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So, we're going to finish now by
just talking more about this amazing

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immune system we have,
the adaptive immune system.

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As I said on Friday, this is really
an astonishing recognition system

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that just plays a key role in us
being able to survive in this world

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that's full of bacteria,
and yeast, and fungi, and viruses,

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parasites.
There are things just all the time

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trying to do us in,
and the reason we don't succumb is

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because we have this amazing immune
system.  And there are several

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features about it which I summarized
the other day.

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One is its diversity.
It has this incredible ability to

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recognize entities,
including things that are

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synthesized in a lab that had never
been seen on Earth before.

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It's amazing in terms of that side
of it.  Coupled with this is this

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incredible specificity.
As I indicated the other day,

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for example, if it was seeing a
benzene ring with a methyl on it,

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it might be able to recognize this,
but it could tell the difference

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from having the methyl over here.
It's got that level of

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sophistication.
In spite of that,

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in spite of the fact that it can
recognize everything else,

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it's able to  avoid self recognition,

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which is a bit of a trick if you

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think about it,
that you have a system that's able

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to see essentially anything,
including things that never existed

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before.  And how does it avoid
seeing all of our molecules,

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and all the many, many things that
makes us up?  So,

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it has to be able to tell self from
non-self.

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And then, I also talked about this
memory aspects of the immune system,

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that if you get exposed to a virus
or bacterium or something,

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but the first immune response is
relatively weak.

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But then if you get subsequently
exposed, you get a very powerful

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response.  And that's the principle
of a vaccine.  If you think someone

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is going to be exposed to chickenpox
but they haven't had it,

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if you could somehow elicit the
initial response without making them

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sick by using a killed virus or
something like that;

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polio is one of the examples you
hear about in the paper right at the

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moment.  Then,
if someone does encounter that virus

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or that bacterium,
because that's second response,

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it's very quick and it's very
powerful, and that's what vaccines

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are all about.
So, the issue,

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I guess, today is how does that
happen?  And this is one of these

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amazing insights into biology that's
come by an application of all these

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tools, recombinant DNA,
and sequencing, and all the fancy

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sort of things we've been talking
about in the past few lectures.

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So, the first part I need to let you
know, is there are two parts to this

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immune response, or two
kinds of responses.

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One's called the humoral response

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and one's called the cellular
response.  And this takes place in

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the plasma of your blood.
So, in the liquid part of the blood

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if you spin down the red cells and
the white cells,

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what you're left with is the plasma.

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And, what this humoral response
response does,

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it's able to target bacteria,
viruses, proteins.

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And the recognition is done by a

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special kind of protein called
antibodies.  And I'll tell you about

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that in just a moment because
they're a very important class of

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protein in this Earth.
And the cellular immune response is

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carried out by a special kind of
white blood cell.

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For this lecture I think I'll just

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abbreviate those as WBC if I need it.
What this targets is not the actual

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pathogen itself.
But it targets cells that are

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infected with a virus or a bacterium,
etc. and that might seem to be even

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a little bit more of a trick.
It's hard enough probably to figure

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out how to take something that's an
entity like a virus that's floating

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around your blood and figure out how
to find something that binds to it.

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What do you do if the thing's gone
into one of your own cells and it's

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hiding out in their replicating in
the same way that,

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let's say, a phage does or something
like that

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How do you see one of your own cells
that's been infected by something

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like that?  And there is a special
type of cells called cytotoxic T

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cell that's very important.
It's often abbreviated as that.

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So let me first say a word about
antibodies.  These are proteins that

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consist of four polypeptide chains.
Two of the chains are bigger.  So

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they're called heavy chains.
There's two of those.  And there

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are two chains that are smaller,
so those are usually called light

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chains.  So, there's four
of them altogether.

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And, ignoring secondary structure
and stuff for the moment,

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let me just sort of give you an idea
of how these are laid out.

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These are the two heavy chains.

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And these are joined together by
disulfide bridges.

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You remember disulfide bridges?
If you had two cystines they can

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form a covalent bond between them
under oxidizing conditions.

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So, those heavy chains are locked
together.  They're actually

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physically covalently joined.
In fact, there's the light chains

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here.  So, this is the light.
And this part up here is highly

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variable between different
antibodies.

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And the part down here is constant
between antibodies.

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And it's this huge amount of
variability that the body produces

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many, many, many types of antibodies,
and then figures out which ones will

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work to find the particular entity
it's trying to recognize.

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And I'll come back and tell you in
a moment how that is done.

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There is a diagram of what I showed
you, but of course these are

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proteins.  They have
three-dimensional structures,

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and so if you were to look at them
with the secondary structure showing,

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you can see the different,
especially here, a lot of beta

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sheets should be leaping
out at you.

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Now, the part where the recognition
is done is up at this end.

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So, it's essentially right here.
And here's a little movie.  You

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could see how the thing looks in
three dimensional space.

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You see the part that's over on the
left at the moment; that's the light

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chain and the blue chain is that
part of the heavy chain complex with

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the light chain.
And here is the,

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it's been tilted up this way so this
is the yellow and blue part

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you were looking at
And the recognition pocket is right

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at the end of that.
And at this picture,

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it's showing how a particular
protein was shown in red.

