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JOHN ESSIGMANN: I work in
the field of genetic change.

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In a perfect world,
you would say,

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guanine would always
pair with cytosine

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and adenine would always
pair with thymine.

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It turns out, however,
that sometimes chemicals

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from the environment can react
with our normal nucleotides

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and change their coding
characteristics so

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that mistakes are made when
polymerases try to read them.

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These are mutations,
and mutations

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cause genetic diseases.

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My role in the
field of toxicology

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is as a person, who is both
a biologist and a chemist,

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who studies how chemical damage
to our informational molecules

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is converted into
changes in coding

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that results in genetic change.

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I'll emphasize,
of course, this is

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the basis for all
genetic disease,

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but it's also the
basis for evolution.

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In other words, mutations
happen naturally.

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That means that we're not
all-- we don't all look alike.

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And that means there's
diversity in a population,

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and that's because of mutations.

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And evolution is a
really good thing,

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because if we were all alike
when the environment changed,

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then the chance of extinction
might be very high.

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If there's diversity
in a population,

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that's actually a hedge
that life uses in order

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to be able to make sure
something's going to survive,

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because some members
in the population,

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while they may be
considered quote

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unquote "weaker" in the
initial environment, when

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the environment changes--

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they're the ones, for
example, with hair on them,

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and survive the global
winter that happens

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after the meteor strikes.

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So, we are interested
in chemical modification

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of DNA and RNA as it relates
to the causation of disease,

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but we're also
interested in the rates

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at which genetic change
happens in a population,

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and how that's a good
thing, and that it provides

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for the continuance of life.

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One example of our
work in evolution

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comes from recent work that
we've been doing on HIV.

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When a virus infects
one of our cells,

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our cells respond by trying to
limit the growth of the virus.

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They try to kill it.

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And one of the
strategies that used

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by what's called our
innate immune system

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is to induce a number
of enzymes that start

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to rip apart the DNA bases.

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They really take
the amino groups off

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of cytosines and
adenines in order

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to try to convert them
into non-coding nucleotides

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or miscoding nucleotides.

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What happens is, if
you take a cytosine

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and you take away
it's amino group,

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it makes it into a uracil,
and then, rather than

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pair with a guanine, it'll
pair with an adenine.

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Because these are
enzymes that kind of move

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along the viral genome,
they create a huge number

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of mutations.

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The process is called
lethal mutagenesis,

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because what happens
is, eventually

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the number of mutations
is so large that you

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can no longer
produce a functional

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protein or nucleic acid.

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That's a natural
strategy that we use.

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And thinking about
this, some years ago,

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given my lab's
expertise in knowing

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about the structural
modification of normal bases

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that makes them
mutagenic, we wondered

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if we could contaminate the
nucleotide pool of a cell

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with mutagenic nucleotides
that would force a virus

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to mutate even quicker.

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HIV, it turns out, almost
goes extinct, but not quite.

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In other words, our innate
immune system, in one day,

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creates every single point
mutation in the virus,

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but it also creates every
single drug-resistant variant.

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And it just doesn't
push hard enough

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to be able to push the
virus to extinction.

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So, we wondered whether-- if
we could push a little harder

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by using creatively
designed molecules--

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derivatives of cytosine,
that would pretend sometimes

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they're a cytosine and sometimes
they pretended that they were

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a thymine--

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that we could push the
virus over the top.

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And we found that
it did work, OK.

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In other words, we were
able to push the virus

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to a technical state
of extinction using

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our understanding of the
chemistry of the molecules

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that the cell has the capability
to use in replication.

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It may seem unwise
to intentionally put

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mutagenic chemicals into
people, and, obviously,

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we worked out a strategy to
prevent mutations in people

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in the drug design process.

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Specifically, it turns
out there are pathways

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called DNA repair
pathways that repair

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damage in our nuclear genomes,
and they happen in the nucleus.

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That's where the
enzymes are located.

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It turns out that the early
stage in HIV replication

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involved replication
in the cytoplasm.

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There are no repair
enzymes in the cytoplasm.

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So, the virus has no defense
against the mutagenic affects

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of these compounds.

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We picked compounds
that, if they

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were to get into our nuclei--

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it turns out that our
polymerases don't like them

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very much, anyway, but
if they did get in,

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they're very rapidly repaired.

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So, it creates what we call
a therapeutic index which

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is very favorable in
favor of killing the virus

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but not putting mutagenic
chemicals into us.