thought now that just can’t be right
I’m a chemist to be specific I study how
two or more chemical compounds say a
biological target and a binder come into
contact with each other through weak
reversible interactions simply put it’s
like when you hug someone you become an
aggregate of two people but you don’t
find yourself glued together forever
it’s temporary you can let go in our
bodies this kind of interaction between
chemical compounds happens all the time
every time we inhale a very large
molecule picks up the oxygen in our
lungs carries it through our bloodstream
and drops it off for our bodies needed
most
another example is DNA most commonly
found in the form of a double helix two
strands recognizing each other coming
together like a zipper all of this
happening through reversible
interactions and these interactions can
lead to some pretty important outcomes
three years ago I found myself in France
working in the Matheny lab searching for
new chemical binders for an unusual form
of DNA implicated in the development of
human diseases trying to find the binder
of this kind is a lot like having to
sort through 200 different keys to find
one that might open a locked door some
keys won’t fit in the lock at all some
might only fit partway others might fit
but failed to turn very few of those
keys are going to be able to unlock that
door in theory we could examine the
features of the lock in great detail and
design the key to fit it but in practice
a different story imagine you’ve gone to
all that trouble designing the perfect
key and now the moment you introduce it
into the lock the presence of the key
actually makes the lock change shape add
to this the fact that we’re working in
the molecular level we can’t see these
interactions with the naked eye so
rather than design a key
I was trying to see whether any of the
chemical compounds previously made in
the Petit Jean lab here would fit our
DNA target to speed up this process the
Murray lab had developed a screening
method that would eventually allow me to
test up to 48 keys at the same time the
data from these tests could be converted
into numbers that look something like
this so the higher the number the better
the key fits the lock so I was initially
looking at a number of relatively weak
binders compared to a known gold
standard in the field but then I got
this result scientists are trained to
think critically and objectively about
their work so I took a look at this
amazing result and was fairly sure I’d
made a mistake somewhere when your car
fails to start you don’t call a tow
truck
immediately right you try to start it
again and again before you come to a key
conclusion the same holds true for
scientific research
so I reran that experiment three times
but the results checked out I was
looking at a hit a chemical compound
that was right up there with some of the
best miners previously developed in the
field
something that could strongly and
selectively bind to an unusual fold of
DNA that we call a guanine quadruplex
now I could take that hit back to the
drawing board and moff modify its
chemical structure in order to fine tune
its properties and all of this all of
these exciting possibilities were
opening up because we’ve just barely
scratched the surface of the roles that
these quadruplex is these biological
targets play in the development of
diseases like cancer let’s talk about
DNA for a minute most of your cells have
a complete and identical library and
that’s DNA the building blocks of life
information is stored in book-like units
called genes and each gene is made up of
where it’s spelled from the same four
letters one book may dictate the color
of your eyes
another may define your risk of
developing breast cancer different books
are open and read to drive specific
cellular events controlling everything
from your hormone levels to your immune
response cancer happens when some of
those books are not copied properly you
start to see typos appear in the text
are the books that promotes cellular
events leading to the development of
cancer what we would call oncogenes are
left open to be read and process
continuously all of this ultimately
leads to the uncontrolled growth and
division of abnormal cells now in order
for any of these books to be read the
normal double helix of DNA has to unzip
becoming temporarily single-stranded for
the purposes of this talk let’s think
about it like this the single strand of
DNA is the chain of a necklace and the
cell machinery that reads and processes
that DNA moves down the chain like beads
if they happen to come across a region
in the chain that’s formed a knot those
beads can’t go any further but or not is
a guanine quadruplex and we’ve known
about their formation for a long time
now we also know that our cells have
ways to unravel these knots but there’s
a reason why we might not want this to
happen bioinformatics has recently
highlighted the tendency of these knots
to form in the DNA chain right before
oncogenes so if there was a way to make
these knots into more permanent barriers
to the beads on the chain then we could
potentially prevent the processing of
these oncogenes and these are genes
involved in all aspects of cancer
development from the formation of new
blood vessels to the spreading of cancer
cells through the body the implications
are clear we’re developing chemical
binders that can stabilize quantum cloud
reflexes that can tighten the knot to
the point where it forms a physical
barrier between the cell machinery and
the oncogene ongoing research in the
field has shown us that by forming this
knot we can in fact block the reader
from opening
that book in other words we can
potentially prevent the cellular
processes that lead to cancer from a
current do our binders work like this
our studies are showing that our binders
do interact strongly with our desired
DNA target but they don’t interact much
with the more common double helix of DNA
which is an advantage if we’re thinking
about side effects down the line we also
have some fairly promising preliminary
results from an anti-cancer screening
program in the presence of our binders
five other 60 human cancer cell lines
tested do show a decrease in cell growth
and division all that being said most of
what I do in the lab still involves the
study of two molecules one quadruplex
one binder on their own
these studies are critical we need to
know how these molecules interact before
we move them into more complex
environments even the transition to
studying these binders in human cells in
a lab raises questions a human cell
contains hundreds of different molecules
is the effect we’re seeing actually do
the interaction between the targeted
quadruplex and our binder and if it is
the more will it work the same way in a
mouse remember living organisms are made
up of millions of cells a whole other
level of complexity at this stage there
are also other considerations can the
binder exit the bloodstream and enter
itself will it target cancer cells
specifically how is it going to get out
of the body if everything is going well
then how do we formulate this binder for
human consumption how do we administer
it all questions that must be answered
before we move to clinical trials the
media attention this research has
recently received and the public
response has been both humbling and
overwhelming my supervisors and I have
been swamped with questions about
clinical trials from cancer patients
friends and families to be honest though
we’re still in the early stages of
research and there’s still a lot of
questions that we need to answer if
nothing else I hope I leave you today
with a better appreciation of the
scientific process involved in this kind
of research the tech points that must be
passed so that we can be absolutely
certain that the chemical binder we want
to put into a human body is safe or at
least that we’re fully aware of the
risks it’s a process that often starts
with a somewhat serendipitous discovery
does not always go in a straight forward
path and build on the past research of
the scientific community it’s made me
realize how critical curiosity driven
research can be if scientists had never
thought hey I wonder why these knots are
forming and where and how all of this
works then we as a field would never
have reached the stage where we can ask
the question how can we use this and I
wouldn’t be here today giving you a
snapshot into how the stabilization of
guanine Quadra fluxes is now emerging as
one of the many exciting new strategies
in anti-cancer therapeutics I can’t tell
you where our research and the field as
a whole will be ten years from now
because we’re still learning new things
about these quadruplex targets every day
we know so much more about cancer today
than we did ten years ago
translating the fundamental research
we’re doing in the lab now into a
clinical setting is a long road and it’s
going to take a whole community of
experts not just chemists like me but
biochemists biologists cancer
specialists and clinicians to get there
I’m hopeful though that this work
represents a step forward along that path thank you