Dr. Wickersham
[0:00]
I’m trusting you
Peter.
Peter [0:03]
If you could use
one word to describe it.
Dr. Wickersham
[0:06]
Bread-y, I’m
feeling like that’s a hot dog. I only got the bun, I think
Peter [0:15]
That is fine. You
can open up your eyes now. It was a hot dog on gluten free bread (we made sure).
I think the reason we ended up choosing a hot dog was we think that dogs are
associated with rabies, so what’s the closest food we could go for and we
thought of hot dog.
Dr. Wickersham
[0:31]
Yeah. Nice.
Peter [0:41]
Hi, my name is
Peter and I will be your host for the Gastronauts podcast. Here at Gastronauts,
we are committed to understanding communication in the body, and in particular
how our gut talks to our brain. In this podcast, we take a deeper dive into the
mind and motivations of leading science and their work. We hope that by getting
to know the scientists behind the science, we will be able to bridge the gap
between different scientific spheres, and between the scientific community and
mainstream culture. So let’s dive right in, The Gastronauts Podcast: Between Two
Spheres.
We’re really
thrilled to have Dr. Ian Wickersham here today. Ian studied physics as an
undergrad here at Duke University and then went on to do his PhD at UCSD in
neurobiology. He later did his postdoc at MIT, and now serves as head of the
genetic neuro-engineering group at MIT. He focuses on developing powerful and
precise techniques to study the structure of the brain. He’s taken advantage of
really unique features of viruses and modified them so that they can infect
particular cells and light up so we can visualize brain networks. One of these
viruses that he’s worked with is rabies virus. And I’ll be honest, when I first
heard of using rabies virus as a tool, I got a picture of […] a rabid
salivating dog with somewhat of a crazed look. And I was wondering, […] how did
you get drawn to rabies? Did it take some convincing to get you to work with a
virus that has somewhat of a scary reputation?
Dr. Wickersham
[2:40]
Well, no. And of
course, I actively wanted to work with it, so I had to convince others more
than the other way around. But the thing about rabies virus is that while it is
terrible pathogen that does kill many people worldwide every year, it is a
tremendously useful, naturally occurring tool for neuroscientists, because the
way that it spreads is between synaptically-connected neurons. It spreads
between neurons in a way that doesn’t kill the neurons outright for quite some
time. So when I started my PhD, we were looking for ways of identifying
connected neurons in the brain. Because neurons in the brain are of very many
different cell types and they’re all mixed in together and they have these long
processes, axons and dendrites that overlap. And it’s impossible to tell just
by looking at them, even if you are lighting up different types of them or
staining them. It’s impossible to tell which are connected to each other. And
the exquisitely precise connectivity between neurons is basically maybe the
most unique aspect of the brain as opposed to other organs. So it’s very important
for understanding how the brain works, or how one little aspect of the brain works,
to understand how the neurons that are involved in that behavior that you’re
interested in, are connected to each other. So we needed a tool that would
allow us to identify cells that are connected to a targeted group of other
cells and rabies virus was beckoning as the most promising way of doing that.
Peter [4:29]
That’s really
interesting. You mentioned rabies, more so as a tool, than kind of a pathogen.
And your lab really focuses on developing tools and prototypes and modifying
these viruses so that we can use them to understand different circuits and
different connections. And I was wondering, when we go through developing these
tools, we go through an iterative process where you go through prototype one or
generation one, generation two, generation three. How do you know when
generation one is ready? How do you know when you’ve made a construct that you
think this is kind of a tool that we can sell to other people or let other
people know about?
Dr. Wickersham
[5:06]
Well, as far as
the first-generation version went, there was nothing else out there. And so as
soon as we had a basic sort of demonstration that we could do this, and I
should say that the system that we were trying to invent was a way of specifically
labeling neurons that are directly connected to a targeted group of neurons. So
basically, we would be able to selectively infect whatever type of neuron one
wanted in the brain with a modified form of rabies virus and allow the rabies
virus to spread not throughout the entire brain, like wild type rabies virus
does, but only to the cells, which are directly synaptically connected to the
starting neuron population.
Peter [5:55]
So you control
kind of the specificity of how its spread.
Dr. Wickersham
[5:58]
We control two
things, actually, one was the specificity of which cells it would infect to
start with, and we also controlled the number of synaptic steps that it would
travel, basically. So naturally occurring rabies virus will infect essentially
any neurons it encounters if you were inject in the brain. And it would, once
it infected those cells, it would spread in a retrograde direction, that is
from the starting cells to the cells, which are pre-synaptic to them.
Peter [6:29]
And pre-synaptic
means that it forms the connection upstream of it.
