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So we're going to start by talking
about this story.

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This is a famous moment in the
treatment of infectious diseases and

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the prevention of infectious
diseases.

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This is the first human vaccination,
at least the first purposeful human

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vaccination where the famous British
doctor, Edward Jenner,

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is vaccinating a child for the
prevention of smallpox,

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a devastating disease at that time
and for centuries before that time

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which would wipe out literally
millions of people due to its very

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aggressive nature.
Not everybody who died or was

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infected by smallpox would die from
it, but a lot of people did.

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And it was an important infectious
agent throughout the world,

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actually brought, for example,
by colonizing troops in Mexico and

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wiped out Native peoples there,
used purposely as a biological agent

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in warfare.  Smallpox was used by
the British to suppress Native

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Americans in warfare.
In fact, the town of Amherst,

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Massachusetts was named after
Jeffrey Amherst,

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I think, who was an officer in the
British Army whom ordered that

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smallpox infected blankets,
or blankets from smallpox infected

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individuals be sent as a gift to
Indian tribes in the region so as to

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spread the disease to them thereby
limiting their ability to fight in

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an oncoming war.
So this is an important agent,

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and this is an important moment in
the treatment and prevention of this

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particular agent.
So I want to tell you this story

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because it illustrates some
important points about immunology.

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Edward Jenner, who as you see, was
doing this work in the late 1700s,

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made two important observations.
One was that milkmaids,

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people who got milk from cows,
milkmaids had smooth skin.

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And that was unusual in the time,

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because most people had been
infected by this agent smallpox,

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developed the smallpox disease which
led to a pocking of their skin if

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they survived.
So most people did not have smooth

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skin, but milkmaids had surprisingly
smooth skin.  One wonders what was

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behind this observation by Jenner,
but it doesn't really matter.

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He also noticed that milkmaids had
previously been exposed,

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in many instances, to a related
disease of cows called cowpox.

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And this was manifested on their
hands, they developed sores on their

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hands, but it didn't progress into a
disease that looked

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like smallpox.
And so Jenner made a hypothesis that

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prior exposure to cowpox,
whatever the agent was that caused

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cowpox, prior exposure to cowpox
protected against smallpox.

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And this was the suggestion of a
phenomenon known as immunological

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memory.

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And it was well known by then that
you only got a disease once.

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You only got exposed, if you got
exposed to a disease and developed

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symptoms and recovered,
you were protected against getting

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that disease in the future.
And this is a phenomenon of

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immunological memory,
which we now understand in some

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detail, and I'll tell you
how it all works.

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But that was known already by then.
And so what Jenner said was that

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maybe you develop immunological
memory to your cowpox exposure which

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then protects you against smallpox.
Well, so that was the hypothesis.

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He needed to do an experiment.
And the experiment is illustrated

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up there.

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He started with a milkmaid by the
name of Sarah Nelms who had a cowpox

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sore on her hand.

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He took that cowpox sore from her
hand and injected it into

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James Phipps --

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-- who was a clueless neighbor's boy.
He just happened to live in the

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neighborhood wandering by one day
and where Jenner invited him in for

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some cocoa or something and said,
by the way, since you're here, let

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me just inject you with some of this
stuff.  [LAUGHTER]  And that's

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exactly what's depicted here.
Sarah Nelms is holding the boy and

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Jenner is injecting him with
some cowpox stuff.

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He then waited three weeks,
and he injected him with smallpox.

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A known lethal agent.

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He then waited six weeks and
injected him again.  [LAUGHTER]

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Then he waited and waited and waited.
And the kid was disease-free.

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He had, in fact, protected the boy
against the development of smallpox.

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The first purposeful vaccination.

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It's called vaccination,
by the way, because cowpox,

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which is the agent used to vaccinate
the boy, is caused by a virus known

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as vaccinia.  So in honor of that,
the whole field, the whole approach

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is called vaccination.
So this is an example of

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introducing an agent which the body
then responds to.

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And based on the body's response to
that agent, the body is protected

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against further disease.
Now, this works because the agent

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that was used to vaccinate the boy,
vaccinia is very similar to the

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agent that causes smallpox.
It's not identical but it's

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sufficiently similar that the body's
response to that agent is compatible

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with a response to the dangerous
agent.  This is called a

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heterologous vaccine.
And I'll briefly mention other

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vaccine strategies towards the end.
Jenner succeeded in doing this with

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a number of patients directly
after that.

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And he actually published his paper,
or he tried to publish a paper on

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this finding in the early 1800s.
He was actually blocked from doing

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so.  People didn't want to believe
it.  People were extremely nervous

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about this approach.
It lead to editorials in local

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magazines such as shown here.
This is a cartoon of Jenner with

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young James Phipps and a bunch of
people getting vaccinated with this

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cow thing.  And the consequence,
as you might be able to see, is that

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these people are sprouting cows out
of their arms,

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out of their faces,
out of their butts.

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And there was general nervousness
about tinkering with the natural

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species in the world in this
deliberate way.

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But it was generally accepted,
used extensively in Europe and

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actually in the United States.
And now it's sufficiently

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successful, has been sufficiently
successful over the last couple of

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centuries that smallpox is
no longer a problem.

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It's been eradicated through proper
vaccination using this approach.

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So there is no longer smallpox out
there, although there are vials of

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smallpox sitting in freezers which
have been a concern to governments

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in the sense that bioterrorists
might get their hands on it.

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And there have actually been
efforts to bring back smallpox

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vaccination as a protective against
the potential use of the smallpox

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agent for some sort
of bioterrorism.

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Do you have a question?
OK.  Now, as you know, vaccinations

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against viral agents and other
pathogens are commonplace.

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You've all been vaccinated against
lots of things.

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They've changed the course of human
history in a dramatic way.

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This was not very long ago,
1952, a bunch of children who were

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infected with polio virus.
It led to deaths of many kids and

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paralysis of many more.
And this is a picture in a hospital

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ward of children in iron lungs,
which is how they were kept alive

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because of their paralysis.
Many of them survived this early

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phase but then went on to develop
paralysis in their extremities.

