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So this is a slice of an actual human brain,
which is the most complicated and the most versatile computer
that we know. It isn't the best computer these days for crunching really big
numbers,
or for playing chess or even for playing Jeopardy,
but it's terribly versatile. It's capable of
unlimited creative thought, of artistic
appreciation, of artistic creativity. It's capable of
moral judgments and it's capable of personal empathy.
My objective tonight is to tell you something about how this apparatus works,
the general rules for the the way in which the nervous system
sends and receives it signals and then since
many of you are parents, I want to focus in particular on how it gets put together
what are the processes that are involved in elaborating this remarkably complex
organ
and seeing that it's put together properly. So
to begin, I just want to remind you of the structure of the brain.
As you know, we have a spinal cord
which ends in a brain stem. This is the region that is responsible for
automatic functions such as breathing,
control the heart, control of digestion and what not.
Above that lies the cerebellum, which is involved in coordinated motions:
athletic endeavors, anything that requires fine balance
or fast activity. And everything else on the top
is the cerebrum, which has a frontal lobe, a parietal lobe, occipital lobe
and temporal lobe, of which I'm sure you've heard. This is
where we live. This is where the complex human activities reside.
This is where we sense our environment;
this is where we make decisions; this is where we take actions and most of the
presentation
will be about that. Now there's a daunting problem that one confronts
in thinking about the nervous system which is that there something on the
order of 100 billion
nerve cells in our brains. There's something on the order 100
trillion connections among all of those. So
it's such a bewildering amount of complexity that it seems almost
impossible
that we understand how it works but as I'll show you in a few minutes, the basic
underlying principles
are actually rather few in number and are quite accessible. The other point
that
I'll be dealing with is the fact that all of this apparatus
has to be specified by only about 20,000 genes.
We're still counting genes — it might be thirty thousand, some people think it
might be forty thousand. But this is a paltry number
by comparison to the other two. How can it be that this very small amount of
genetic information
can accurately and repetitively specify
an organ as complex as the human brain? This gives you a sense of the
complexity I'm talking about.
This represents about 1 billionth of the brain's complexity.
That is about a hundred nerve cells. And you can see that these nerve cells have
very complicated individual personalities,
all kinds of branching, all kinds of elaborate interactions
that are a bit bewildering. And even isolated, individual nerve cells
have this complex series of processes hanging off of them. The Christmas tree
sort of arrangement
or this large flap sort of arrangement.
Again how is all of this put together?
The first general principle is that all the activity stems from that of the nerve
cells from neurons
and neurons have only a few very
specific parts. Like every cell, the neuron has a cell body
and is that cell body is a nucleus which has
DNA and that's where the genetic information, all of the wiring diagram
for the cell, is stored. Neurons are special because they have these antennae
called dendrites that are processes emanating from the cell body
and radiating out in all directions and as you'll see in a moment
this is the site at which incoming information is received by the nerve cell.
They also have an axon, which is a process that can
conduct a particular type of electrical signal down to its end, and then again I'll
show you what that signal is
in just a moment. And finally, they have a synaptic terminal
where that information is transmitted to the next set of cells
in the network. So there's a full information
into this end of the cell along the axon and finally transmission
to cells that lie beyond.
The signals that we're dealing with have to do with ions
and membranes. And as you will remember
every cell has got a membrane around it. It's terribly thin - a 5 billionth of
an inch.
But it covers every square inch of every cell.
And this membrane has the property being relatively impermeable to ions.
So ordinary ions, which are things like sodium and potassium from your diet,
from daily salt, those things ordinarily cannot get across a membrane.
It's an impermeable barrier. But there are ways in which cells
have contrived to move ions across. Cells can make pumps
that are just what the name suggests. They actually do work
pulling ions across to one side. They use the cellular energy reserve —
ATP — which is made from the glucose and done.
So the idea of this is it's like charging up a battery.
If you push all the ions over to one side, say the left hand side,
you've done some work, you've stored up energy, and you can then release that
energy
for signaling purposes. This is where our
brain consumes most of its energy.
A brain runs at about the same power as a light bulb. A twenty watt lightbulb.
And most of the energies involved in what I just showed you, pumping ions across
the membrane
to one side and storing up energy.
So the energy is released by the activity of ion channels.
An ion channel is just a little pore — a protein molecule with a hole through it
that can allow ions to run out. But this pore is closed by a gate —
this yellow thing here — so that the channel doesn't have to let ions run all the time.
It could be turned on or switched off. When the channel is turned on,
which can be done by several different mechanisms: voltage,
nerve transmitters, mechanical stimulation, whatever, now ions can run
through,
some of the electrical current flows out, and that sends an electrical signal
in the cell. So the battery is charged up by the pump
and it's discharged by the flow of ions out.
Now this flow of ions produces something called an
action potential, which is the special nerve signal that propagates along
the entire length of the cell. And this is a sort of frightening diagram, of what
the action potential comprises.
The idea is that inside the cell normally
are potassium ions. They're the blue ones as mentioned down here.
When an action potential comes by, the membrane has ion channels that suddenly
let sodium,
which are the orange ions, run in. And those positive ions make the interior
of the cell
more positive. A little later the potassium ions
run out, also through a set of ion channels.
And that makes the interior more negative. And then the whole thing is
repeated again and again.
