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So, when I first came to town, the
Red Sox hadn't won for 42 years.

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Now it's been 86 years, so the
whole town all of a sudden changes

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00:00:08,000 --> 00:00:13,000
its psychology. A time
for great celebration,

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at least for you Red Sox fans. At
the, after last lecture I had an

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interesting conversation with one
of you. One of you came up to me and

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said very politely, Professor
Weinberg, do you have some

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lecture notes that you have written
out what the important points of the

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lecture are that you could give
me or that you could give us?

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And I said, you know, I,
I'm not really interested in

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doing that. And the reason I'm not
really interested in doing that is

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that the main function of this
course is to enable you to listen to,

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when somebody is talking about
conceptually complex things and to

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distil what's being said and to
figure out in your own mind what's

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important and what is just another
piece of drivel coming out of my

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mouth or Eric Lander's mouth.
In fact, speaking for him,

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if I will allow, can allow myself,
and myself, in the end we don't

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really care that much whether you
know the difference between DNA and

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RNA or proteins and phospholipids.
What we're really interested in

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doing is to use this course as a
vehicle for pushing you to get your

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brains functioning even
better than they already are.

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And, therefore, if you
learn in this course how to,

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to think about very complex subjects
and figure out what's really going

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on then this course will have more
than paid for itself in terms of the

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energy you put into it. So,
that's part of the reason why we

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don't provide you with lecture
outlines. We want you to figure out

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what's important on your own.
Being able to do so will itself be

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a major triumph. At the
end of our discussion last

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time we talked about the cell cycle,
the fact that it has, has four major

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active phases. G1,
S, G2 and mitosis.

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We talked about mitosis. And
we talked about the fact that

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when cells emerge from mitosis,
from M phase in the absence of

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growth stimulatory factors
then they go into G zero.

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And if they're provided with growth
stimulatory factors then they'll go

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back into the active cell cycle.
And this G zero phase we talked

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about is a quiescence
phase, it's a resting phase.

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In fact, there are two kinds of
quiescent cells in our bodies.

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Those that go into quiescence,
non-growth reversibly, and are able

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to reemerge back into the active
cell cycle, and those cells which

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have irreversibly retreated
from the active cell cycle.

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So, for example, there are many
cells in our brain where no matter

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what you do to them they will never
be able to go back into the active

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cell cycle. And they are, in
that sense, considered to be

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00:03:00,000 --> 00:03:04,000
post-mitotic. Post-mitotic
meaning that they will

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00:03:04,000 --> 00:03:09,000
never again grow. It's
really not clear which of the

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00:03:09,000 --> 00:03:13,000
post-mitotic cells, which
tissues in the body harbor,

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00:03:13,000 --> 00:03:18,000
harbor post-mitotic cells. We
used to think that most of the

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differentiated cells in our body
are post-mitotic. And when I say

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differentiated, a topic we
will not get into for the

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moment, what I mean is that
different cells in different parts

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of the body have become
differentiated by becoming very

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specialized to become neurons or
becoming liver cells or to becoming

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skin cells and so forth. And
it is probably the case that

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there are many kinds of
differentiated cells in the body

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which once they differentiate will
no longer enter into the active cell

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cycle. Now, getting
back to this.

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As I also mentioned, if we
look at a Petri dish then and

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we put cells like fibroblast,
connective tissue cells in the

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bottom of the Petri dish, as
I told you last time, if you

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provide those cells with medium
which contains all the requisite

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nutrients, these cells will sit here
happily for an extended period of

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time but will not proliferate.
However, if you add to their serum,

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add their medium, you add serum
to this medium. Serum usually comes

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from cows, so therefore
it's called bovine serum.

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Then the serum, in addition
to the nutrients present

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in the, in the medium will indeed
provoke these cells to proliferate,

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and there are agents in the serum,
in fact there are agents which are

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called growth factors which are
contained within the serum which are

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responsible for inducing these,
these cells to begin to proliferate.

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Well, it's instructive just for
a moment to step back and ask

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00:04:57,000 --> 00:05:01,000
ourselves what actually is
serum? How do you get serum?

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And the way you get serum is you
take blood and you allow it to clot.

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And when blood clots the
platelets in the, in the blood,

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platelets are small cellular
fragments, they have an intact

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00:05:13,000 --> 00:05:16,000
plasma membrane but they're just,
they're very tiny, they don't have a

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00:05:16,000 --> 00:05:20,000
nucleus, and these A, A nuclear
fragments, these platelets,

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00:05:20,000 --> 00:05:24,000
when blood is induced to clot the
platelets aggregate with one another

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00:05:24,000 --> 00:05:28,000
and you form a big clump, and
that, a clot settles to the

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bottom of the test-tube. But
in the context of wounding,

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let's say you make a cut on your
skin, what happens is that blood

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00:05:36,000 --> 00:05:40,000
rushes into the site of, of
the, the cut or the wound,

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clotting occurs in order to create
coagulation. And why is there

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00:05:44,000 --> 00:05:48,000
coagulation? In order to staunch
the bleeding. In order to prevent

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00:05:48,000 --> 00:05:52,000
there to be further hemorrhage,
further loss of blood. But at the

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00:05:52,000 --> 00:05:56,000
same time, as the platelets
are aggregating to help form the

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00:05:56,000 --> 00:06:00,000
structure of the clot that, that
creates a physical barrier to

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00:06:00,000 --> 00:06:04,000
prevent further bleeding,
simultaneously the platelets are

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00:06:04,000 --> 00:06:08,000
releasing a lot of growth factors
into the medium around them.

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00:06:08,000 --> 00:06:13,000
Why are they doing that?
Because what's happening

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00:06:13,000 --> 00:06:18,000
simultaneous with stopping the
bleeding is that the platelets are,

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00:06:18,000 --> 00:06:23,000
are releasing growth factors
which are used in order to begin to

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00:06:23,000 --> 00:06:28,000
reconstruct and heal the site
of wounding. Consequently,

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00:06:28,000 --> 00:06:33,000
what happens is that the
platelets release growth factors.

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00:06:33,000 --> 00:06:37,000
These growth factors stimulate cells
right around the sides of the wound

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00:06:37,000 --> 00:06:42,000
which are still viable and have
not been destroyed to begin to

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00:06:42,000 --> 00:06:46,000
proliferate in order to
reconstruct and intact tissue.

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00:06:46,000 --> 00:06:51,000
One of the most important of these,
of these, of these factors that they

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00:06:51,000 --> 00:06:55,000
release is platelet-derived
growth factor. Remember GF is

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00:06:55,000 --> 00:07:00,000
just growth factor. And
platelet-derived growth factor,

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00:07:00,000 --> 00:07:04,000
or as it's called in the trade PDGF,
I mentioned it briefly last time, is

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00:07:04,000 --> 00:07:09,000
a very potent mitogen. A
mitogen is a growth stimulatory

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00:07:09,000 --> 00:07:14,000
agent. It's an important
mitogen for fibroblasts.

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00:07:14,000 --> 00:07:18,000
Fibroblasts, as you recall,
are the connective tissue, the

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00:07:18,000 --> 00:07:23,000
connective tissue cells that
are found throughout the body.

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00:07:23,000 --> 00:07:28,000
And, therefore, if you were to,
for example, add platelet-derived

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00:07:28,000 --> 00:07:32,000
growth factor, PDGF to
those fibroblasts that were

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00:07:32,000 --> 00:07:37,000
sitting there in G zero, PDGF
will stimulate the fibroblasts

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00:07:37,000 --> 00:07:42,000
to begin to enter into the active
cell cycle, to exit from G zero,

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00:07:42,000 --> 00:07:47,000
to enter into G1, and therefore
to complete a, a full cell cycle.

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00:07:47,000 --> 00:07:51,000
And, by the way, recall
what I said before,

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00:07:51,000 --> 00:07:55,000
that after the cells leave the
active, leave G zero and move

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00:07:55,000 --> 00:07:59,000
throughout the active cell cycle and
they have a lot of growth factors,

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00:07:59,000 --> 00:08:03,000
they'll go all the way around the
active growth cycle to mitosis.

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00:08:03,000 --> 00:08:07,000
And when they emerge from mitosis,
once again they'll ask themselves

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00:08:07,000 --> 00:08:12,000
the question whether it's a good
idea to continue to be in the active

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00:08:12,000 --> 00:08:16,000
cell cycle or whether they
should exit into G zero,

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00:08:16,000 --> 00:08:21,000
perhaps doing so reversibly.
Interestingly, if you look at the

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00:08:21,000 --> 00:08:25,000
way that the cell cycle is organized
then what you see is the following,

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if I can draw the cell
cycle again. Here's G1.

