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Summer Ash: When we look at the fragments
of the past, it can be hard to figure out
how they all fit together. How can we use
the evidence we collect to build a more complete
picture, a model, to improve our understanding
and ask more informed questions?
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For example, we know that in the second century
the emperor Hadrian built a huge villa in
the town of Tivoli, near Rome. But little
of that villa remains today. So how can we
know what it looked like, or how it was used?
Archaeologist Bernard Frischer and his team
are working on this very problem. They're
building a virtual 3D model of the villa using
data from surveys of the site, documents and
artwork of the time, and actual artifacts
that survive in museums around the world.
They're even using historical, astronomical
data from NASA to reveal how Romans aligned
certain buildings with the sun and with the
planets.
But historians aren't the only ones that have
to come up with new solutions to complicated
puzzles. Scientists also have to pull together
different lines of evidence, see how they
connect, and then build models to better understand
their data and direct their research.
New discoveries often come from putting together
pieces you already have. In this video, we'll
talk to scientists who are developing new
drugs. We'll hear about their research and
some novel approaches and even some venomous
snails. Chemical biologist Derek Tan explains
how scientists working on new drugs need to
bring together a wide range of skills and
approaches.
Derek Tan: Some of the specific skills that
we use in organic chemistry are a knowledge
of the literature, of reactions that are available.
Pattern recognition, to know when to apply
those reactions, and a deep understanding
of reaction mechanisms. A chemist has to integrate
that knowledge as well as an ability to view
molecules in three dimensions. To consider
their conformations and the impacts that that
has on reactivity.
Chemical biologists, then, have to take all
of that chemical knowledge to be able to apply
the chemistry to study and controlling those
systems. That's the challenge for us in training
the next generation of chemical biologists,
and that's one of the things that we do in
our tri-institutional PhD program in chemical
biology.
Summer Ash: What is rational drug design?
Derek Tan: Rational drug design is one of
the major approaches to developing drugs whereby
one chooses a target that the biology says
is going to be useful for therapeutic indications.
We try to develop a molecule to often inhibit
the activity of that target, or otherwise
interact with it. In our lab, we use both
rational therapy approaches and serendipitous
approaches to drug discovery.
Summer Ash: This is a very important part
of the way scientists and science can work.
Using multiple approaches at the same time
provides more avenues and more information.
It also allows for stronger confirmation and
better reliability of results. Laura Juszczak
Of Brooklyn College explains.
 Summer Ash: Why is it important to both study these proteins
from an experimental standpoint and from a
computer modeling standpoint?
Laura Juszczak: Because one validates the
other. One method validates the other. You
have the real world, what's happening in the
real world. You shine light on these proteins.
How do they behave in the real world? Then
you have the modeling.
In the laboratory we're exploring different
molecular systems and just waiting, or hoping
that we'll get some result that will either
confirm our hypotheses. But even more significantly
and more exciting is when we don't get the
results we expect, so there's this real aha
and hooray moment when that happens. It's
that joy of discovery, of finding something
new, that really keeps scientists going.
Summer Ash: Drug discovery, like so much of
science, involves moving back and forth between
discovery and testing. Finding new questions
and using new techniques to answer them. Sometimes
new ideas and new solutions begin in very
unusual places.
Mandë Holford: We study the evolutionary
history of venomous marine snails in order
to figure out why it is that these snails
have venom to begin with, and also what are
the components in their venom that might have
therapeutic appeal, or appeal for biomedical
research purposes.
Juliette Gorson: We go about finding potential
drugs in nature by actually going out into
the field and collecting snails. I've been
very, very lucky as the biologist in the lab
to be able to accompany Mandë Holford in
the field. I've been out to Hawaii, I've been
to Papua New Guinea twice, and hopefully we'll
be going to Abu Dhabi in November to collect.
We're also lucky because these snails have
about 500 species in the family, so there
are a lot of different bioactive compounds
that we can take from these snails.
The family of snails that we work with is
the Terebridae family. This is a close relative
of the Conoidea family, which are more commonly
known as cone snails.
These snails are like any other snail. They
crawl along the ground very, very slowly.
But the proboscis, so that hunting organ,
shoots really quickly. They can shoot their
prey in less than a second.
They're really exciting to watch. I've actually,
when I was looking at snail-hunting snails,
cone snails, they actually both slowly move
around the tank. It's a really, really slow
game of a predator trying to catch the prey.
Eventually, once the cone snail gets close
enough to its prey, it's going to stab it
quickly and then consume it quickly.
Mandë Holford: There's an arms race happening
between the predator and the prey, and so
the venom has been evolutionary tested and
approved. It's the best FDA in the world,
because these compounds have to work.
We combine tools from chemistry and biology
in order to investigate and try to figure
out what's happening both in the snail, and
also to identify novel peptides that can manipulate
functioning and cellular physiology. Our biological
tools are for the most part based in taxonomy,
genetics, and evolution.
More recently, sequencing and bioinformatics.
We use those tools because we're trying to
identify which species are the ones that seem
to be giving us bioactive compounds. We trace
the evolutionary history of these venomous
snails and we try to identify which lineages
are the ones that seem to be doing what we
are most interested in.
Once we have that information we then pair
it with the chemical side in that we synthesize
the peptide synthetically, and that is putting
together the amino acids on a chain in a particular
order. Then we fold, because peptides are
only functional when they're in a folded format.
If you think of a pearl necklace, all those
beads on the string, those are different amino
acids. But you can't wear the necklace until
you clasp it behind your neck. That's what
folding is. Until you fold the peptide, it
won't be functional.
After that, we then go through a series of
biological assays to try to identify, what
is the molecular target of this particular
peptide? That'll tell us, OK, what we've synthesized
is correct, and it seems to be bioactive.
It doesn't tell us what the specific target
is. It's like a funnel effect. You start very
broad, and then you get narrower and narrower
with each step.
One of the biggest misconceptions in my field
is that discovery research is not relevant.
I find that really troubling, because there
seems to be this tension between hypothesis-driven work
and discovery driven work. Really,
all of it is good work.
When you think that 70 percent of the drugs
on the market right now were derived from
natural compounds, the only way we're going
to find those compounds is if we go out and
do discovery work.
There are systematic ways to go about doing
discovery work, which is what we hope we're
doing by looking at the evolutionary history,
identifying species from phylogenetic trees
that look promising, and then going out and
targeting those species, instead of just going
randomly to the beach and picking everything
up.
But discovery research is very, very relevant,
and it's very important, and it shouldn't
be diminished in any way, shape, or form.
Because nature has a lot of the answers that
we're looking for in science, and if we're
learning to listen more and to better identify
what those teachings are, then I feel we can
make significant advances in science.
Laura Juszczak: The most interesting thing is the possibility that I'll get an unexpected
result. That's what's really the driving force,
the driving interest in science. Because you
always think you're going to get a result,
but then nature pulls the rug out from under
your feet, and you get something totally unexpected.
Mandë: It's a lot of what we should be doing
when we think about science as a whole. No
one knows the answers, and if you're so tied
to your hypothesis that you don't allow other
things or observe other things that happened,
then we're in danger and it slows down the
rate at which we advance science.
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