Dr. Wickersham
[6:33]
That’s right, to cells,
which release neural transmitter on to the cells that you’re starting with. And
wild-type rabies virus will simply replicate within those cells, and keep
spreading to the cells, which are pre-synaptic to them, and so on, and spread
throughout the entire brain. And we wanted a system that would allow us to
label only the directly pre-synaptic cells, so that we could very precisely
identify sort of a connection matrix between cell types in the brain.
Peter [7:01]
So kind of like a
controlled rabies infection.
Dr. Wickersham
[7:05]
Yeah, that is the
first-generation system being able to do that. And of course, we publish it as
soon as we had any kind [of data], like one does basically in neuroscience. Once
you have something which is novel, no one has ever shown before, even if it’s
not perfect, you want to get it out there. So without waiting for perfection,
one simply publishes each new, major advance.
Peter [7:30]
But at the same
time, you want to make sure that the toxicity or the lethality of the rabies is
controlled as well.
Dr. Wickersham
[7:36]
Exactly, and the
toxicity of rabies viruses is maybe its biggest downside. It’s certainly less toxic
than many other viruses. And the reason, if you will, that it’s less toxic is
the rabies virus wants to keep the cells of the of the nervous system intact,
so that the host, the infected animal, will be able to go on and transmit the
virus. Basically, the viral life cycle depends on not trashing the nervous
system as it spreads through it so that the animal is in a position to
implement that behavior, which causes the spread the virus. So basically, the
virus is already fairly non-toxic. But within neuroscience, there are many,
many experiments that one would like to do that involve manipulations or study
over a long period of time, not just a few days or a couple of weeks. But in
mice, for example, that are learning a task, that are developing over time, and
one would want to see how the synaptic connected networks of neurons evolve
their responses over time as the mouse learns a task, for example, something
like that. And that basically has not really been possible with the rabies
virus systems that have been out there, or mainly the system that has been out
there, because it does kill the neurons. And so a huge effort in my lab has
been in recent years to develop non-toxic versions of the so called model
synaptic tracing system, the rabies virus tracing system.
Peter [9:13]
And the mono-synaptic
tracing system is kind of just having a jump one synapse, right and not
continuing to spread, and that’s how you control a little bit of the toxicity?
Dr. Wickersham
[9:17]
Well, that’s how
we control the spread of the virus, but that doesn’t directly do anything about
the toxicity per se, of the virus to the infected cells. So in the second, and
now, third generation versions that we have underway, the rabies virus appears
to be completely non-toxic. And so that means that we can label pre-synaptic
cells, and then leave them alive indefinitely so that they can be studied and
manipulate for long-term behavioral experiments.
Peter [9:52]
Okay, so what I’m
getting is kind of your generation one is […] you have this vision set forth,
you want to be able to label a pathway and […] you found a way to do it. It is
modestly toxic, relatively low toxicity. And then when you went to generation
two, you’re really trying to focus on how can we reduce this toxicity almost zero? And then how can we get this
labeling to persist?
Dr. Wickersham
[10:16]
Yeah, exactly. I
mean, the very first pass was, if I may say so is a huge step forward, because
basically, it is, and remains the only way of identifying cells which are
directly connected to some population of the brain that you’re interested in,
without already having a hypothesis that you can then test. So for example,
let’s say you’re interested in dopaminergic cells of the membrane. These are
cells which project to the cortex and depending on the cells, the striatum, and
other places in the brain, and they’re tremendously important for motivation,
and reward and movement control. And being able to identify what the inputs are
to the those tremendously important, dopaminergic neurons in the membrane will
allow neuroscientists to map out the entire circuit manipulates various inputs
and see something basic about how the organization of this key system of the
brain or the systems probably more properly, is put together. Now, the first order
question that one has is what are those cells and where are they? And so the
first generation rabies virus system was just to answer that […] anatomical
question: what and where are the cells which are present? Wherever they are in
the brain, it will label them. And so just to be able to do that anatomical
mapping before going on, and then maybe manipulating pre-synaptic cells with
other means.
Peter [11:48]
So what really
makes this rabies still powerful is kind of the resolution that you get, is
that correct? Because my previous understanding of neurobiology is we have
these brain regions, and we know they’re, to anthropomorphize, talking to one
another. But we don’t know specifically, what neuron is talking within this
brain region to this other neuron, right? And the rabies virus gives you the
ability to look at this direct connection between two cells.
Dr. Wickersham
[12:12]
That’s correct.
That’s exactly right. So what one can do without rabies virus or with a variety
of other tracers, and what people had done before this came along was see where
in the brain there are cells that project to a brain region. But with any of
those techniques, there’s no way of seeing which cells in the targeted region,
those upstream neurons project to. So you basically can get, with high
resolution, mapping of cells everywhere in the brain, that project to a place.