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00:08:30,000 --> 00:08:34,000
Here's S phase. And
here's G2. And right at,

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00:08:34,000 --> 00:08:38,000
at a distinct point toward the
end of G1 is something called the

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00:08:38,000 --> 00:08:42,000
restriction point,
which is going to be very

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00:08:42,000 --> 00:08:46,000
interesting shortly. And
what happens is after cells

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00:08:46,000 --> 00:08:50,000
emerge from G, from
mitosis and they move

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00:08:50,000 --> 00:08:54,000
throughout the, the most
of G1 they're continually

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00:08:54,000 --> 00:08:58,000
assessing their extracellular
environment to determine whether or

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00:08:58,000 --> 00:09:02,000
not there are enough growth factors
around to justify their continuing

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00:09:02,000 --> 00:09:07,000
the rest of the cell cycle. And
ultimately they'll reach this

128
00:09:07,000 --> 00:09:11,000
restriction point, or as
it's sometimes called the R

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00:09:11,000 --> 00:09:15,000
point, and here they will make
the final go versus no-go decision.

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00:09:15,000 --> 00:09:19,000
So, if there have historically
been enough growth factors from the

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00:09:19,000 --> 00:09:23,000
beginning of G1 all the way to
the R point then cells will commit

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00:09:23,000 --> 00:09:27,000
themselves essentially irreversibly
to going through the entire rest of

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00:09:27,000 --> 00:09:31,000
the cell cycle, through M.
Conversely, if cells reach up to

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00:09:31,000 --> 00:09:35,000
this R point and they
calculate that there are enough,

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00:09:35,000 --> 00:09:39,000
there are not enough mitogenic
growth factors to justify

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00:09:39,000 --> 00:09:43,000
proliferation then they'll jump out
of the active cell cycle and go back

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00:09:43,000 --> 00:09:46,000
to G zero. What that means, in
effect, is as follows. Once the

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00:09:46,000 --> 00:09:50,000
cells have passed through the R
point and they're over here and they

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00:09:50,000 --> 00:09:54,000
are committed to complete the rest
of the cell cycle then you can take

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00:09:54,000 --> 00:09:58,000
growth factors out of their medium
and they don't care because they

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00:09:58,000 --> 00:10:02,000
only want to receive
these stimulatory signals.

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00:10:02,000 --> 00:10:06,000
They only care about in this
window of time. Hereafter,

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00:10:06,000 --> 00:10:11,000
they're committed essentially
irreversibly to go through the rest

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00:10:11,000 --> 00:10:15,000
of the cell cycle. There
are, as it turns out,

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00:10:15,000 --> 00:10:20,000
also growth inhibitory factors.
So, here we've been talking about

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00:10:20,000 --> 00:10:25,000
mitogens, the growth inhibitory
factors. So, an important growth

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00:10:25,000 --> 00:10:30,000
inhibitory factor is,
for example, TGF beta.

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00:10:30,000 --> 00:10:34,000
And TGF beta works exactly opposite
to PDGF because it is a single which

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00:10:34,000 --> 00:10:38,000
is present in extracellular space
and tells the cell it should stop

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00:10:38,000 --> 00:10:42,000
proliferating.
And, therefore,

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00:10:42,000 --> 00:10:47,000
TGF beta, if it's present in large
amounts in this part of the cell

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00:10:47,000 --> 00:10:51,000
cycle, if the cell experiences
it in large amounts,

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00:10:51,000 --> 00:10:55,000
that will influence the cell not to
move through the restriction point.

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00:10:55,000 --> 00:10:59,000
Conversely, if it's absent then
obviously PDGF can have the,

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00:10:59,000 --> 00:11:04,000
the undiluted tensions of
the cell. And, therefore,

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00:11:04,000 --> 00:11:08,000
what I'm trying to convey by this is
to tell you that cell balances both

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00:11:08,000 --> 00:11:12,000
its growth stimulatory and growth
inhibitory signals that it's

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00:11:12,000 --> 00:11:16,000
receiving from extracellular space,
these decisions are weighed, and

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00:11:16,000 --> 00:11:20,000
finally down here the cell with make
the, the binary decision to go ahead

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00:11:20,000 --> 00:11:24,000
or not to go ahead, depending
on historically how many

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00:11:24,000 --> 00:11:29,000
of these factors its recruited
in this specific window of time.

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00:11:29,000 --> 00:11:33,000
Recall, as we said last time,
that once a growth factor like PDGF

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00:11:33,000 --> 00:11:37,000
goes to the plasma membrane it
encounters a receptor on the surface

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00:11:37,000 --> 00:11:42,000
which let's say we call the PDGF
receptor. And I'll just draw it

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00:11:42,000 --> 00:11:46,000
like this for the moment.
It's a transmembrane protein.

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00:11:46,000 --> 00:11:51,000
The extracellular domain is on the
outside. And I'm drawing two copies

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00:11:51,000 --> 00:11:55,000
of the PDGF receptor here
for reasons that will become

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00:11:55,000 --> 00:12:00,000
apparent in a moment. And what
happens is that PDGF which,

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00:12:00,000 --> 00:12:04,000
for example, can be itself a dimer-,
it can be a dimeric growth factor.

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00:12:04,000 --> 00:12:09,000
So, it has two distinct subunits
in it. They're both essentially

171
00:12:09,000 --> 00:12:13,000
equivalent to one another but it is
dimeric. And this dimeric structure,

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00:12:13,000 --> 00:12:18,000
PDGF, allows it to bind to
two growth factor receptors

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00:12:18,000 --> 00:12:22,000
simultaneously. Well,
why is that interesting?

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00:12:22,000 --> 00:12:27,000
It's interesting for
the following reason.

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00:12:27,000 --> 00:12:31,000
These transmembrane PDGF receptors,
like the ones I've indicated right

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00:12:31,000 --> 00:12:35,000
here, they're anchored in the plasma
membrane because there's a portion

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00:12:35,000 --> 00:12:39,000
of their sequence right in here
in the transmembrane domain,

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00:12:39,000 --> 00:12:43,000
I'm indicating it here in the orange,
which contains highly hydrophobic

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00:12:43,000 --> 00:12:47,000
amino acids. And those hydrophobic
amino acids obviously love to be in

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00:12:47,000 --> 00:12:51,000
this hydrophobic environment
of the lipid bilayer and their,

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00:12:51,000 --> 00:12:55,000
by they don't, they have no effect
at all on whether the PDGF receptors

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00:12:55,000 --> 00:13:00,000
can move, can traverse in the
plane of the plasma membrane.

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00:13:00,000 --> 00:13:03,000
So, the PDGF receptors can move
across the face of the plasma

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00:13:03,000 --> 00:13:07,000
membrane. These ones can
move to the right or the left,

185
00:13:07,000 --> 00:13:10,000
but they're not going to come in or
out because they're anchored in this

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00:13:10,000 --> 00:13:14,000
lipid bilayer by this stretch
of hydrophobic amino acids.

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00:13:14,000 --> 00:13:17,000
Now, what happens interestingly
when PDGF, the dimeric receptor

188
00:13:17,000 --> 00:13:21,000
binds to two of these PDGF
receptor molecules, which,

189
00:13:21,000 --> 00:13:24,000
as I told you, have lateral freedom
to translate laterally on the plane

190
00:13:24,000 --> 00:13:28,000
of a plasma membrane, what
happens is it will bind two of

191
00:13:28,000 --> 00:13:32,000
these receptors.
And, in so doing,

192
00:13:32,000 --> 00:13:36,000
it will pull the two receptor
molecules next to one another.

193
00:13:36,000 --> 00:13:41,000
Previously, they were just floating
around in the plane of the plasma

194
00:13:41,000 --> 00:13:46,000
membrane having bound their ligand,
recall that PDGF is considered a

195
00:13:46,000 --> 00:13:50,000
ligand for the PDGF receptor,
having, it will cause these two

196
00:13:50,000 --> 00:13:55,000
receptor molecules to now become,
become pulled very close to one

197
00:13:55,000 --> 00:14:00,000
another. So, I'll
redraw it now like this.

198
00:14:00,000 --> 00:14:03,000
Now these two receptor
molecules look like this,

199
00:14:03,000 --> 00:14:07,000
they're right, they're cheek by jowl,
they're right next to one another,

200
00:14:07,000 --> 00:14:11,000
and this has some interesting
consequences. Of great interest

201
00:14:11,000 --> 00:14:15,000
here is the affect this has on the
ability of the PDGF receptor to emit

202
00:14:15,000 --> 00:14:18,000
signals into the cytoplasm.
Because recall that the end game

203
00:14:18,000 --> 00:14:22,000
here is always how does the, how
does the intracellular part of

204
00:14:22,000 --> 00:14:26,000
the cell know that this, there's
been an encounter with the

205
00:14:26,000 --> 00:14:30,000
growth factor in the
extracellular space?