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This is an anti-body that can very,
very precisely recognize that

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particular protein.
You can't really tell it from the

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three-dimensional shape shown on the
left because it just shows the

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secondary structure.
But, if you could see the full

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space filling model,
you'd be amazed.  The surfaces are

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absolutely complementary.
It goes back to one of those

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principles I've said over and over
and over again that so much of

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biology works by having
complementary surfaces.

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And there's a little movie you
could see how this thing is setting

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up there at the top.
So, these antibodies are produced

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by a special type of what
are called B cells.

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These are cells that play roles in
the humoral part of the immune

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system.  And they're called plasma
cells.  And each plasma cell makes

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one particular antibody.
And that's it.

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So you have many different types of
plasma cells, but each one only

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expresses one particular gene that
encodes one particular antibody.

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So, for years, this is something
that people struggled with just

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conceptually.  They could sort of
calculate that there were so many

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antibodies that if your entire
genome was nothing but antibody

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genes, we still wouldn't have enough
DNA to account for all this ability

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to recognize things.
So, some other principle had to be

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involved.  And there are all sorts
of speculations about what it was.

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I had shown you, I'd managed to not
get Bob Horvitz's thing on here,

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but this then, who is our fourth
Nobel laureate,

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I've been sort of working through
these.

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Susumu Tonegawa,
who is in the cancer center,

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he's in the biology department.
He's also heading, now, this

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Picower Center of learning and
memory.  So, since doing this work

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I'm telling you about on the immune
system, he's gone to do some

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wonderful stuff more on the big
problem of how we learn,

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and trying to get more molecular
insights into that process.

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But what Susumu managed to figure
out was that this variation and

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diversity in the immune system was,
at its roots, a combinatorial sort

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of process.  So,
if you look in the DNA of a zygote,

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so that's the fertilized egg.  We're
just getting started with one of our

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cells.  You've got a single cell.
We're looking in the DNA to see

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what would happen.
We come to the part of the DNA

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that's involved in producing
antibodies.  What he found was that

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if you looked along the DNA,
there were sequences that looked

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like part of the stuff that you'd
find in antibodies,

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but there were a whole series of
them.  So, he called this particular

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segment V1, V2,
V3, up to VN.  There were a whole

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set of these basically side by side
by side by side.

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There are about 300 of these in
humans.  And then down the DNA a

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little bit he found another set of
sequences that are all variations of

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each other.  And these were given D1,
D2, D3, D4, up to DN.

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And there are many of these.
And then down the DNA a little

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farther, there were three other
sections that were called joining

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segments.  They were called J1,
J2, J3.  And a little bit farther

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down there was a block of DNA coding
the constant part of this

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polypeptide chain that goes
into an antibody.

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And what Susumu Tonegawa was able to
show, and this led to the Nobel

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Prize.  So, what happens during the
development of these B cells is

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there are rearrangements.
And a lot of DNA is thrown around.

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And the basic strategy is to take,
if you think this as being column A,

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you take one from column A, one from
column B, just picking them randomly,

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one from column C over here,
and throw away everything else.

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So you might have,
for example, in one B cell,

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you might have V32, D15, J2,
and then the constant region.

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And, what's in between is an intron
that will be spliced out at the time

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that the gene's expressed.
In another B cell, you might

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have V11, D22, J3.
So, this rearrangement is random in

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the sense of which V segment is
chosen, which D segment is chosen,

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and which J segment.  I don't mean
that it all just joins together in a

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completely uncontrolled way.
And then the rest of the DNA is

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deleted.

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So a consequence of this,
is each B cell expresses only one

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antibody.  It's true that they're
diploid, but only one chromosome

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is expressed.
So that's how they avoid,

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you can imagine they might make to
two.  But they only make one.

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In the process, as you can see,
that part is random.  Furthermore,

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the joining events are what I think
you could call sloppy.

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And this leads to even more
variation than you would have

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imagined simply looking at the
number of segments.

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So, what this part of the process
does is it explains why the system

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can be has the diversity it has,
because it's using this

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combinatorial process.
If you know the number you can

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calculate how many possible
combinations there are.

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But then there's much more
variation because when it joins

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together a little segments that are
joined are done in a sloppy way so

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that the DNA sequence that shows up
where the joints occur doesn't look

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like anything that was in the DNA at
all.  It was something like a

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polymerase that wasn't very faithful
copying and making mistakes

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as it went along.
So what the system does,

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is it doesn't get you a response.
It just explains why there is so

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much diversity,
and why it is that I can go into the

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lab and synthesize a compound that's
never been on this earth before,

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inject a rabbit to it, and the
rabbit will probably produce an

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antibody that's able to recognize
that.  That's because it's made this

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whole set of them.
And they all are going to have

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somewhat different surfaces.
And they make so many that one of

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those surfaces is going to fit the
molecule that I'm testing.

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You can sort of see,
that's only part of the trick.

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So, how do you now get an immune
response?  Because you've got

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millions of these things.
But what you now need is a whole

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lot of one particular antibody
that's going to recognize the

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pathogen that you are being exposed
to.  And the principle of that is

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really cute.  It's a process called
clonal selection.

