggesting that those families in particular
might have been vulnerable to the spontaneous new mutations,
de novo mutations,
contributing to their disorder and then there were
two key papers in 2007 and 2008,
I think the most relevant one and truly seminal paper was,
the lead author was Jonathan Sebat
who's a professor here at UCSD,
showing that de novo mutations in fine chromosomal structure
were much more frequent in kids with autism if they came
from a family without a family history
than any other group that they compared to.
We then got very lucky and were able to study
a group of kids in the Simons Simplex collection
that was designed to try to help us promote
these kinds of mutations and this diagram shows really
the experimental design which is to find families
that look essentially like they'd been hit
by a bolt of lightning where the blue represents unaffected
and red affected.
So to have unaffected parents and if there were siblings,
to have them be unaffected as well and only be able
to have a single affected member in the family
in order to be able to participate in this cohort
and then what we were able to do then is to take a look
and compare the parents to the children and anything
that was present in the children that was not present
in the parents was either a mistake or a de novo mutation
and the second thing that we were able to do is then
to compare affected children to their unaffected siblings.
So a beautifully controlled experiment that allows us
to ask the same question again that Jonathan Sebat
and Mike Wiggler asked.
I wanna give you two other kind of senses about why
de novo mutation can be so powerful to the extent
that it contributes to disease.
The first is that I've already told you that there
are about 30 million differences between you
and the person sitting next to you so you can think
about that as a forest of genetic variation and, in fact,
with de novo mutation,
I love this picture because it really represents
about one de novo mutation per generation
in the human genome so out of,
in a section of that, that codes for genes.
So it gives you very strong signal-to-noise properties.
You can really identify where that is
and you're counting to very low numbers and since I,
like Jay apparently, am mathematically challenged,
counting to one is something that we've been able to do
in the laboratory.
(audience laughs)
Now the second think is that this is a big, a large area,
this forest and we have very few events
so we could also leverage an approach
to statistical analysis that allowed us really
to just ask the question,
if we saw kind of de novo mutations per particular spot
in the genome,
if we looked at an unrelated child,
could we see lightning striking twice?
So we put those two things together.
This good signal-to-noise ratio and this idea of recurrence
of these very rare spontaneous events in order
to identify genes contributing to ASD.
One of the first findings that we published in 2011,
first replicated what Jonathan Sebat and Mike Wigler
had done with about 10 times the sample size,
which was an enormous relief, I imagine,
to the entire field given that psychiatric genetics
had spent many years as I said arguing with each other
about why we could not replicate.
So replication was kind of a pop the cork moment
but this finding in particular, in addition to that,
we were able to identify a new small region of the genome
contributing to ASD, Autism Spectrum Disorders,
and that was on chromosome 7
and we found that if you had an extra copy
of the small number of genes within this chromosomal region,
there are about 25 that reside there,
that you would have classically defined autism
and look very much like the child that I showed you
in the first video.
We also knew though that there was another syndrome
that had previously been described that was the consequence
of the loss of exactly the same gene.
So autism, there were additional copies,
and in this case, there was a loss
and I'm gonna show you another video.
Here we do need sound.
- Hello, buddy.
How are you?
- I really watch you on ABC news.
- Oh, thank you.
Thank you.
- What's your favorite color
and what's your favorite TV show?
- [Narrator] Kids love to ask questions but not as much
as these kids.
- My favorite color is blue.
I have met Barney the Dinosaur.
(group cheers)
- Where do you live?
- I live in New York City.
- [Male] Do you have any sons or daughters?
- I do.
I have two daughters and a son.
- [Male] Wow!
- [Narrator] And kids love to make friends
but not like these kids.
- [Male] What nationality are you?
- I'm Italian.
- [Male] Ciao to you, buddy.
- So that is William Syndrome.
Fascinating syndrome.
We could spend the rest of the talk here
and probably several others telling you
about how interesting that syndrome is
but for the sake of this talk,
what I wanted to point out is that, again,
you don't need any clinical training to see
the profound differences and interest in social relations
in affiliation in this group of kids versus kind
of the example that I gave you of the first child
where the core deficit is a failure
of that reciprocal social communication.
So when you think about this,
so what we laid out was a hypothesis that you could go
from a complex behavioral phenotype,
go to the genome and then work your way back
and I think it would be reasonable to be skeptical about.
That's a long distance between a change and a small section
of the genome going through molecules, cells, circuits,
behavior and brain and invoking additional things
like environment and experience
but this gave us, I think, a shot in the arm about thinking
that at least in some cases,
this was a viable approach
because if you do the thought experiment,
if we could understand what it was about these 25 genes
in the genome or the subset of them
that we're contributing to this difference,
that you're looking at a powerful rheostat of something
as complex as social affiliation.
