October 25, 2024 • 32 mins
In this episode of Neuroscience Perspectives, we dive into the microscopic world of C. elegans—tiny roundworms that are revolutionizing our understanding of genetics and behavior. Join host John Foxe, PhD, director of the Del Monte Institute for Neuroscience at the University of Rochester as he chats with Doug Portman, PhD, the Donald M. Foster Professor of Biomedical Genetics, Biology, and Neuroscience, at URMC. Portman’s research unravels the intriguing ways that biological sex shapes neural development and influences behaviors, like the eternal quest for food versus the search for a mate.
Discover how these unassuming creatures serve as a powerful model for understanding complex questions about the brain. What happens in the male C. elegans brain when the urge to find a mate overrides the basic need to eat? And how can these insights inform our understanding of sex differences in human health and disease susceptibility?
Whether you’re a neuroscience enthusiast or just curious about how tiny organisms can help answer big questions—listen, learn, and subscribe to Neuroscience Perspectives today!
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:00):
You know, one of the big surprises of the genetic and genomic era is just how much of
(00:07):
our DNA is shared with all other animals, really.
It depends on how you do the math exactly, but something like half of the genes that
the worm uses are genes that we use too, right?
So we're something like half worm, if you like.
The basic building blocks are all there.
(00:36):
I'm John Foxe, Director of the Del Monte Institute for Neuroscience at the University of Rochester.
I'd like to welcome you to another episode of Neuroscience Perspectives.
Today I'm absolutely thrilled to be joined by one of our own here at the University of
Rochester, Dr. Doug Portman, who is the Donald M. Foster Professor of Biomedical Genetics,
Biology and Neuroscience here at our Medical Center.
(00:57):
He has also very recently elected a fellow of the American Association for the Advancement
of Science, and his lab uses C. elegans, microscopic roundworms, to study our understanding of
the genetic underpinnings of sex differences in neural development, behavior and disease
susceptibility.
He's also a renowned trainer of trainees here at Rochester, providing guidance and inspiration
(01:21):
to our fellows and to our students.
We'll get into all of that with him.
Doug, thank you so much for being here.
Oh, thanks, John.
It's a privilege and an honor, and I appreciate the invitation.
Well, listen, I was thinking about this, you know, you show up in an event, and somebody
says, what do you do?
I'm a geneticist, I'm a neuroscientist.
(01:44):
And then the next piece is going to land on eye work and worms.
And I'm sure every now and again you get one of those looks like, what?
So why worms?
Hit us with that.
Yeah, that's a good place to start.
C. elegans is an amazing model system that has provided numerous profound insights into
(02:06):
lots of different areas of modern biology.
There are a number of reasons why it's a very powerful system.
We can talk about some of those in detail if you'd like to.
I can talk about worms all day.
But I guess the quick answer to that is that worms allow us to approach important fundamental
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biological problems at a level where we can sort of view them from, I don't want to say
necessarily a reductionist perspective, but from a reduced perspective.
You know, as somebody who trained originally as a biochemist, my mind thinks, you know,
sort of bottom up.
And C. elegans in many ways is sort of the simplest instance of a creature that has extraordinary,
(02:53):
fascinating, beautiful biological complexity.
And so for me, that's the reason why we study it.
So in some ways, it's stripping away all the noise of complex, super complex creatures
like ourselves, our first cousin in the primate.
And I see our backdrop here has some of these.
Most people, they show the picture of their puppy or their cat.
(03:15):
These are your pets, right?
Absolutely.
I feel very close to these creatures.
But it's that simplicity of the organism and yet the behaviors are profoundly complex,
right?
Yeah.
In fact, I tend to shy away from the word simple because C. elegans is a simpler organism.
(03:38):
It's a reduced organism, but it's still extraordinarily complex.
And there are lots and lots of things that we are just in some ways fundamentally clueless
about in terms of the way it works.
So yes, behavior, the function of the nervous system, developmental programs, lots of aspects
of biology are extraordinarily complex, even in this sort of highly reduced context.
(04:00):
And for me, that makes it a great place to sort of start.
If we have any hope of understanding at a really high resolution level, how the human
brain works, how it integrates information and where our consciousness comes from.
If we can't understand how neural circuits work when we're talking about a few hundred
neurons, then there's a fundamental disconnect and we still have some work to do.
(04:23):
Yeah.
Yeah.
And just for the viewer out there, they say, well, what the hell is a worm to do with a
human?
But we have a lot of shared biology, right?
Oh, indeed.
And a lot of shared genomics or genetics.
That's right.
That's right.
And so one of the big surprises of the genetic and genomic era is just how much of our DNA
(04:46):
is shared with all other animals, really.
It depends on how you do the math exactly, but something like half of the genes that
the worm uses are genes that we use too, right?
So we're something like half worm, if you like.
The basic building blocks are all there.
And maybe they work in somewhat simplified ways.
(05:09):
But yeah, the same genes that specify the difference between our head and our, I was
going to say our tail, our feet during development work in a worm.
The same genes are involved in specifying, telling cells to become different from each
other during development.
They're very same genes.
Right.
Right.
(05:29):
Yeah.
In some ways, I think this is a concept that makes a lot of people a little bit uncomfortable,
right?
Because obviously there's been lots of controversy, but you know, we're all part of the same biological
chemistry.
And again, going back to that business of this tiny little creature that you can literally
see through and just how easy it is then are not easy.
Nothing's easy in our world, but how much easier it is to actually get a tractable question
(05:55):
about a specific gene and that.
That's right.
It brings me to two thoughts, actually.
One is you mentioned a few hundred neurons and I happen to know you trained with the
very eminent worm biologist, worm neuroscientist, Scott Emmons, who we both know very well.
Yes.
I'm, you know, Scott's really famous for literally mapping the entire neuronal network of the
(06:21):
C. elegans.
Can you tell us a little bit about that?
Tell us about your time with Scott and how that played into your career.
Yeah, well, I can say a bit about training with Scott, which was a wonderful experience.
And then I can also say a little bit about this, you know, the value of the mapping that
Scott and others have done and how it's sort of opened exciting new doors for the field.
So I decided to train with Scott because I came, you know, I came from a background,
(06:46):
as I mentioned before, I sort of trained as a biochemist and cell biologist.
At the University of Pennsylvania.