But before the rabies virus system came along, there was no way of identifying
which cells in that target location, were post-synaptic to, all these pre-synaptic
neurons. So what we can do with the rabies virus is select the cells that
you’re interested in, mapping the inputs to, and then map the inputs
specifically to them. And they’re different, essentially, everywhere in the
brain, there are many different cell types and they differ in their
conductivity by and large. And so essentially, you may have differences just in
degree of the numbers of neurons in a particular brain region that project to
one type of cell in, let’s say the cortex, or another. Or you may have
completely non overlapping types of cells, which are pre-synaptic to the two,
for example. And this allows you a much higher resolution ability to map conductivity.
Peter [14:00]
Yeah, so that
really shows like even neurons that are close in space that are localized may
not be part of this network that we’re looking at. To pick your brain a little
bit. Where do you see the future of this going? I think structure belies
function. And I think understanding this network is important for us to really
know how the brain works. And I was wondering […] where do we see this going
forward? How do you think, our understanding of these networks? Or how do you
think we can better understand these networks with new techniques within the
next 10 years or so?
Dr. Wickersham
[14:32]
Yeah, well, for
one thing, be able to see more about those specifically pre-synaptic cells than
just where they are and what they look like, and what they express and so on,
would be good. So if you can, with a non-toxic version of all of this, do
patterned stimulation of pre-synaptic neurons to be able to perturb the
activity of these pre-synaptic cells, and see how that affects the activity of
these targeted post -synaptic cells. And one can with the rabies virus, do
mapping of inputs to not just a group of neurons, but a single neuron. And this
allows beautiful anatomical mapping for a start of inputs to individual
cortical neurons, but so you can express calcium indicators in those pre-synaptic
cells, and be able to image, for example, visual response properties of all of
those pre-synaptic cells, as well as of the single targeted synaptic cell and
then see, for example, whether a neuron in the visual cortex, for example, that
responds in a certain way to visual stimuli, gets input from primarily other
neurons that respond in that same way, or whether it’s doing something maybe a
bit more interesting. So in other words, answering the question, which I think
is one of the most fundamental questions of neuroscience, how does a single
neuron take the input that it’s getting and process that information to produce
its own output?
Peter [16:02]
So what I’m
hearing is moving forward, you think kind of understanding these on a single
cell level, how we integrate information, more how these neurons integrate
information in a single cell level and how they can take that information and
integrate and send that message over that synapse to another cell, is where you
see the future of these techniques moving forward.
Dr. Wickersham
[16:23]
Yeah, well, so I
think that’s, that’s a really great goal and a motivating goal. In terms of the
futures of the techniques themselves, we should soon have a highly efficient,
completely non-toxic mono-synaptic tracing system that would allow those sorts
of experiments. I mean, at that point, neuroscientists of all stripes can use
the technique and do whatever exciting science they want with it. We as the
tool developers are going on and developing other tools that will allow other
exciting science.
Peter [16:55]
Now that’s really
exciting moving forward, I can’t wait to see what your group does in the
future. I’m going to go transition a little bit more now towards you as a
scientist in your own career development. Moving from physics to neuroscience
is kind of a big jump. And I think that I’d be interested in hearing how you
made the jump from being a student in one field into a researcher in another?
Dr. Wickersham
[17:23]
So I mean, in my
case, I was always interested in in the brain, not necessarily neuroscience,
per se. But from the perspective of wanting to understand how it worked. I was
always interested in physics, too. I enjoyed it. So that was my major in
college. But I also became interested in the brain, and minored in neuroscience
here at Duke. And was thinking about, though, from the perspective of neural
networks [and] that was my, that was my motivation. So I was thinking, Okay,
how can how can we build a brain? So now, I think the majority of people
probably go into neuroscience, the goal of understanding the brain in its
entirety, and so on, you know, figuring out how consciousness works, or
building robots that think and that sort of thing. And then you sort of get to
neuroscience, and it’s like, “okay, well, what you can actually do is this…” [What]
might be a more direct path to take for actually building architectures that
are more like thinking in a sense than, than we’ve had before. But going into
neuroscience, my motivation was just to understand as much as I could about the
organization of the brain.
Peter [18:28]
What about the
brain in particular? Is it just the fact that it is such a poorly understood
network? Is it because we don’t know much about it? What drew you towards the
brain?
Dr. Wickersham
[18:37]
Oh, I just think intelligence is cool. And, you know, it seems like okay, well, we should be able to build a machine that does that. So that really was the motivation. And I better start by understanding what we do know about the brain. So I ended up joining a PhD program- but, it just turns out that we don’t understand all that much is the truth of it and that’s sort of the glass half empty, or 99% empty, kind of a view of it. But in fact, in fact, we know an enormous amount, it must be said, but that basically, that was my trajectory, I was coming at it from a from a neural network sort of point of view, and interest and in construction, doing programs and architectures that […] were intelligent, and so on. But [when I] got to actual neuroscience, and realized that what I wanted to know- that information was not out there. From my perspective, what I wanted to know, for starters, was okay, what are the connections between all these different types of […] cells? What are the connections between them? What are they doing? And the tools for knowing all that didn’t exist.