206
00:14:30,000 --> 00:14:35,000
And this signal-emitting power to
PDGF receptor comes from the fact

207
00:14:35,000 --> 00:14:40,000
that once these two domains
are brought together,

208
00:14:40,000 --> 00:14:45,000
each of these two domains is able
to modify the other and change the

209
00:14:45,000 --> 00:14:50,000
other, i.e., subunit A modifies
subunit B, subunit B modifies

210
00:14:50,000 --> 00:14:55,000
subunit A. And how is
this modification achieved?

211
00:14:55,000 --> 00:15:00,000
For the follow, it is
achieved in the following way.

212
00:15:00,000 --> 00:15:04,000
That the, this domain,
which I've been calling,

213
00:15:04,000 --> 00:15:08,000
I've just been writing like this,
as a rectangle, is actually a

214
00:15:08,000 --> 00:15:13,000
catalytic agent. It's
actually a tyrosine kinase.

215
00:15:13,000 --> 00:15:17,000
So, it's an enzyme. And a tyrosine
kinase is an enzyme that takes the

216
00:15:17,000 --> 00:15:22,000
gamma phosphate from ATP, the
high energy phosphate from APT,

217
00:15:22,000 --> 00:15:26,000
ATP and transfers it to tyrosine
amino acids that are present

218
00:15:26,000 --> 00:15:31,000
on substrates. So, if
here is an amino acid

219
00:15:31,000 --> 00:15:35,000
sequence in the single letter,
letter code, and if we admit that Y

220
00:15:35,000 --> 00:15:40,000
is the, is the code for tyrosine
then if here's a protein that it

221
00:15:40,000 --> 00:15:44,000
functions as a substrate
for a tyrosine kinase,

222
00:15:44,000 --> 00:15:48,000
a tyrosine kinase will add a
phosphate group to the side chain of

223
00:15:48,000 --> 00:15:53,000
the tyrosine, which I'm not drawing
here, but tyrosine has a hydroxyl

224
00:15:53,000 --> 00:15:57,000
group in its side chain and,
therefore, it will phosphorilate

225
00:15:57,000 --> 00:16:02,000
this tyrosine. That is
to say will tetraphosphate

226
00:16:02,000 --> 00:16:06,000
group do it? It will
phosphorilate this tyrosine.

227
00:16:06,000 --> 00:16:11,000
So, these two rectangles are, in
fact, tyrosine kinases. And what

228
00:16:11,000 --> 00:16:16,000
happens, after the two subunits
of the receptor have been brought

229
00:16:16,000 --> 00:16:20,000
together, is thereafter, what
one finds is that each of these

230
00:16:20,000 --> 00:16:25,000
receptor subunits becomes
multiply phosphorilated.

231
00:16:25,000 --> 00:16:30,000
And each of these lollipops that
I'm indicating here are sites where

232
00:16:30,000 --> 00:16:35,000
there, a tyrosine residue
has become phosphorilated.

233
00:16:35,000 --> 00:16:38,000
In fact, there's a tail of the PDGF
receptor that extends even further

234
00:16:38,000 --> 00:16:42,000
to the cytoplasm which also acquires
a number of different phosphates on

235
00:16:42,000 --> 00:16:46,000
it. And, again, I'd
remind us that this

236
00:16:46,000 --> 00:16:50,000
phosphorylation is really what's
often called transphosphorylation

237
00:16:50,000 --> 00:16:53,000
because each receptor molecule
phosphorilates the tyrosine residues

238
00:16:53,000 --> 00:16:57,000
on the other. Obviously, when
these two receptor molecules

239
00:16:57,000 --> 00:17:01,000
are far apart in the plain
of the plasma membrane,

240
00:17:01,000 --> 00:17:05,000
this transphosphorylation
cannot occur.

241
00:17:05,000 --> 00:17:09,000
But once the two tyrosine kinase
residues, once the two tyrosine

242
00:17:09,000 --> 00:17:13,000
kinases have been brought together,
pulled together by the dimerization

243
00:17:13,000 --> 00:17:17,000
of the receptor, now this cross-phosphorylation,

244
00:17:17,000 --> 00:17:22,000
on each phosphorylating the other
can occur, and soon the receptors

245
00:17:22,000 --> 00:17:26,000
are highly phosphorilated.
All of these phosphate groups,

246
00:17:26,000 --> 00:17:30,000
to repeat myself, being attached
to tyrosine residues in their

247
00:17:30,000 --> 00:17:35,000
cytoplasmic domains.
And this, in turn,

248
00:17:35,000 --> 00:17:39,000
creates interesting docking sites
for a variety of other cytoplasmic

249
00:17:39,000 --> 00:17:44,000
signaling proteins. And we'll
talk about some today and

250
00:17:44,000 --> 00:17:49,000
next time, but what I want to leave
you with is the following impression.

251
00:17:49,000 --> 00:17:53,000
That after this phosphorylation
actually occurs there are a number

252
00:17:53,000 --> 00:17:58,000
of molecules in the cytoplasm,
signaling molecules that have

253
00:17:58,000 --> 00:18:03,000
affinity for binding
these phosphotyrosines.

254
00:18:03,000 --> 00:18:07,000
When I say phosphotyrosine,
obviously, I'm referring to the

255
00:18:07,000 --> 00:18:11,000
phosphorilated form of tyrosine
that's been created by a tyrosine

256
00:18:11,000 --> 00:18:15,000
kinase enzyme. So, here's
one molecule that can

257
00:18:15,000 --> 00:18:19,000
bind. Here's molecule A combined
to one of these phosphates,

258
00:18:19,000 --> 00:18:23,000
another one combined to
this phosphate specifically,

259
00:18:23,000 --> 00:18:27,000
and each of these molecules,
once they're attracted to this

260
00:18:27,000 --> 00:18:31,000
phosphorilated receptor, can
then emit downstream signals,

261
00:18:31,000 --> 00:18:35,000
send a variety of signals into
the cell that ultimately end up in

262
00:18:35,000 --> 00:18:40,000
persuading the
cell to proliferate.

263
00:18:40,000 --> 00:18:45,000
And so these effects here of growth
factors in the G1 phase of the cell

264
00:18:45,000 --> 00:18:50,000
cycle are mediated by this
transmembrane signaling,

265
00:18:50,000 --> 00:18:55,000
by the activation of these, of
this PDGF receptor, for example,

266
00:18:55,000 --> 00:19:00,000
and by the resulting a release of
downstream signals into the cell

267
00:19:00,000 --> 00:19:05,000
which pursued the cell to
proliferate or not to proliferate.

268
00:19:05,000 --> 00:19:08,000
To be sure the,
when platelets clot,

269
00:19:08,000 --> 00:19:12,000
when platelets aggregate and they
release PDGF, they also release

270
00:19:12,000 --> 00:19:15,000
other kinds of growth factors.
For instance, there's another

271
00:19:15,000 --> 00:19:19,000
growth factor that's called IGF1,
insulin-like growth factor, and that

272
00:19:19,000 --> 00:19:22,000
has its own receptor on the
surface of cells. And there are,

273
00:19:22,000 --> 00:19:26,000
on a cell, hundreds to thousands
of these PDGF receptors,

274
00:19:26,000 --> 00:19:30,000
there are IGF receptors,
there are EGF receptors.

275
00:19:30,000 --> 00:19:34,000
And a cell often will require
several distinct kinds of growth

276
00:19:34,000 --> 00:19:38,000
factor activations in
order to proliferate. So,

277
00:19:38,000 --> 00:19:42,000
this is only a minor part of
the entire exposure that a cell

278
00:19:42,000 --> 00:19:47,000
experiences in the G1 phase of the
cell cycle. To elaborate on a point

279
00:19:47,000 --> 00:19:51,000
that I made last time, an
important biological distinction

280
00:19:51,000 --> 00:19:55,000
between normal cells and cancer
cells is the fact that cancer cells

281
00:19:55,000 --> 00:19:59,000
require relatively little growth
factors or in the medium in order to

282
00:19:59,000 --> 00:20:04,000
proliferate. Normal
cells have a very strong

283
00:20:04,000 --> 00:20:08,000
requirement for growth
factors in their medium. And,

284
00:20:08,000 --> 00:20:13,000
therefore, what we can already
imagine is the following kind of

285
00:20:13,000 --> 00:20:17,000
scenario. That cancer cells have
someone deregulated this signaling

286
00:20:17,000 --> 00:20:21,000
pathway. Somehow they have become
independent of the stimulation that

287
00:20:21,000 --> 00:20:26,000
is normally required,
usually required for cells to

288
00:20:26,000 --> 00:20:30,000
proliferate. And, in
fact, we know of several

289
00:20:30,000 --> 00:20:35,000
different ways by which cancer
cells can acquire this independence.

