Textbooks have always lied to us about what neurons are.
The human brain is the most complex structure
in the known universe.
And we are in the middle of a scientific revolution
to understand its inner workings.
Join us for a conversation
with world renowned neuroscientists
as they visit Rochester.
I am Dr. John Foxe, director of the Del Monte Institute
for Neuroscience at the University of Rochester.
And you are listening to Neuroscience Perspectives.
So Jeffrey Matlas, it's great to have you here in Rochester.
I know you've been a repeat visitor
to the University of Rochester over the years.
So I have a few questions for you about your work
and your thoughts about the field and where we're going.
And I mean, let's kick off with stem cells.
When can a person out there with neurological disease,
when do you think we'll be at a point
where stem cells will be transfected
or inserted into the brain
and be providing effective therapy?
For the general audience,
we'll take this opportunity
to do a little bit of education that I think.
I think the very term stem cell in the nervous system
has been misused to great loss and confusion
because those of us in the field from the mid late 90s,
when progenitors were identified in the nervous system
used to call them progenitors.
And we call them by where they are
of what molecular origin they are,
of what neuron types they can become
or glial types they can become.
And then there's this totally parallel field
of embryonic stem cell and IPS stem cell biology.
And I think it's only been because of companies
and intellectual property,
and frankly, a lot of bad behaviors in the field
where the very term stem cell is thought to be
by the general public, a thing.
So I'll declare right now, there is no such thing.
It's not a thing.
It's a range of things.
It's like, it would be the equivalent of going to a doctor
and saying, my friend had his cancer treated
with liquid nitrogen.
And that would be true on the scalp
by the dermatologist of a dermatologic cancer.
And then ask if their lung cancer or colon cancer
couldn't be treated since it's cancer after all.
So I think that imprecision has been purposefully used
to mislead.
That said, I think there's a huge amount
of developmentally guided biology
by which many of us in the field
are learning the molecular pathways
that build individual neuron types or astrogalel types
or oligodendrogalel types of the brain.
So I would say for certain human illnesses
in which a specific cell type might want to be replaced
and in which a couple of decades
of precise developmental knowledge has advanced
to the point where one can now try to make
that kind of cell type, that one could do that.
And that I'd say we already know that hematopoietic
stem cells can repopulate the blood system.
But we have no such thing in the nervous system.
Hematopoietic stem cells are those that can make
all the lineages and that can engraft in bone marrow.
And in the nervous system, we have no such thing
as a stem cell that can make all the nervous system lineages.
So all of those clinics in Mexico and the Caribbean
and other places that I won't mention
that promise the therapy that you offered
of putting a stem cell in the nervous system
to treat something, either are performing,
and I'm not gonna use this term,
but as many of my colleagues term charlatans,
or we're talking about those stem cells performing
things like immune functions.
Because there's no way to think of an undifferentiated cell
just being placed in the nervous system
and knowing what it should become.
Knowing what it should become.
You know, when I'm out of my travels around the country
and talking to people, particularly we were talking,
you and I, about autism spectrum disorder and that,
and the number of parents and caregivers
who are being drawn into this, who are looking for hope
and being provided very unrealistic answers.
And it's important that there's a corrective.
Now I'll give you the optimistic answer.
The optimistic answer is within certain human illnesses
where pathology of a single cell type at a time
is so centrally causal that even partial reversal of that
could bring huge, immense impact to humans.
I think stem cell biology is going to be
exceptionally important.
But those illnesses, for example,
are gonna be very difficult.
They're gonna range from illnesses where demyelination
happens and there's not simply a dysregulation
of the myelinating cells already in the brain.
Because we know there are already progenitors.
There are already oligodendroglio progenitor stem cells
in the nervous system.
So we're gonna have to find out if those guys
are not operating right, then one might bring in
oligodendroglio progenitors or stem cells
that are functioning correctly to be therapeutic.
Same thing with astroglia.