That's right.
That's right.
From undergrad and your graduate.
Exactly right.
From undergrad and graduate school.
And I, by the, you know, and I loved my time there.
I learned a tremendous amount.
I felt like I was able to do some good work.
(07:07):
But I got to a point where all of the experiments that I were doing were mixing things together
in test tubes and running gels and sort of, you know, doing things that were very, in
some ways, divorced from real biology.
And I wanted to get my hands on a living creature, you know, that, but a living creature in which
we could really, we really had the power to understand at this very basic mechanistic
(07:32):
level how genes and molecules work.
What is the function of those individual components that we can, you know, study in isolation?
But how do they work together to build an organism that develops?
So I decided that C. elegans was an ideal creature in which to do that.
And for personal reasons, I was interested in staying in the New York City area in the
Northeast.
(07:52):
And Scott became the sort of immediately most logical candidate to train with Scott, has
been in the worm fields really since its founding.
And there aren't very many people really who can say that anymore.
Scott has a tremendous perspective on the, you know, holistic perspective on the field
(08:13):
and understanding how it's, where it started, how it got to be where it is, who's contributed
what.
And it's really valuable for me in my training because it's given me a really solid foundation
in terms of just kind of understanding the system without necessarily diving immediately
into some little detail, but to be able to understand it at a holistic level.
(08:33):
And so Scott was really instrumental in kind of instilling that kind of a view, I think,
in me and all of us who worked with him.
Give us a number.
So I work mainly in humans.
Yeah.
And I'm stuck dealing with 70 to 100 billion neurons in this extraordinary connective mass.
(08:54):
Indeed.
Yes.
And so the, and of course that's, there's an intractability to the complexity of the
circuits that make up the human brain.
I shouldn't say intractability, but they're difficult to study.
Sure.
But the number is in the C. elegans?
Well, the number depends on which sex we're talking about.
In C. elegans, there are two sexes.
They're not male and female.
They're male and hermaphrodite.
So the C. elegans, essentially the female has learned this little parlor trick over evolution
(09:18):
of being able to make its own self sperm.
So it's a self fertile female, if you like, but we call it a hermaphrodite.
For many years, we've known that the hermaphrodite, the adult hermaphrodite has exactly 302 neurons.
302 neurons.
The male has somewhat more than that.
The number is about 395.
The you know, you alluded to the connectome before.
One of the initial visions for C. elegans when it was first being established as a model
(09:44):
system in the late 60s and early 70s by the great late Sidney Brenner was that there he
could imagine that in a system like this that you might have the opportunity to really get
a level of anatomical description of the nervous system that's unparalleled in any other system,
to identify every single cell and not only that, to understand how they connect to each
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other.
Neuron in isolation doesn't do very much.
The brain works as you alluded to because neurons are connected into circuits that can
do all kinds of amazing things.
And so actually there was this initial feeling that once the field, if the field were able
to do this thing, which at the time was a tremendously daunting task of identifying
all those cells and identifying all the synaptic connections between them, that the answer
(10:34):
would fall out, that we would understand how it works, that the structure would lead immediately
to an aha moment.
Exactly, exactly.
To this eureka, I see, I get it.
Now it all makes sense.
And unfortunately, something like the opposite happens.
So the hermaphrodite, we call this the connectome, right?
The wiring diagram of the entire nervous system.
(10:54):
The connectome of the adult hermaphrodite was an arduous task led by John White at the
MRC, done mostly in the mid 80s.
So we've had that information for quite a while.
And I think one of the really astounding things about that is that it's a tremendously valuable
tool, but in itself, the structure of the nervous system is not sufficient to tell you
(11:20):
about its function.
And so that has been, the field has been struggling with that ever since.
Maybe a good thing in terms of like if this eureka moment came, we'd all be out of business.
That could be true.
And so an important advance in that field has been, you mentioned Scott Emmons' role
in this.
(11:40):
Scott was the first to really decide to tackle the nervous system of the adult male.
And after the adult hermaphrodite had been finished in the 1980s, it was a tremendous
task and they sort of breathed a big sigh and said, we're not doing that again.
And it wasn't until there were some technological developments, and also Scott just had the
(12:01):
patience and the fortitude and the drive to get it done.
And over the past 10 years has spearheaded the effort to drive the connectome of the
adult male.
And now because of additional technological advances, we have multiple connectomes.
We have connectomes for multiple developmental states, multiple individuals of both sexes.
But we're still stuck at this place where having the connectome itself is a really valuable
(12:25):
foundation, but it doesn't in itself tell us how behavior works.
And it gives you that ability then, right?
You should mention that all of this work was done in the Bronx, in New York, at Albert
Einstein College of Medicine, placed near and dear to both of our hearts.
But having that wiring diagram so precisely mapped then allows you to focus in on a neuron
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or a cluster of neurons and really ask very specific mechanistic questions about what
this piece of the circuit or that piece of the circuit does, and that has a level of
tractability in a creature with 390 neurons that it's just utterly impossible in almost
every other species, right?
Yeah, that's right.
I mean, I think of that in a sense you can divide that up into two overlapping halves.
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One is how does information in the genome specify the identities of all those neurons
and specify their ability to wire up into circuits?
And then how do those circuits do what they do, right?
How do they take in and integrate and process information and choose to make a decision
about executing a behavior, and then how does that behavior actually get executed?
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And we can approach those questions at the level of single neurons, single synapses,
single genes in a way that has not been possible really in any other system.
Right, right.
It's absolutely extraordinary.
Coming to some of the specifics of your work, you're very interested in this issue of sex
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differentiation and you have these two sexes, a male and a hermaphrodite, and the programming
of these genes can really lead to very different types of behavior in terms of feeding versus
mating and so on.
Tell us a little bit about that and what you've learned and the kinds of systems that those
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urges or desires rely on.
Yeah, yeah, sure.
So right, we've been interested in trying to use biological sex as an entry point to
understand sort of where there are points of plasticity in the development and function
of the nervous system that can lead to adaptive differences in behavior.
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And so one, because of this extraordinarily high level of resolution with which we understand
the structure of the C. elegans nervous system, we know exactly what those sex differences
look like.
We know that each sex has its own set of sex specific neurons and sex specific circuits
that are dedicated to purely sex specific behaviors.