290
00:20:35,000 --> 00:20:39,000
One of the most important ways,
it's, it a really interesting one,

291
00:20:39,000 --> 00:20:43,000
is here's a cancer cell, which
we'll talk about very shortly.

292
00:20:43,000 --> 00:20:47,000
And what you find in certain kinds
of cancer cells is that the cancer

293
00:20:47,000 --> 00:20:52,000
cells themselves release
growth factors into the medium.

294
00:20:52,000 --> 00:20:56,000
So, there are certain kinds of
cancer cells that will release,

295
00:20:56,000 --> 00:21:00,000
let's say, a growth factor that's
like EGF into the medium around it,

296
00:21:00,000 --> 00:21:05,000
around themselves. Well,
you'll say that's kind of

297
00:21:05,000 --> 00:21:09,000
amusing. But so what. The
important part here is that

298
00:21:09,000 --> 00:21:13,000
these same cancer cells
have receptors for TG,

299
00:21:13,000 --> 00:21:17,000
for EGF on their surface.
So, they're producing a growth

300
00:21:17,000 --> 00:21:21,000
factor and they can also respond
to the same growth factor.

301
00:21:21,000 --> 00:21:25,000
And, therefore, this EGF, once
it's released, can swim over

302
00:21:25,000 --> 00:21:29,000
here, activate the receptor
and pursued the cell to start

303
00:21:29,000 --> 00:21:33,000
proliferating. This
is, if you will,

304
00:21:33,000 --> 00:21:37,000
a positive feedback loop. But
note here importantly that this,

305
00:21:37,000 --> 00:21:41,000
the growth of this cell is not being
controlled by growth factors coming

306
00:21:41,000 --> 00:21:45,000
from cells elsewhere in the tissue
or the body. Here we're not talking

307
00:21:45,000 --> 00:21:49,000
about different cells talking to one
another. Here we're talking about a

308
00:21:49,000 --> 00:21:53,000
monologue where this cell is talking
to itself. This is sometimes called

309
00:21:53,000 --> 00:21:57,000
autocrine signaling and refers
to the fact that certain kinds of

310
00:21:57,000 --> 00:22:02,000
cancer cells are able to make growth
factors to which they can respond.

311
00:22:02,000 --> 00:22:05,000
In fact, in normal tissues it's rare
for a single cell type in a normal

312
00:22:05,000 --> 00:22:09,000
tissue to be able to make a growth
factor and to be able to respond to

313
00:22:09,000 --> 00:22:13,000
the same growth factor. Why
can it normally not respond to

314
00:22:13,000 --> 00:22:17,000
that growth factor? Because
it won't make the receptor

315
00:22:17,000 --> 00:22:21,000
for the growth factor. For
example, epithelial cells like

316
00:22:21,000 --> 00:22:25,000
the cells in your skin or
the cells lining the gut,

317
00:22:25,000 --> 00:22:29,000
they can release PDGF, but
they don't have a PDGF receptor

318
00:22:29,000 --> 00:22:32,000
on their surface.
And, therefore,

319
00:22:32,000 --> 00:22:36,000
even though they release
copious amounts of PDGF,

320
00:22:36,000 --> 00:22:40,000
that will not result in this auto
stimulatory proliferation and,

321
00:22:40,000 --> 00:22:44,000
therefore, you don't have this
decontrolled self-proliferation that

322
00:22:44,000 --> 00:22:48,000
you see often in cancer cells,
this autocrine loop. In many kinds

323
00:22:48,000 --> 00:22:52,000
of cancer cells you have another
alteration of this growth factor

324
00:22:52,000 --> 00:22:56,000
signaling pathway. And
here what we see is the

325
00:22:56,000 --> 00:23:00,000
following. Instead of there being
a small number of growth factor

326
00:23:00,000 --> 00:23:04,000
receptors on the cell surface, now
there are ten or twenty or fifty

327
00:23:04,000 --> 00:23:08,000
times more than are normally
present on the cell surface.

328
00:23:08,000 --> 00:23:11,000
In other words, this
growth, the growth factor

329
00:23:11,000 --> 00:23:14,000
receptors are what is
called overexpressed.

330
00:23:14,000 --> 00:23:23,000
And, therefore,

331
00:23:23,000 --> 00:23:27,000
a delicate balance is
disrupted because normally,

332
00:23:27,000 --> 00:23:31,000
let's say, a cell with have on
its surface 500 EGF receptors,

333
00:23:31,000 --> 00:23:35,000
but in many kinds of cancers
probably 30% or 40% of all

334
00:23:35,000 --> 00:23:39,000
carcinomas, carcinomas are the
tumors from epithelial tissues,

335
00:23:39,000 --> 00:23:42,000
you'll find overexpressed
EGF receptor. Well,

336
00:23:42,000 --> 00:23:46,000
why is that interesting? It's
interesting for the following

337
00:23:46,000 --> 00:23:50,000
reason. I told you before that the
activation of a receptor depends on

338
00:23:50,000 --> 00:23:54,000
its ligand to persuading two
receptor subunits to come together

339
00:23:54,000 --> 00:23:58,000
and start firing,
as we just discussed.

340
00:23:58,000 --> 00:24:01,000
But if now all of a sudden the
cell contains large amounts of this

341
00:24:01,000 --> 00:24:04,000
growth being expressed, of the
growth factor receptor being

342
00:24:04,000 --> 00:24:07,000
expressed on the surface, ten
or a hundred times more than

343
00:24:07,000 --> 00:24:11,000
normal, then these growth factor
receptors are going to be rather

344
00:24:11,000 --> 00:24:14,000
densely packed on the cell surface.
And now they may just come together

345
00:24:14,000 --> 00:24:17,000
because they happen to bump
into each other very frequently.

346
00:24:17,000 --> 00:24:21,000
They don't need the growth factor
to pull them together just because

347
00:24:21,000 --> 00:24:24,000
there are so many of them. So,
there's random interactions,

348
00:24:24,000 --> 00:24:27,000
random bumping together
And these two growth factor

349
00:24:27,000 --> 00:24:31,000
receptors may just bump together and
thereby send signals into the cell

350
00:24:31,000 --> 00:24:35,000
persuading the cell that there's
been some kind of growth factor in

351
00:24:35,000 --> 00:24:39,000
the extracellular domain
that's been encountered when,

352
00:24:39,000 --> 00:24:42,000
in fact, all that's happened is that
there are so many of these growth

353
00:24:42,000 --> 00:24:46,000
factor receptors around that they're
constantly bumping into each other,

354
00:24:46,000 --> 00:24:50,000
and while they've collided with one
another they can activate signaling

355
00:24:50,000 --> 00:24:54,000
and release growth stimulatory
signals into the cell.

356
00:24:54,000 --> 00:24:58,000
There's another kind of, of
alteration of growth factor

357
00:24:58,000 --> 00:25:03,000
receptors that's also seen
in many kinds of human tumors.

358
00:25:03,000 --> 00:25:08,000
For example, in, in glioblastomas,
which is a brain tumor. And a

359
00:25:08,000 --> 00:25:13,000
glioblastoma has the following
kind of, of receptor on the surface.

360
00:25:13,000 --> 00:25:18,000
It has truncated forms of the EGF
receptor on the surface where a lot

361
00:25:18,000 --> 00:25:22,000
of the ectodomain is simply not
present. So, here's the normal EGF

362
00:25:22,000 --> 00:25:27,000
receptor, here is a truncated
EGF receptor where a lot of the

363
00:25:27,000 --> 00:25:32,000
extracellular domain, which
I'm calling the ectodomain,

364
00:25:32,000 --> 00:25:37,000
has simply been lopped off.
How has it be lopped off?

365
00:25:37,000 --> 00:25:41,000
Well, there's been a mutation
it the gene which has,

366
00:25:41,000 --> 00:25:45,000
in effect, deleted segments
in coding the N-terminus of the

367
00:25:45,000 --> 00:25:49,000
receptor protein, which
normally sticks its head out

368
00:25:49,000 --> 00:25:54,000
of the cell. And now you have
these truncated receptors.

369
00:25:54,000 --> 00:25:58,000
And such truncated EGF receptors
are able to fire constitutively.

370
00:25:58,000 --> 00:26:02,000
Constitutively implies that these
receptors are able to fire in a

371
00:26:02,000 --> 00:26:07,000
fashion that is no longer
regulated by physiologic signals.