But the important point is that this sends an electrical messages rather
like a little blip
running down a wire or a bit of cable, carrying
a computerized message. In this case the whole action potential
slides down the axon to it's tip, carrying information from one end
to the other. This
wastes a certain amount of energy and the cell has to build up its energy reserves
again
by using glucose to make more ATP pumping more ions
and so when we're busy at thinking hard, we burn off energy,
then we recoup it, then we burn it off, we regain it and so on again and again.
And it's rather like a bank account. You draw down the bank account for a big
expenditure, then you build it back up, draw it down, and so forth and so on.
Individual cells are doing the same thing.
Now when the signal reaches the end to the axon,
it's got to be transmitted to another cell and that's done at what's called a
chemical synapse.
So here's the end of the axon and at its very end
the synaptic terminal. There are little bags of a chemical called
a neurotransmitter. Their are various kinds; you may have heard about acid choline,
dopamine or other things,
but these are all chemicals that are released from the little bags
when the cell is excited. They then fall through the space
to the adjacent cell, the so-called postsynaptic cell and they then excite it.
This is where our various pharmacological agents
act. For example anti-depressants or almost anything else you can think of.
They tend to act on the functioning at the synapses.
The importance of the synapse is that this nerve cell that I have shown here in
blue
is not receiving just the one input. It's receiving tens of inputs, hundreds of inputs, thousands,
hundreds of thousands of inputs. So the computation is done at this level.
Each cell is looking all the time at all of these inputs.
It's weighing them and then deciding whether it should be excited or not.
And if it is excited, then the flow of information here
across the synapse is propagated into the cell
which in turn becomes active and passes on the message
further down the line.
So this is the basis of all of the signaling in our nervous system.
Here's a very schematic diagram showing how
the information flows. Imagine that light comes in the eye.
It would excite this particular cell, which would send a message through this
one
to this one, finally excite this cell. It sends its
axon down the spinal cord, it excites the motor neuron,
(the dark red one here), which causes the muscle fiber here in that arm
to move and maybe a finger to twitch.
Or you might hear a sound — and I'll introduce this cell in a minute —
it sends information through this channel again down and causes
say a reaction, twitching a muscle. The same thing happens in the heart.
The lub-dub stem from the activity of ion channels
and the same sort of signaling in the muscle cells that make up the heart.
Now to get an input into the system requires that we convert
information from the external world into an electrical signal that the brain can then
interpret.
That's the process of sensory transduction. I'll give you a very brief example of this
dealing with the sense of hearing.
This represents a bit of speech, two-and-a-half seconds in length.
Up here, you see an electrical signal of the sort you would record.
If you look at what's coming out of the microphone I'm not wearing.
And below, you can see the syllables of speech broken down by frequency.
So these are low frequencies, these are progressively higher frequencies for
higher tones.
So this speech has some relatively low frequency parts
it has other chirps at other and higher frequency.
And this is actually a bit of a poem. This is
the end of "Fern Hill" by Dylan Thomas.
"As I was young and easy in the mercy of his means/ Time held me green
and dying/ Though I sang in my chains like the sea."
This piece is the last "Though I sang my chains like the sea"
and you can see that the low frequencies with the vowels,
like "though" and "sang"
and so forth in the high frequencies are the consonants.
"Sang" "chains" "sea" and what have you.
And the ear has to constantly capture this stream of complicated sounds,
break them down in terms of the different frequencies, and then tell the
brain what it's hearing
in order for you to understand speech. The cell that does that is called the hair cell.
It isn't a neuron, but it's a smooth cell that does make synapses
at its base. The thing that gives it its name is the so-called hair bundle,
this little cluster of feelers sticking out of the top.
And you can see that in a different kind of microscope. This very elaborate and
elegant structure
is somewhat like a set of organ pipes. It has a short edge
and then grows progressively taller as you go across. It has something like
fifty
to 100 pipes in the particular order.
This device is mechanically sensitive so each of the hair cells in your ear
responds with a mechanical stimulus reaches it and
tweaks this organ pipe array back and forth.
So each ear hair cell is a mechanical receptor,
the sound is covered into vibrations, the vibrations then cause
the cell to be excited. And the way in which the cell
is excited is simplicity itself.
At the top of each of these little hairs there's an ion channel. So 1 - 2 - 3 of
them. They're tied with little strings that are made out of protein,
When the hair bundle is pushed you can see that these little springs will be
stretched
by the sliding between the successive rods. That stretch
pops the channels open and just as you saw ions will now flow in through the channel
changing the voltage — the electrical signal inside the cell —
and that information will be propagated.
Now the organ that breaks down sound into its constituent frequencies
is the cochlea, the name coming from the Greek for a snail.
And the cochlea can be simply thought of as being a long tube,
about an inch and a half long, filled with liquid and with this
elastic structure like a rubber band running down its length.
When you hear a sound, the sound pushes and pulls on the eardrum
and the three little bones at the middle ear which you'll remember from
somewhere in high school or junior high, those three little bones move back and
forth
transmitting information into the cochlea and causing this rubber
band-like structured oscillate up and down.
The thing that's special about this membrane is it isn't like a guitar
string or something
that's homogeneous, the same everywhere. It's a magical string.
At this end at the apex or top-end, it's broad and floppy
that this end is very taut and very narrow and as a consequence different
frequencies of sound excite it in different places.