And in the nervous, in the neuron systems,
I think for disorders like spinal cord injury,
where it's not replacement of some kind of spinal cord
tissue, but rather it's connections from the cerebral cortex
to the spinal cord or from sensory system up,
one might imagine very careful cellular engineering
to build new developmental embryonic-like neurons
that will grow past lesions and provide recovery.
That all said, I think what many clinics
around the world are doing in the orthopedic,
rheumatologic, cerebral palsy nervous system
in certain countries is setting back
that progress by decades.
Right, because failure, because of failures to really.
Well, it's not just failure.
I think it's no rational basis.
And by using this confusing term of saying stem cells
rather than we are using carefully designed
progenitor derived cells to do X,
there's almost like the Wild West of snake oil
and cure-all disease potions.
You and I are too young to remember that in the 1920s,
radiothor, radiation was claimed to cure all ills.
Right, right.
I'm gonna read, I quote, I read of yours.
It'll get us into some of the work
that your lab is directly famous for really.
And you were talking about neurons,
it's like a federal system with both central
and independent local government
when you're talking about the growth cone.
Can you help people understand that distinction
between the cell body and its emanations?
The idea is where the motivating truths are
that textbooks have always lied to us
about what neurons are.
And they will show a cell in the kidney
as my hand with its nucleus and its membrane,
and it's that big.
And then they'll show a neuron with its nucleus
and its membrane, and then I'll say,
and that's the axon and that's its synapse.
But that's not true at all.
If a neuron had a cell body the size of my hand,
its axon would be the size of my pinky in diameter
and would extend that same cell
on the order of two to three to seven to 10 kilometers.
So one and a half to three to five or six miles
with precision and would find a target with accuracy
of our two chairs talking to each other.
And that's extraordinary.
And it's never been at all clear
how the control center nucleus of such a neuron
can actually control things
that are happening that far away.
And it turns out we know a lot about neurons
over the last 30 or 40 years,
the fastest signaling method
for the tip of this growing pinky
two miles down the road with precision
would be almost like an old stagecoach.
And it would take between eight and 15 hours
in each direction to signal back.
Well, I've gotten to this sign post eight hours later,
what do I do?
And then eight hours later, turn left.
And that doesn't work.
So the work that you're alluding to
has taken an approach of asking
now that there are extremely powerful methods
in molecular biology to look at every coding RNA
or non-coding RNA molecule and every protein,
we asked what is the actual molecular machinery
out at those growing tips compared to the same cell.
And neurons have long been viewed like that kidney cell.
It's one cell, it does a thing.
But in fact, what we found is that
what we term subcellular compartments
have entirely independent control mechanisms
as if they're their own operating cell.
They have not just a subset of what's happening back
in my hand, but things that you don't even see back
in my hand.
And I actually liken these things more to NASA
designing deep space satellites
that are going out past the solar system or into the sun.
And they have to go out and be pretty autonomous.
They can't radio back.
Turns out from Pluto, it takes about eight to 15 hours
for radio signals.
It's a remarkable coincidence.
So these things appear to be one cell
functioning without a single command structure,
but rather for decisions based on local context
and local needs for decision-making,
if that makes sense to your question.
I think that was an absolutely elegant explanation.
That was really wonderful.
Let me switch gears a little bit.
Maybe I can add in. Please.
To connect to you, who's a world expert in autism
and intellectual disability and abnormalities
of the human intellect developing brain.
It turns out that if we think about all of these
disabilities, you and I know that there is evidence
in different subgroups of humans
for not only misrouting circuit abnormalities,
but as your work has shown,
dysfunction of the actual computations at synapses.
Well, the growing ends of those axons,
now I'm gonna blow up as if we're going
in a big microscope.
Now, if my body is the cell body,
my axon would be the size of my arm,
six feet more or less and six inches.
And this would then go 20 to 30 to 50 to 70 kilometers.
It would take me beyond Canandaigua.
I don't know where that would take me.