372
00:26:07,000 --> 00:26:10,000
It's a high steady rate. So
now these receptor molecules,

373
00:26:10,000 --> 00:26:14,000
these truncated receptor molecules
flood the cell with growth

374
00:26:14,000 --> 00:26:18,000
stimulatory signal and, for
reasons that aren't really clear

375
00:26:18,000 --> 00:26:22,000
to this day, these two, these
receptor, truncated receptor

376
00:26:22,000 --> 00:26:26,000
molecules can dimerize, they
can come together even if

377
00:26:26,000 --> 00:26:30,000
there's no extracellular ligand
present, even if there's no growth

378
00:26:30,000 --> 00:26:34,000
factor in the extracellular
space. And we now realize,

379
00:26:34,000 --> 00:26:38,000
for example, that there are a
variety of structurally altered

380
00:26:38,000 --> 00:26:42,000
receptors that fire constitutively
into a cell in many kinds of human

381
00:26:42,000 --> 00:26:46,000
tumors. And in each case the cancer
cell is deluded into thinking that

382
00:26:46,000 --> 00:26:50,000
some growth factor has been
encountered out here when,

383
00:26:50,000 --> 00:26:54,000
in fact, there's not at all.
Once again, what we see is a

384
00:26:54,000 --> 00:26:58,000
situation in which the cell,
the cancer cell is being deluded

385
00:26:58,000 --> 00:27:03,000
into thinking there's growth
factors present, extracellular space.

386
00:27:03,000 --> 00:27:07,000
None has been present at all.
There have been a variety of drugs

387
00:27:07,000 --> 00:27:12,000
developed against, for
example, lung cancer.

388
00:27:12,000 --> 00:27:17,000
And there are a variety of
different kinds of lung cancers.

389
00:27:17,000 --> 00:27:22,000
One is called non-small cell lung
carcinoma. We don't have to deal

390
00:27:22,000 --> 00:27:26,000
with the subsets of lung cancers.
And it turned out, it turned out

391
00:27:26,000 --> 00:27:31,000
that one of these drugs, it's
called Iressa, had very mixed

392
00:27:31,000 --> 00:27:38,000
effects on patients.

393
00:27:38,000 --> 00:27:42,000
In about 90% of these, of
the class of lung cancers,

394
00:27:42,000 --> 00:27:47,000
patients that were treated, the drug
Iressa, used over the last several

395
00:27:47,000 --> 00:27:51,000
years, had almost no effect on the
tumor treatment and the patients

396
00:27:51,000 --> 00:27:56,000
continued to, to proceed
to their death. It had,

397
00:27:56,000 --> 00:28:00,000
it really had no effect. But
in 10%, in fact, there was some

398
00:28:00,000 --> 00:28:05,000
dramatic responses
and tumors shrunk down.

399
00:28:05,000 --> 00:28:09,000
Now, normally a 10% response rate
would be enough to cause a drug

400
00:28:09,000 --> 00:28:13,000
company to abandon all further
development of the drug because it's

401
00:28:13,000 --> 00:28:17,000
just too low a response and who
wants to take a drug where the

402
00:28:17,000 --> 00:28:21,000
chances of having a good
response are as low as 10%?

403
00:28:21,000 --> 00:28:25,000
It's just not a good situation.
But then some geneticists here in

404
00:28:25,000 --> 00:28:29,000
Boston, one group at the MGH and
another over at the Dana Farber,

405
00:28:29,000 --> 00:28:33,000
began to look at the lung
cancer cells that responded,

406
00:28:33,000 --> 00:28:37,000
i.e., from tumors of patients that
responded and shrank in response to

407
00:28:37,000 --> 00:28:41,000
the drug and the lung, and
the lung cancer cells of

408
00:28:41,000 --> 00:28:44,000
patients who didn't. It
turns out that Iressa is an

409
00:28:44,000 --> 00:28:48,000
inhibitor of the tyrosine
kinase of the EGF receptor.

410
00:28:48,000 --> 00:28:52,000
That's how it was designed. In
other words, this drug, it's a

411
00:28:52,000 --> 00:28:56,000
low molecular weight drug and it
goes into the tyrosine kinase domain,

412
00:28:56,000 --> 00:29:00,000
that rectangular thing I showed
you before very schematically,

413
00:29:00,000 --> 00:29:04,000
and it shuts down the
firing of the receptor.

414
00:29:04,000 --> 00:29:08,000
That was the motivation
behind creating this drug.

415
00:29:08,000 --> 00:29:13,000
So, Iressa shuts down the EGF
receptor and 10% of lung cancer

416
00:29:13,000 --> 00:29:18,000
patients, their tumor shrank,
the other 90% didn't, weren't

417
00:29:18,000 --> 00:29:22,000
effected at all. And
what these two groups of

418
00:29:22,000 --> 00:29:27,000
geneticists found over the last
three or four months is that the

419
00:29:27,000 --> 00:29:32,000
patients whose tumors responded had
tumor cells where the EGF receptor

420
00:29:32,000 --> 00:29:37,000
was mutated and therefore firing
in a constitutively active fashion.

421
00:29:37,000 --> 00:29:40,000
That is to say there were actually
structural alterations in the

422
00:29:40,000 --> 00:29:44,000
receptor. This is a massive
structural alteration of the

423
00:29:44,000 --> 00:29:48,000
receptor here,
this truncation.

424
00:29:48,000 --> 00:29:52,000
But, in fact, in certain patients
the 10% of patients that responded,

425
00:29:52,000 --> 00:29:56,000
there were much more subtle changes
in the cytoplasmic domain of the

426
00:29:56,000 --> 00:30:00,000
protein which allowed these
receptors to constitutively dimerize,

427
00:30:00,000 --> 00:30:04,000
once again, in a ligand
independent fashion.

428
00:30:04,000 --> 00:30:08,000
So, these subtle mutations mimic,
in effect, the consequences of

429
00:30:08,000 --> 00:30:12,000
deleting or truncating the
extracellular domain in that in both

430
00:30:12,000 --> 00:30:16,000
cases one gets a ligand independent
receptor. In those cases where

431
00:30:16,000 --> 00:30:20,000
these, where the patients
had a mutant EGF receptor,

432
00:30:20,000 --> 00:30:24,000
structurally altered EGF receptor
that was firing constitutively,

433
00:30:24,000 --> 00:30:28,000
there were dramatic
responses to the Iressa drug.

434
00:30:28,000 --> 00:30:31,000
In the 90% of patients where there
was no effective response to the

435
00:30:31,000 --> 00:30:35,000
drug, the EGF receptor was wild-type,
it was present in a wild-type

436
00:30:35,000 --> 00:30:39,000
configuration. It
might have been slightly

437
00:30:39,000 --> 00:30:43,000
overexpressed but it wasn't,
but it continued to, to function

438
00:30:43,000 --> 00:30:46,000
essentially as a normal EGF receptor.
And this represents a major advance

439
00:30:46,000 --> 00:30:50,000
in cancer therapy because it
suggests that one has to begin to

440
00:30:50,000 --> 00:30:54,000
understand what subsets of patients
one should treat with a drug which

441
00:30:54,000 --> 00:30:58,000
can, on its own, have
quite toxic effects on the

442
00:30:58,000 --> 00:31:01,000
patient. And,
from now on,

443
00:31:01,000 --> 00:31:05,000
to state the obvious, when
one gets lung cancer patients

444
00:31:05,000 --> 00:31:09,000
one will check quickly using various
reactions, like the PCR reaction,

445
00:31:09,000 --> 00:31:13,000
to see whether or not their cancer
cells have a mutated EGF receptor.

446
00:31:13,000 --> 00:31:16,000
And, if they do, they will be
candidates for Iressa treatment with

447
00:31:16,000 --> 00:31:20,000
the expectation that 60%, 80%
or even 100% of them will have

448
00:31:20,000 --> 00:31:24,000
tumors that respond. And
if they don't have a mutated

449
00:31:24,000 --> 00:31:28,000
EGF receptor then they will
not be subjected to a treatment

450
00:31:28,000 --> 00:31:31,000
by this drug. This is
the beginning of a new era

451
00:31:31,000 --> 00:31:35,000
of cancer drug treatment. It's
called rational drug design,

452
00:31:35,000 --> 00:31:39,000
or rational treatment, where you
don't just lump all the patients

453
00:31:39,000 --> 00:31:43,000
with a certain disease together and
say let's give them all this drug

454
00:31:43,000 --> 00:31:46,000
and throw things up in the
air and see what happens.