So low frequencies make it vibrate up here. High frequencies make it vibrate
down there
and other frequencies are represented in between and the really important thing
is that if you hear a complex sound like my voice
it sets the basilar membrane — this elastic structure —
into vibration in multiple different places corresponding to the different
frequencies you're hearing at any instant.
So this device is sort of the inverse of a piano.
In a piano you have a series of separates strings,
each carrying the particular note and the sound that comes out is the
combination of all other activities.
In this case we're taking a complex sound like the voice
we break it down into different components representing each of those in
a different place
and hair cells in those different positions then report
what is being heard. Now,
since we're in the Upper East Side it seems worth mentioning this other snail
like structure.
The Guggenheim Museum. The Guggenheim Museum in this map is at the end of
88 Street next to Central Park and it turns out that one can make a nice
simulacrum of the cochlea by imagining
that one could unroll that. And if you did and stretch it all the way down
88th Street to Carl Schurz Park you would have something
that, like the cochlea, has different frequencies represented in different
places.
So the cochlea has high frequencies here progressively lower ones as you
move down.
And this very much mimics the price apartments.
Up. [laughter]
There are some extra zeros that you can just barely hear but if you
— just barely really see — but if you want to live here you going to pay
$20 million,
two million, two hundred thousand or so.
$20,000 sounds very cheap, but that's the squirrels in Carl Schurz Park.
So what happens when you hear a complex sound, like the word
"chains." "Chaaaains" is that there is
a series of different oscillations along this membrane.
"Chains" with relatively high frequency the "ains" part with
lower frequencies and the "ffff" [?] at the end with high frequencies.
Each of those excites particular hair cells lined up along the road,
along this membrane and those in turn signaled by these blue nerve fibers
and actually the active nerve fibers are red in this diagram
that carries information into the brain about what you've heard.
So the next issue, having introduced how the signaling works, is how
things get that way. How do you put the brain together and
there are a series of steps that are highly choreographed by genetic information
and that are key to brain formation. The first of these
is growth, obviously, and the brain start out just
peanut-sized as a little layer of cells
with liquid inside. [blowing] And like this glove, it gets sort of inflated by the liquid
but it has just the very thin wall. The cells
in that wall then undergo a series of divisions so as time goes on, the wall
gets thicker and thicker as new cells are added.
So as cells are piled on, it gets thicker.
Like this. This isn't easy with a rubber glove, by the way.
And it gets thicker. So layer after layer it piles up until you get something
that is more or less brain size.
Now the most remarkable thing about this apparatus, after its assembled,
after all the cells are piled in there, is that
the cerebral cortex, which is, as I said, the really important part,
has to be crammed into this tight space.
The cerebral cortex is where we do our thinking and we need as much of it as
possible.
But this is a very tiny object. It has to be crammed into a
a head, to a skull, of fixed size.
So what nature's done is folded the brain
its corrugated the brain. So just as a way of reminding you of this,
this gives you an idea of how big the cerebral cortex really is. I don't have
a pizza,
but I have piece aluminum that's the size of a pizza.
That's how big your cerebral cortex is if you fold the thing up.
So this is corrugated in the way that we see.
Its folded over the brain, like that,
until you finally get this corrugated rough structure
cramming the size of a 16 or 20 inch pizza
into a much smaller container.
The next issue is pathfinding. Nerve cells that have been created
have to somehow get to their appropriate targets and
the way this is done involves a whole set of chemical signals
that we understand in part. In fact, Marc Tessier-Lavigne is a
person who has
contributed in an important way to our understanding in how this comes about.
So here's a schematic diagram of the brain, similar to what you've seen before.
This represents the cerebrum, the cerebellum and brain stem
and here's the spinal cord. So let's take a very simple example
something like a muscle. Perhaps the muscle that contracts with a doctor taps
on your knees
and it makes a reflex occur.
There are small muscle fibers that are sensory in nature.
They were enervated. They receive a nerve input from nerve fibers that wrap
around
those nerve fibers then go into the spinal cord
here's the nerve cell and cell body. Once it gets into the spinal cord,
the nerve fiber has to find its way to the appropriate target.
It uses a set of chemical cues. It uses gradients of the sort that'I'll show you in a
few minutes,
various other kinds of information. It knows that it should grow up in this
direction,
end at this point, and contact another cell. This all has a different set of
motivations,
a different set of chemical sensitivities and it does something
interesting.
It crosses the midline and we know something about the factors that cause
it to cross the midline.
Moreover, once it crosses the midline, it loses all interest in going back.
There's a switch that's thrown, a new set of genes are turned on.
And the cell now progresses up on this side and we'll never pulse back again.
And finally there's another synaptic connection that sends information
all the way up to the cerebral cortex so this is where, for example, you might
actually feel
a response as a result of this tap on the knee.
At the same time, information needs to flow in the other direction
to cause a motion to occur.
So we have other connections. We have neurons up here in the brain.
They can send a message down to cause a contraction. So this message
flows like this. It also crosses the midline.
And then runs with the separate set of chemical cues
down this fault. It then makes a contact with another neuron still
and that last neuron is the motor neuron (so-called) that actually sends a signal
out
and makes the muscle contract. There's also a direct connection between the
first cell,
the blue one, and the motor neuron. So
(this is another sentence) when you're tapped on the knee,
this signal goes right to the spinal cord, comes right back,
and causes your knee to twitch but at the same time the information goes up to
your brain
and tells you what's happened. And at the same time with the green neuron,
you could turn the system on and voluntarily move that muscle;
it isn't just driven by reflexes, but you can make it do what you want.