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And it was a very devastating
disease.  Fortunately,

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both Drs. Sabin and Salk in the
early 1950s developed vaccines using

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the principles laid out by Jenner
150 years before.  And these

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were successful.
And so kids were treated with polio

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vaccines for the next 30 or so years.
And polio itself was wiped out.

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So there are no, or very, very few
examples of active polio outbreaks

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these days.  And,
in fact, kids are not vaccinated

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with polio vaccines in this country
because it's not a threat.

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It's not that it's not a threat
worldwide.  In fact,

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last year when I was teaching this
course we read that there were some

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new outbreaks of polio.
So it's not that the virus is gone.

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It hasn't been fully eradicated.
But it's very,

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very uncommon thanks to these kinds
of efforts.  And we think about this

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also again to protect against
deliberate use of pathogens.

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Here, Anthrax, I've shown you this
slide before.  So there are now

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efforts to develop vaccines against
Anthrax.  In case somebody were to

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use it as an agent,
you could protect people from

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getting exposed to Anthrax.
And pathogens are important out

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there.
Many of the diseases that have been

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scourges of humanity over the
millennia are due to pathogens.

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It's been a constant battle between
humans and pathogens,

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viruses, bacteria, other single-cell
organisms.  And our greatest hope

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against controlling these infections
is to protect them through

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vaccination.  Where that's worked
it's been extremely successful.

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Where it hasn't worked, like in the
case of HIV, it's been much

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more problematic.
So vaccination in general,

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immunological response,
immunological memory are extremely

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important.  OK.
So to understand what's happening

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with respect to vaccination and
immunological memory,

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you have to think about what happens
in an infection and how your body

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responds to it.
So if you plot a time course of

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infection where this might be the
very earliest stages.

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When you get exposed to a pathogen,

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virus, bacterium, it enters your
body and it begins to

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reproduce itself.

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It will build up.
And it might peak in its

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concentrations at about a week or so,
maybe two weeks.

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And it's at this stage where you're
developing symptoms.

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And those symptoms might be
sufficiently severe that it can

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cause death.  But if you live then
you observe typically that the

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pathogen concentrations drop and can
be eliminated all together within

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two or three weeks.
The reason that they drop is because

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your body is making defense
mechanisms against it in two forms,

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antibodies and specialized cells
called T cells that are built to

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eradicate the agent.
And so if you plot the

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concentration of antibodies and T
cells that are active against this

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agent, you find that initially
there's a delay.

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And then the concentrations of these
antibodies and T cells rises.

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And as they do they are acting on
either the agent itself or the cells

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that the agent has infected.
And a combined activity then leads

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to the elimination of those agents.
Concentrations stay up and then

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they fall, but they don't go to zero.
They stay around.

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You have low levels of these
specific antibody-producing cells or

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T cells that are directed against
this agent that stay in your blood

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forever such that if you get a
second infection,

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even years later, these cells are
already there set aside such that

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the response to that agent is very
rapid and the concentrations of the

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agent never rise very high.
So you're able to control it before

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the amounts of the agents build up
and cause symptoms or death.

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And that's why you don't develop
secondary infection.

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This process is called
immunological memory.

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And, as I said,

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it's the setting aside of cells that
are specific to the thing that's

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causing the disease.
And we'll talk about how that

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happens in a moment.
So this phase, I should have said,

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is called recovery.  OK.

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Now, I mentioned two cell types that
are important in this process.

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There are B cells and T cells,
and they are the ones that I'm going

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to focus on.
But it's important for you to know

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that they are not the only cells of
your immune system.

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The body produces a whole series of
cells shown here in addition to B

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cells and T cells and a specialized
form of B cells called plasma cells.

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And these cells also contribute to
your immune response.

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They're part of what's called the
innate immune response.

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And they act in a way that is

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nonspecific.  So they recognize
classes of agents,

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viruses as a class or bacteria as a
class.  They recognize things that

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are common to all viruses or most or
all bacteria or most.

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And they're very important in the
early phases of an infection.

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And, in fact, in this first phase
where you're ramping up the antibody

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producing cells in the T cells,
it's those cells that are acting to

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help suppress the proliferation
of the agent.

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And so this is where the innate
immune response is taking place.

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And Claudette will review for you
some of those cell types in the next

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lecture.  We're going to focus on B
cells and T cells.

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And they fall into what's called
the adaptive or specific

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immune response.

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And that can be broken down,
as I said, into these two cell types.

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There are T cells which are T
lymphocytes.  And the T lymphocytes

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constitute what's called
cell-based immunity.

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It's the cells themselves that are

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participating in the eradication of
the agent.  And then there are B

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lymphocytes, and they participate in
what's called humoral which is also

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liquid phase immunity.
And what that means is that they're

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producing something that gets
secreted into the bodily fluids,

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blood or whatever.
And it's that which is participating

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in the eradication of the agent.
In particular, what that is, is

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antibodies, as we'll talk about.

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These cells have these names,
B cells and T cells, because where

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they mature.  So both B lymphocytes
and T lymphocytes start off in the

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bone marrow, or I should say the
precursors of these cells start off

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in the bone marrow.
The precursors to B lymphocytes make

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their way either to the spleen or
they stay in the bone marrow,

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and that's why they're called B
cells.  And they go on to make B

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lymphocytes, including these cells
called plasma cells, which

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produce antibodies.

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A separate precursor called the T
cell precursor makes its way to the

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thymus which is a lymphoid organ in
your chest, and there the cells

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00:20:29,000 --> 00:20:41,000
mature into two types of T cells,
cytotoxic T cells, otherwise known

225
00:20:41,000 --> 00:20:53,000
as CTLs, or TC cells,
and helper T cells or TH cells.

226
00:20:53,000 --> 00:20:57,000
OK?  And because they go to the
thymus they're called T cells.

227
00:20:57,000 --> 00:21:02,000
Now, these cells are
distinguishable based on the types

228
00:21:02,000 --> 00:21:07,000
of protective molecules
that they produce.