455
00:31:46,000 --> 00:31:50,000
Here one begins to do a genetic
diagnosis of the genomes of the

456
00:31:50,000 --> 00:31:54,000
patient's cancer cells in order to
determine whether or not they have

457
00:31:54,000 --> 00:31:58,000
certain mutated genes. In this
case we're referring to one

458
00:31:58,000 --> 00:32:02,000
of these growth factor receptors.
By the way, we're talking about lung

459
00:32:02,000 --> 00:32:06,000
cancer today, right?
If you are smoking now,

460
00:32:06,000 --> 00:32:10,000
I always ask the class how
many people are smoking,

461
00:32:10,000 --> 00:32:14,000
and nobody has the, has the moral
fortitude to raise their hands.

462
00:32:14,000 --> 00:32:18,000
But if you are smoking now and you
started at this age and you continue.

463
00:32:18,000 --> 00:32:22,000
And, by the way, if you
start at your age and you

464
00:32:22,000 --> 00:32:26,000
continue smoke, stopping
smoking is actually a bit

465
00:32:26,000 --> 00:32:30,000
more difficult, quite a
bit more difficult than

466
00:32:30,000 --> 00:32:34,000
stopping heroine. That's
pretty interesting,

467
00:32:34,000 --> 00:32:38,000
right? So, if you continue to smoke
now you will be healthy for a pretty

468
00:32:38,000 --> 00:32:42,000
long period of time, probably
another 20 or 30 years.

469
00:32:42,000 --> 00:32:46,000
And for you that sounds like
forever, but when you get to be

470
00:32:46,000 --> 00:32:50,000
about 40 or 50 things are
going to start falling apart.

471
00:32:50,000 --> 00:32:54,000
Soon you won't be able to be very
athletic, soon your lungs are going

472
00:32:54,000 --> 00:32:58,000
to be able, are going to degrade,
and by the time you reach your

473
00:32:58,000 --> 00:33:02,000
fifties, sixties or seventies
what's going to happen is you will,

474
00:33:02,000 --> 00:33:06,000
on average, have a six to eight
year shortened life expectancy.

475
00:33:06,000 --> 00:33:09,000
Now you say six to eight
years is not that much,

476
00:33:09,000 --> 00:33:13,000
but it really is. You know,
when you get to be 70 and

477
00:33:13,000 --> 00:33:17,000
you think you're going to die next
year or you're going to die in six

478
00:33:17,000 --> 00:33:20,000
or eight years it makes a big
difference. Six to eight years is

479
00:33:20,000 --> 00:33:24,000
an enormous difference in life
expectancy. 20% of all people who

480
00:33:24,000 --> 00:33:28,000
died last year in this country,
20% of all deaths came from

481
00:33:28,000 --> 00:33:32,000
cigarette smoking. Imagine that.
And when you die from cigarette

482
00:33:32,000 --> 00:33:36,000
smokes, smoking sometimes you get
lung cancer. There probably were,

483
00:33:36,000 --> 00:33:40,000
I think, 600,000 people who
died from smoking last year.

484
00:33:40,000 --> 00:33:44,000
Six hundred thousand. There were
55,000 American soldiers who died in

485
00:33:44,000 --> 00:33:48,000
Vietnam in the whole war, there
were 220,000 American soldiers

486
00:33:48,000 --> 00:33:52,000
who died in all of World War II,
and last year in this, and there

487
00:33:52,000 --> 00:33:56,000
were 3,000, or 2, 00
people who died in the World

488
00:33:56,000 --> 00:34:00,000
Trade Center. All right?
Got all those numbers?

489
00:34:00,000 --> 00:34:05,000
So, last year 600, 00
people died premature deaths

490
00:34:05,000 --> 00:34:10,000
because they were smoking. How
many people died last year from

491
00:34:10,000 --> 00:34:15,000
smoking marijuana?
Maybe two or three,

492
00:34:15,000 --> 00:34:20,000
I don't know. [APPLAUSE] Am I
urging you to do any kind of smoking?

493
00:34:20,000 --> 00:34:25,000
I'm not saying marijuana smoking is
good for you, but I just want you to

494
00:34:25,000 --> 00:34:30,000
get these things in
mind, the perspective.

495
00:34:30,000 --> 00:34:33,000
If you smoke, you know, in
many countries, including this

496
00:34:33,000 --> 00:34:37,000
one, there isn't much tension
by, given by the government to,

497
00:34:37,000 --> 00:34:40,000
dissuading people from smoking,
and here's the reason why. If you

498
00:34:40,000 --> 00:34:44,000
smoke, and you going to get, get
sick eventually, eventually the

499
00:34:44,000 --> 00:34:47,000
country is always going to have
to pay for your medical costs,

500
00:34:47,000 --> 00:34:51,000
right? Sooner or later we all have
to pay for the costs of people who

501
00:34:51,000 --> 00:34:54,000
get sick. It's all shared
in one way or another.

502
00:34:54,000 --> 00:34:58,000
But it's not such a big problem
for a government like the

503
00:34:58,000 --> 00:35:02,000
American government. Because
if you smoke you're going to

504
00:35:02,000 --> 00:35:06,000
die early enough that you
won't draw on social security.

505
00:35:06,000 --> 00:35:10,000
And, therefore, the government
actually saves money by your smoking,

506
00:35:10,000 --> 00:35:14,000
because by the time they add up how
much they get on the tobacco tax and

507
00:35:14,000 --> 00:35:18,000
how much they earn by your not
living long enough to draw a pension,

508
00:35:18,000 --> 00:35:22,000
it's much better, it's much
more money than how much

509
00:35:22,000 --> 00:35:26,000
it's going to cost to take care
of you while you're dying from

510
00:35:26,000 --> 00:35:30,000
emphysema or bladder cancer or
lung cancer or heart disease.

511
00:35:30,000 --> 00:35:33,000
Many more people die from heart
attacks due to smoking than die from

512
00:35:33,000 --> 00:35:37,000
lung cancer, in fact.
So, think about this.

513
00:35:37,000 --> 00:35:41,000
Think about this. If you smoke
it's probably a good time to stop

514
00:35:41,000 --> 00:35:45,000
because if you continue at your age,
especially if you're women, which is

515
00:35:45,000 --> 00:35:48,000
women, for some reason women have
a harder time stopping than men,

516
00:35:48,000 --> 00:35:52,000
they can't say why. It's
probably some physiological thing.

517
00:35:52,000 --> 00:35:56,000
If you, if you continue now at your
age, it will be almost impossible to

518
00:35:56,000 --> 00:36:00,000
stop. If you live with smokers
ask them to leave. [LAUGHTER]

519
00:36:00,000 --> 00:36:04,000
If you live at home with your
parents and they smoke tell them

520
00:36:04,000 --> 00:36:08,000
it's time for them to leave.
Throw them out of the house.

521
00:36:08,000 --> 00:36:12,000
Smoke, second-hand smoking
killed probably between 60,

522
00:36:12,000 --> 00:36:16,000
00 and 80,000 people last year in
this country. Second-hand smoke.

523
00:36:16,000 --> 00:36:20,000
And, by the way, if you want to
see an interesting phenomenon,

524
00:36:20,000 --> 00:36:24,000
go to a veterinary hospital because
there they with great frequently,

525
00:36:24,000 --> 00:36:28,000
frequency treat dogs who have
lung cancer. And why do they

526
00:36:28,000 --> 00:36:32,000
have lung cancer? Not
in 99% of the cases,

527
00:36:32,000 --> 00:36:36,000
in 100% of the cases these
dogs live with owners who smoke.

528
00:36:36,000 --> 00:36:40,000
An average tobacco smoker goes
through six or eight dogs in his or

529
00:36:40,000 --> 00:36:44,000
her lifetime. [LAUGHTER] It's
true. It's absolutely true.

530
00:36:44,000 --> 00:36:49,000
So if you, if you think the dogs,
if that's a fact for the, for the,

531
00:36:49,000 --> 00:36:53,000
for the dog owners, think
about what's happening to the

532
00:36:53,000 --> 00:36:57,000
inside of your lungs. And so
I'm going to take back what

533
00:36:57,000 --> 00:37:02,000
I said before. Before
I told you that the most

534
00:37:02,000 --> 00:37:06,000
important thing for you to do in
this course is to learn how to think

535
00:37:06,000 --> 00:37:10,000
clearly and to assess and to distil
conceptually complex material,

536
00:37:10,000 --> 00:37:14,000
there's actually one more thing
that's even more important to get

537
00:37:14,000 --> 00:37:18,000
out of this course, if
you do, and that is to stop

538
00:37:18,000 --> 00:37:22,000
smoking. If you do that, if
you do that it'll be vastly more

539
00:37:22,000 --> 00:37:26,000
important for the rest of your
life than anything you learn here.