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And the idea is that each

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B cell displays

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a sample of its antibody on  its
surface.  So, we might think of it

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this sort of way,
that after this process is through

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we have one B cell.
Of course, these are way out of

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proportion.  The cells would be huge,
and these would be molecules.

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So, they're small.  But here would
be an antibody that can recognize

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squares, say, this one would have an
antibody that could recognize

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triangle.
This one would have an antibody that

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could recognize a semicircle and so
on, millions and millions of

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different shapes.
And these cells don't divide,

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though.  They've been made, and they
just sit there.

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And then, when you stimulate them
with an antigen,

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and I used that word the other day,
an antigen is just anything that

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will elicit an immune response.
It could be a piece of a foreign

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protein, carbohydrate,
just about anything that's a small

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molecule you've made in the lab.
But let's say we exposed now this

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00:21:09,000 --> 00:21:19,000
individual to an antigen,
which in this case can fit into that

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00:21:19,000 --> 00:21:30,000
receptor.  And what happens,
then, this one becomes stimulated to

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00:21:30,000 --> 00:21:40,000
divide.
So what we have now is this B cell

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00:21:40,000 --> 00:21:49,000
that has this antigen stuck into its
binding pocket on the sample of its

225
00:21:49,000 --> 00:21:59,000
antibody.  And then,
the cells divide and they give rise

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00:21:59,000 --> 00:22:08,000
to two populations.
They give rise to the plasma cells,

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00:22:08,000 --> 00:22:17,000
which are very short-lived, on the
order of a few days.

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00:22:17,000 --> 00:22:26,000
And what these do, so they would
look like this,

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00:22:26,000 --> 00:22:35,000
what they do is secrete antibodies
into the plasma.

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00:22:35,000 --> 00:22:40,000
So what you end up with,
then, are a lot of these antibodies

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00:22:40,000 --> 00:22:45,000
that have exactly the specificity
that the original sample had on the

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outside of that particular B cell.
This takes a few days.  So back

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00:22:50,000 --> 00:22:55,000
when we were talking about the
discovery of DNA,

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00:22:55,000 --> 00:23:00,000
I was telling you about
Streptococcus pneumonia,

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00:23:00,000 --> 00:23:05,000
and you get infected by the
Streptococcus.

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00:23:05,000 --> 00:23:09,000
And there would be this period of
five or six days where this person

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00:23:09,000 --> 00:23:13,000
was very sick,
and then either they'd survive or

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00:23:13,000 --> 00:23:17,000
they didn't survive.
If they survived, they'd been able

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00:23:17,000 --> 00:23:22,000
to mount an immune response and make
these antibodies before they got

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00:23:22,000 --> 00:23:26,000
killed by the bacteria.
And the reason it takes a few days

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00:23:26,000 --> 00:23:30,000
is when you start out there could be
just one B cell that's able with an

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00:23:30,000 --> 00:23:35,000
antibody, makes an antibody that is
capable of recognizing the capsule.

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00:23:35,000 --> 00:23:39,000
Maybe there are a few.
Anyway, but they were very,

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00:23:39,000 --> 00:23:43,000
very tiny number, and there were
probably a lot of bacteria.

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00:23:43,000 --> 00:23:47,000
So what had to happen, then,
is that the original cell or small

246
00:23:47,000 --> 00:23:51,000
number of cells that could recognize
the Streptococcus had to be

247
00:23:51,000 --> 00:23:55,000
amplified.  They had to make a lot
of plasma cells that have the

248
00:23:55,000 --> 00:23:59,000
potential to make the antibody,
and then they had to secrete the

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00:23:59,000 --> 00:24:03,000
antibody into the plasma.
And I'll tell you in just a minute

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00:24:03,000 --> 00:24:08,000
some of the strategies that that
uses to help kill the pathogen.

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00:24:08,000 --> 00:24:14,000
And the other population, just
before I go on there,

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00:24:14,000 --> 00:24:19,000
are what are called memory cells.
There's not as many of these made,

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00:24:19,000 --> 00:24:24,000
but they're very long-lived.  And so,
what they have is exactly the same

254
00:24:24,000 --> 00:24:30,000
capacity to make the same antibody,
but they're not actively dividing.

255
00:24:30,000 --> 00:24:37,000
They'll just sit there,

256
00:24:37,000 --> 00:24:45,000
float around in your bloodstream,
and then if you get a second

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00:24:45,000 --> 00:24:54,000
exposure to the antigen,
you get a very fast and strong

258
00:24:54,000 --> 00:25:03,000
response because the selection for
finding the cells that had

259
00:25:03,000 --> 00:25:12,000
antibodies that can recognize the
antigen has already been done.

260
00:25:12,000 --> 00:25:15,000
And there's already a few of them
around, and then after you do that

261
00:25:15,000 --> 00:25:19,000
then you're able to make,
once again, the binding of the

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00:25:19,000 --> 00:25:22,000
antigen stimulates these guys to
start dividing.

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00:25:22,000 --> 00:25:26,000
They make a lot of plasma cells.
And going back to the principal of

264
00:25:26,000 --> 00:25:30,000
vaccination, your first response is
fairly modest.