229
00:21:07,000 --> 00:21:11,000
This slide just shows you an
overview of the lymphoid system in

230
00:21:11,000 --> 00:21:15,000
your body emphasizing the points I
just made.  The bone marrow is

231
00:21:15,000 --> 00:21:20,000
important based on the origin of the
cells, as well as it's where B cells

232
00:21:20,000 --> 00:21:24,000
mature.  B cells also mature in the
spleen.  And here's the thymus where

233
00:21:24,000 --> 00:21:28,000
T cells mature.
And in green here you see the

234
00:21:28,000 --> 00:21:32,000
lymphatic system.
These are the vessels that carry

235
00:21:32,000 --> 00:21:36,000
your lymph fluids where many of
these cells move to get to the sites

236
00:21:36,000 --> 00:21:40,000
of infection.  And what's not so
obvious to see are lymph nodes,

237
00:21:40,000 --> 00:21:43,000
which is again where many of these
cells mature and turn into fully

238
00:21:43,000 --> 00:21:47,000
blown antibody producing cells or
matured T cells.

239
00:21:47,000 --> 00:21:51,000
I also want to point out that the
handout that you have has the wrong

240
00:21:51,000 --> 00:21:55,000
numbers.  I was looking at least
year's book when I took

241
00:21:55,000 --> 00:21:59,000
these numbers down.
So the figures are what I'm showing

242
00:21:59,000 --> 00:22:03,000
you here.  And on the Web,
the version that's on the Web has

243
00:22:03,000 --> 00:22:07,000
been corrected,
so you might want to pay attention

244
00:22:07,000 --> 00:22:12,000
to that.  Now,
what the antibodies that are

245
00:22:12,000 --> 00:22:16,000
produced by B cells and the
molecules on the surface of T cells

246
00:22:16,000 --> 00:22:21,000
are recognizing are things
called antigens.

247
00:22:21,000 --> 00:22:36,000
Antigens are one of a number of

248
00:22:36,000 --> 00:22:46,000
different types of molecules,
lipids, carbohydrates, proteins,

249
00:22:46,000 --> 00:22:59,000
that are specific to the pathogen.

250
00:22:59,000 --> 00:23:02,000
And your body makes antibodies
produced by T cells,

251
00:23:02,000 --> 00:23:06,000
produced by B cells, as well as
proteins on the surface of T cells

252
00:23:06,000 --> 00:23:10,000
that will specifically recognize
these antigens.

253
00:23:10,000 --> 00:23:14,000
And that's why it's called a
specific immune response,

254
00:23:14,000 --> 00:23:17,000
because the protein that the
lymphocytes are producing

255
00:23:17,000 --> 00:23:21,000
specifically recognizes the antigen,
whether it be a lipid antigen, a

256
00:23:21,000 --> 00:23:25,000
carbohydrate antigen or a protein
antigen.  And that's illustrated on

257
00:23:25,000 --> 00:23:29,000
this side where you have a virus
particle here or a secreted protein

258
00:23:29,000 --> 00:23:33,000
that might be floating
around in the blood.

259
00:23:33,000 --> 00:23:37,000
And you can see that there are bound
to it these colored structures.

260
00:23:37,000 --> 00:23:41,000
These are antibodies.  And the
different colors are recognizing

261
00:23:41,000 --> 00:23:45,000
different antigens.
So this orange colored antigen is

262
00:23:45,000 --> 00:23:49,000
being recognized by that orange
colored antibody.

263
00:23:49,000 --> 00:23:53,000
The purple colored antigen is being
recognized by the purple antibody.

264
00:23:53,000 --> 00:23:57,000
Your body has an amazing ability to
generate tremendous diversity in the

265
00:23:57,000 --> 00:24:01,000
structures, these antibodies or T
cell receptors that recognize

266
00:24:01,000 --> 00:24:08,000
particular antigens.

267
00:24:08,000 --> 00:24:15,000
B cells, B lymphocytes start off by
producing on their surface antibody

268
00:24:15,000 --> 00:24:23,000
molecules.  These antibody molecules
are heterotetromers.

269
00:24:23,000 --> 00:24:32,000
They have two heavy chains and two

270
00:24:32,000 --> 00:24:41,000
light chains.  And we'll talk about
how those produced in a moment.

271
00:24:41,000 --> 00:24:50,000
B cells mature and they turn into
plasma cells.  And plasma cells

272
00:24:50,000 --> 00:25:00,000
secrete the antibody into
the bodily fluids.  OK?

273
00:25:00,000 --> 00:25:13,000
T cells have on their surface a
protein called the T cell receptor.

274
00:25:13,000 --> 00:25:20,000
And likewise it is very specific.

275
00:25:20,000 --> 00:25:24,000
Just like antibodies, as depicted
up here, have a particular sequence

276
00:25:24,000 --> 00:25:28,000
at the end, which is the
antigen binding site.

277
00:25:28,000 --> 00:25:36,000
And no two antibodies produced by

278
00:25:36,000 --> 00:25:40,000
different B cells would be the same
with respect to their antigen

279
00:25:40,000 --> 00:25:44,000
binding site.  Likewise,
this region of the T cell receptor

280
00:25:44,000 --> 00:25:54,000
is unique.

281
00:25:54,000 --> 00:25:57,000
And, again, that's what gives
specificity to the immune system.

282
00:25:57,000 --> 00:26:01,000
There are B cells that produce
particular antibodies that recognize

283
00:26:01,000 --> 00:26:04,000
particular antigens.
And T cells that have on their

284
00:26:04,000 --> 00:26:08,000
surface T cell receptors that are
specific to particular antigens

285
00:26:08,000 --> 00:26:12,000
compared to other T cells.
This is a detail from your book

286
00:26:12,000 --> 00:26:16,000
which shows again an antibody
molecule.  You can see that it's a

287
00:26:16,000 --> 00:26:20,000
heterotetromer,
two heavy chains,

288
00:26:20,000 --> 00:26:24,000
two light chains, and at the very
tips, both of these arms are these

289
00:26:24,000 --> 00:26:28,000
antigen binding sites.
And, again, this is where the

290
00:26:28,000 --> 00:26:32,000
diversity comes from.
This antibody,

291
00:26:32,000 --> 00:26:36,000
with its particular structure,
will bind to this particular antigen

292
00:26:36,000 --> 00:26:40,000
because that antigen fits into the
pocket formed by that antigen

293
00:26:40,000 --> 00:26:44,000
binding site specifically.
Likewise, on the surface of T cells

294
00:26:44,000 --> 00:26:48,000
there are T cell receptor proteins.
They're composed of two chains, an

295
00:26:48,000 --> 00:26:52,000
alpha chain and a beta chain.
And the coming together of the

296
00:26:52,000 --> 00:26:56,000
alpha chain and the beta chain
produces, again,

297
00:26:56,000 --> 00:27:00,000
an antigen binding site that is
unique to that particular

298
00:27:00,000 --> 00:27:04,000
T cell receptor.
OK.  So this is interesting.