(15:03):
Hermaphrodites have to lay eggs, males don't, males don't have eggs, right?
And so there's a dedicated circuit in hermaphrodites that controls egg laying behavior.
There's a dedicated circuit in males that controls courtship or mating behavior, which
is a behavior that hermaphrodites don't do.
What my lab has been interested in is a discovery that came out of a serendipitous observation
(15:26):
actually when I was first starting the lab here in Rochester that led us to wonder about
what about the rest of the nervous system?
294, exactly 294 neurons are shared between both sexes.
And that means they're linearly, anatomically, morphologically essentially equivalent, right?
So most of the worm's brain is the same as it is in most species.
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And yet what we found is that those shared circuits can be tuned in different ways to
allow animals to prioritize differently among shared behaviors or to execute those shared
behaviors in different ways.
So that the features of those behaviors lead to differential outcomes.
So an example of this is that often hermaphrodites will tend to prioritize feeding behavior because
(16:14):
for hermaphrodite, fertilizing your own oocytes and producing progeny is an important part
of your life.
For a male, males need to find mates.
And so males will often sacrifice their ability to feed and go out and search for hermaphrodites,
often abandoning a food source to do so.
And so those aren't sex-specific behaviors necessarily.
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They're just really differential modulation of feeding and exploration.
Both sexes can do that.
And so we're interested in finding the knobs and dials that evolution has engineered that
permit the sexes to do those different kinds of things.
So that the male biases towards looking for a mate at the expense of feeding.
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And essentially the risk ratio there is quite different, right?
And the risk, it's maybe a proxy for risk taking in a worm.
In fact, we do sometimes think of it that way, that males are a bit less risk averse
than hermaphrodites are.
So some of the things that we've been doing in the lab recently is trying to ask questions
like how willing is a male going to be to cross an aversive barrier or something that
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tastes terrible or is toxic compared to a hermaphrodite?
And does that differ depending on whether an animal is hungry or not or whether it's
mated recently or not?
And if those, we have some instances where it seems like there are some interesting things
going on there.
And then we can go in and ask where in the nervous system are things being modulated
to bring about those outcomes.
(17:43):
Amazing, right?
A few hundred neurons, 80 billion neurons, very, very similar behavior.
Yeah, absolutely.
It's extraordinary.
And remind me now, maybe I'm wrong about this, but actually quite a lot of this relies on
the chemo sensory system, right?
The smell system and that you see these changes in genes coding for smell that actually change
(18:07):
risk taking behaviors.
Yeah.
If I could put it that way.
Right, and that I think is one of the most interesting and unexpected things that we've
found in the lab.
When we started this work, I guess my intuition about scientific problems is often completely
wrong, and this is a good example of that.
We imagined that the way that animals were going to be prioritizing different behaviors
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differently according to their internal and external needs and signals, the way that would
work, at least naively to me, I would imagine that evolution would design an animal so that
it can gather as much information as possible about its world, and then fancy things happen
in neural circuits, inputs get weighed, and essentially a decision gets made about what
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to do.
And so according to that, we expected to find that the sex differences would be in neurons
that are a few layers deep in the system, in interneurons that are integrating information.
We might find that maybe one input is a little bit stronger in a male, or a particular neuron
is modulated differently to bring about a different behavioral outcome.
(19:14):
And I think that probably is happening, but we haven't really found any good examples
of that.
Instead, what we've found is that the way evolution has engineered in the ability for
animals to behave differently is by front loading it at the very sort of the entry points
of the nervous system, the sensory system, and in particular, the chemo sensory system.
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Chemo sensory behavior, smell and taste, are essential to a worm.
They can't see, they can feel a little bit, but really their primary mode of gathering
information about their world is smell and taste.
Does this taste like something I should eat?
Should I run away from this?
Is it toxic?
Is it a predator?
Is it potential meat?
And so there are chemical signatures for all of those things.
And the worm sensory system has specialized sensory neurons and receptors, individual
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proteins within those neurons that detect all of those stimuli.
And what we found is that the expression of those receptors that detect those stimuli
can themselves be changed by biological sex and also by things like feeding status.
So for example, an adult male, one reason that it's able to leave food is simply because
a food receptor that detects the presence of food is down regulated in the male.
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So males just don't smell food as well as hermaphrodites do, but they smell sex pheromone
much better than hermaphrodites do.
And so rather than gathering all the information that you can and making a decision, evolution
has sort of decided, forces the worm to pay attention to what it has decided is the most
salient cue for it at that, according to that time and stage in its life, which I find fascinating.
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Absolutely astounding.
It reminds me actually of, you're talking about evolution as this force, which of course
it is over time, but a lot of it was Stephen Jay Gould, he used to talk about not adaptive,
but ex-aptive functions.
This idea that random stuff happens in the genome, like down regulation of a chemo sensory
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receptor.
And then those few worms that have that down regulation are more likely to drift away from
food and they're going to be more successful in identifying mates and it's just happenstance.
But then that of course becomes re-asphied in the genome.
I mean, it's extraordinary.
Really beautiful examples of that.
We'll switch gears a little bit.
(21:31):
We'll stop geeking out about the worm just for a moment.
You know, you and I have known each other best part of a decade now.
And I know some of our earliest conversations were around students and trainees, because
at the time you were really helping direct our graduate program.
And I think I have a couple of questions for you.
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You are an extremely dedicated mentor and very involved in the student body.
I'd like to know about your motivations there.
And then I'd also like to ask as an addendum, have you seen change and is that change for
the better over the last decade or so in the makeup of our classes, in the way in which
we're approaching the academic efforts, the recruitment?
(22:16):
Yeah.
That second question is a tricky one.
The first one is a bit easier for me.
My motivation, right?
I find interacting with trainees to be one of the, if not the most rewarding part of
doing academic science.
We get to interact with bright, young, energetic, creative people all the time.
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And for me, that's a tonic.
It keeps me from getting old.
And so I find it really gratifying to see a student come in, like many students coming
into a PhD program, maybe somewhat unsure of themselves or what they're interested,
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not sure if they're really up for this thing that they've signed up for, and then thrive
and really just blossom and go on to do fantastic things.
And so playing some small role in that is an honor and a privilege.
So that really is what drives my interest in mentoring.
I think you raise a really interesting point that I think graduate school, graduate training
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has changed, certainly since you and I did it.