540
00:37:26,000 --> 00:37:30,000
So, write that down, vastly more
important. You may think it's

541
00:37:30,000 --> 00:37:34,000
glamorous, you may think it's
exciting, but keep in mind,

542
00:37:34,000 --> 00:37:38,000
people who stop smoking have vastly
greater effects on reducing the

543
00:37:38,000 --> 00:37:42,000
morbidity and the mortality in this
country than anything that cancer

544
00:37:42,000 --> 00:37:46,000
researchers can do.
Keep that in mind.

545
00:37:46,000 --> 00:37:50,000
And if you start smoking now and
you think that somehow the cancer

546
00:37:50,000 --> 00:37:53,000
researchers are going to be able
to come up with some miracle cure by

547
00:37:53,000 --> 00:37:56,000
this time you start coughing
and start spitting up blood,

548
00:37:56,000 --> 00:38:00,000
don't be so certain. They
may not be able to save you,

549
00:38:00,000 --> 00:38:04,000
to pull your fat out of the
fire. So, I don't know whether I,

550
00:38:04,000 --> 00:38:08,000
I gave this message in a very subtle
way or I hit you over the head with

551
00:38:08,000 --> 00:38:12,000
it. [LAUGHTER] But think,
think about that. Now, now we're

552
00:38:12,000 --> 00:38:16,000
going to focus on lung cancer,
we're going to focus on cancer

553
00:38:16,000 --> 00:38:20,000
because it's one of the
consequences of cigarette smoking,

554
00:38:20,000 --> 00:38:24,000
but it's a disease we want to talk
about both this time and next time,

555
00:38:24,000 --> 00:38:28,000
and we want to relate it
here to the cell cycle and,

556
00:38:28,000 --> 00:38:32,000
and how the growth of
cell proliferation occurs.

557
00:38:32,000 --> 00:38:36,000
I told you last time that a human
tumor is roughly-speaking about,

558
00:38:36,000 --> 00:38:40,000
a human body roughly carries three
times ten to the thirteenth cells.

559
00:38:40,000 --> 00:38:44,000
So, that's quite a few cells.
That's how many cells there are in

560
00:38:44,000 --> 00:38:48,000
the human body, plus or
minus. A human tumor of one,

561
00:38:48,000 --> 00:38:52,000
let's say one cubic centimeter
is roughly ten to the ninth cells.

562
00:38:52,000 --> 00:38:56,000
So, a tiny tumor this way
already has a billion cells in it.

563
00:38:56,000 --> 00:39:00,000
And what I want to say is
that those billion cells,

564
00:39:00,000 --> 00:39:04,000
or if the tumor grows larger to
ten to a hundred billion cells,

565
00:39:04,000 --> 00:39:09,000
it's still not that much compared
with the overall size of the body.

566
00:39:09,000 --> 00:39:14,000
But tumors of that size can kill
you. And one, an interesting and

567
00:39:14,000 --> 00:39:19,000
important thing to realize about all
the cancer cells in that tumor mass

568
00:39:19,000 --> 00:39:24,000
is that they all descend
from a single progenitor.

569
00:39:24,000 --> 00:39:29,000
In other words, if we imagine a
situation where here are a whole

570
00:39:29,000 --> 00:39:34,000
bunch of normal cells and here's
the boundary between normalcy up here

571
00:39:34,000 --> 00:39:40,000
and malignancy, malignancy
obviously refers to

572
00:39:40,000 --> 00:39:45,000
cancer, we could imagine where there
are many cells which independently

573
00:39:45,000 --> 00:39:50,000
cross the boundary from one to the
other and become the progenitors of

574
00:39:50,000 --> 00:39:55,000
a vast tumor mass. But
that's not what happens.

575
00:39:55,000 --> 00:40:00,000
What happens, in fact, is that only
one cell gets converted or becomes,

576
00:40:00,000 --> 00:40:05,000
as one says here, it becomes
transformed from a normal cell into

577
00:40:05,000 --> 00:40:10,000
a cancer cell. And this
transformation causes this

578
00:40:10,000 --> 00:40:15,000
one cell to become the progenitor,
the ancestor of all the cells in the

579
00:40:15,000 --> 00:40:20,000
tumor mass. So, one
important realization we have

580
00:40:20,000 --> 00:40:25,000
about looking at different tumors is
that cancers are monoclonal growths,

581
00:40:25,000 --> 00:40:30,000
i.e., they form clonal populations.
They're monoclonal in the sense that

582
00:40:30,000 --> 00:40:35,000
they all are genetically derived
from a single common ancestor rather

583
00:40:35,000 --> 00:40:40,000
than being polyclonal. What
else can we say about cancer

584
00:40:40,000 --> 00:40:44,000
cells or the cells in a tumor? If
you take cells out of Petri dish,

585
00:40:44,000 --> 00:40:48,000
out of an animal or a human
and put them on a Petri dish,

586
00:40:48,000 --> 00:40:52,000
excuse me, and you put them there,
then what you'll see is following

587
00:40:52,000 --> 00:40:56,000
interesting behavior. If you
put normal cells in a Petri

588
00:40:56,000 --> 00:41:00,000
dish they'll grow across the bottom
of the Petri dish until they cover

589
00:41:00,000 --> 00:41:04,000
the entire bottom
of the Petri dish.

590
00:41:04,000 --> 00:41:08,000
So, you can put a hundred cells in
and they'll continue to proliferate.

591
00:41:08,000 --> 00:41:12,000
Let's look at the Petri dish from
top down, so you might have a small

592
00:41:12,000 --> 00:41:16,000
number of cells here and here,
and normal cells will continue to

593
00:41:16,000 --> 00:41:21,000
proliferate until they
begin to touch one another,

594
00:41:21,000 --> 00:41:25,000
and then they'll stop growing.
And this stopping of growing is,

595
00:41:25,000 --> 00:41:30,000
is the phenomenon that's
called contact inhibition.

596
00:41:30,000 --> 00:41:33,000
So, a normal cell will
indicate contact inhibition.

597
00:41:33,000 --> 00:41:37,000
And to state, to state the obvious,
this phenomenon or this behavior of

598
00:41:37,000 --> 00:41:40,000
contact inhibition creates what's
called a cell monolayer because if

599
00:41:40,000 --> 00:41:44,000
the cell stopped growing once they
touch each other they're not going

600
00:41:44,000 --> 00:41:47,000
to be two or three or four
layers of cells in the Petri dish.

601
00:41:47,000 --> 00:41:51,000
So, here we're looking at this
Petri dish in cross-section and

602
00:41:51,000 --> 00:41:55,000
there's a monolayer
of normal cells here.

603
00:41:55,000 --> 00:41:58,000
If you put a cancer cell in the
Petri dish, or let's put here a

604
00:41:58,000 --> 00:42:02,000
cancer cell, we'll seed it amidst
normal cells, what will happen is

605
00:42:02,000 --> 00:42:06,000
that the cancer cell lacks,
has lost contact inhibition,

606
00:42:06,000 --> 00:42:09,000
and the cancer cell will continue to
proliferate even after it's touched

607
00:42:09,000 --> 00:42:13,000
its neighbors. So,
it has lost cancer,

608
00:42:13,000 --> 00:42:17,000
it has lost contact inhibition
and will start growing on top of,

609
00:42:17,000 --> 00:42:20,000
the cancer cells will start growing
on top of each other because they

610
00:42:20,000 --> 00:42:24,000
don't mind growing in spite of
their having intimate contact with

611
00:42:24,000 --> 00:42:28,000
neighboring cells. And,
in fact, what you can do is

612
00:42:28,000 --> 00:42:32,000
the following experiment. You
can put cells in a Petri dish

613
00:42:32,000 --> 00:42:37,000
like this, a whole bunch of
normal cells in a Petri dish,

614
00:42:37,000 --> 00:42:42,000
and then you can put into them
some kind of transforming influence,

615
00:42:42,000 --> 00:42:47,000
which we'll talk about very shortly,
i.e., you can influence some of

616
00:42:47,000 --> 00:42:52,000
these cells to become transformed.
And how we do so we'll tell, we'll

617
00:42:52,000 --> 00:42:57,000
hold in abeyance just for a moment.
So, we'll have this cell. We'll do

618
00:42:57,000 --> 00:43:02,000
this cell to become transformed
and this cell to become transformed.

619
00:43:02,000 --> 00:43:05,000
And what will happen is that those
cells will begin to form a very

620
00:43:05,000 --> 00:43:09,000
thick clump of cells, these
blue ones, the ones that are

621
00:43:09,000 --> 00:43:13,000
transformed. Whereas, all the
other cells will grow until

622
00:43:13,000 --> 00:43:16,000
they form a monolayer at which
point they'll stop proliferating.