As genomic tools advance,
we're able to move from looking at segments of the genome,
this fine structure of chromosomes,
to do the same experiments again at much higher resolution,
now to the single letter of the genetic code
in all the genes of the genome simultaneously
and what you're looking at here is a summary from 2015
that's giving you now a picture of all of the reliable genes
that we've been able to identify that are contributing
to autism spectrum disorders,
again with a substantial portion of these conferring many,
many fold increases in risk.
They're individually rare in people but in the person
that they exist,
they are having profound biological effects.
This is Stephan Sanders on the right.
He was a post doc at the time in the lab,
now a junior faculty at UCSF,
brilliant young guy who led several of the studies
that led to this kind of summary statement
that includes not only our work but work of laboratories
around the world that have replicated both
the initial observations around de novo mutations
as well as the specific gene shown here.
So where does that leave us?
Now, we've gone from a situation where,
at least for the first 15 years of my career,
it was like wandering in the desert.
I would've given anything to find a single gene
associated with autism spectrum disorder that I felt
I knew reliably and now we have a series of genes.
There are 60 genes that were represented in that picture
as well as a number of chromosomal segments.
So, and that reflects only a small number of the genes
that we now predict are going to be found
that can contribute to autism spectrum disorders.
This is a version of a diagram actually that we put together
with Pat Levitt before the advances that I've described
for you because they have been fairly recent
and at the time was aspirational but has turned out to be
actually I think a pretty good representation of sort of
where we are and where we're heading.
So the diagram is supposed to show the same kind
of progression where we have genes and there are many
of them distributed across the genome that then underlie
some biology and we hypothesized before we found the genes
that they would not be randomly associated but,
in fact, would point us to specific biological processes
and that has turned out to be the case.
One of the strongest signals that we have
is that these mutations preferentially target genes
that are involved in synaptic formation and function.
There are other broad areas of biology but it's turned out,
you've heard all day about the importance of synapses
and it turns out that they are quite important
for autism as well.
That somehow that's mediated through the developing brain,
this is a picture of the brain developing in a circle
from embryo all the way to the adult brain.
Just to remind you that while we found some biology,
that that biology's being expressed across development
in the brain and that we don't go directly from genes
to behavior and that we know that we're now
about to find genes that dramatically increase
the risk for autism.
There's some additional complexities here and one of them
that we found right off the bat
is that while we were finding genes
that were very reliably associated with
a dramatically increased risk for autism,
our colleagues studying intellectual disability, epilepsy,
and schizophrenia were finding some
of the exact same regions of the genome.
So this presents an important but I think
a not only challenging but optimistic kind of concept
because you've heard about this notion
of the potential plasticity and what this tells us
is that even if you have a gene that it profoundly increases
the risk for autism,
that for some people, you see nothing for the first 15,
18 years of life suggesting that genes are not fate
even ones that carry large risk but somehow that all
the things that we're talking about today could potentially
be important in determining how these play out over time
and this diagram shows at the bottom there that there
are a variety of things that you could hypothesize
might be involved in that,
epigenetics involvement of the kind
of cellular molecular environment,
other kind of genetic variance that have smaller effect
but help dictate how these large genetic risks play out
and potentially for some individuals' luck
but it does also open up this notion
of potential plasticity.
Something I also, that Mark did a beautiful job
of laying out the three hypotheses about the development
of neurodevelopmental disorders,
the pessimistic one and the optimistic one,
and I think it's important to keep that in mind,
particularly in autism,
something where there's a large genetic complement
and you see this playing out in very life.
It is also the case that despite the fact that we are not
anywhere near satisfied with the treatments
that we're able to provide,
that kids do improve with early intervention.
Again, I think pointing to the fact that genes
are not fate and that beginning to use this body
of knowledge to understand how this genetic risk plays out
over time leading either to multiple disorders or not
or improving over time is something that is quite important.
So I think where we end is that,
this talk at least but hopefully not in the field (laughs),
is that on the left side of the diagram,
we now have made significant progress not only
in understanding the genetic substrate
but beginning to define what the biological processes
are and many labs using the kinds of tools
that you heard about all day today are now beginning
to place in a developmental context to understand
the timing of the genetic risk and how that's playing out.
I think that leads to, we hope,
the substrate to begin to attack these problems in the way
that you've been hearing all day that we're attacking
other complex disorders where the underlying biology
has been more clear than it's been for complex
neuropsychiatric disorders and so I want to end by,
as with everyone else, you know,
I get to stand up and give the talk and have a list
of people who did all the heavy lifting
and particularly want to point to Stephan Sanders
for the remarkable work that he's done on gene discovery
and my collaborators really around the country
who've made this work possible
and can't end without also thanking not only the funders
but most importantly the families that contributed
to the Simons Simplex collection that we were able
to study so productively for the last decade or so.
Thanks very much.
(audience applause)
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