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00:25:30,000 --> 00:25:34,000
But if you get a second response,
what you're doing now is the memory

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00:25:34,000 --> 00:25:39,000
cells are already there.
They have the specificity for

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00:25:39,000 --> 00:25:43,000
recognizing the antigen in question.
And you can make a whole lot of

268
00:25:43,000 --> 00:25:48,000
them.  So, if you had chickenpox
when you were little,

269
00:25:48,000 --> 00:25:52,000
you have memory cells that know how
to recognize the chickenpox virus.

270
00:25:52,000 --> 00:25:57,000
And then when your kid gets
chickenpox like mine did,

271
00:25:57,000 --> 00:26:01,000
I didn't get sick because I had
memory cells that were able

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00:26:01,000 --> 00:26:07,000
to recognize that.
OK, so what happens if you get an

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00:26:07,000 --> 00:26:14,000
antibody?  How does this help the
organism, or in our case someone

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00:26:14,000 --> 00:26:22,000
like you or me,
avoid getting sick?

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00:26:22,000 --> 00:26:29,000
So there are a couple of strategies.
One we might think of

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00:26:29,000 --> 00:26:35,000
is bind and block.
For example, you are a virus and you

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00:26:35,000 --> 00:26:40,000
get covered by antibodies.
Viruses: it's exactly the same

278
00:26:40,000 --> 00:26:46,000
logic as bacteriophage,
except that instead of affecting a

279
00:26:46,000 --> 00:26:51,000
bacterial cell a virus would be
infecting one of our cells.

280
00:26:51,000 --> 00:26:56,000
And as the virus has receptors or
something, it has to recognize

281
00:26:56,000 --> 00:27:02,000
something on my cell,
in order to attach and then to

282
00:27:02,000 --> 00:27:08,000
inject its DNA.
So if we've got an antibody sitting

283
00:27:08,000 --> 00:27:15,000
here, then it can't find its way to
the host cell.

284
00:27:15,000 --> 00:27:22,000
And then, there are a couple of
other ways.  They can target for

285
00:27:22,000 --> 00:27:29,000
destruction.  And there's basically
two ways.  There's something called

286
00:27:29,000 --> 00:27:36,000
the complement system,
that if it is able to recognize,

287
00:27:36,000 --> 00:27:44,000
say, the bacterial cell and their
antibodies are sticking to the

288
00:27:44,000 --> 00:27:52,000
outside, what the complement system
does is it's able to make little

289
00:27:52,000 --> 00:28:00,000
pores in the membrane
of the pathogen.

290
00:28:00,000 --> 00:28:03,000
And I think one of the things I hope
you will remember is that one of the

291
00:28:03,000 --> 00:28:07,000
secrets of life is that we have to
keep that membrane around there.

292
00:28:07,000 --> 00:28:10,000
We have to keep all of our insides
in, and the rest of the world

293
00:28:10,000 --> 00:28:14,000
outside.  We have hydrogen ion
gradients across the membrane.

294
00:28:14,000 --> 00:28:18,000
So, if you want to kill a cell and
you, say, insert a protein that has

295
00:28:18,000 --> 00:28:21,000
a little hole and it,
and that thing sits and sticks in

296
00:28:21,000 --> 00:28:25,000
the membrane, that cell is dead.
It can't maintain an ion gradient,

297
00:28:25,000 --> 00:28:29,000
and things can leak out through the
hole.

298
00:28:29,000 --> 00:28:35,000
So that's one of the ways of killing
it.  The other ways are macrophages.

299
00:28:35,000 --> 00:28:42,000
These are a type of white blood
cell, as well,

300
00:28:42,000 --> 00:28:48,000
are very good at recognizing
bacteria that have antibodies stuck

301
00:28:48,000 --> 00:28:55,000
to the outside.
And in fact, that was the principle

302
00:28:55,000 --> 00:29:02,000
of that.  We have the Streptococcus,
and we have the capsule.

303
00:29:02,000 --> 00:29:06,000
And you may remember that little
movie I showed of a white blood cell

304
00:29:06,000 --> 00:29:10,000
that was trying to eat it,
and it couldn't get hold of the

305
00:29:10,000 --> 00:29:14,000
thing, whereas we saw another
example where a bacterium without a

306
00:29:14,000 --> 00:29:18,000
capsule, there was sort of principle
I said is that the white blood cell

307
00:29:18,000 --> 00:29:22,000
was able to recognize the bacterium
and then it pinches it off inside of

308
00:29:22,000 --> 00:29:26,000
a membrane bubble.
And I sort of said at least in

309
00:29:26,000 --> 00:29:30,000
principle that there is another
little bubble with poisons,

310
00:29:30,000 --> 00:29:35,000
and it brings it together so that
you have the bacterium and the

311
00:29:35,000 --> 00:29:40,000
poison together inside of some
intracellular compartment,

312
00:29:40,000 --> 00:29:45,000
so that macrophages know how to kill
a bacterium if they bring it inside.

313
00:29:45,000 --> 00:29:50,000
The problem in the case of
something like Streptococcus was

314
00:29:50,000 --> 00:29:55,000
being able to recognize it because
it couldn't get hold of that capsule.