But even over the last 10 years, I think there are a number of reasons for that.
One that I think about a lot is that the amount of things that a student has to learn in order
to master a field has grown exponentially.
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When we, I don't know about you, I remember being in grad school and being overwhelmed
by the literature.
How can I possibly master all this?
Small fraction of what it is.
Tiny fraction, right.
It's a tiny fraction.
And so now students will come in and I don't even know where to start sometimes in terms
of getting them up to speed, not only on our field, but on a field that is essential as
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a scientist to know about other things.
So that you can find those connections.
That's right.
There's a massive intersectionality now.
Absolutely.
In the old days, you could learn microscopy around this system and that's what you did
for most of your career.
There's no way to be that specialized today.
Yeah, well, I think you can look at this in different ways.
Sometimes I get concerned that students become hyper specialized too quickly because the
(24:31):
frontier of, by its nature, as science advances, we drill down deeper and deeper into these
sort of veins of gold that we've found until you find yourself sort of at the bottom and
you can hardly see up again.
And I think it's really easy to fall into that and not be able to step back out and
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understand why did you go down that vein in the first place?
What was the point of studying that and how is it connected to all of these other things?
And I think exciting advances in science so often come from interdisciplinary kinds of
thinking.
People, some of us are lucky enough to have had the opportunity to train in multiple fields
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or have interests in multiple fields and be able to see those connections, but also just
to be able to interact with people regularly whose perspectives and whose background are
a bit different than yours, I think is tremendously stimulating.
And we need to foster that in the next generation of scientists.
And I get concerned sometimes that we focus so much on you need to learn your field, you
(25:36):
need to focus on doing your experiments, that we don't give students enough time to step
back and think about the bigger picture and understand why they're studying what they're
studying.
We're not, we all study our own individual little problems, but we're not, ultimately
we shouldn't be studying them for their own sake.
We should be studying them because they're a critical piece in this larger puzzle.
(25:56):
If you don't understand, you can't see the larger puzzle, you're lost.
Right, right, right.
That's very well put, yeah.
Talk to me, so if you don't mind me getting a little personal, we've had a huge drive
here at Rochester, but I know most of the big, great institutions in the country have
already worked hard on diversifying the student body, diversifying the faculty body and that.
(26:21):
And you're from a minoritized community in the LGBTQ world and that.
How has that played into your career?
What have been the challenges?
What would you say to a young LGBTQ person coming into the field today?
What are the minefields?
What are the advantages?
Yeah, great question.
I feel really privileged and fortunate to have always had training experiences.
(26:46):
In my training, I was always in very supportive environments.
I've been out and had a partner since I was in college.
So being out in grad school in the early 90s, that was a different time.
And in fact, it was unusual to encounter another person from the LGBTQ community in science
(27:11):
or certainly a person who was sort of out and open about their situation.
It's tremendously gratifying to have seen that change so much, right?
We have an abundance of trainees in our programs here in Rochester who make up this beautiful
(27:33):
diverse spectrum of people in the LGBTQ plus communities.
But I guess I would say that still we do know that LGBTQ people tend to shy away from careers
in STEM a bit more than their counterparts.
And they also tend to sadly drop out of their training more commonly than people from other
(27:58):
groups.
What's driving that?
What's the root cause there?
I don't know the answer to that.
I think that our job as...
I think the answer is going to be complicated.
Probably there are a lot of case by case issues.
But I think ultimately what we have to do is realize that our job as educators is to
(28:19):
help everyone reach their potential and be the best scientist they can.
And that means welcoming and supporting and including all kinds of people, and even if
we don't understand necessarily what we're going through, what they're going through,
simply to provide that message that we're there and we understand that they may be facing
(28:41):
special challenges and we want to help them.
And that we would hate to see somebody leave science for a reason that is ultimately maybe
not the best choice for that person's future.
Going back to in the 1990s and you're starting out on your scientific career, could you look
(29:04):
to people in the field?
I mean, I just think about this walking in the shoes, right?
Could you look and say, oh, there's a successful person like me?
Or that was...
No.
Yeah, right.
So is that a key component here?
Well, so let me say there's a big qualification to my know because that did change at a certain
stage in my career, but I think back to when I was an undergrad and I was very involved
(29:26):
in the LGBTQ student group at the time in college, but it was a different world, right?
People's views on gay people and the place of gay people in society was so different.
We had Anita Bryan out there, you know, preaching homophobic messages that were resonating with
(29:49):
and lots of other things like that.
I remember having...
It hasn't stopped.
No, it certainly hasn't stopped.
And for a number of unfortunate reasons, many of those voices have become amplified recently.
But I remember very clearly being in college, being a senior in college in my biochemistry
senior seminar and the professor, we were talking about fruit fly genetics and there's
(30:13):
an interesting fruit fly mutant where the males don't court.
And it's called fruitless.
And I remember the professor making a homophobic joke about the sexual behavior of fruit flies
and everybody in the class laughs and nobody at that time would have thought about raising
a ruckus.
Yeah, like that was just like, oh, ha ha ha.
(30:37):
So that...
And that hits home though when you're sitting there as a gay person, of course.
Right.
It says to me, like, is this, you know, do I belong here?
It really makes you sort of question what your role is, what your potential is.
So I mentioned there was a big asterisk.
So my graduate school training was great.
(30:58):
There was a fellow person from the LGBTQ community in the lab at the time.
It was a big lab.
And so there was that nice support and there was acceptance from friends and colleagues.
When I went to do my postdoc by happenstance, it turns out that my postdoc advisor is also
(31:18):
a gay man.
And so that was...
And that was pure happenstance.
It absolutely was, yes.
And so having that experience sort of really cemented in my mind the idea that one could
be a successful, and in the case of Scott Eman's, fantastic, successful scientist and
still be a happy, healthy, productive gay man in society.
(31:41):
And a great runner as well, Scott.
That's really fantastic.
And you know, mentioning walking in the shoes, and I think what you just did, I know from
folks in my own family who are gay, it's not easy because they grew up at the same time
and you have that ingrained in you, that sort of sense of threat and worry about being out
(32:04):
and being open.
But by being that, being here with us and being willing to talk about that, you know,
you're also part of the solution.
And I know I've been able to witness that as well with the way you deal with students
and trainees and the community here in neuroscience at Rochester.
