Dr. Austin: The NIH Molecular Libraries
Initiative was started in 2003 as a translational initiative
after the Human Genome Project, and it really had two purposes.
One was to determine the function and biological and
therapeutic potential of all human genes using small molecule
compounds to study those functions. The other was
explicitly therapeutic intent, which was to provide starting
points for the development of new therapeutics for human
disease. The way the Molecular Libraries
program was operationalized was on the principle that there are
common mechanisms which underlie many different diseases, and as
were taught in kindergarten, the knee bone is connected to the
leg bone, which is connected to the hip bone. But much of
science is done in a quite silo-driven way where one person
will work on the knee bone, one person will work on the hip
bone, and one person will work on the leg bone. But this
organization, because its funded by the Common Fund, is able to
look on all of those bones simultaneously in a much more
holistic way. So we have people, collaborators, coming to
us who have different interests in aging, environmental
toxicology, and cancer, and development, for instance, in
rare diseases. And in many cases, they are all interested
in the same biological pathway, but that same pathway is
involved in many different diseases.
Now, under a normal circumstance, it would be very
difficult for one lab to work on a project with those many
different disease or biological implications. But here, because
the organization was built to be trans-NIH, to be something which
is agnostic to the disease, and in fact, looking for
cross-cutting mechanisms, were able to leapfrog many of the
problems. What we started with this
initiative was a completely new model of creating a
pre-competitive space, so-called, for this kind of
science to happen. Previously, this kind of science had only
happened at this scale and at this level of sophistication
within biotech and pharmaceutical companies. And
we sought to, and have now done a project to bring the best of
the technologies, the lessons, the team-driven,
deliverable-driven culture from the best biopharmaceutical
companies into the academic domain and set those
technologies and those people loose on the many targets and
many diseases that simply cant be worked on easily in the
private sector due to poor return on investment.
In order to do this, weve had to set up a number of really
cutting-edge, innovative centers, one of which is here,
where were sitting, at the NIH Chemical Genomics Center, to
develop what we call an assay, which is a testing system which
allows us to test well above a hundred thousand compounds in a
day as a starting point for the kind of work that we do. So,
the robotics that is required gives us the start of the
chemical material which might eventually become a drug.
So what do I mean by that? When we develop an assay, that assay
is a testing system which allows us to test currently 400,000
different compounds in seven different concentrations in a
little less than a week. Now, in order for a person to do
that, would require constant work, seven days a week, eight
hours a day for 12 years, and we do that in five days. Now, what
that allows us to do is take the new gene, or the new protein, or
the new pathway in a cell, or a cellular phenotype, so-called,
that is something that a cell does thats abnormal, which is
representative of the disease. We put those cells in each one
of the wells of this plate, which is a 1,536-well plate,
which has -- which can contain 1,536 different experiments.
Ill give you one example that were working on right now, as
a matter of fact. Theres a project that was brought to us
by an investigator at Illinois State University, David
Williams, who's now at Rush University in Chicago, who came
to us with an enzyme that he thought was involved in a very
prevalent parasitic disease known as schistosomiasis. It
affects about 280 million people worldwide. And he came to us
with this idea that this novel enzyme that he had discovered,
if inhibited, could safely kill the worms without hurting the
individual who has the infection. And so working with
him over the course of two years, we developed these just
such compounds and were able to prove, in fact, that his
hypothesis was right: that in worms in a dish or in an animal
model of those diseases, of that disease, schistosomiasis, that
these compounds actually do cure those mice.
And then as an example of the kind of leapfrogging Im talking
about, through our various connections, through Davids
connections and ours, we identified an investigator,
Michael Cappello at Yale, who works on a completely different
disorder known as hookworm infection, so another parasite,
and it turns out that variants of these compounds, these very
same compounds, also work in hookworm. Hookworm is another
tremendously prevalent disease, affects about a half a billion
people worldwide, and they havent really been thought of as
being related before, but here we have one set of compounds
that may actually be curative of both disorders.
The important issue is that its a collaboration. Its a
multifaceted collaboration between biologists and chemists
and informatics of scientists and engineers here and a very
tight collaboration with academic investigators all over
the world who are working in a network of investigation to look
across targets, across diseases to try to identify these keys
into these various locks that will work not only for one
disease, but for multiple diseases.