It's pretty close to Buffalo.
Oh, so close to Buffalo.
And that's quite remarkable.
But at the end of my growing axon,
making all the decisions to turn on the whatever it is,
the 490 and then on the this and then on route 90
and then it will then transition and develop into synapses.
So everything I just told you about,
I think of not just about building the circuits,
but that means the decisions of whether I'm going to be
bolted with steel or with Velcro so I can be plastic
and learn to change are all coded
in the subcellular organelles of neurons.
And that means that subtle dysfunction of those mechanisms
might account for what goes wrong
and the relatively subtle dysfunctions of humans
with certain forms of social behavioral
autism spectrum disorders.
And if that was just a speculation, it would be one thing.
But if we look at most of the candidate genes,
guess what?
Many of them are actually differentially localized
with splice variants and various variant forms
between cell body and growth cones
now that we're looking at these things.
So I think this basic cell biology that you asked me about
is quite relevant to the immensely complicated
human biology of the brain.
I have a colleague in New York, Charlie Schroeder,
who obviously he always says this term,
he says, wiring is computation.
When it comes to the brain, exactly the routing
of the wiring systems is incredible,
massively complex system.
It's important that things end up
where they need to end up.
We start out life though as an infant
with massive over exuberance of neuronal development.
Is that part of the process?
So that we have, when we talk about pruning,
so we lose cells, it's because many of these things,
maybe there's an imprecision that's in the system
that can be tolerated because as long as most of the,
or substantial number of these neurons
end up where they're targeted so you can function.
So I'll give you two or three answers on that.
And I don't mean to be argumentative on this.
Please feel free to be argumentative.
But you and I grew up being taught that.
But I think over the last 20 years,
the evidence has become vanishingly small
for the two to one dying out.
In fact, one doesn't see that at all
during the development of cortex.
What one does see, and I think that those data
came from the 70s and 80s, where there were
fewer and fewer connection axons seen.
And there used to, I think, be a textbook view
that a neuron sends an axon.
But now it's increasingly clear,
and my lab was the first to discover these in rodents,
but they've been hinted about in
non-human primates and humans.
There are many neuron types that send from the same nucleus
and cell body two or three distinct axons
that precisely target different targets.
And then the question you ask, I think,
becomes really insightful and important.
And it's clear during development that many of them
will prune one of these axons.
And in fact, some of the human autism associated genes
we have identified are responsible for
inaccurate pruning of such axons.
So it's another version of your question,
but rather than it being, I think,
it's not just that we have so many extra cells,
it can be sloppy.
It's that the nervous system has even more elegantly evolved
to precisely pull back certain connections,
and when those are not pulled back,
or when they're pulled back too much,
that's, to your friend's point,
bad circuitry and bad computation.
Let's take a switch in direction here,
because one of the things,
noticing your extraordinary CV and all the prizes,
you're trained as a medical doctor, first and foremost,
and indeed you kept, is that correct?
Well, I don't know what first and foremost means.
I was trained in science, and I have an MD,
and I'm fully trained as a neurologist, and as a scientist.
I was in a combined medical school, graduate school program
at Harvard and MIT, and I expected to have a dual career
in the Boston, New York, Baltimore,
San Francisco style of 90-10,
and I have not seen patients for many years.
That's my question.
Right, so, I mean, because this is quite a tension, I think,
for many, there'll be trainees, MD, PhDs,
we train a lot of people with MDs and PhDs
who spend a large chunk of their career
then really feeling these two things
in somewhat in competition.
Was that your experience?
And when did you make the decision
to be completely in basic science?
Well, so I'm gonna push back on that.
We're doing this in a friendly way,
only because I like to be provocative on these things.
I don't find binary choices
as illustrative as gradation.
So my view is that my lab is large enough
that some folks are thinking about the questions
we were just discussing as the basic building
of this amazing processing unit, the brain,
its organization, its cellular structure,
its molecular development and function,
but all of them are also interested in the fact
that leads to insights into neurodegenerative disease,
ALS in particular, the regeneration of spinal cord injury,
autism and intellectual disabilities.