Thanks.
I appreciate that.
I mean, I think it's very important for those of us who are in a position where we can have
(32:26):
some influence to talk about those things and set an example.
Well, Doug Portman, you do that in spades.
And thank you for being here and thank you for taking the time out with us.
Really appreciate it.
And it's been a pleasure.
Thank you.
You know, one of the big surprises of the genetic and genomic era is just how much of
(00:07):
our DNA is shared with all other animals, really.
It depends on how you do the math exactly, but something like half of the genes that
the worm uses are genes that we use too, right?
So we're something like half worm, if you like.
The basic building blocks are all there.
(00:36):
I'm John Foxe, Director of the Del Monte Institute for Neuroscience at the University of Rochester.
I'd like to welcome you to another episode of Neuroscience Perspectives.
Today I'm absolutely thrilled to be joined by one of our own here at the University of
Rochester, Dr. Doug Portman, who is the Donald M. Foster Professor of Biomedical Genetics,
Biology and Neuroscience here at our Medical Center.
(00:57):
He has also very recently elected a fellow of the American Association for the Advancement
of Science, and his lab uses C. elegans, microscopic roundworms, to study our understanding of
the genetic underpinnings of sex differences in neural development, behavior and disease
susceptibility.
He's also a renowned trainer of trainees here at Rochester, providing guidance and inspiration
(01:21):
to our fellows and to our students.
We'll get into all of that with him.
Doug, thank you so much for being here.
Oh, thanks, John.
It's a privilege and an honor, and I appreciate the invitation.
Well, listen, I was thinking about this, you know, you show up in an event, and somebody
says, what do you do?
I'm a geneticist, I'm a neuroscientist.
(01:44):
And then the next piece is going to land on eye work and worms.
And I'm sure every now and again you get one of those looks like, what?
So why worms?
Hit us with that.
Yeah, that's a good place to start.
C. elegans is an amazing model system that has provided numerous profound insights into
(02:06):
lots of different areas of modern biology.
There are a number of reasons why it's a very powerful system.
We can talk about some of those in detail if you'd like to.
I can talk about worms all day.
But I guess the quick answer to that is that worms allow us to approach important fundamental
(02:26):
biological problems at a level where we can sort of view them from, I don't want to say
necessarily a reductionist perspective, but from a reduced perspective.
You know, as somebody who trained originally as a biochemist, my mind thinks, you know,
sort of bottom up.
And C. elegans in many ways is sort of the simplest instance of a creature that has extraordinary,
(02:53):
fascinating, beautiful biological complexity.
And so for me, that's the reason why we study it.
So in some ways, it's stripping away all the noise of complex, super complex creatures
like ourselves, our first cousin in the primate.
And I see our backdrop here has some of these.
Most people, they show the picture of their puppy or their cat.
(03:15):
These are your pets, right?
Absolutely.
I feel very close to these creatures.
But it's that simplicity of the organism and yet the behaviors are profoundly complex,
right?
Yeah.
In fact, I tend to shy away from the word simple because C. elegans is a simpler organism.
(03:38):
It's a reduced organism, but it's still extraordinarily complex.
And there are lots and lots of things that we are just in some ways fundamentally clueless
about in terms of the way it works.
So yes, behavior, the function of the nervous system, developmental programs, lots of aspects
of biology are extraordinarily complex, even in this sort of highly reduced context.
(04:00):
And for me, that makes it a great place to sort of start.
If we have any hope of understanding at a really high resolution level, how the human
brain works, how it integrates information and where our consciousness comes from.
If we can't understand how neural circuits work when we're talking about a few hundred
neurons, then there's a fundamental disconnect and we still have some work to do.
(04:23):
Yeah.
Yeah.
And just for the viewer out there, they say, well, what the hell is a worm to do with a
human?
But we have a lot of shared biology, right?
Oh, indeed.
And a lot of shared genomics or genetics.
That's right.
That's right.
And so one of the big surprises of the genetic and genomic era is just how much of our DNA
(04:46):
is shared with all other animals, really.
It depends on how you do the math exactly, but something like half of the genes that
the worm uses are genes that we use too, right?
So we're something like half worm, if you like.
The basic building blocks are all there.
And maybe they work in somewhat simplified ways.
(05:09):
But yeah, the same genes that specify the difference between our head and our, I was
going to say our tail, our feet during development work in a worm.
The same genes are involved in specifying, telling cells to become different from each
other during development.
They're very same genes.
Right.
Right.
(05:29):
Yeah.
In some ways, I think this is a concept that makes a lot of people a little bit uncomfortable,
right?
Because obviously there's been lots of controversy, but you know, we're all part of the same biological
chemistry.
And again, going back to that business of this tiny little creature that you can literally
see through and just how easy it is then are not easy.
Nothing's easy in our world, but how much easier it is to actually get a tractable question
(05:55):
about a specific gene and that.
That's right.
It brings me to two thoughts, actually.
One is you mentioned a few hundred neurons and I happen to know you trained with the
very eminent worm biologist, worm neuroscientist, Scott Emmons, who we both know very well.
Yes.
I'm, you know, Scott's really famous for literally mapping the entire neuronal network of the
(06:21):
C. elegans.
Can you tell us a little bit about that?
Tell us about your time with Scott and how that played into your career.
Yeah, well, I can say a bit about training with Scott, which was a wonderful experience.
And then I can also say a little bit about this, you know, the value of the mapping that
Scott and others have done and how it's sort of opened exciting new doors for the field.
So I decided to train with Scott because I came, you know, I came from a background,
(06:46):
as I mentioned before, I sort of trained as a biochemist and cell biologist.
At the University of Pennsylvania.
That's right.
That's right.
From undergrad and your graduate.
Exactly right.
From undergrad and graduate school.
And I, by the, you know, and I loved my time there.
I learned a tremendous amount.
I felt like I was able to do some good work.
(07:07):
But I got to a point where all of the experiments that I were doing were mixing things together
in test tubes and running gels and sort of, you know, doing things that were very, in
some ways, divorced from real biology.
And I wanted to get my hands on a living creature, you know, that, but a living creature in which
we could really, we really had the power to understand at this very basic mechanistic
(07:32):
level how genes and molecules work.
What is the function of those individual components that we can, you know, study in isolation?
But how do they work together to build an organism that develops?