315
00:29:55,000 --> 00:30:01,000
So, those antibodies that guy made
during that five day thing decorate

316
00:30:01,000 --> 00:30:06,000
the outside of the capsule because
their specificity is to recognize

317
00:30:06,000 --> 00:30:11,000
the capsule and bind to it.
But a macrophage,

318
00:30:11,000 --> 00:30:15,000
even if it couldn't get hold of the
bacterium with a capsule is able to

319
00:30:15,000 --> 00:30:20,000
ingest something that has antibodies
stuck on the outside.

320
00:30:20,000 --> 00:30:24,000
And once it gets inside,
it can kill the bacterium.

321
00:30:24,000 --> 00:30:29,000
In fact, immunologists call this
process opsinization,

322
00:30:29,000 --> 00:30:33,000
which is derived from the Greek
words for seasoning,

323
00:30:33,000 --> 00:30:38,000
like putting salt on your food.
And the idea was that when they were

324
00:30:38,000 --> 00:30:42,000
giving that word,
with these macrophages,

325
00:30:42,000 --> 00:30:46,000
which liked to eat bacteria,
they have a little seasoning that

326
00:30:46,000 --> 00:30:50,000
they have these little antibodies
decorating their outsides.

327
00:30:50,000 --> 00:30:54,000
So here you can see it least in the
humoral response how you generate a

328
00:30:54,000 --> 00:30:59,000
whole lot of diversity.
Then this principle of what's called

329
00:30:59,000 --> 00:31:03,000
clonal selection identifies a B cell
that's able to make an antibody that

330
00:31:03,000 --> 00:31:07,000
can recognize the particular
pathogen or molecule that you're

331
00:31:07,000 --> 00:31:12,000
being exposed to amplify that,
make a lot of antibodies, and then

332
00:31:12,000 --> 00:31:16,000
it can either just stick to the
pathogen like a virus and mess it up

333
00:31:16,000 --> 00:31:21,000
that way, or it can decorate it if
it's something like a bacterium,

334
00:31:21,000 --> 00:31:25,000
and then pull in a couple of other
systems that are capable of killing

335
00:31:25,000 --> 00:31:30,000
the pathogen.  I mean,
it's an absolutely amazing system.

336
00:31:30,000 --> 00:31:33,000
It sounded like science fiction when
I first heard about it.

337
00:31:33,000 --> 00:31:36,000
When I heard people talking about
it, everyone could see there was an

338
00:31:36,000 --> 00:31:40,000
information theory problem.
How do you encode all that

339
00:31:40,000 --> 00:31:43,000
information with just this amount of
DNA in a cell?

340
00:31:43,000 --> 00:31:47,000
Now we understand.
And there's even another part that

341
00:31:47,000 --> 00:31:50,000
I'm leaving out here.
But once this whole thing has been

342
00:31:50,000 --> 00:31:54,000
selected, there's another whole
round of sort of refinement where

343
00:31:54,000 --> 00:31:57,000
the cells do kind of a very kind of
localized mutagenesis one base pair

344
00:31:57,000 --> 00:32:01,000
at a time in the vicinity
of this binding pocket.

345
00:32:01,000 --> 00:32:07,000
And they're able to make,
if they're given more time and more

346
00:32:07,000 --> 00:32:13,000
exposure to the antigen,
they can make a better and better

347
00:32:13,000 --> 00:32:19,000
binding surface until you begin to
approach sort of the theoretical

348
00:32:19,000 --> 00:32:25,000
maximum.  Now,
the T cell, in this case this

349
00:32:25,000 --> 00:32:34,000
involves the cytotoxic T cells,
and they have a specific recognition

350
00:32:34,000 --> 00:32:47,000
molecule on their surface.
It's called the T cell receptor.

351
00:32:47,000 --> 00:33:00,000
And in this case, it's attached.

352
00:33:00,000 --> 00:33:04,000
So, this is the membrane of the T
cell.  And this is the cytoplasm

353
00:33:04,000 --> 00:33:08,000
down on this side.
There's a little bit of the protein

354
00:33:08,000 --> 00:33:12,000
that goes into that.
And then there's an alpha helix

355
00:33:12,000 --> 00:33:17,000
that goes through,
and then a segment that comes up

356
00:33:17,000 --> 00:33:21,000
like this.  And there's another
chain that does the same thing.

357
00:33:21,000 --> 00:33:25,000
So, there are two segments that
span the membrane.

358
00:33:25,000 --> 00:33:30,000
This thing is anchored in the
membrane.

359
00:33:30,000 --> 00:33:34,000
And then it's essentially the same
principle as with antibodies.

360
00:33:34,000 --> 00:33:39,000
There's a variable region, and
there's a constant region.