299
00:27:04,000 --> 00:27:10,000
And it raises an important question,
an important problem.

300
00:27:10,000 --> 00:27:16,000
There are lots of pathogens.
There are lots and lots and lots of

301
00:27:16,000 --> 00:27:22,000
things out there that can get into
your body and cause you harm.

302
00:27:22,000 --> 00:27:28,000
And, therefore, in order to
effectively fight those things you

303
00:27:28,000 --> 00:27:41,000
need many different antibodies --

304
00:27:41,000 --> 00:27:50,000
-- and many different T cell
receptors.  It's actually estimated

305
00:27:50,000 --> 00:27:59,000
that there are ten to the seventh
distinct B cells and T cells in your

306
00:27:59,000 --> 00:28:06,000
body at any time.
So you've got ten million different

307
00:28:06,000 --> 00:28:11,000
B cells and T cells that make
different antibodies or different T

308
00:28:11,000 --> 00:28:16,000
cell receptors on the surface.
So where does that diversity come

309
00:28:16,000 --> 00:28:21,000
from?  How do you get ten million
different B cells or T cells in your

310
00:28:21,000 --> 00:28:26,000
body?  Well, one possibility would
be that there are ten million

311
00:28:26,000 --> 00:28:34,000
different genes.

312
00:28:34,000 --> 00:28:37,000
That there are ten million different
antibody genes or ten million

313
00:28:37,000 --> 00:28:41,000
different alpha genes and beta genes
in the T cell receptor.

314
00:28:41,000 --> 00:28:45,000
Is that the likely explanation?
How do you know it's not true?

315
00:28:45,000 --> 00:28:48,000
Because I've already told you that
there are only 30,

316
00:28:48,000 --> 00:28:52,000
00 genes total throughout your
genome.  So there sure as hell

317
00:28:52,000 --> 00:28:56,000
aren't ten to the seventh different
antibody genes.  So that

318
00:28:56,000 --> 00:28:59,000
answer is wrong.
It could have been from

319
00:28:59,000 --> 00:29:08,000
alternative splicing.

320
00:29:08,000 --> 00:29:12,000
Maybe there are genes with many,
many exons.  And depending on how

321
00:29:12,000 --> 00:29:16,000
those exons get joined together,
through a process of alternative

322
00:29:16,000 --> 00:29:21,000
splicing, you could produce diverse
antibodies or T cell receptors.

323
00:29:21,000 --> 00:29:25,000
That could be true.  And we
actually think a lot of diversity in

324
00:29:25,000 --> 00:29:29,000
biology does come from alternative
splicing of complex genes,

325
00:29:29,000 --> 00:29:34,000
but that's not the answer here.
Instead, the answer has to do with a

326
00:29:34,000 --> 00:29:43,000
process known as DNA rearrangement.

327
00:29:43,000 --> 00:29:46,000
This is a process that was
discovered, in the context of the

328
00:29:46,000 --> 00:29:49,000
immune system,
by Susumu Tonegawa who was a

329
00:29:49,000 --> 00:29:53,000
professor in the Cancer Center at
MIT.  And, actually,

330
00:29:53,000 --> 00:29:56,000
he won the Nobel Prize for that
discovery some years ago.

331
00:29:56,000 --> 00:30:00,000
We now know that the generation of
all of these different antibodies

332
00:30:00,000 --> 00:30:03,000
and all of these different T cells
is due to complex rearrangements of

333
00:30:03,000 --> 00:30:07,000
a very small number
of complex genes.

334
00:30:07,000 --> 00:30:11,000
And I want to go through that with
you now.  And it is a little

335
00:30:11,000 --> 00:30:16,000
complicated.  And so I warn you that
I'm going to show you slides which

336
00:30:16,000 --> 00:30:20,000
come directly out of your book.
And we'll walk through them.  But

337
00:30:20,000 --> 00:30:25,000
then I advise you to read your book
which I think does a good job

338
00:30:25,000 --> 00:30:30,000
explaining how this rearrangement
process takes place.

339
00:30:30,000 --> 00:30:34,000
And hopefully together that will
solidify the concepts for you.

340
00:30:34,000 --> 00:30:38,000
So, again, immunological diversity
means that each B cell produces

341
00:30:38,000 --> 00:30:43,000
particular antibodies,
as I've said.  And these are the

342
00:30:43,000 --> 00:30:47,000
product of uniquely rearranged heavy
chain genes and a uniquely

343
00:30:47,000 --> 00:30:51,000
rearranged light chain gene.
And, likewise, each T cell, each

344
00:30:51,000 --> 00:30:56,000
distinct T cell has a specific T
cell receptor on its surface which

345
00:30:56,000 --> 00:31:00,000
is the product of a uniquely
rearranged T cell alpha genes and a

346
00:31:00,000 --> 00:31:05,000
uniquely rearranged
T cell beta gene.

347
00:31:05,000 --> 00:31:08,000
And you can kind of think about the
process that we're going to talk

348
00:31:08,000 --> 00:31:11,000
about like a roulette wheel that in
roulette, as you know,

349
00:31:11,000 --> 00:31:14,000
one wheel spins and a particular
object shows up and the next wheel

350
00:31:14,000 --> 00:31:17,000
spins and a different object shows
up or the same one,

351
00:31:17,000 --> 00:31:20,000
and likewise the third way.
And you end up with a unique

352
00:31:20,000 --> 00:31:23,000
combination of objects.
The same is true is here.

353
00:31:23,000 --> 00:31:27,000
And there are lots of different
combinations that can come up.