623
00:43:16,000 --> 00:43:20,000
So, the cancer cells keep piling
up and the transformed cells,

624
00:43:20,000 --> 00:43:24,000
transformed by one or another
agent, we won't talk about that yet,

625
00:43:24,000 --> 00:43:28,000
continue to proliferate long
after the normal cells have stopped

626
00:43:28,000 --> 00:43:31,000
proliferating. The normal
cells having stopped

627
00:43:31,000 --> 00:43:35,000
proliferating because
they're contact inhibited.

628
00:43:35,000 --> 00:43:38,000
And, therefore, they'll form this
clump of cells which we'll call a

629
00:43:38,000 --> 00:43:42,000
focus. And if you hold the Petri
dish up to the light and you look at

630
00:43:42,000 --> 00:43:45,000
it and there are some
transformed cells present,

631
00:43:45,000 --> 00:43:49,000
you can see the foci,
they're very thick. Whereas,

632
00:43:49,000 --> 00:43:52,000
the thin monolayer of cells will
just look pretty transparent.

633
00:43:52,000 --> 00:43:56,000
But this focus will look highly
opaque by virtue of the multiple

634
00:43:56,000 --> 00:44:00,000
layers of cells that
are involved in it.

635
00:44:00,000 --> 00:44:05,000
Now, in fact, we can begin to ask
the question of how and why cells

636
00:44:05,000 --> 00:44:10,000
like this become transformed
and exhibit this behavior.

637
00:44:10,000 --> 00:44:16,000
In fact, until the 1980s there
wasn't really a clear understanding

638
00:44:16,000 --> 00:44:21,000
about how that happened. I've
already given you some clues

639
00:44:21,000 --> 00:44:27,000
because I've already told you the
fact that certain cancer cells carry

640
00:44:27,000 --> 00:44:32,000
mutant genes. What
kind of mutant genes?

641
00:44:32,000 --> 00:44:36,000
Well, I gave you, in
anticipation of discussion,

642
00:44:36,000 --> 00:44:40,000
the fact that certain cancer cells
carry mutant genes that specify

643
00:44:40,000 --> 00:44:44,000
mutant growth factor receptors.
And these mutant growth factor

644
00:44:44,000 --> 00:44:49,000
receptors, as I indicated,
begin to push the cell the

645
00:44:49,000 --> 00:44:53,000
proliferate. And so that already
anticipates a conclusion we're about

646
00:44:53,000 --> 00:44:57,000
to make, which is that the reason
why cancer cells behave abnormally

647
00:44:57,000 --> 00:45:02,000
is that they carry mutant genes.
Now, let's talk about the nature of

648
00:45:02,000 --> 00:45:07,000
these mutant genes because, if
you look at these mutant genes,

649
00:45:07,000 --> 00:45:12,000
invariably they are the consequences
of what we call somatic mutations.

650
00:45:12,000 --> 00:45:17,000
By that I mean, I mean the
following. Let's say we all start

651
00:45:17,000 --> 00:45:22,000
out with a really good set of genes.
And, thank the good Lord, we all do.

652
00:45:22,000 --> 00:45:27,000
But as we go through life through
accidents or through intent we can

653
00:45:27,000 --> 00:45:32,000
damage these genes. We can
muck them up in different

654
00:45:32,000 --> 00:45:36,000
ways. And these genes, this
damage may occur to cells in

655
00:45:36,000 --> 00:45:41,000
the skin, they may occur to cells in
your belly, they may occur to cells

656
00:45:41,000 --> 00:45:45,000
in the brain, and these are called
somatic mutations in contrast to the

657
00:45:45,000 --> 00:45:50,000
germline mutations that affect
one's offspring. Because,

658
00:45:50,000 --> 00:45:54,000
as you must realize by now, the
only way you can have mutations

659
00:45:54,000 --> 00:45:59,000
that affect your descendents is if
those mutations strike in the gonads

660
00:45:59,000 --> 00:46:04,000
and affect the genomes
of either sperm or egg.

661
00:46:04,000 --> 00:46:08,000
But the mutations occurring
everywhere else in the body outside

662
00:46:08,000 --> 00:46:12,000
of the gonads,
because they occur in,

663
00:46:12,000 --> 00:46:16,000
I think I, this is somatic, excuse
me, because they occur in the

664
00:46:16,000 --> 00:46:21,000
soma, the soma is defined as the
entirety of the body outside of the

665
00:46:21,000 --> 00:46:25,000
gonads, outside of the germi,
these somatic mutations might affect

666
00:46:25,000 --> 00:46:29,000
the tissues around them but they
will not be transmitted from one

667
00:46:29,000 --> 00:46:34,000
organismic generation to
the next. And, accordingly,

668
00:46:34,000 --> 00:46:38,000
we begin to imagine, in
fact, correctly we begin to

669
00:46:38,000 --> 00:46:42,000
construct this model that one of
the most important mechanisms of

670
00:46:42,000 --> 00:46:46,000
creating a cancer cell is
to damage its genome. So,

671
00:46:46,000 --> 00:46:50,000
I'll tell you a story now,
which I'm only going to finish on

672
00:46:50,000 --> 00:46:54,000
Monday. We have, let's
imagine, a 55-year-old,

673
00:46:54,000 --> 00:46:58,000
this is a true story, 55-year-old
man who's been smoking since he or

674
00:46:58,000 --> 00:47:02,000
she, he was 15 years old. So,
he's been smoking for 40 years.

675
00:47:02,000 --> 00:47:06,000
And during those periods of 40 years,
by the way, I'm not saying whether

676
00:47:06,000 --> 00:47:10,000
I'm for or against smoking,
you understand that. During that

677
00:47:10,000 --> 00:47:15,000
period of 40 years this person has
been introducing large amounts of

678
00:47:15,000 --> 00:47:19,000
tobacco smoke compounds into his
lungs. Now, it turns out that these

679
00:47:19,000 --> 00:47:23,000
compounds, this tobacco smoke
compounds are carcinogens.

680
00:47:23,000 --> 00:47:28,000
You know carcinogen means it causes
cancer. But it happens also to be

681
00:47:28,000 --> 00:47:32,000
the case that a lot of carcinogens,
cancer-causing compounds are also

682
00:47:32,000 --> 00:47:37,000
mutagens. That is to
say they can mutate DNA.

683
00:47:37,000 --> 00:47:41,000
So, here we have a scenario that
we're going to set up for next time.

684
00:47:41,000 --> 00:47:46,000
55-year-old man. Smokes for 40
years. Dumps a lot of carcinogens

685
00:47:46,000 --> 00:47:50,000
into his lungs. The
carcinogens which are highly,

686
00:47:50,000 --> 00:47:55,000
which induce mutations very potently
are passed from his lungs into his

687
00:47:55,000 --> 00:48:00,000
blood and there go from
the blood into the kidneys.

688
00:48:00,000 --> 00:48:04,000
And from the kidneys they are
excreted into the urine and then

689
00:48:04,000 --> 00:48:09,000
they sit around in the bladder for
a while. And let's imagine now that

690
00:48:09,000 --> 00:48:13,000
the urine of this man has all
of these highly mutation-active

691
00:48:13,000 --> 00:48:18,000
carcinogens in his urine, which,
in principle, can begin now

692
00:48:18,000 --> 00:48:23,000
to strike out and attack the genomes
of the cells lining the urinary

693
00:48:23,000 --> 00:48:27,000
bladder. In other words, by,
by smoking cigarettes you can

694
00:48:27,000 --> 00:48:32,000
actually mutate the genomes,
somatic mutation, the genomes of

695
00:48:32,000 --> 00:48:37,000
cells lining the bladder of the,
the urinary bladder, or, of course,

696
00:48:37,000 --> 00:48:41,000
to state the obvious, you can also
mutate the genomes of the cells

697
00:48:41,000 --> 00:48:46,000
lining the alveoli in the lungs.
That's why you get lung cancer.

698
00:48:46,000 --> 00:48:50,000
And a consequence of this can be,
with serious probability, that now

699
00:48:50,000 --> 00:48:54,000
some of these cells become
mutated and that, in turn,

700
00:48:54,000 --> 00:48:58,000
will lead to a life-threatening
tumor. So, on this very cheerful

701
00:48:58,000 --> 00:49:02,000
note and your having heard two
major take-home lessons, have

702
00:49:02,000 --> 00:49:07,000
a great weekend. See
you on Monday. Enjoy

703
00:49:07,000 --> 00:49:12,000
the parade tomorrow.