So this is something that is still being worked out. We want to understand what
all this chemical cues are
and, of course, as was mentioned in the introduction, those cues are very
important when something goes wrong in the nervous system.
Various diseases can disrupt the process. We would like to understand
what goes wrong and what can be done to prevent or reverse those problems.
The next thing is mapping. We have a prodigious number of neurons, as I mentioned.
Billions and billions of them. How do you make all of those connections?
Here is just a particular example in the visual system.
Visual information flows to the so-called visual cortex at the back of
the cerebrum.
And there are a number of separate areas there. V1, the first visual area,
V2, V3, V4 and so on. And then other areas with names like middle temporal
and there's yet another one here that we're not seeing very well: there's a purple
area down here.
Those subserve different functions. So
the first visual area, V1, looks at oriented edges.
It makes a sort of impressionistic or even
cubist drawing of the world around us. It tells us where all the edges of
things are. The second area, V2, is very good at parsing
stereoscopic depth. The third area
or the fourth area, V4, looks at different colors.
This purple area that you can't see so well notes faces.
MT detects motion such as this falling feather.
So the information that's coming in is spread
sequentially through each of these areas not directly to the next but
one to another in various combinations. Each of those areas
has to conduct a separate set of calculations and has to
deduce particular things about the environment around us.
The same thing occurs in hearing.
Information flows to the first auditory area, then to various
areas that are still uncharacterized around them. Some of that information goes to
Wernicke's area. And
this is the important part of the brain that parses our speech. It breaks down
the sounds like I showed you before
and decides what syllables are what and what the person is actually saying.
And that area is highly connected to a motor area: Broca's area.
This is the region in which, at least in part, we generate speech. In which we
generate responses
to what we've just heard. So how do you make connections among this
huge, huge number of cells?
Here's a diagram showing what the problem is. There are various levels; this
might be the first, the second, third and fourth
visual area. Each of them contains hundreds of millions if not billions of
cells
and they've all got to be connected up in a highly specific way
layer after layer. Not only is there this hierarchical organization from lower to
higher areas,
there's also a lot of parallel processing. That is, information branches
off
from one pathway to others and to yet others.
So at this level there are three different, separate things going on.
This might be color processing, this might be motion,
this might be stereoscopic depth. How do you make all those connections?
So here's sort of a diagram of what goes on conceptually.
This represents the lower part of Manhattan. This represents
Brooklyn. And each of these is a street corner say First Avenue
and 1st Street. Let's suppose for whatever reason and I don't know what
the motive might be
let's suppose you want to connect these things together so that you would
connect
1st Street in Manhattan and First Avenue to 1st Street and First Avenue
in Brooklyn. You would put some sort of a wire between the two
and go on and connect all the other corresponding points in this array.
This is what you would get. It's something that looks just like the nervous system. This
complicated set
of connections. The problem is to do it this way,
corner by corner, would require a huge amount of information.
It would require 1200 wires but more importantly it would require
specifying each of 2400 different corners
and connecting them up appropriately. The brain does not have the genetic
information to do that.
It can't specify each of billions and billions of neurons.
It must have more generic rules and in a way this is a little bit like what goes on
when you build a house.
Right? If you have plans for a house that your architect has drawn,
those lay down where the walls should go within an inch or two,
and they say where the electrical amenities should be and the like. But they don't
specify where every stud is or where every nail is to be driven.
And the nervous system has to work the same way. It has some broad
blueprint, but then it has to make decisions cell by cell
about the final wiring. So how can you solve the problem.
Here's a way of thinking about it. Instead of specifying
every street corner, the brain specifies just a couple
of axes, or dimensions. And I have arbitrarily made them
brightness — so this end of Manhattan is darker, this end is brighter —
and yellowness, so this end is more yellow, this end is less yellow.
So this might be because something yellow is coming out of the Hudson, which
seems
plausible and and sort of oozing across Manhattan,
but it's setting up a gradient, right? And similarly you can do the same thing in
Brooklyn.
The idea is then that you connect similar points.
It's hard to see, sorry, but the idea is that the brightest
or rather, the darkest yellow point is connected to the darkest young point,
the brightest point is connected to the brightest yellow point. The point in the
center is connected to the point in center
and so on. By doing this, you can make
all of these connections just by letting every nerve cell here
grow to a corresponding position over here. But now you don't need
thousands of pieces of information just these two gradients, just these two
shadings of brightness
and yellowness is all you need and this is in fact the way the nervous system works.
So here's a projection from the two eyeballs back
to part of the brain. And exactly this sort of arrangement works.
There's one chemical thats shaded in this direction. Nerve cells use that
information
to go to the other side of the brain and to wire up in corresponding positions
along the same axis.
And the side to side positions of the retina have another corresponding
gradient
of intensity that the nervous system uses. So each cell
can find its appropriate position and make the appropriate connection.
So with using just a few chemicals, you can specify how billions of cells
can wire themselves. The final important thing that goes on is competition.
Nerve cells fight with each other. They fight over their targets.
So here's an initial configuration with three nerve cells, or would-be nerve
cells,
trying to innervate these 30 different nerve cells, the blue ones down below.
And depending on how things start, when the different cells were born, so on,
some of them do better than others. So this arm cell, for example, is not
being very successful.