So to me, my clinical training,
though I took care of patients as a primary, secondary
and tertiary neurologist for, well, altogether,
including residency about 15 years,
I still think about patients centrally.
And what I'm struck by is that so many folks
see the two as distinct.
So I have a new form of translation for them.
My form of translation is to say that all the time
that I spent with patients understanding human biology,
some people who call themselves basic scientists, whatever,
I did a second postdoc in the neuropharmacology drugs,
neurobehavior, neuroanatomy, pathobiology, circuit biology
of non-non-human primates.
So for those out there, that would mean humans.
So I think actually understanding what happens
in human disease and knowing which systems
and which neurons and which pathologies happen,
which don't actually enable in many ways a deeper insight
that we've been able to take to attack fundamental problems
of molecular and cellular neuroscience.
But to me, it was not a switch anymore than someone
who was an attorney, because they went to law school
and were in a firm and are now being a judge.
That's not a switch.
That's a different form of the same field.
And I always wanted to understand
why do humans get these remarkable diseases?
And when I first asked in about 1983 as a graduate student,
why are these genes being discovered that are mutant
in every cell in the body and in every neuron in the brain?
And why do only two neuron types die in this disease?
Professor, all the professors would say,
and they still do today, we don't have the foggiest idea.
And I thought that that was a problem.
So I set a career goal of defogging that problem,
which I think might bring us right back to patients,
which is the career goal for the rest of my career.
So a medic at heart, basic science is not,
you just don't see them as a distinction there at all.
I think if we go back a century,
Santiago Ramon y Cajal, who discovered about 95%
of what we know in the nervous system,
was originally trained, not even as a physician,
because that was a higher form, but as a surgeon,
sent off to Cuba as a military surgeon,
came back retrained as a physician.
What does that mean?
He wasn't a keen scientist?
My mentors at Harvard Medical School,
Torsten Wiesel and David Hubel,
were trained as physicians.
I think their Nobel Prize discovering
the understanding of computation in the cerebral cortex
was not to that deficit.
So I actually find that the reason I'm giving you
such a long answer is I find within our progressive world
of science, the siloing and almost xenophobia
between the two.
Now to get to your point more pointedly,
I don't think it's an easy decision for students
deciding whether they should train duly as physician
scientists or not.
And I think too many don't have that clarity
of what that means and end up doing one or the other,
but not both.
And if it hasn't actually benefited the one they do,
it's unclear whether the training has been fully worthwhile.
But when it does, I don't think it gets measured
on the axes that you laid out, if that makes sense.
I think some of my very clinically focused
hematology oncology colleagues who are deeply
scientifically trained think about cell cycle dynamics
and how to disrupt cancers in elegant ways
that are not cookie cutter recipes.
And some of my colleagues who are working purely
on fly visual system, ask questions that will inform
what they know from their medical training
about the human visual system.
So, but I'm a troublemaker.
The field needs troublemakers, people to start up
and ask the tough questions and call out the nonsense
where you see it and issue correctives
and then if we can't rely on people like you to do that,
we're lost, I think.
The nicer answer to your question is,
I think there are ranges of people who work
across all kinds of levels.
And in many ways, a deeply scientifically trained
physician scientist can be somebody who thinks
at a level of mammalian primate and human biology
with keen insights.
And that might be very diametrically opposed
to somebody who thinks about bacteria or worms or flies,
but that's a whole continuum that contributes
to how we ultimately think about human disease
and its treatment.
Right.
You're on the local bus going back into Rochester
to get a bit of dinner.
And you're talking to somebody who,
conversation strikes up with somebody
who doesn't know the scientific enterprise.
And they ask you, what on earth,
why are my tax dollars being spent to study
the life cycle of a fly, of a fruit fly,
or the sexual proclivities of a fruit fly?
What do you say?