361
00:33:39,000 --> 00:33:44,000
And to a first approximation anyway
the logic by which the cell

362
00:33:44,000 --> 00:33:49,000
generates a huge,
diverse set of T cell receptors is

363
00:33:49,000 --> 00:33:54,000
the same logic that underlies the
generation of a whole lot of

364
00:33:54,000 --> 00:33:59,000
different antibodies by taking
segments, joining them,

365
00:33:59,000 --> 00:34:04,000
picking them randomly out of column
A, column B, and then joining them

366
00:34:04,000 --> 00:34:09,000
together, sloppy joining all the
other processes to increase the pool

367
00:34:09,000 --> 00:34:19,000
of diversity.
Now, what these B cells are able to

368
00:34:19,000 --> 00:34:33,000
do, then, these T cells are able to
do is something quite remarkable.

369
00:34:33,000 --> 00:34:38,000
We have on our cells,
this is, say, one of my cells,

370
00:34:38,000 --> 00:34:43,000
little sort of proteins that
function as sort of display cases or

371
00:34:43,000 --> 00:34:48,000
something.  And what they do is they
show samples of all of the different

372
00:34:48,000 --> 00:34:53,000
proteins that are inside us at any
given moment.  Proteins are turned

373
00:34:53,000 --> 00:34:59,000
over, and chopped up,
and things are recycled and so on.

374
00:34:59,000 --> 00:35:07,000
So there are always little peptides,
little pieces of proteins around.

375
00:35:07,000 --> 00:35:16,000
And, the display case,
if you will, has got a major

376
00:35:16,000 --> 00:35:25,000
histocompatibility complex,
which is usually abbreviated as MHC

377
00:35:25,000 --> 00:35:32,000
because it's such an unwieldy name.
And there are many,

378
00:35:32,000 --> 00:35:36,000
many alleles of MHC in the
population, which means that we each

379
00:35:36,000 --> 00:35:40,000
have, for the most part,
a sort of individually designed

380
00:35:40,000 --> 00:35:44,000
display case for showing these
peptides.  The property of these

381
00:35:44,000 --> 00:35:49,000
display cases,
they take some little piece of a

382
00:35:49,000 --> 00:35:53,000
protein just a few amino acids long,
it binds into the display case, and

383
00:35:53,000 --> 00:35:57,000
that sticks on the outside of our
cell.  And so we have

384
00:35:57,000 --> 00:36:02,000
a lot of these.
And so on the surface of our cells

385
00:36:02,000 --> 00:36:07,000
are these little individualized MHC
display cases showing little samples

386
00:36:07,000 --> 00:36:12,000
of the peptides of the proteins from
the proteins that are inside us.

387
00:36:12,000 --> 00:36:17,000
So, if everything is fine, all of
the peptides that are in the display

388
00:36:17,000 --> 00:36:22,000
cases are our own.
And I'll tell you in a minute why

389
00:36:22,000 --> 00:36:27,000
that doesn't cause a problem.
But then if you get infected by a

390
00:36:27,000 --> 00:36:32,000
virus, and it injects DNA or its RNA
inside of you and then starts to

391
00:36:32,000 --> 00:36:37,000
replicate, now you have some virus
proteins that don't belong to you.

392
00:36:37,000 --> 00:36:43,000
They get chopped into pieces,
and they begin to appear on these

393
00:36:43,000 --> 00:36:49,000
major histocompatibility display
cases.  So if you think here,

394
00:36:49,000 --> 00:36:56,000
this could be, perhaps, a little
piece of, let's call it self protein,

395
00:36:56,000 --> 00:37:02,000
it could be a little piece of my own
DNA polymerase or something

396
00:37:02,000 --> 00:37:09,000
like that.
And over in this one,

397
00:37:09,000 --> 00:37:17,000
let's say we have a little piece of
a viral protein.

398
00:37:17,000 --> 00:37:25,000
So that's something that would not
be normally there.

399
00:37:25,000 --> 00:37:33,000
So what this T-cell receptor does
is it recognizes, so this

400
00:37:33,000 --> 00:37:40,000
is non-self or foreign.
What the T-cell receptor does is it

401
00:37:40,000 --> 00:37:46,000
recognizes these foreign peptides.
But it does it in the context of

402
00:37:46,000 --> 00:37:53,000
the display case.
Otherwise the peptides would be

403
00:37:53,000 --> 00:37:59,000
floating around.
So, in essence, the T-cell receptor,

404
00:37:59,000 --> 00:38:06,000
if this is a cytotoxic T cell it's
able to see the individual display

405
00:38:06,000 --> 00:38:13,000
case with a bit of viral
protein in it.

406
00:38:13,000 --> 00:38:17,000
And then it knows that it should
kill that cell because it's got

407
00:38:17,000 --> 00:38:21,000
something in it that shouldn't be
there.  I mean,

408
00:38:21,000 --> 00:38:25,000
it's a brutal but very effective
strategy.  If we applied it here,

409
00:38:25,000 --> 00:38:29,000
I go around if I found any of you
had a cold, I could just take a gun

410
00:38:29,000 --> 00:38:33,000
and shoot you and it would cut down
on the number of sick days for the

411
00:38:33,000 --> 00:38:38,000
rest of us because it wouldn't
spread the infection.

412
00:38:38,000 --> 00:38:42,000
But in essence,
at a molecular level,

413
00:38:42,000 --> 00:38:46,000
that's the strategy.  Try to
identify a cell that's got something

414
00:38:46,000 --> 00:38:50,000
inside it that shouldn't be there,
and then the cytotoxic T cells kill

415
00:38:50,000 --> 00:38:54,000
that.  And let me just show you a
couple of quick movies of this.

