[MUSIC]
So, everything that's happened to you since you've come into
this room is a result of information that has come in
through your sensory systems.
The people that you've recognized, the conversations
you've had, the bitter taste of the tonic in your gin and tonic.
>> [LAUGH] >> The smell of the wine.
Have all come in through sensory systems and, in fact, have for
your entire life.
So, everything you know about the outside world
is really a consequence of your sensory systems.
And these sensory systems have a remarkable challenge.
First, they have to work at the very threshold of detection.
The visual system can detect a single photon of light.
The auditory system can detect sound at
incredibly low concentrations.
The olfactory system of a mammal can detect odorance and
concentrations as low as a few parts per trillion in air.
And mosquitoes, if you're one of the people here, Chris Potter,
wherever he is, works on fruit flies and mosquitoes, and
we both all well know how their amazing ability to find us and
our food at the most inopportune times.
And so, they work at the incredible threshold of
detection.
At the same time, they sit right out at the sort of frontier
of between ourselves and the outside world.
And as such, they are constantly being assaulted and
insulted by either intense stimulus, or
alternatively by pathogenic, or other environmental insults.
And so, we've been very interested to try and
understand how these systems have taken particular
adaptations in their ability to achieve these balanced
remarkable capabilities.
So, in the Center for Sensory Biology, we wanna know what
the mechanisms by which sensitivity and specificity or
selectivities achieved.
Secondly, how do these systems adapt and
protect themselves from an incredible spectrum and breadth
of stimuli, from the softest sound to the loudest rock band.
And then, at the same time, how disease, in a variety of ways,
impacts to reduce sensory function,
and in some cases, eliminate it.
Loss of hearing, loss of olfactory acuity,
loss of sense of taste, etc.
So, those are really the functions
that we really have focused on across the center.
And when we first started the center, now nearly a decade ago,
the thought was that investigators working on
different sensory systems which typically had relatively
little interactions with each other, could, in fact,
benefit from a more collaborative environment.
And secondly, we could teach each other about particular
things, inform, and assist.
And you may hear an example of that from Paul Fuchs in
a few moments.
And at the same time,
that our work on sensory systems would spill out much more
broadly to other areas of medically important biology.
And so, we began those and I thought now I'd turn and
tell you a little bit about my own sort of experience.
I had been interested in the olfactory system from the time I
was a graduate student, and Hopkins provided me
with a really unparalleled opportunity for
the freedom to do research in whatever area I wanted to do.
And so, I decided I was gonna tackle olfaction.
And there were really a couple of challenges.
The first challenge was that, I never worked on it
in my entire graduate career or as a post-doctoral fellow.
I worked on bacterial antibiotic resistance as a graduate
student.
I worked on immunology, as did Steve, as a post-doc.
So, I came to Hopkins as a new faculty member wanting
to tackle a new problem.
The second problem was no one new anything about olfaction at
a kind of molecular level.
And then, finally, the third problem was,
that it had been described actually about 100 years before
by a famous physician as being clearly the sense
that was least useful to man in the state of civilization.
So, this isn't gonna get me very much money from NAH,
none, at least these days it wouldn't.
Nonetheless, I thought it was an interesting problem.
And we, then, set out to tackle the very exciting time in
molecular biology and molecular neurobiology.
And in the course of a few years,
we took the two examples that we knew about,
about how signals were detected in other systems.
That was in vision where we knew work,
Jeremy Nathans, another one of our center members,
had discovered rhodopsin, the thing that detects light and
is in your eye, so it can detect light.
And work by Lubert Stryer,
the classic biochemist book that many of us used,
who had shown that there was a G-protein involved.
And we decided that that system and how vision worked, and
we knew about one other system,
that was the beta-adrenergic system.
We knew there was a G-protein there.
We thought it's a great system.
Maybe olfaction works that way, we'll take a hunch.
And so, we went hunting.
And in the course of a few years, our lab and
many others as well, began to start looking, and
we discovered a G-protein that was clearly involved in
olfaction, and we'll tell you how we did that, but
it was clearly the one involved in olfaction.
But in the course of those studies,
we basically discovered a menagerie of additional proteins
that were expressed in brain and liver and everywhere else,
suggesting that, in fact, G-protein signalling,
in general, was incredibly important.
We now know it is, in fact, the most probably important
signalling transduction pathway in humans.
And then, in parallel, we went onto of our other components in
that system, adenylyl cyclase, discovered that those
proteins were involved in learning of memory in the brain,
and there was a specific form in the olfactory system.
And likewise, with a couple of other components,
I recognized that one of those was shared in vision.
So, out of this study of this least useful to man in a state
of civilization, there were many spillovers that went broadly
through science, and in fact, our host tonight was interested
in G-proteins and G-protein signaling in slime molds.
And we actually collaborated with her mentor to find some of
those as well.
So, clearly there were lots of things along the way.
More recently, now that we've actually had a pretty good
understanding of what the common transduction component is,
we've been interested, how do you detect so many odors,
100,000 odors in mammals and similar numbers,
maybe not quite as high, in fruit flies and other organisms.
And what we understand is, is that there, in fact,
is an incredibly large family of similar related proteins called,
G-protein coupled receptors, selectively expressed in our
olfactory system at the back of our nose.
And all of those different receptors converge on to
this common pathway.
How do we generate specificity?
We put different receptors in each cell.