So I decided that C. elegans was an ideal creature in which to do that.
And for personal reasons, I was interested in staying in the New York City area in the
Northeast.
(07:52):
And Scott became the sort of immediately most logical candidate to train with Scott, has
been in the worm fields really since its founding.
And there aren't very many people really who can say that anymore.
Scott has a tremendous perspective on the, you know, holistic perspective on the field
(08:13):
and understanding how it's, where it started, how it got to be where it is, who's contributed
what.
And it's really valuable for me in my training because it's given me a really solid foundation
in terms of just kind of understanding the system without necessarily diving immediately
into some little detail, but to be able to understand it at a holistic level.
(08:33):
And so Scott was really instrumental in kind of instilling that kind of a view, I think,
in me and all of us who worked with him.
Give us a number.
So I work mainly in humans.
Yeah.
And I'm stuck dealing with 70 to 100 billion neurons in this extraordinary connective mass.
(08:54):
Indeed.
Yes.
And so the, and of course that's, there's an intractability to the complexity of the
circuits that make up the human brain.
I shouldn't say intractability, but they're difficult to study.
Sure.
But the number is in the C. elegans?
Well, the number depends on which sex we're talking about.
In C. elegans, there are two sexes.
They're not male and female.
They're male and hermaphrodite.
So the C. elegans, essentially the female has learned this little parlor trick over evolution
(09:18):
of being able to make its own self sperm.
So it's a self fertile female, if you like, but we call it a hermaphrodite.
For many years, we've known that the hermaphrodite, the adult hermaphrodite has exactly 302 neurons.
302 neurons.
The male has somewhat more than that.
The number is about 395.
The you know, you alluded to the connectome before.
One of the initial visions for C. elegans when it was first being established as a model
(09:44):
system in the late 60s and early 70s by the great late Sidney Brenner was that there he
could imagine that in a system like this that you might have the opportunity to really get
a level of anatomical description of the nervous system that's unparalleled in any other system,
to identify every single cell and not only that, to understand how they connect to each
(10:10):
other.
Neuron in isolation doesn't do very much.
The brain works as you alluded to because neurons are connected into circuits that can
do all kinds of amazing things.
And so actually there was this initial feeling that once the field, if the field were able
to do this thing, which at the time was a tremendously daunting task of identifying
all those cells and identifying all the synaptic connections between them, that the answer
(10:34):
would fall out, that we would understand how it works, that the structure would lead immediately
to an aha moment.
Exactly, exactly.
To this eureka, I see, I get it.
Now it all makes sense.
And unfortunately, something like the opposite happens.
So the hermaphrodite, we call this the connectome, right?
The wiring diagram of the entire nervous system.
(10:54):
The connectome of the adult hermaphrodite was an arduous task led by John White at the
MRC, done mostly in the mid 80s.
So we've had that information for quite a while.
And I think one of the really astounding things about that is that it's a tremendously valuable
tool, but in itself, the structure of the nervous system is not sufficient to tell you
(11:20):
about its function.
And so that has been, the field has been struggling with that ever since.
Maybe a good thing in terms of like if this eureka moment came, we'd all be out of business.
That could be true.
And so an important advance in that field has been, you mentioned Scott Emmons' role
in this.
(11:40):
Scott was the first to really decide to tackle the nervous system of the adult male.
And after the adult hermaphrodite had been finished in the 1980s, it was a tremendous
task and they sort of breathed a big sigh and said, we're not doing that again.
And it wasn't until there were some technological developments, and also Scott just had the
(12:01):
patience and the fortitude and the drive to get it done.
And over the past 10 years has spearheaded the effort to drive the connectome of the
adult male.
And now because of additional technological advances, we have multiple connectomes.
We have connectomes for multiple developmental states, multiple individuals of both sexes.
But we're still stuck at this place where having the connectome itself is a really valuable
(12:25):
foundation, but it doesn't in itself tell us how behavior works.
And it gives you that ability then, right?
You should mention that all of this work was done in the Bronx, in New York, at Albert
Einstein College of Medicine, placed near and dear to both of our hearts.
But having that wiring diagram so precisely mapped then allows you to focus in on a neuron
(12:49):
or a cluster of neurons and really ask very specific mechanistic questions about what
this piece of the circuit or that piece of the circuit does, and that has a level of
tractability in a creature with 390 neurons that it's just utterly impossible in almost
every other species, right?
Yeah, that's right.
I mean, I think of that in a sense you can divide that up into two overlapping halves.
(13:15):
One is how does information in the genome specify the identities of all those neurons
and specify their ability to wire up into circuits?
And then how do those circuits do what they do, right?
How do they take in and integrate and process information and choose to make a decision
about executing a behavior, and then how does that behavior actually get executed?
(13:36):
And we can approach those questions at the level of single neurons, single synapses,
single genes in a way that has not been possible really in any other system.
Right, right.
It's absolutely extraordinary.
Coming to some of the specifics of your work, you're very interested in this issue of sex
(13:56):
differentiation and you have these two sexes, a male and a hermaphrodite, and the programming
of these genes can really lead to very different types of behavior in terms of feeding versus
mating and so on.
Tell us a little bit about that and what you've learned and the kinds of systems that those
(14:18):
urges or desires rely on.
Yeah, yeah, sure.
So right, we've been interested in trying to use biological sex as an entry point to
understand sort of where there are points of plasticity in the development and function
of the nervous system that can lead to adaptive differences in behavior.
(14:41):
And so one, because of this extraordinarily high level of resolution with which we understand
the structure of the C. elegans nervous system, we know exactly what those sex differences
look like.
We know that each sex has its own set of sex specific neurons and sex specific circuits
that are dedicated to purely sex specific behaviors.
(15:03):
Hermaphrodites have to lay eggs, males don't, males don't have eggs, right?
And so there's a dedicated circuit in hermaphrodites that controls egg laying behavior.
There's a dedicated circuit in males that controls courtship or mating behavior, which
is a behavior that hermaphrodites don't do.
What my lab has been interested in is a discovery that came out of a serendipitous observation
(15:26):
actually when I was first starting the lab here in Rochester that led us to wonder about
what about the rest of the nervous system?
294, exactly 294 neurons are shared between both sexes.
And that means they're linearly, anatomically, morphologically essentially equivalent, right?