416
00:38:54,000 --> 00:38:58,000
At this point, these will be the
last protein structures you're going

417
00:38:58,000 --> 00:39:03,000
to see from me, I think.
Here's a representation of that T

418
00:39:03,000 --> 00:39:07,000
cell just as a cartoon as you see it
in a textbook.

419
00:39:07,000 --> 00:39:11,000
Here it is.  This is the binding
pocket up here.

420
00:39:11,000 --> 00:39:15,000
And there's a little tiny peptide,
nine and amino acids from the HIV

421
00:39:15,000 --> 00:39:19,000
virus bound in here.
Somebody did a crystal structure,

422
00:39:19,000 --> 00:39:23,000
and was able to work that out.  And,
if you look at it in three

423
00:39:23,000 --> 00:39:27,000
dimensions, you'll see how
beautifully this little binding

424
00:39:27,000 --> 00:39:31,000
pocket and the peptide
lies in there.

425
00:39:31,000 --> 00:39:35,000
So that red part is the piece of
chalk, and the other part is what

426
00:39:35,000 --> 00:39:39,000
I'm describing as my hand.
It's not a bad analogy, actually,

427
00:39:39,000 --> 00:39:44,000
even on a structural level.  And
then, here's another representation.

428
00:39:44,000 --> 00:39:48,000
This is sort of showing the hand
with a piece of peptide in it.

429
00:39:48,000 --> 00:39:53,000
And then the T cell is able to see
this whole thing in recognize it.

430
00:39:53,000 --> 00:39:57,000
And, if you look at it in a
structural form, here's

431
00:39:57,000 --> 00:40:02,000
the little peptide.
This is the part,

432
00:40:02,000 --> 00:40:07,000
the display case you're looking at.
And here's the T cell receptor now

433
00:40:07,000 --> 00:40:11,000
fitting down in seeing the peptide
in the context of this major

434
00:40:11,000 --> 00:40:16,000
histocompatibility antigen.
And again, these things are all

435
00:40:16,000 --> 00:40:21,000
beautifully complementary a three
dimensional level.

436
00:40:21,000 --> 00:40:26,000
Again, at the heart of this is the
principle of complementary surfaces

437
00:40:26,000 --> 00:40:31,000
fitting together that underlies so
much biology.  What's this?

438
00:40:31,000 --> 00:40:36,000
This is a tumor cell.
These are cytotoxic T cells that

439
00:40:36,000 --> 00:40:41,000
have recognized this tumor cell is
doing something it shouldn't that a

440
00:40:41,000 --> 00:40:46,000
normal cell wouldn't do.
And it's attacking it, and it's

441
00:40:46,000 --> 00:40:52,000
killing them.  So,
not only does the cellular immune

442
00:40:52,000 --> 00:40:57,000
response help us against things like
infections from virus and bacteria,

443
00:40:57,000 --> 00:41:03,000
it also will help prevent cancer.
So obviously there must be some

444
00:41:03,000 --> 00:41:10,000
trick here to why we don't see our
own peptides.  This is the self

445
00:41:10,000 --> 00:41:17,000
versus non-self  And it's a
relatively simple principle.

446
00:41:17,000 --> 00:41:24,000
So, distinguishing self versus
non-self is a problem throughout

447
00:41:24,000 --> 00:41:32,000
this whole part of the
immune system.

448
00:41:32,000 --> 00:41:41,000
And here's the principle.
During embryogenesis, the cell

449
00:41:41,000 --> 00:41:50,000
makes, the organism I guess,
makes the assumption.  I mean

450
00:41:50,000 --> 00:42:00,000
obviously it's not thinking
about it.

451
00:42:00,000 --> 00:42:10,000
This is a way of understanding
what's happening.

452
00:42:10,000 --> 00:42:20,000
It makes the assumption that no
pathogens are present.

453
00:42:20,000 --> 00:42:36,000
Any B or T cell recognizing
something must be recognizing itself.

454
00:42:36,000 --> 00:42:52,000
And so, it deletes those B and T
cells.  This process is given a name.

455
00:42:52,000 --> 00:43:05,000
It's called education.
And it happens in this organ called

456
00:43:05,000 --> 00:43:16,000
thymus.  So, and then after birth,
then it switches.  And now B and T

457
00:43:16,000 --> 00:43:28,000
cells, if they recognize something,
the body makes the assumption it

458
00:43:28,000 --> 00:43:36,000
must be a pathogen.
And it goes after it.

459
00:43:36,000 --> 00:43:41,000
We have this huge human disease
where that goes awry: rheumatoid

460
00:43:41,000 --> 00:43:45,000
arthritis, or multiple sclerosis are
cases where the self versus non-self

461
00:43:45,000 --> 00:43:50,000
recognition has broken down.
OK, so for example multiple

462
00:43:50,000 --> 00:43:55,000
sclerosis, a very difficult disease,
because there's a gradual

463
00:43:55,000 --> 00:44:00,000
deterioration of the
nervous system.