Peter [19:45]
And you decided to
make them yourself!
Dr. Wickersham
[19:46]
Yeah. So […] it
just seemed like the bigger bang for the buck, as it were, in terms of the
impact that I could have, rather than using existing tools to study laboriously
some circuit in the brain and get, you know, sort of incomplete answers about
that circuit would be to develop tools that would allow people working in any
aspect of the brain to just have much more powerful and precise experiments.
Peter [20:19]
Yeah, something
that just came to my mind was, your research is really focused on the synaptic
labeling, or, first off, this mono-synaptic labeling how you jump from one cell
to another. I was thinking, […] this kind of reminds me about how people make
the jump from being a trainee to being a mentor. So how did you make that
transition from kind of being a scientist, learning about neurobiology,
learning about these neural circuits to being someone who was a pioneer in the
field. Were there some tools or mindsets that you could […] share with people
who are trying to make that transition from trainee to mentor.
Dr. Wickersham
[21:00]
So I guess my
focus has always throughout been pretty much the same in just trying to develop
tools that would just basically allow a huge increase in the abilities of
experimental neuroscientists to study circuitry. So I mean, that was kind of
like the driving characteristic in the PhD and throughout, it’s still the same
thing. It’s just that now I can do a lot more, because I don’t have to do it
all myself. And so that is, it is a different role, for sure. But analogously,
if you can just make tools that will allow other people to find out things
about the brain, then more will be found out than if you were trying to just do
it yourself with the existing tool. Similarly, if you have ideas, and can
delegate them to your co-workers, a lot can get done.
Peter [21:55]
So it certainly
sounds to me that when you were a trainee, kind of, the fascination with the
tools to understand the network is what kind of drew you in, when you were
first getting interested in research. But then, as you were trying to study
these networks, you realized that you needed to build your own network of, you
know, collaborators that would help develop this.
Dr. Wickersham
[22:15]
Throughout I was
learning from mentors, postdocs in the same lab-
Peter [22:20]
And how do you go
about looking for this help, do kind of just see who’s in the area reach out to
them,?
Dr. Wickersham
[22:25]
That’s a really
good way to do it. The truth is, they’re there are great people all over the
place, wherever you are. And so you want to find them. It’s just certainly at a
place like the Salk, or MIT or Duke, it’s easy to find world class people who
are happy to teach you. The degree of collegiality, I think, differs between
places, but I’ve had certainly good luck with people being happy to help.
Peter [22:51]
That’s really
nice to hear, kind of, how collegial it is for science, because I remembering […]
going back [to our earlier conversation], you’re thinking, Oh, you know, when I
discover something, I really need to push it out. There’s a sense of
competition, and having people that are available to you having, you know, a
group of people within your institute or between institutes that are really
driven and motivated to kind of help you succeed is important to taking that
next step.
Dr. Wickersham
[23:18]
That’s right.
That’s right. And it’s almost always win-win. And that’s the only really
effective way of collaborating. Generally, it’s an academic collaboration and
if there’s a significant amount of help, they’ll get some of the credit for the
work and in many cases, be able to use the technology or whatever that’s being
developed in their own work. People have a stake in the outcome like that, then
they’ll be more motivated to help.
Peter [23:42]
Right? So when
forming collaborations, you want to make sure that it is a win-win for both
parties, right? So we’re both people can advance their own work to advance the
field and develop.
Dr. Wickersham
[23:51]
And generally
people share authorship on the paper. And if the project is exciting enough
that it’s going to be a high impact publication, just to put it in that sort of
crass form, then […] that’s in their interests to participate in the
development of that.
Peter [24:10]
That’s really
great. Well, I really want to thank you for taking the time to be on this
podcast. Dr. Wickersham. Oh, I think we learned a lot about forming connections
in the brain in our science, then yeah, thank you so much for your time.
Dr. Wickersham
[24:23]
My pleasure.
Thank you very much.
Peter [24:34]
Well, there you have it. Forming a collaborative network is easy when you take the time to get to know your colleagues. We challenge you to reach out. Share your ideas with the people down the hall, or the person sitting next to you at your next lunch or seminar. Thank you all so much for listening, and we’ll see you on the next episode. For more of our content, you can follow us on Twitter @gutbrains, or visit our website at thinkgastronauts.com. The Gastronauts Podcast would be impossible without the incredible team that we have here. Meredith Schmehl is our producer and the music composer. Dr. Laura Rupprecht is our social media manager. And special thanks to the founders of Gastronauts: Dr. Diego Bohórquez and the Bohórquez laboratory.