And what typically happens in that case is that that the cell retracts its axon
and often goes ahead and dies. Similarly,
if a cell is not innervated by anybody, it will often
die. In fact in much of our nervous system, there are twice as many cells as we
need
and during youth the excess number are trimmed away by this kind of competitive
process.
And by cell death. So when things work
right, you end up with a neat arrangement in which each of these two surviving
cells
encompasses about half of the array of the postsynaptic target cells
and they more or less equally share. There can also be problems if
one of these cells is at a comparative disadvantage. For example
in this case, we have two cells that start out innervating about
equal number of targets. But suppose something bad happens to this cell.
The cell becomes somehow weakened. Then the yellow cell tends to expand
farther and farther, the red cell gives up territory,
and again it may ultimately fade from from view.
This is what goes on in something like the problem with amblyopia
or what happens with "lazy eye." As you know, if a child has an eye
that deviates, that eye often is weakened in its connections to the brain.
The eye functions perfectly well, the nerve fibers function well,
the information flows into the brain, but as with this red cell,
the fibers are basically disconnected and the other eye,
here represented by the yellow cell, takes over.
There was a former president of this university, Torsten Wiesel, who many
have you know,
who with his partner David Hubel, worked out a good fraction of our understanding
of this competitive interaction
and what they were able to show is that there's a so-called critical period —
a narrow window during the first months or first years of life
when this kind of competition goes on. And it's key that during that period
one see to it that the weakened eye be given advantage.
For example, we could do surgery to repair an eye that's deviated
and one can then catch the other eye, making the yellow cell less competitive,
allowing the red cell to reassert itself and to produce
a normal cell connection.
Finally we come to the issue of genetics. As I said at the outset,
all this is encoded by a small number of genes.
Just twenty thousand or so. And those genes shape us
in every way. They have an enormous influence on what we—
who we are and what we can do. Well, what does 20,000 genes look like? What is that
information?
It's about this much. Here's a medium-size library.
If each of these books has about 200 lines per page
of small type, like that in the telephone book, this is the size of
all your genetic information. So on the one hand
its imposing. Its a lot of books, a lot of small print. But on the other hand
it's
a number books that we can readily read in a few years time
and in fact this is of course all now been parsed and is available on discs.
Every single letter in every single one of those books
is at least to some precision now known.
Now it's interesting to ask what happens when a mistake is made; when there's a
typo in one of those
these books and I will attempt another demonstration to give you an idea about
this.
This demonstration has to do with color vision and you'll see what's going on in a
moment. I hope I won't be in your way.
Shh.
I apologize. This machine is getting old. Slide projectors are nearly extinct as
you might suppose.
Okay.
So what we have here is
first, on your right,
a yellowish orange color. Its a pure
yellowish orange being shown on the screen. On the left, there's a combination of two different
colors.
And the combination of two colors looks like this. If I displace it,
you can see there's a purer red and a purer green.
And we've learned somewhere in junior high school that red plus green
makes yellow. So the object of this
exercise is to match the two to control the amount of red and green
until they match. So one can turn the *** here. Make it greener.
Make it redder. And somewhere along in here there will be a match
where they look more or less the same. They won't look exactly the same, but it's
close.
as they can get. Now I'm cheating.
I'm looking at the *** and I know sort of according to Kathy
where they should match. If I do this match myself,
I get this. I hear snickering in the back.
That's about the best I can do.
Those two things match for me. I dare say I'm in the minority. Leslie [Vosshall] is laughing
at me.
Would you care? Maybe would you care to come up
and do a match for us? All you have to do is turn the ***. So just turn this
one way or the other
and it'll get redder or greener until it looks about the same.
What do you think? Is that better than mine? Or what? [clapping] Yes. Quick, don't go away yet
you get this valuable
Rockefeller University coffee cup. Give it to your Mom.
Yep. The question is:
does anybody else agree with me? I don't know if anybody
cares to say, but there may be other people in the audience
who disagree with the majority opinion. Anybody willing to admit as much?
Maybe not tonight? 5 percent of men
have conditions similar to mine and they will match
with varying degrees the red and green in different ways.
Let me show you what this is all about. Why, what it has to do with genetics.
I'm a mutant. you see.
And here's what's happened.
Thirty billion years ago,
our ancestors in Africa had one gene
that controlled color vision and 30 million years ago, the old world apes, including
ourselves,
have a duplication of the gene. It was copied
twice and it diversified into making
a gene that is sensitive to red and a gene that is sensitive to green.
They both sit on the X chromosome. Now the X chromosome part is important
because of course
women get two X chromosomes; men
only get one. And that makes a difference in what happens as a result of this.
So normally,
when eggs and *** are being made, there's something called crossing over.
So here is the red gene and a green gene, say from one's father.
Here are the same genes, say from one's mother.
As an egg or *** is being made, the DNA from this
one combines with the DNA from that one and this crisscrosses the other way
so this becomes the new combination
AB' Green, AB' Green,
and this becomes another combination:
BA' Green, and so on down here. So this is fine. It just assorted the
genetic information
but all the information has been preserved more less in normal form.
But mistakes can be made. These two genes, because they diversified so recently from
each other,
look a lot alike and sometimes the copying process gets confused
so it makes a crossover like this one. Where you have part of a red gene
hooked to the green gene instead and part of this green gene
hooked to the red. So let's see what the product is. This gene now becomes
half red, half green and that's all. This gene has red
half a red, half a green and it looks like that. An individual like this which
is about five percent of the population of
men is red green colorblind. He cannot tell the difference between red and
green.