So most of the worm's brain is the same as it is in most species.
(15:48):
And yet what we found is that those shared circuits can be tuned in different ways to
allow animals to prioritize differently among shared behaviors or to execute those shared
behaviors in different ways.
So that the features of those behaviors lead to differential outcomes.
So an example of this is that often hermaphrodites will tend to prioritize feeding behavior because
(16:14):
for hermaphrodite, fertilizing your own oocytes and producing progeny is an important part
of your life.
For a male, males need to find mates.
And so males will often sacrifice their ability to feed and go out and search for hermaphrodites,
often abandoning a food source to do so.
And so those aren't sex-specific behaviors necessarily.
(16:37):
They're just really differential modulation of feeding and exploration.
Both sexes can do that.
And so we're interested in finding the knobs and dials that evolution has engineered that
permit the sexes to do those different kinds of things.
So that the male biases towards looking for a mate at the expense of feeding.
(16:58):
And essentially the risk ratio there is quite different, right?
And the risk, it's maybe a proxy for risk taking in a worm.
In fact, we do sometimes think of it that way, that males are a bit less risk averse
than hermaphrodites are.
So some of the things that we've been doing in the lab recently is trying to ask questions
like how willing is a male going to be to cross an aversive barrier or something that
(17:22):
tastes terrible or is toxic compared to a hermaphrodite?
And does that differ depending on whether an animal is hungry or not or whether it's
mated recently or not?
And if those, we have some instances where it seems like there are some interesting things
going on there.
And then we can go in and ask where in the nervous system are things being modulated
to bring about those outcomes.
(17:43):
Amazing, right?
A few hundred neurons, 80 billion neurons, very, very similar behavior.
Yeah, absolutely.
It's extraordinary.
And remind me now, maybe I'm wrong about this, but actually quite a lot of this relies on
the chemo sensory system, right?
The smell system and that you see these changes in genes coding for smell that actually change
(18:07):
risk taking behaviors.
Yeah.
If I could put it that way.
Right, and that I think is one of the most interesting and unexpected things that we've
found in the lab.
When we started this work, I guess my intuition about scientific problems is often completely
wrong, and this is a good example of that.
We imagined that the way that animals were going to be prioritizing different behaviors
(18:32):
differently according to their internal and external needs and signals, the way that would
work, at least naively to me, I would imagine that evolution would design an animal so that
it can gather as much information as possible about its world, and then fancy things happen
in neural circuits, inputs get weighed, and essentially a decision gets made about what
(18:53):
to do.
And so according to that, we expected to find that the sex differences would be in neurons
that are a few layers deep in the system, in interneurons that are integrating information.
We might find that maybe one input is a little bit stronger in a male, or a particular neuron
is modulated differently to bring about a different behavioral outcome.
(19:14):
And I think that probably is happening, but we haven't really found any good examples
of that.
Instead, what we've found is that the way evolution has engineered in the ability for
animals to behave differently is by front loading it at the very sort of the entry points
of the nervous system, the sensory system, and in particular, the chemo sensory system.
(19:38):
Chemo sensory behavior, smell and taste, are essential to a worm.
They can't see, they can feel a little bit, but really their primary mode of gathering
information about their world is smell and taste.
Does this taste like something I should eat?
Should I run away from this?
Is it toxic?
Is it a predator?
Is it potential meat?
And so there are chemical signatures for all of those things.
And the worm sensory system has specialized sensory neurons and receptors, individual
(20:03):
proteins within those neurons that detect all of those stimuli.
And what we found is that the expression of those receptors that detect those stimuli
can themselves be changed by biological sex and also by things like feeding status.
So for example, an adult male, one reason that it's able to leave food is simply because
a food receptor that detects the presence of food is down regulated in the male.
(20:27):
So males just don't smell food as well as hermaphrodites do, but they smell sex pheromone
much better than hermaphrodites do.
And so rather than gathering all the information that you can and making a decision, evolution
has sort of decided, forces the worm to pay attention to what it has decided is the most
salient cue for it at that, according to that time and stage in its life, which I find fascinating.
(20:49):
Absolutely astounding.
It reminds me actually of, you're talking about evolution as this force, which of course
it is over time, but a lot of it was Stephen Jay Gould, he used to talk about not adaptive,
but ex-aptive functions.
This idea that random stuff happens in the genome, like down regulation of a chemo sensory
(21:09):
receptor.
And then those few worms that have that down regulation are more likely to drift away from
food and they're going to be more successful in identifying mates and it's just happenstance.
But then that of course becomes re-asphied in the genome.
I mean, it's extraordinary.
Really beautiful examples of that.
We'll switch gears a little bit.
(21:31):
We'll stop geeking out about the worm just for a moment.
You know, you and I have known each other best part of a decade now.
And I know some of our earliest conversations were around students and trainees, because
at the time you were really helping direct our graduate program.
And I think I have a couple of questions for you.
(21:52):
You are an extremely dedicated mentor and very involved in the student body.
I'd like to know about your motivations there.
And then I'd also like to ask as an addendum, have you seen change and is that change for
the better over the last decade or so in the makeup of our classes, in the way in which
we're approaching the academic efforts, the recruitment?
(22:16):
Yeah.
That second question is a tricky one.
The first one is a bit easier for me.
My motivation, right?
I find interacting with trainees to be one of the, if not the most rewarding part of
doing academic science.
We get to interact with bright, young, energetic, creative people all the time.
(22:36):
And for me, that's a tonic.
It keeps me from getting old.
And so I find it really gratifying to see a student come in, like many students coming
into a PhD program, maybe somewhat unsure of themselves or what they're interested,
(22:57):
not sure if they're really up for this thing that they've signed up for, and then thrive
and really just blossom and go on to do fantastic things.
And so playing some small role in that is an honor and a privilege.
So that really is what drives my interest in mentoring.
I think you raise a really interesting point that I think graduate school, graduate training
(23:24):
has changed, certainly since you and I did it.
But even over the last 10 years, I think there are a number of reasons for that.
One that I think about a lot is that the amount of things that a student has to learn in order
to master a field has grown exponentially.
(23:46):
When we, I don't know about you, I remember being in grad school and being overwhelmed
by the literature.
How can I possibly master all this?
Small fraction of what it is.
Tiny fraction, right.
It's a tiny fraction.
