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JOHN ESSIGMANN: At the end
of the course, when there's

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so many pathways out there that
things start to get really,

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really complicated,
we try to increase

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the number of
physiological scenarios,

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again, to try to get the
students sufficiently

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interested in a
pathway and thinking

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about how the whole
pathway works,

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not just each individual step--

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to get the student to like the
example so that he or she will

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go right in there and study it.

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And one of the areas that
I think really important

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these days in basic
metabolic biochemistry

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is in oncology-- cancer biology.

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JoAnne mentioned that
not that many years ago,

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academic programs
wondered whether teaching

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metabolic pathways was
really the best use of time,

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because so many
other things were

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happening in the molecular
biology revolution.

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And certainly in 5.07 we decided
to maintain emphasis in this,

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because we--

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just because these are the
first pathways that were studied

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doesn't mean they
aren't important.

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They're medically
very important.

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They were originally
studied because

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of medical or economic
reasons that--

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fermentation, for example--
that these pathways

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were right in front and center.

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They're always very topical.

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But what happened in I'd
say the last 10 years

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is that there's
been a reawakening

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of the understanding of how
metabolic pathways redirect

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themselves in order to
accomplish disease goals--

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for example, with a tumor.

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And one of the things
we teach is that a tumor

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is a lot like a running muscle.

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And Matthew Vander Heiden,
who is here in our biology

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department and teaches
the comparable course

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is a real expert, a
pioneer in this area.

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But what we've learned
is that cancer cells

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tend to be addicted to glucose.

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They would much prefer
glucose over any other fuel.

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In fact, they-- when you think
about what a cancer cell really

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is, it's a cell
that's not terribly

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different from all
our other cells.

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It's acquired some
small number--

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we'll call driver mutations,
maybe seven or so driver

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mutations.

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There are many more passenger
mutations, but maybe

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seven or so genetic
differences that

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separate it from a normal cell.

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But among the things
that has happened to

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it is reprogramming of
its metabolic needs.

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And it has acquired
the commitment

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to unremitting cell division.

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If you think about what's
needed for a cell to divide,

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probably the principal
structural resource-- which,

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again, this would come from
JoAnne's part of the course--

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is membranes.

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You've got to recreate the
outside of the cell and all

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those organelles.

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And what that means is
fatty acid biosynthesis

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is absolutely going
to be paramount.

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One way that we now know that
tumors work, if you understand

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all the pathways, is a
tumor will consume glucose,

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it will convert that
glucose to acetyl-CoA.

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The acetyl-CoA takes a ride on
the molecule citrate until it

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gets put out into the cytoplasm,
and then in the cytoplasm it

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becomes a factory
for producing--

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out of acetyl-CoA, it
produces the lipids

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that are necessary
for membranogenesis.

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That's absolutely critical
for cancer cell development.

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Now, the reason that's important
is that understanding it,

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it tells us that,
well, there are

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certain enzymes in the pathway.

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One of them is called
ATP citrate lyase.

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Another one is
called malic enzyme.

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So, when you look at the
charts, you'll see these things.

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These are enzymes that are
necessary for cell division,

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because they're necessary
for fatty acid biosynthesis,

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and they represent
good targets--

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next-generation targets--
for cancer chemotherapy.

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A normal cell, you can
tell it not to divide,

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and it won't divide.

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But if you can tell a cell
that's committed to divide

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and you tell it not to
divide, oftentimes that cell

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will kill itself.

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So by blocking these
critical points--

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test points, we'll call them,
in this metabolic chart--

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you're able to selectively kill
cancer cells-- we hope, anyway.

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But this study of
metabolic biochemistry

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has identified
these new targets.

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Another thing that's, I
think, an important anecdote

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about cancer cells is that
they need other cells in order

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to survive.

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If you think about the
problems that a tumor faces--

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remember, it started
from a normal cell

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that acquired new mutations,
converted into a cancer cell,

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and then started to
grow out into a tumor.

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As it grows, it becomes more
remotely placed relative

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to the blood supply.

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OK, now, certainly there
will be a response,

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and the blood supply will try
to grow toward the tumor cells.

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But the core of a
tumor is hypoxic.

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It doesn't have enough oxygen
to do real respiration.

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So, what happens
is, the cancer cell

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tries to hard-wire the
glycolysis pathway to be on.

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And rough estimates are that
through this-- initially,

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a hypoxia-inducing factor, which
is a transcription factor-- you

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get an upregulation by 10
to 20-fold of almost all

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of the enzymes of the
glycolytic pathway.

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So, what happens
is, the cancer cell

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becomes a specialist
at glycolysis.

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It does high-throughput
glycolysis-- glucose

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to pyruvate.

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But, again, we don't have
the metabolic equipment

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to do a lot of--

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we don't have the
metabolic equipment

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to be able to do respiration
if you're removed from oxygen.

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So, the pyruvate gets
converted into lactate.

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Lactate gets pumped
out into the blood,

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and, as I mentioned before,
it acidifies the blood.

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That's what happens
with a working muscle.

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But the tumor sends the
lactate into the blood.

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It's picked up by the liver.

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The liver is a specialist
in gluconeogenesis.

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The liver then rebuilds
the lactate into glucose,

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sends this back
out into the blood.

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So, the tumor is then
able to re-eat the lactate

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that it sent out.

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So a partnership emerges
between the liver--

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the gluconeogenic organ--

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and the tumor.

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So, the tumor finds
that it's fed by--

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unwittingly-- by the liver.

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And the liver is contributing to
providing the nutrition that's

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eventually going to kill the
organism if something doesn't

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go in to stop it.

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But, again, understanding
the pathways

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can give you ideas with
regard to how to intervene.

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So, metabolic
biochemistry is pretty

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critical to understanding
this generation's cancer

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scientific agenda.