It turns out that, in mammals, we have about a million
sensory cells, sensory neurons, and they fire action potentials.
And about a thousand different receptors,
each of which is individually encoded into the genome.
And remarkably, each olfactory neuron picks only one receptor
out of those thousand scattered across your entire genome, and
activates it for expression in the particular cell.
So, you have 1,000 different kinds of cells and
about 1,000 of each specificity.
How the cell does that?
We've learned a lot, us and some of our colleagues.
In fact, it's a remarkable process.
They essentially do a random stochastic selection process,
epigenetic process, has become very popular these days.
And then, just to be sure you do it right, do it once and
only once.
There's a mechanism that shuts off all the other receptors
scattered across your whole genome.
It is one of the most remarkable epigenetic processes that,
I think, we know about in mammalian cells.
So, we've learned a lot about that process.
Now, in fact, we don't detect odors in the cell
bodies of each of these neurons.
These neurons sit in the back of your nose.
They send out a little process.
The wave goes out into the mucous and therefore,
the air that you breathe in.
And they send a process all the way back, deep into the brain.
And that's kind of,
if you think about it, kind of a bit of a risky thing to do.
You stick something in the outside world and
you send the same wire all the way into your brain.
It really is like the superhighway from
getting from outside to inside.
And moreover, everytime you smell not wine, but say,
ammonia, you can do damage to those cells.
So, we've been really interested in how those sensory cells
basically can get assaulted with damage and
maintain their connections.
And what we've learned is that, in fact, they do so by
burying their cell bodies down in a tissue more like your skin,
but because they have to detect chemicals.
They have to send something out,
and what they send out are cilia.
And cilia, in fact, we didn't recognize for
a long time, are very long, spider-like processes.
You can see them on some of the pictures as you go through here,
and these are the only parts of the cell that are actually
spread out in the outside world.
And in fact, all of those transduction components I told
you about, are actually localized in the cilia, and
that's where all the initial events by chemical.
Then, it turns out that those, all the cells that make
the same receptor go to the same place in the brain.
And as a consequence, when one kind of cell fires, we'll call
it the red cell, a little spot in the brain lights up.
And your brain basically reads that pattern to know what
the odors are.
So, we're really interested in how all those proteins get out
the cilia.
And in fact, we used one of those transduction components as
our model.
And the other thing we've learned is, is that protein that
goes out the cilia to maintain that process is in fact,
not expressed only in olfactory cells, but in other neurons in
you body, and in fact, in a few other places like in kidney.
And in fact,
what makes that particular version of the protein special
is that it can go out to these special structure, cilia.
And we're now beginning to realize from looking at some
genetic diseases in human, that, in fact,
putting transduction components into cilia, whether it be
olfactory cilia, the most elaborate cilia in your body, or
in photoreceptors, also specialized cilia, or
in fact, in brain neurons, is very important.
And we know about a number of signaling pathways, called
Sonic Hedgehog, for example, that must go through cilia to
send their signals to the cell and to the rest of the body.
And that suggests that, in fact, being able to have cilia and
being able to transmit signals like neuroendocrine signals for
feeding, perhaps, and behavioral changes, might be important for
them to come through cilia and
provide some new things that we never knew about.
We never actually knew that neurons had cilia
until we began to look using some of these tools, and
the fact the tool from olfaction turns out to be one of the most
popular defined cilia in your brain, so
that's the story about cilia cell biology.
And then, the last story I'll tell you is one that,
I think I'll begin by saying, if I were in a little black
turtleneck, I would say one more thing.
And I'm not, so I won't do that.
But I will tell you that there is one more thing that makes
this whole story even more remarkable in olfaction,
at least to me, and was the second thing that really drove
me to study this problem more than two decades ago.
And that was that your olfactory neurons, because they're being
constantly assaulted, have the ability to undergo continual
replacement throughout adult life about every 60 days.
And moreover, if you give them a really traumatic insult, for
example, 20 years ago, when you weren't wearing seatbelts and
you hit your head on the windshield, and
cut all the nerves that went back to the brain, there's
conduits I told you about, that all the neurons would die.
But within a few days, they would all come back again,
within two to three weeks, if you were lucky and
didn't have too much scar tissue.
Additionally, when you have a cold and
you lose your sense of smell, in some cases, what's happening is
you've losing your olfactory neurons and then,
they're regenerated again, all million neurons.
And we now appreciate that for cases of sinusitis inflammatory
processes involving a variety of infections, for example,
that those cells also can undergo regeneration.
But recently, we're now exploring the idea,
an observation that, in fact, those cells regenerate only
after the inflammation has been resolved.
And we think about teleologically,
I hate teleologic arguments, but
at least you can imagine in the case of an inflammation,
you would want to not regenerate those conduits back to the brain
until you resolve the information.
So, we've really focused ourselves on olfaction
as this curiosity for
the last two decades, continuing to do that, but in the process,
we've had really just a wonderful trip of being able to
see things throw off, that have impacted science broadly.
And we're beginning to learn something about the principles,
about why, for example, olfactory systems do this.
And Angelica, you'll hear about in a few minutes, and Paul,
that other sensory systems actually take slightly different
strategies, or lack the ability to do this.
And clearly, in an aging population, olfactory,
as well as other sensory modalities, begin to fade,
as I and others are beginning to notice.
And we really need to understand about ways of protecting and
with that, I think I'll stop, thanks.