And so now students will come in and I don't even know where to start sometimes in terms
of getting them up to speed, not only on our field, but on a field that is essential as
(24:07):
a scientist to know about other things.
So that you can find those connections.
That's right.
There's a massive intersectionality now.
Absolutely.
In the old days, you could learn microscopy around this system and that's what you did
for most of your career.
There's no way to be that specialized today.
Yeah, well, I think you can look at this in different ways.
Sometimes I get concerned that students become hyper specialized too quickly because the
(24:31):
frontier of, by its nature, as science advances, we drill down deeper and deeper into these
sort of veins of gold that we've found until you find yourself sort of at the bottom and
you can hardly see up again.
And I think it's really easy to fall into that and not be able to step back out and
(24:51):
understand why did you go down that vein in the first place?
What was the point of studying that and how is it connected to all of these other things?
And I think exciting advances in science so often come from interdisciplinary kinds of
thinking.
People, some of us are lucky enough to have had the opportunity to train in multiple fields
(25:14):
or have interests in multiple fields and be able to see those connections, but also just
to be able to interact with people regularly whose perspectives and whose background are
a bit different than yours, I think is tremendously stimulating.
And we need to foster that in the next generation of scientists.
And I get concerned sometimes that we focus so much on you need to learn your field, you
(25:36):
need to focus on doing your experiments, that we don't give students enough time to step
back and think about the bigger picture and understand why they're studying what they're
studying.
We're not, we all study our own individual little problems, but we're not, ultimately
we shouldn't be studying them for their own sake.
We should be studying them because they're a critical piece in this larger puzzle.
(25:56):
If you don't understand, you can't see the larger puzzle, you're lost.
Right, right, right.
That's very well put, yeah.
Talk to me, so if you don't mind me getting a little personal, we've had a huge drive
here at Rochester, but I know most of the big, great institutions in the country have
already worked hard on diversifying the student body, diversifying the faculty body and that.
(26:21):
And you're from a minoritized community in the LGBTQ world and that.
How has that played into your career?
What have been the challenges?
What would you say to a young LGBTQ person coming into the field today?
What are the minefields?
What are the advantages?
Yeah, great question.
I feel really privileged and fortunate to have always had training experiences.
(26:46):
In my training, I was always in very supportive environments.
I've been out and had a partner since I was in college.
So being out in grad school in the early 90s, that was a different time.
And in fact, it was unusual to encounter another person from the LGBTQ community in science
(27:11):
or certainly a person who was sort of out and open about their situation.
It's tremendously gratifying to have seen that change so much, right?
We have an abundance of trainees in our programs here in Rochester who make up this beautiful
(27:33):
diverse spectrum of people in the LGBTQ plus communities.
But I guess I would say that still we do know that LGBTQ people tend to shy away from careers
in STEM a bit more than their counterparts.
And they also tend to sadly drop out of their training more commonly than people from other
(27:58):
groups.
What's driving that?
What's the root cause there?
I don't know the answer to that.
I think that our job as...
I think the answer is going to be complicated.
Probably there are a lot of case by case issues.
But I think ultimately what we have to do is realize that our job as educators is to
(28:19):
help everyone reach their potential and be the best scientist they can.
And that means welcoming and supporting and including all kinds of people, and even if
we don't understand necessarily what we're going through, what they're going through,
simply to provide that message that we're there and we understand that they may be facing
(28:41):
special challenges and we want to help them.
And that we would hate to see somebody leave science for a reason that is ultimately maybe
not the best choice for that person's future.
Going back to in the 1990s and you're starting out on your scientific career, could you look
(29:04):
to people in the field?
I mean, I just think about this walking in the shoes, right?
Could you look and say, oh, there's a successful person like me?
Or that was...
No.
Yeah, right.
So is that a key component here?
Well, so let me say there's a big qualification to my know because that did change at a certain
stage in my career, but I think back to when I was an undergrad and I was very involved
(29:26):
in the LGBTQ student group at the time in college, but it was a different world, right?
People's views on gay people and the place of gay people in society was so different.
We had Anita Bryan out there, you know, preaching homophobic messages that were resonating with
(29:49):
and lots of other things like that.
I remember having...
It hasn't stopped.
No, it certainly hasn't stopped.
And for a number of unfortunate reasons, many of those voices have become amplified recently.
But I remember very clearly being in college, being a senior in college in my biochemistry
senior seminar and the professor, we were talking about fruit fly genetics and there's
(30:13):
an interesting fruit fly mutant where the males don't court.
And it's called fruitless.
And I remember the professor making a homophobic joke about the sexual behavior of fruit flies
and everybody in the class laughs and nobody at that time would have thought about raising
a ruckus.
Yeah, like that was just like, oh, ha ha ha.
(30:37):
So that...
And that hits home though when you're sitting there as a gay person, of course.
Right.
It says to me, like, is this, you know, do I belong here?
It really makes you sort of question what your role is, what your potential is.
So I mentioned there was a big asterisk.
So my graduate school training was great.
(30:58):
There was a fellow person from the LGBTQ community in the lab at the time.
It was a big lab.
And so there was that nice support and there was acceptance from friends and colleagues.
When I went to do my postdoc by happenstance, it turns out that my postdoc advisor is also
(31:18):
a gay man.
And so that was...
And that was pure happenstance.
It absolutely was, yes.
And so having that experience sort of really cemented in my mind the idea that one could
be a successful, and in the case of Scott Eman's, fantastic, successful scientist and
still be a happy, healthy, productive gay man in society.
(31:41):
And a great runner as well, Scott.
That's really fantastic.
And you know, mentioning walking in the shoes, and I think what you just did, I know from
folks in my own family who are gay, it's not easy because they grew up at the same time
and you have that ingrained in you, that sort of sense of threat and worry about being out
(32:04):
and being open.
But by being that, being here with us and being willing to talk about that, you know,
you're also part of the solution.
And I know I've been able to witness that as well with the way you deal with students
and trainees and the community here in neuroscience at Rochester.
Thanks.
I appreciate that.
I mean, I think it's very important for those of us who are in a position where we can have
(32:26):
some influence to talk about those things and set an example.
Well, Doug Portman, you do that in spades.
And thank you for being here and thank you for taking the time out with us.
Really appreciate it.
And it's been a pleasure.
Thank you.
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