Even though— and in looking at this picture it would be very hard to
tell that they're two parts to that.
Perhaps your individual, like myself
gets this combination. I have a normal red gene,
I have a hybrid gene that is half green and half red,
and I finally then have an intact green gene.
We should turn this noise off. So as a consequence of this,
the protein made from this gene doesn't have enough green sensitivity.
I have to use a lot more green light to make a match,
so my match looks to you perhaps long green her match looks to me
more or less cherry red. There's that much difference in the two.
So the point of all this is not just
to make fun of me or or you or of anyone else
but the points is that this shows how evolution actually goes about its business.
This kind of mistake
occurs not infrequently. In fact, going back to this point,
genetic duplications can often occur. Usually when these genetic duplications
occur, they're inconsequential.
The second copy may be deleterious; it will then be weeded out,
or it may be neutral it may have no impact at all, in which case it'll hang around
but it'll just be converted into junk in the genome. Next,
this type of crossing over is a normal mechanism
and this crossing over allows the assortment
all kinds of different genetic combinations. It means that every child
who's created
has an absolutely unique combination of genes
contributed by one parent, by the other parent, in all kinds of
complicated mixtures. This means that each child is sorta of a separate story,
each child may have
extraordinary abilities that will then, we hope, get fixed, can be propagated to
the rest of the population.
And finally, mistakes get made. So here's a mistake.
A mistaken crossover. Genes get lost. Genes get duplicated.
Genes get mutated in other ways and this constantly is
affecting all us. Most of the results are inconsequential.
So all of us have a number genetic mutations.
Some of them are very small changes that allow us to do things such as DNA
sequencing to recognize criminals and the like
but they have no effect at all on one's life.
A few these mutations are beneficial and again
one hopes that they get fixed in the population, that they get preserved
and propagate. And a few of them are problematical.
They lead to sickness. They lead to death. And
there is something inexorable about this
process.
I guess that the final point I want to make is that
in this country, we have enormous advantages. We have
terrific equality, we have an enormous and unparalleled range of opportunities
before us
but we also do faced some genetic determinism.
Each of us is dealt a particular hand genetically.
Some people are born with exceptional abilities. Some people are born with
really crushing disabilities.
And if indeed a society is defined, if its evaluated by how it treats its
most vulnerable people
it's important to remember that. So I thank you for your attention. [clapping]
Marc: Thank you, Jim. Very fascinating lecture. I'd like to open the floor
to questions and there're three roving microphones. I'd ask that you wait for the
microphone
so that everyone can hear the question.
Man in Audience: Thank you for an extraordinary
lecture. I noticed that the powerhouse in the brain seems to be glucose and
maybe there are some suggestions for people's diets that might
increase our brain power. Jim Hudspeth: Unfortunately, I don't know of any.
Glucose is a major source of energy. The brain can also burn fat,
which doesn't help dietarily, but
obviously keeping the brain going is a primary responsibility of the body.
So basically, the brain has unusual metabolic capabilities
that keep it fired up even after everything else is running out of energy
because it's absolutely necessary.
Man2: Why the crossover?
Dr. Hudspeth: So the crossover assorts the genetic information and mixes it.
[con't] This is what sex is for. One thinks of it as just a chore, but
[laughter] Man2: Different crossover.
Man2 con't: Why the crossover from— Dr. Hudspeth: Ah, that. This crossover.
Man2: Yes. Dr. Hudspeth: Okay, let me finish answering the other question while I'm at it.
Since I got, since I've gotten that far. Crossing over
in genetics is what stirs things up together and allows genes that were separate in the
in the parents or in grandparents to be recombined in original and new ways
and so that's what really stirs the pot and produces all the new genetic information.
Why the crossing over? Nobody knows.
This has been a problem ever since neuroanatomists
identified it. It makes no particular sense. There have been many hypotheses. I don't know if
Marc has any of his own, but there's nothing intrinsical about the nervous system
that says that information
from your right side should go to the left side of your brain and
correspondingly
that action originating on the left side of your brain should end up moving your right side.
So, its imponderable. Sorry.
Woman1: I was really curious about what you said about the mutations
that have some benefit and some have no benefit and some just kind of sit there.
Could you comment on some mutations that we're aware of in populations?
For example, the asparagus issue.
That you can smell asparagus. The the issue about some people
can taste cilantro in a way that tastes like soap and it seems to be
consistent within the population that hates cilantro.
Can you comment on those or are those simply useless evolutionary
advantages or disadvantages of small mutations?
So yes, you're exactly right.
Those things do represent what are called different alleles. That is, different
flavors of the same gene.
And our olfactory system,
our smell apparatus, is a particularly striking example of that.
We have something on the order of I believe 600
active—400 I'm told—active odorant genes.
Mice and rats and so on have a thousand. They
are really very olfactory animals. Their life depends upon
their olfactory capabilities. We've lost more than half of our genetic complement.
We have a lot of what are called pseudogenes; genes that have been corrupted because
they're no longer necessary.
So in addition to those corrupted genes, we have, as you said,
differently alleles, different flavors of genes that make us sensitive or insensitive
to various things in the environment. And those taste examples and the smell examples you mentioned
reflect exactly those differences in two proteins.
Now we have in each of our genomes
a number of genes, present in two copies,
one which is mutated in such a way that we would be dead.
if we had two. So genes such as that of persistant fibrosis
have a prevalence of about 5 percent in our population.