354
00:31:27,000 --> 00:31:30,000
Actually, last year when I was
talking about this,

355
00:31:30,000 --> 00:31:33,000
I realized that an even better
analogy is Mr.

356
00:31:33,000 --> 00:31:36,000
Potato Head.  And I thought to bring
this morning the Mr.

357
00:31:36,000 --> 00:31:39,000
Potato Head thing from my
three-year-old daughter,

358
00:31:39,000 --> 00:31:42,000
but she threw herself across the
door.  So I actually was unable to

359
00:31:42,000 --> 00:31:45,000
bring Mr. Potato Head with me,
but hopefully you remember Mr.

360
00:31:45,000 --> 00:31:48,000
Potato Head.  It's a bland head,
and you can put a different mouth or

361
00:31:48,000 --> 00:31:52,000
a different nose or a different pair
of eyes or hair.

362
00:31:52,000 --> 00:31:55,000
And based on the combination that
you choose you get a very different

363
00:31:55,000 --> 00:31:58,000
looking face.  The same thing is
true in the generation of antibodies

364
00:31:58,000 --> 00:32:02,000
and T cell receptors.
It's a choice at different positions,

365
00:32:02,000 --> 00:32:06,000
and based on the choice that's made
you make a unique looking antibody

366
00:32:06,000 --> 00:32:11,000
or T cell receptor.
So this is illustrated here.

367
00:32:11,000 --> 00:32:16,000
What we're looking at is a piece of
DNA that constitutes the

368
00:32:16,000 --> 00:32:20,000
un-rearranged heavy chain gene of
antibodies.  And you can see that

369
00:32:20,000 --> 00:32:25,000
there are different regions colored
differently.  There's a region

370
00:32:25,000 --> 00:32:30,000
called the V region which has
several segments,

371
00:32:30,000 --> 00:32:35,000
several bits, which are similar but
a little bit different.

372
00:32:35,000 --> 00:32:39,000
There might be a hundred or so of
these V segment exons clustered

373
00:32:39,000 --> 00:32:43,000
together here.
Next door is another set of

374
00:32:43,000 --> 00:32:47,000
segments called the D segments,
and there are about 30 of those.

375
00:32:47,000 --> 00:32:51,000
And then next to them are the J
segments, and there are about six of

376
00:32:51,000 --> 00:32:55,000
those.  Next door is another set of
segments called the constant region

377
00:32:55,000 --> 00:33:00,000
exons.  These actually get used in a
slightly different way.

378
00:33:00,000 --> 00:33:04,000
They don't come together by DNA
rearrangement but rather by splicing,

379
00:33:04,000 --> 00:33:08,000
but this also adds to the diversity.
When this rearrangement process is

380
00:33:08,000 --> 00:33:12,000
done you can choose a different exon
down here by alternative splicing.

381
00:33:12,000 --> 00:33:17,000
So you can maybe get a sense, if
we're going to pick one of these and

382
00:33:17,000 --> 00:33:21,000
then randomly one of these and then
randomly one of these we can

383
00:33:21,000 --> 00:33:25,000
generate a lot of diversity.
This happens, as I said, through an

384
00:33:25,000 --> 00:33:30,000
ordered process of DNA
rearrangement.

385
00:33:30,000 --> 00:33:34,000
Our goal is to take an immature B
cell, B cell precursor and then

386
00:33:34,000 --> 00:33:39,000
sequentially rearrange the heavy
chain gene and the light chain gene.

387
00:33:39,000 --> 00:33:44,000
And then finally, when that's all
done, that mature B cell is going to

388
00:33:44,000 --> 00:33:48,000
be sticking on its surface a
specific antibody molecule which

389
00:33:48,000 --> 00:33:53,000
will have this structure here.
And the region of the antigen

390
00:33:53,000 --> 00:33:58,000
binding site will be the unique
product of the coming together of

391
00:33:58,000 --> 00:34:03,000
those V segments, D segments
and J segments.

392
00:34:03,000 --> 00:34:07,000
So the first step that happens is,
with respect to the heavy chain gene,

393
00:34:07,000 --> 00:34:11,000
rearrangements take place.
There are enzymes that get turned

394
00:34:11,000 --> 00:34:16,000
on in the immature B cell which
specifically recognizes sequences

395
00:34:16,000 --> 00:34:20,000
next door to these segments.
The first segments that recombine

396
00:34:20,000 --> 00:34:25,000
together involve the D region
and the J region.

397
00:34:25,000 --> 00:34:29,000
So randomly one of the D region
segments and one of the J region

398
00:34:29,000 --> 00:34:34,000
segments gets chosen,
and the enzyme comes along and clips

399
00:34:34,000 --> 00:34:39,000
the DNA right next door to that
segment and right upstream of that

400
00:34:39,000 --> 00:34:43,000
segment looping out the stuff in the
middle, getting rid of it and

401
00:34:43,000 --> 00:34:48,000
joining together that particular
pair of segments.

402
00:34:48,000 --> 00:34:53,000
So now you have a unique new piece
of DNA which joins one of the D

403
00:34:53,000 --> 00:34:58,000
segments with one of the J segments.
Next, one of the V segments is

404
00:34:58,000 --> 00:35:02,000
chosen which then gets clipped,
and this region up here also gets

405
00:35:02,000 --> 00:35:07,000
clipped such that the middle piece
gets taken away and the two pieces

406
00:35:07,000 --> 00:35:12,000
get joined together.
And the product of that is a new

407
00:35:12,000 --> 00:35:16,000
piece of DNA that has a unique V
region joined to a D region joined

408
00:35:16,000 --> 00:35:21,000
to a J region.
OK?  So there's a series of cut and

409
00:35:21,000 --> 00:35:26,000
paste reactions that produces a
unique combination of V,

410
00:35:26,000 --> 00:35:30,000
D and J.  Once that process is done
then an RNA is produced

411
00:35:30,000 --> 00:35:35,000
from that locus.
The RNA gets spliced,

412
00:35:35,000 --> 00:35:40,000
as I said, to allow the VDJ segment
to get joined to one of the constant

413
00:35:40,000 --> 00:35:44,000
region segments.
That mRNA product then gets

414
00:35:44,000 --> 00:35:49,000
translated into the heavy chain.
Once you make the heavy chain you

415
00:35:49,000 --> 00:35:54,000
more or less go ahead and do the
exact same thing with the light

416
00:35:54,000 --> 00:35:59,000
chain.  You do a VDJ recombination.
Join it up with a constant region.