464
00:44:00,000 --> 00:44:04,000
And what happens is the body of the
person with that mounts an immune

465
00:44:04,000 --> 00:44:08,000
response against the sheath that
covers the nerves,

466
00:44:08,000 --> 00:44:12,000
and then that sheath gets destroyed,
and that the nervous system,

467
00:44:12,000 --> 00:44:16,000
somebody with multiple sclerosis,
starts to break down.  And so, if

468
00:44:16,000 --> 00:44:20,000
you lose this self versus non-self
you get what's called an autoimmune

469
00:44:20,000 --> 00:44:24,000
disease.  You may have heard that
phrase.  It's very important.

470
00:44:24,000 --> 00:44:28,000
It's a very tough thing if you have
one of these.  But that's what lies

471
00:44:28,000 --> 00:44:31,000
at the heart of it.
And people still don't know,

472
00:44:31,000 --> 00:44:35,000
but there is certainly some evidence
for some of these that are triggered

473
00:44:35,000 --> 00:44:39,000
by a bacterial infection.
So, it could be that perhaps maybe

474
00:44:39,000 --> 00:44:43,000
a bacterial protein looked close
enough to one of your own proteins,

475
00:44:43,000 --> 00:44:47,000
that somehow you got antibodies
against the bacterium,

476
00:44:47,000 --> 00:44:50,000
and then it turned out it could also
recognize something in your body.

477
00:44:50,000 --> 00:44:54,000
There are some other immune
diseases you probably heard of,

478
00:44:54,000 --> 00:44:58,000
the baby in a bubble kind of thing.
There are a few people who were

479
00:44:58,000 --> 00:45:02,000
born who have no immune response at
all because one of the basic pieces

480
00:45:02,000 --> 00:45:06,000
for doing those DNA gymnastics I
talked about isn't there.

481
00:45:06,000 --> 00:45:10,000
Those people have no B cells or T
cells.  They die unless they are

482
00:45:10,000 --> 00:45:14,000
absolutely shielded from everything
else.  And that's one of those cases

483
00:45:14,000 --> 00:45:18,000
when gene therapy,
if you could get that gene into that

484
00:45:18,000 --> 00:45:23,000
person, they'd have an immune system
and they could live.

485
00:45:23,000 --> 00:45:27,000
There are other kinds of immune
deficiencies that are less extreme,

486
00:45:27,000 --> 00:45:32,000
but nevertheless, people will be
susceptible to infection.

487
00:45:32,000 --> 00:45:36,000
The other one which I've already
talked about, but now you can see in

488
00:45:36,000 --> 00:45:40,000
another context is AIDS,
Acquired Immune Deficiency Syndrome.

489
00:45:40,000 --> 00:45:44,000
And I told you what the HIV virus
does is it injects its RNA.

490
00:45:44,000 --> 00:45:48,000
That makes a DNA copy.  It goes
into protein.  The cells that it

491
00:45:48,000 --> 00:45:52,000
affects our special type of T cell
called T helper cells.

492
00:45:52,000 --> 00:45:56,000
What they are doesn't matter so
much, but what's important to know

493
00:45:56,000 --> 00:46:00,000
is they're needed for both branches
of the immune system.

494
00:46:00,000 --> 00:46:04,000
They play roles in the humoral
response and cellular response.

495
00:46:04,000 --> 00:46:08,000
So, someone who gets infected with
HIV, what happens is the virus is

496
00:46:08,000 --> 00:46:12,000
replicating in these helper T cells.
And so their immune system is

497
00:46:12,000 --> 00:46:16,000
slowly, slowly being knocked away.
And the last thing, which I won't

498
00:46:16,000 --> 00:46:20,000
have time to talk about,
but if you have an allergy,

499
00:46:20,000 --> 00:46:24,000
that's an overreaction of the immune
system.  So this is my last lecture.

500
00:46:24,000 --> 00:46:28,000
I've got to let you guys go.  It's
been a true pleasure to talk to you;

501
00:46:28,000 --> 00:46:32,000
A real honor to meet many of you.
And many of you put a lot of effort

502
00:46:32,000 --> 00:46:36,000
into those little answers.
I really, really appreciate that.

503
00:46:36,000 --> 00:46:41,000
For those who'd rather not be here,
I hope that somewhere down the line

504
00:46:41,000 --> 00:46:46,000
when you're confronted with a
medical situation dealing with your

505
00:46:46,000 --> 00:46:50,000
parents, your child,
yourself, whatever it is,

506
00:46:50,000 --> 00:46:55,000
that some of the stuff that you
heard will reemerge to help you with

507
00:46:55,000 --> 00:47:00,000
those decisions.
And I wish you the best of luck for

508
00:47:00,000 --> 00:47:04,000
the rest of the course,
and the rest of your careers at MIT

509
00:47:04,000 --> 00:47:09,000
and beyond.  Thanks very much.
And as I leave,

510
00:47:09,000 --> 00:47:13,000
too, I've had the pleasure of just
having an incredible teaching staff.

511
00:47:13,000 --> 00:47:18,000
I don't think you guys know how
hard they work behind the scenes,

512
00:47:18,000 --> 00:47:21,000
but thanks to all of you for being
with me.