How do you explain to somebody how important that is?
When I was growing up, and I'm not sure
if you and I grew up in the same place,
so I'm not sure if you heard the same jokester,
but there was a senator,
William Proxmire, who, when I was a tiny child,
I don't know why I remember this.
I was probably three or four, used to come on television
and give what he called the Golden Fleece Award
for things like you just described.
Why are we being fleeced as taxpayers
to study the asexual reproduction of treponemes,
worm or whatever?
And it turns out, those basic studies
of how bacteria replicate, or worms infect,
or flies modulate pheromones and sexual attraction
have led to countless thousands of human drugs
that now have children that used to die of leukemia live,
and people who used to die within two years
with certain neurodegenerative diseases live,
and people around the world having antimicrobials
that cure hookworms and tapeworms and malaria
and countless infections.
And it's that we as scientists, the work should be funded,
the public should know and want us to do
because it's to the benefit of the public and health.
There's a secondary benefit of discovery,
but I think that's not really the strongest driving force,
but I think it's in some ways the scientific system
that forces us to describe things in very technical ways
that our taxpaying public doesn't understand.
So it's our job to translate for people.
So when William Proxmire complained
about the asexual replication in helmets,
somebody should have said, or Senator Proxmire,
how hookworms infect 85% of children in tropical areas
from Mississippi and Georgia and Florida
down through the central Congo.
So it matters to all of us.
And maybe Proxmire would have said,
oh, now that you explained it to me, that's worthwhile.
So, Jeffrey, you know, the public have sort of a notion
of scientists beavering away in the lab,
maybe not eating, forgetting for a few days to eat.
Speak to this business of work-life balance.
Now, I happen to know that you were a really excellent
squash player before sports.
I was a mediocre competitive squash player.
But how do you keep the balance, the work-life balance?
Well, it depends on whether you ask me
or whether you ask my wife and our two children.
It might be imbalanced, but I think the public sometimes
was led astray by television shows
and movies of the 60s and 70s, 80s,
showing scientists of being some odd form.
But I garden, I move rocks around in the yard, I rake,
I ski, I work out every morning,
I've played multiple sports, even growing up in Pennsylvania,
the quintessential Pennsylvania sports
of football and wrestling.
So I think scientists can have balance in life.
I think a more pointed answer is,
my lab is my second family, we're quite active together,
we hike together, we ski together.
These kinds of activities often lead to the most informal
of brainstorming and of thinking
and are quite useful distractions
because scientists don't just go to a lab and pipette.
It's ultimately a creative discipline
or at least at the highest forums,
thinking of new ways to ask questions
and to sculpt the discovery of new knowledge.
Students out there working away in labs
and the neuroscience labs
and the cell and molecular biology labs
with their eye on the prize,
as somebody who's really had a fantastic career,
what's that one pearl of wisdom?
What do you say to them?
What's gonna get them through?
Yeah, so single pearls are always a problem for me.
We have one minute, you can do five.
But I think one might be to identify
not a problem right this moment
that you wanna attack that's important,
but what would give your entire career
in its inevitable arc meaning and importance
so that if you got there,
you would have felt fulfilled.
And to some of us, that has some sort of highfalutin
kinds of words like changing the world
or discovering things that will help large classes.
To some people, it might be equally important,
but to answer this question that's always been unknown.
And if you have that, I think the complexities of life
become just steps toward that fascinating goal.
And that might be toward human health,
toward the betterment of the world,
or maybe just discovering the subatomic forces
that explain black holes.
Just that.
I do think sometimes to describe that moment,
and all scientists who've been in the business
will know this, where you, for just a brief moment
when a discovery's been made in the lab,
you and your colleagues,
whoever happens to be there at that moment,
are the only people on the planet
to ever have known this piece of information.
It's rather an extraordinary thing.
The idea, of course, is to share it afterwards.
Thank you so much.
That was really fantastic.
Thank you very much.
Where you are connected.