417
00:35:59,000 --> 00:36:03,000
Now that cell is able to produce
both a heavy chain and a light chain

418
00:36:03,000 --> 00:36:08,000
which is unique.
Those come together to form a

419
00:36:08,000 --> 00:36:12,000
unique specific antibody molecule.
So, again, that's complicated stuff.

420
00:36:12,000 --> 00:36:16,000
I don't expect that those of you
who haven't heard it before will

421
00:36:16,000 --> 00:36:19,000
understand it from what I've just
said, but all of what I told you is

422
00:36:19,000 --> 00:36:23,000
in the book.  And there's an
animation, which is where this comes

423
00:36:23,000 --> 00:36:27,000
from.  So I advise you to read your
textbook.  OK?

424
00:36:27,000 --> 00:36:30,000
The important point is that
recombination of these individual

425
00:36:30,000 --> 00:36:34,000
segments, random joining together of
these distinct segments gives

426
00:36:34,000 --> 00:36:38,000
tremendous diversity.
It allows you to produce ten to the

427
00:36:38,000 --> 00:36:42,000
seventh different T cells,
sorry, B cells.  The exact same

428
00:36:42,000 --> 00:36:46,000
process happens in the rearrangement
of the alpha genes and the beta

429
00:36:46,000 --> 00:36:50,000
genes in the T cell receptor.
So you get, again, tremendous

430
00:36:50,000 --> 00:36:54,000
diversity in that way.
Now, I'm just going to mention this

431
00:36:54,000 --> 00:36:58,000
but I don't expect you to know it
for life.  Well,

432
00:36:58,000 --> 00:37:02,000
you might know it for life but you
don't need to know it for a test.

433
00:37:02,000 --> 00:37:06,000
There are still other mechanisms
that the body uses to add even more

434
00:37:06,000 --> 00:37:10,000
diversity.  It turns out that this
process of joining is actually

435
00:37:10,000 --> 00:37:14,000
intentionally messy so that the
joints that occur between these

436
00:37:14,000 --> 00:37:19,000
segments are not all the same from
one cell to another.

437
00:37:19,000 --> 00:37:23,000
Even if the cells were to rearrange
the same two or three segments,

438
00:37:23,000 --> 00:37:27,000
they wouldn't necessarily produce
the exact same antigen binding site

439
00:37:27,000 --> 00:37:31,000
because the process is inherently
sloppy in order to even

440
00:37:31,000 --> 00:37:37,000
make more diversity.
OK?  But you don't really need to

441
00:37:37,000 --> 00:37:44,000
know about that specific aspect of
it.  OK.  So through this process of

442
00:37:44,000 --> 00:37:51,000
rearrangement,
through this process of

443
00:37:51,000 --> 00:37:58,000
rearrangement we are able to make,
in the case of B cells, lots and

444
00:37:58,000 --> 00:38:05,000
lots and lots of distinct unique B
cells that are circulating

445
00:38:05,000 --> 00:38:11,000
throughout your body.
They're different from one another

446
00:38:11,000 --> 00:38:15,000
because they have on their surface,
initially in the case of B cells

447
00:38:15,000 --> 00:38:19,000
they have on their surface these
antibody molecules which are

448
00:38:19,000 --> 00:38:23,000
different from one another in these
regions.  So these antigen

449
00:38:23,000 --> 00:38:31,000
binding sites --

450
00:38:31,000 --> 00:38:35,000
-- are unique.
This one is different from this one.

451
00:38:35,000 --> 00:38:39,000
And I should have mentioned I
wanted to emphasize that because of

452
00:38:39,000 --> 00:38:43,000
this rearrangement process the DNA
of this cell is different from the

453
00:38:43,000 --> 00:38:47,000
DNA of that cell.
I point that out because we've

454
00:38:47,000 --> 00:38:51,000
emphasized in the past that the
genome that you get when you're

455
00:38:51,000 --> 00:38:55,000
first fertilized is stable and
exactly the same in

456
00:38:55,000 --> 00:38:59,000
all of your cells.
That's actually clearly not true in

457
00:38:59,000 --> 00:39:03,000
the case of B cells and T cells
because they purposely rearranged

458
00:39:03,000 --> 00:39:07,000
the genome in the production of
antibodies in T cell receptor genes.

459
00:39:07,000 --> 00:39:10,000
So the genome actually is a little
bit different,

460
00:39:10,000 --> 00:39:14,000
at least in the case of the lymphoid
cells.  So these cells then are

461
00:39:14,000 --> 00:39:18,000
produced and they're quietly
circulating in your blood.

462
00:39:18,000 --> 00:39:22,000
So how do you mount an immune
response?

463
00:39:22,000 --> 00:39:31,000
You're now infected by some pathogen.

464
00:39:31,000 --> 00:39:35,000
How do you build up the
concentrations of one of these

465
00:39:35,000 --> 00:39:39,000
particular B cells or T cells that
can recognize that pathogen?

466
00:39:39,000 --> 00:39:43,000
How do you mount an immune response?
Well, the way you do it through a

467
00:39:43,000 --> 00:39:48,000
process of clonal selection.
And, again, this comes right out of

468
00:39:48,000 --> 00:39:52,000
your book.  These cells which are
floating around in the blood and not

469
00:39:52,000 --> 00:39:56,000
doing very much in terms of making
more of themselves,

470
00:39:56,000 --> 00:40:00,000
they're not proliferating,
can respond through the exposure to

471
00:40:00,000 --> 00:40:04,000
the antigen.
So if floating around the blood

472
00:40:04,000 --> 00:40:08,000
along with these cells is a
particular antigen,

473
00:40:08,000 --> 00:40:12,000
and it's able to bind to that
antibody molecule which is sitting

474
00:40:12,000 --> 00:40:16,000
on the surface,
that sends a signal to that cell

475
00:40:16,000 --> 00:40:20,000
it's time to divide.
There's something in the

476
00:40:20,000 --> 00:40:24,000
environment that we like so that we
need to make more of ourselves in

477
00:40:24,000 --> 00:40:28,000
order to fight off whatever
that thing is.