Quite a high percentage. It's only if one has the bad luck of getting two copies that
the disease is apparent.
But. The disease is there, latent, in anybody who's heterozygotic.
In many cases, having a heterozygotic state for
a gene may be deleterious may confer some advantage.
It's thought, for example, that the cystic fibrosis gene in people who have one normal
copy and one abnormal copy may be somewhat more immune
to various kinds of enteric problems that were an issue
for Northern Europeans. Similarly, for African-Americans,
as you know, there is sickle cell disease. Having two sickle cell mutations can be deadly,
but having only one confers immunity to malaria.
There is similarly in the Southeast Asian population
What is it? Glucose six? Hydrogenase? Di-hydrogenase?
When mutated in one copy it protects against malaria
but two copies can be deadly. So we are all carrying around this combination
of mutated genes, of genes that are in the process of becoming different things
and again this is assorted in each generation.
Some people have good luck and some people have bad luck in terms of what hand they've been dealt.
Woman2: Hi. Can you share a little bit about some of the research you're doing?
And some of the, especially, for the regrowing of let's say the hair cells for neurosense and
cellular hearing loss? Dr. Hudspeth: Sure.
The two things we're interested in are,
first of all, how does this thing work? It turns out that our ears are not just
passive systems for catching sound. The ear actually has an
amplifier, a biological hearing aid built into it.
And our hearing is about 100 times more sensitive than one would suppose
just from the physics of the situation. It turns out that this hair bundle
doesn't just respond to oscillation, to
say, sound, but it can actually vibrate on its own.
And human ears, normal human ears, can produce sounds that come
out of the ear. Seventy percent of normal ears do that in a quiet environment.
Which seems quite weird. But really what's happening is there is an amplifier in there
and that amplifier, just like the public address system
in this room. If we turned it up too far, it begins to oscillate or howl and the sound comes out.
So we're trying to understand how that works. The other thing we're trying to
understand is why the ear is so vulnerable and what
we can do when these cells are damaged? How can we prevent that or how can we replace them?
Normally these hair cells are not replaced. You're born with 16,000 in each ear
and loud sounds, certain chemicals,
aging... all whittle away at them and we progressively lose our hearing.
We would like to find ways of bringing those cells back,
perhaps by using stem cells, which we're studying in
zebrafish of all things, trying to learn whether it's possible to regenerate the
cells and to regenerate similar cells in our own ears.
Man3: I wanted to ask a question about the competition
among the cells and the connections that are formed. You mentioned that
that competition goes on for a period of time, but I wasn't clear whether that was
months or
years that the brains...the cells are competing with each other to make
these connections.
And as kind of a follow up to that,
what happens when ... is there a way to reverse
when one aspect of the brain is becoming more dominant over the other aspects? Is there a way
to kind of retrain it?
Dr. Hudspeth: Yeah. They're really good questions and the answer is
there are different critical periods for different faculties so that for
vision, that I mention left versus right eye,
extends over a few years of time, so children up to an age of three or four
can still have some or complete remediation if they get the appropriate
eye operation and have an eyepatch.
There are other things that we know occur earlier. So for example
if you look at young children: Every child
in every culture everywhere in the world can understand all speech sounds.
so Japanese children can understand the R-L distinction.
We can, our children, can understand Mandarin Chinese tonality.
People can understand Xhosa other languages that have a click, which I can't do.
Xhosa. By about six months of age,
children begin to lose that. And by a year, they've by and large
lost it all together. So one loses the
sensitivity to sounds that are not in one's native language
after a critical period extending just six months or so.
One can obviously learn a foreign languages later but it becomes
progressively harder thereafter to learn it in an automatic way.
Woman3: Just on practical note, what are the chemicals that affect the ear hair?
Dr. Hudspeth: So there are several things that affect
these cells in a reversible way. Large doses of aspirin,
which people used to take for arthritis, and quinine, which they used to take for
malaria.
Both cause this thing to oscillate spontaneously and give people tinnitus,
or ringing in the ear. But the things that devastate it are two classes.
The first are antibiotics called amino glycosides.
this is Gentamicin, Tobramycin, Neomycin. Drugs of that sort.
Those devastate the internal ear, but they're sometimes necessary
to treat bacterial infections. For example, endocarditis,
a life-threatening infection of the heart.
You simply have to, as a clinician, use those drugs to save a life,
but you may cause partial or complete deafness as a result.
The other major one is Cisplatin, which is the major chemotherapeutic for
ovarian cancer.
And again there many women who have lost some or all of their hearing
but had their lives spared by the use of that drug.
Man5: On an evolutionary time-line,
what do you would you say is next?
[Laugh}
Dr. Hudpeth: I think probably the next stage is going to be
a reception in the lobby. [audience laughter] What do you think?
Marc: I think that's a great idea. I think we could take just a few more questions.
There. We have one there. Woman: What about
the effect of hormones on hearing? Testosterone, for example?
Jim: Yeah, so there are some interesting effects.
Even effects on the sounds that come out of the ears that I mentioned.
At different stages during the menstrual cycle,
women have different degrees of perfect pitch.
