JOHN ESSIGMANN: I work in the field of genetic change.
In a perfect world, you would say,
guanine would always pair with cytosine
and adenine would always pair with thymine.
It turns out, however, that sometimes chemicals
from the environment can react with our normal nucleotides
and change their coding characteristics so
that mistakes are made when polymerases try to read them.
These are mutations, and mutations
cause genetic diseases.
My role in the field of toxicology
is as a person, who is both a biologist and a chemist,
who studies how chemical damage to our informational molecules
is converted into changes in coding
that results in genetic change.
I'll emphasize, of course, this is
the basis for all genetic disease,
but it's also the basis for evolution.
In other words, mutations happen naturally.
That means that we're not all-- we don't all look alike.
And that means there's diversity in a population,
and that's because of mutations.
And evolution is a really good thing,
because if we were all alike when the environment changed,
then the chance of extinction might be very high.
If there's diversity in a population,
that's actually a hedge that life uses in order
to be able to make sure something's going to survive,
because some members in the population,
while they may be considered quote
unquote "weaker" in the initial environment, when
the environment changes--
they're the ones, for example, with hair on them,
and survive the global winter that happens
after the meteor strikes.
So, we are interested in chemical modification
of DNA and RNA as it relates to the causation of disease,
but we're also interested in the rates
at which genetic change happens in a population,
and how that's a good thing, and that it provides
for the continuance of life.
One example of our work in evolution
comes from recent work that we've been doing on HIV.
When a virus infects one of our cells,
our cells respond by trying to limit the growth of the virus.
They try to kill it.
And one of the strategies that used
by what's called our innate immune system
is to induce a number of enzymes that start
to rip apart the DNA bases.
They really take the amino groups off
of cytosines and adenines in order
to try to convert them into non-coding nucleotides
or miscoding nucleotides.
What happens is, if you take a cytosine
and you take away it's amino group,
it makes it into a uracil, and then, rather than
pair with a guanine, it'll pair with an adenine.
Because these are enzymes that kind of move
along the viral genome, they create a huge number
of mutations.
The process is called lethal mutagenesis,
because what happens is, eventually
the number of mutations is so large that you
can no longer produce a functional
protein or nucleic acid.
That's a natural strategy that we use.
And thinking about this, some years ago,
given my lab's expertise in knowing
about the structural modification of normal bases
that makes them mutagenic, we wondered
if we could contaminate the nucleotide pool of a cell
with mutagenic nucleotides that would force a virus
to mutate even quicker.
HIV, it turns out, almost goes extinct, but not quite.
In other words, our innate immune system, in one day,
creates every single point mutation in the virus,
but it also creates every single drug-resistant variant.
And it just doesn't push hard enough
to be able to push the virus to extinction.
So, we wondered whether-- if we could push a little harder
by using creatively designed molecules--
derivatives of cytosine, that would pretend sometimes
they're a cytosine and sometimes they pretended that they were
a thymine--
that we could push the virus over the top.
And we found that it did work, OK.
In other words, we were able to push the virus
to a technical state of extinction using
our understanding of the chemistry of the molecules
that the cell has the capability to use in replication.
It may seem unwise to intentionally put
mutagenic chemicals into people, and, obviously,
we worked out a strategy to prevent mutations in people
in the drug design process.
Specifically, it turns out there are pathways
called DNA repair pathways that repair
damage in our nuclear genomes, and they happen in the nucleus.
That's where the enzymes are located.
It turns out that the early stage in HIV replication
involved replication in the cytoplasm.
There are no repair enzymes in the cytoplasm.
So, the virus has no defense against the mutagenic affects
of these compounds.
We picked compounds that, if they
were to get into our nuclei--
it turns out that our polymerases don't like them
very much, anyway, but if they did get in,
they're very rapidly repaired.
So, it creates what we call a therapeutic index which
is very favorable in favor of killing the virus
but not putting mutagenic chemicals into us.