478
00:40:28,000 --> 00:40:31,000
This induces a rapid and impressive
proliferation.

479
00:40:31,000 --> 00:40:35,000
So you go from one or a small
number of these cells to many,

480
00:40:35,000 --> 00:40:39,000
many of these cells, particularly
these cells.  These cells don't

481
00:40:39,000 --> 00:40:43,000
proliferate because they're not
binding to the antigen.

482
00:40:43,000 --> 00:40:47,000
These cells do proliferate.
They make many, many more of

483
00:40:47,000 --> 00:40:51,000
themselves, and when they get to a
certain point they differentiate.

484
00:40:51,000 --> 00:40:55,000
They begin to make the material
they need to secrete really well.

485
00:40:55,000 --> 00:40:59,000
They actually change their shape
dramatically.  They become very

486
00:40:59,000 --> 00:41:03,000
efficient secretory cells.
And so these B cells that have the

487
00:41:03,000 --> 00:41:07,000
antibody on their surface then
become secretory cells,

488
00:41:07,000 --> 00:41:11,000
these plasma cells.  And the plasma
cells then secrete the antibody into

489
00:41:11,000 --> 00:41:16,000
the bodily fluids allowing the
antibody to then go off and bind to

490
00:41:16,000 --> 00:41:20,000
the antigen whether it is itself
circulating or it's on the surface

491
00:41:20,000 --> 00:41:25,000
of the pathogen like a virus or a
bacterium.  So this process of

492
00:41:25,000 --> 00:41:29,000
clonal selection then allows for the
cells to build up and,

493
00:41:29,000 --> 00:41:34,000
in this case, to differentiate into
antibody-secreting cells.

494
00:41:34,000 --> 00:41:38,000
Now, these are the cells and the
antibodies that are going to fight

495
00:41:38,000 --> 00:41:42,000
the infection.
These are the cells that are

496
00:41:42,000 --> 00:41:46,000
building up right here producing,
in this case, the antibody.  The

497
00:41:46,000 --> 00:41:51,000
same exact thing happens with
respect to T cells which you'll

498
00:41:51,000 --> 00:41:55,000
learn about in detail next time.
However, after the infection is

499
00:41:55,000 --> 00:41:59,000
cleared most of those cells go away.
They're no longer being stimulated

500
00:41:59,000 --> 00:42:04,000
and they actually die off.
But importantly not all of them go

501
00:42:04,000 --> 00:42:08,000
away.  Some of them are set aside as
these memory cells.

502
00:42:08,000 --> 00:42:12,000
And if these memory cells that just
kind of hang around in higher

503
00:42:12,000 --> 00:42:16,000
concentrations than they were at the
very beginning of this process but

504
00:42:16,000 --> 00:42:20,000
it's still relatively low
concentrations,

505
00:42:20,000 --> 00:42:24,000
and it's the presence of those
memory cells that when you're

506
00:42:24,000 --> 00:42:28,000
infected again they kick into action
quickly.  They've already matured to

507
00:42:28,000 --> 00:42:33,000
a very great extent, as
you can see here.

508
00:42:33,000 --> 00:42:37,000
They're on the edge.
They're poised to make a lot of

509
00:42:37,000 --> 00:42:42,000
antibody or be an effective T cell.
They build up very quickly and they

510
00:42:42,000 --> 00:42:46,000
suppress the immune response,
they suppress the infection.  So

511
00:42:46,000 --> 00:42:51,000
this process of clonal expansion is
the early phase.

512
00:42:51,000 --> 00:42:55,000
The setting aside of the memory
cells is the late phase.

513
00:42:55,000 --> 00:43:00,000
And it allows us to effectively
respond in a second infection.

514
00:43:00,000 --> 00:43:04,000
And it's also the reason that you
can respond once vaccinated.

515
00:43:04,000 --> 00:43:08,000
Vaccination is the exact same
process except you're exposed to

516
00:43:08,000 --> 00:43:12,000
something that is not inherently
dangerous.  In the case of an active

517
00:43:12,000 --> 00:43:17,000
infection, you're infected with the
pathogen, the active pathogen,

518
00:43:17,000 --> 00:43:21,000
and it builds up and then you
respond to it.

519
00:43:21,000 --> 00:43:25,000
But there's this dangerous phase
where you might actually die.

520
00:43:25,000 --> 00:43:29,000
In the case of vaccination, you get
exposed to something that is like

521
00:43:29,000 --> 00:43:34,000
the antigen, like the pathogen,
but it's not otherwise dangerous.

522
00:43:34,000 --> 00:43:38,000
But, still, the same stuff happens.
You build up antibody producing

523
00:43:38,000 --> 00:43:43,000
cells.  You build up T cells.
They then get set aside in the

524
00:43:43,000 --> 00:43:47,000
process of immunological memory.
And when you're exposed to the real

525
00:43:47,000 --> 00:43:52,000
thing, if you're exposed to the real
thing later on,

526
00:43:52,000 --> 00:43:57,000
like James Phipps was exposed to
smallpox, you already have those

527
00:43:57,000 --> 00:44:02,000
cells set aside and you can respond
effectively to the agent.

528
00:44:02,000 --> 00:44:08,000
So I want to now just mention in
closing the various vaccine

529
00:44:08,000 --> 00:44:14,000
strategies that are used.
And they all rely on this same

530
00:44:14,000 --> 00:44:20,000
phenomenon of exposing you to a
related agent or antigen allowing

531
00:44:20,000 --> 00:44:26,000
you to make T cells or B cells and
then fight them effectively.