Women museum— women musicians
notice this. Also homosexuals have
somewhat different sounds coming out of their ears. I mean, one does not know why but
some difference in brain structure
causes the sounds to be modulated differently in men,
women, in homosexuals of either sex. So
we don't know the basis of that but there are definitely hormonal
effects. Man: Again on the competition of the brain and when it goes inside,
it seems that there are different phases for this. Is there
any applications in education for this? For example, if there's a phase
where children
are better suited to learn something
as opposed to another phase? Jim: Yeah.
You know, I don't think we know enough about that. Maybe I'll ask the expert.
You don't—my wife is a developmental pediatrician and she shaking her head
so I think the answer is we simply don't know enough.
I would say there almost certainly must be because these things do have critical periods.
There are particular things going on at particular times. And its striking when
you're raising a child
how from day to day things will switch. You can almost hear the genes clicking
as a child's behavior changes radically, for better or worse,
new habits are adopted, old habits simply evaporate. So
during those critical periods where the changes are occurring
it's no doubt there could be ways of accentuating the good,
may be suppressing the bad. But we just don't know enough yet.
Woman: I wonder, there are a lot of children who suffer from sensory integration disorders and I wonder,
you know, if your research or you have theories on
where that issue is coming from. Is it pathfinding? mapping?
You know that the competition and if you have
theories or thoughts. Thanks.
Jim: Maureen. So this has more impact with my wife who is
a developmental pediatrician and she is here to answer the hard questions.
Maureen: We really don't know.
I mean, clearly there are children who have sensory issues, which means that they process
sensations coming in differently that the rest of us.
So for some of these kids, sounds can be really
uh, feel horrible. For some of them, certain textures on their skin is really
aversive. But we don't know. I mean, there is a degree that you can
sort of retrain and certainly the
occupational therapist who do things like the brushing and the rocking...
It makes it better. But we don't understand
why those kids have those issues. And it's something
that is not just brand new because
my husband had had issues like that when he was a kid. I know I did.
I think all of us have them to some extent but for some kids that becomes more impairing.
Jim: Stay here in case there's another hard one. [laughter]
Let me answer one question that came from a gentleman at the back and I didn't give
an answer to the second half of it, but I think it's an important one and that is
is there any way of replasticizing the brain? I mean,
if there are critical periods that are passed,
if the eyes have not been properly wired, can you
have a second chance? And the answer so far is no, but it's clearly an area that
neuroscientists are interested in exploring.
We would very much like to find a pharmacological means, I'm sure you're
erstwhile company has looked into things like this,
of adjusting the brain and allowing connections to reform.
lower animal—so-called—can do this very well.
Even if nerve cells are destroyed, they can sometimes replace them
or they can at least regrow the connections. We can do this to a limited extent
and this is what is involved in, say, the recovery after a stroke.
Some part of the brain may be damaged, but other nerve cells nearby
will grow into that area or nearby areas
and establish a new set of connections. But obviously, our plasticity is limited.
There's a point beyond which we can't recover and that's we would like to to correct in the future.
Man: Perhaps you could comment a little bit on the
process of neural recruitment. My understanding is that
it's reported that when people,
early in life lose sight that
sometimes their hearing is enhanced.
At least that's a report. I don't know if that's actually true,
but, you know, many—interestingly—piano tuners are been blind
and I wonder if
you can comment on the process of the neural recruitment.
Jim: Yes. So that is somewhat related to the foregoing question.
As I mentioned, when a stroke or the like occurs, there can be rewiring.
Something similar happens if, early in life, some particular portion
of the ordinary connections are not present. So if, for example, in a blind person,
the visual cortex may be perfectly intact
even though the eyes are somehow non-functional and its been shown, using
an fMRI—functional magnetic resonance imaging—
that other functions can be taken up by the visual cortex.
It's also been shown in animal studies that if you take the information that
normally is connected to the
say, visual system, and connect it to the auditory cortex,
you nonetheless get some proper function or vice versa.
If you send auditory information to the visual system
the brain still know something about how to process that.
So the recruitment no doubt does involve
the extravagant growth of nerve fibers to places that are not getting a proper
input
and there is some expansion of the faculties as a consequence of that.
Woman: Could you comment on what you know
utility of EMDR
used in treating trauma, eye movement,
desensitization and reprocessing.
Jim: No? I'm afraid not.
I actually don't know the don't know the treatment. I apologize.
Woman: Okay, For the next lecture, then. Jim: Okay, done.
Man: I just wanted asked in regards to nutrition,
vitamins, this and that. In regards to the brain,
is there any correlation to help, to enhance, to make changes?
Jim: So this is certainly an area that a lot of people have worked on
and it's
it's an area where Maureen has a strong opinion.
If you had breakfast with us, you would find a little heap of pills
next to the cereal, so you can tell us what we know about that.
Maureen: We actually don't know as much as we would like to know.
Clearly humans have been around
for a long time and given our diet,
it clearly is enough to make your brain grow and develop.
We do know that if children are iron deficient
that that decreases their IQ later in life.
Jim: Folate. Maureen: Folate
can cause problems. There's a lot of
interest these days in omega-3 oils which clearly
have, in
animal studies, have affects on the membranes.
These coatings at these nerve cells and help
and neurotransmission. How those actually help... I mean, if you're already in good
shape,
does taking more of it make it better? We don't know.
I mean, there's a lot of work on people with dementia. You know, is there
something you can take that will
keep you from, your neurons from going bad?
But we... I don't... there's no clear answer yet.
Marc: Well, I'd like to thank Jim again for
a wonderful presentation. [clapping]