532
00:44:26,000 --> 00:44:32,000
So the first one that I mentioned
is cowpox for smallpox and I used

533
00:44:32,000 --> 00:44:37,000
the term heterologous vaccine.
A heterologous vaccine is an

534
00:44:37,000 --> 00:44:42,000
organism which is very similar to
the organism that causes the disease

535
00:44:42,000 --> 00:44:48,000
cowpox virus versus smallpox virus.
And it's so similar that the

536
00:44:48,000 --> 00:44:53,000
antigens that it produces direct the
development of antibodies or T cells

537
00:44:53,000 --> 00:44:59,000
that will also work against the
dangerous pathogen.

538
00:44:59,000 --> 00:45:02,000
That's a great one if you can have
it, but there aren't very many of

539
00:45:02,000 --> 00:45:06,000
them.  There are very few examples
of heterologous vaccines.

540
00:45:06,000 --> 00:45:10,000
It's just coincidence or luck that
it worked in the case of

541
00:45:10,000 --> 00:45:19,000
cowpox and smallpox.

542
00:45:19,000 --> 00:45:23,000
A more common one is the attenuated
vaccine.  In this case,

543
00:45:23,000 --> 00:45:28,000
you take the active agent like polio
virus and the Sabin polio vaccine is.

544
00:45:28,000 --> 00:45:32,000
You take that active agent and you
grow it in the laboratory for a long

545
00:45:32,000 --> 00:45:37,000
time under conditions
in which it changes.

546
00:45:37,000 --> 00:45:41,000
It adapts to the laboratory
conditions and it's no longer

547
00:45:41,000 --> 00:45:45,000
dangerous to a person.
If infected with this you will not

548
00:45:45,000 --> 00:45:49,000
get polio, but it's sufficiently
similar to the original virulent

549
00:45:49,000 --> 00:45:53,000
pathogen but it has the same
antigens so you mount a proper

550
00:45:53,000 --> 00:45:57,000
immune response.
This is an effective strategy.

551
00:45:57,000 --> 00:46:01,000
It's used all the time.
It's a little bit dangerous because

552
00:46:01,000 --> 00:46:05,000
if the attenuation process isn't
good enough and there's still a

553
00:46:05,000 --> 00:46:08,000
little bit of active pathogen in
there it could cause disease.

554
00:46:08,000 --> 00:46:12,000
And this happens every once in a
while with attenuated vaccines.

555
00:46:12,000 --> 00:46:19,000
Another way is to just take the

556
00:46:19,000 --> 00:46:23,000
agent, whatever it is,
and kill it.  Mix it with a chemical

557
00:46:23,000 --> 00:46:26,000
that will crosslink its genome or
heat it up really high so its DNA

558
00:46:26,000 --> 00:46:30,000
will be destroyed.
That's an agent which cannot

559
00:46:30,000 --> 00:46:34,000
reproduce itself in your body.
Its genome has been destroyed,

560
00:46:34,000 --> 00:46:38,000
but it still has in it the antigens.
It still has on its surface the

561
00:46:38,000 --> 00:46:42,000
antigens.  Your body will still
recognize it, make antibodies and,

562
00:46:42,000 --> 00:46:46,000
therefore, if you were ever exposed
to the live thing you will be

563
00:46:46,000 --> 00:46:51,000
protected.  This is also very
effective.  This is the Salk polio

564
00:46:51,000 --> 00:46:55,000
vaccine.  But every once in a while
the killing process isn't perfectly

565
00:46:55,000 --> 00:46:59,000
effective.  And so there's a little
bit of live virus or whatever in

566
00:46:59,000 --> 00:47:08,000
there and people get disease.

567
00:47:08,000 --> 00:47:12,000
Another strategy is component
vaccines.  Nowadays,

568
00:47:12,000 --> 00:47:16,000
we can purify from the pathogen
virus or bacteria a piece of it.

569
00:47:16,000 --> 00:47:20,000
You can purify some protein from
the virus or from the bacterium and

570
00:47:20,000 --> 00:47:24,000
just use that as the antigen.
That's not dangerous because it

571
00:47:24,000 --> 00:47:28,000
cannot replicate on its own inside
you, but your body makes antibodies

572
00:47:28,000 --> 00:47:32,000
against it.  And,
therefore, you'll be protected at

573
00:47:32,000 --> 00:47:36,000
some later time against
the real thing.

574
00:47:36,000 --> 00:47:46,000
And, increasingly,

575
00:47:46,000 --> 00:47:52,000
we're using recombinant vaccines.
Using molecular biology, genetic

576
00:47:52,000 --> 00:47:58,000
engineering, we can actually build
new agents that carry the genes of

577
00:47:58,000 --> 00:48:03,000
dangerous pathogens.
And, actually,

578
00:48:03,000 --> 00:48:07,000
a commonly used one is vaccinia
itself.  So if you take vaccinia,

579
00:48:07,000 --> 00:48:11,000
the cowpox virus, take some of its
genes out and put in the genes of a

580
00:48:11,000 --> 00:48:16,000
dangerous virus like polio virus,
now that cowpox virus will get into

581
00:48:16,000 --> 00:48:20,000
you.  It will replicate a little bit
and it will start making those

582
00:48:20,000 --> 00:48:24,000
antigens.  Your body will recognize
that with antibodies and T cells.

583
00:48:24,000 --> 00:48:29,000
You'll clear up that infection
because it's not a dangerous agent.

584
00:48:29,000 --> 00:48:32,000
But you will have made antibodies
and T cells that can recognize those

585
00:48:32,000 --> 00:48:36,000
other antigens such that if you were
infected at a later time you would

586
00:48:36,000 --> 00:48:40,000
be protected.  So these are examples
of vaccines, again extremely

587
00:48:40,000 --> 00:48:44,000
effective.  They rely entirely on
immunological memory,

588
00:48:44,000 --> 00:48:47,000
the generation of immunological
diversity.  Now,

589
00:48:47,000 --> 00:48:51,000
importantly, and this is something
that you'll pay attention to next

590
00:48:51,000 --> 00:48:55,000
time, not all of these vaccines are
created equal when it comes to

591
00:48:55,000 --> 00:48:59,000
producing a B cell or
a T cell response.

592
00:48:59,000 --> 00:49:03,000
Some will produce both.
Some will only produce a B cell

593
00:49:03,000 --> 00:49:06,000
response.  And you'll see why that
is in Monday's lecture.