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Dr. R. Adron Harris
Featured Scientist from
Essential
Science IndicatorsSM.
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A recent analysis of
Essential
Science IndicatorsSM
from
Thomson Scientific showed that the work of Dr.
R. Adron Harris moved into the
top 1% in the field of Neuroscience
& Behavior. His current citation record in this
field includes 44 papers with a total of 1,110 citations
from January 1, 1997 to October 31, 2007.
Dr. Harris’s work is already in the top 1% in the
fields of Clinical Medicine (80 papers with a total of
1,896 cites), Biology & Biochemistry (53 papers with a
total of 1,312 cites), and Pharmacology & Toxicology
(26 papers with a total of 862 cites).
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Dr. Harris is the M. June and J. Virgil Waggoner Chair
in Molecular Biology as well as the Director of the
Waggoner Center for Alcohol and Addiction Research at the
University of Texas in Austin.
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In the interview below, Dr.
Harris talks with ScienceWatch.com
about his highly cited work on alcohol
and anesthetic pharmacology.
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Please tell us a little about your research and
educational background.
As a student, I was fascinated with chemistry and wanted to understand how
chemicals affect biology, especially the function of the brain. This led me
to Pharmacology, an area that I learned of only after graduating from
college. I was fortunate to obtain a Ph.D. in Pharmacology from the
University of North Carolina at Chapel Hill and to carry out postdoctoral
training in the Department of Pharmacology at University of California at
San Francisco.
What do you consider the main focus of your research,
and what drew your interest to this particular area?
As a graduate student and postdoctoral fellow, I studied opiate drugs and
was fascinated by the mechanisms responsible for the marked tolerance and
physical dependence that is produced by these drugs in animals, humans, and
even in cells. However, during this work, I became increasingly aware that
alcohol dependence is a much larger social and economic problem than opiate
dependence, yet there were few pharmacologists studying alcohol and related
drugs. When I started my own laboratory, I decided to try and understand
some of the actions of alcohol, sedative drugs, and anesthetics on brain
chemistry.
One of your most-cited papers in our database is the
1997 Nature article, "Sites of alcohol and volatile
anaesthetic action on GABA(A) and glycine receptors," (Mihic SJ,
et al., Nature 389[6649]: 385-9, 25 September 1997). Would
you walk our readers through this paper and its findings?
The nagging question in alcohol and anesthetic pharmacology is: "how can
such small simple molecules alter brain function and produce such a similar
spectrum of behavioral actions?" One theory was that they all dissolve in
the membrane lipids and thereby alter neuronal function. Another was that
they directly affect proteins. If they affect proteins, which proteins and
by what mechanism? Do they have many binding sites on and around the
protein?
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"...I became increasingly aware
that alcohol dependence is a much larger social and
economic problem than opiate dependence, yet there were
few pharmacologists studying alcohol and related
drugs."
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In this collaborative study with Neil Harrison and John Mihic, we
identified ligand gated ion channels (glycine and GABA receptors) that were
sensitive to alcohol and anesthetics and plausible targets for these drugs.
The key was that we found one channel whose function was inhibited by the
drugs and another closely related channel that was enhanced. We proposed
that we could find the part or parts of the protein that were responsible
for these different effects, and those protein regions would be critical to
the interaction of the drugs with the channels.
This experiment could have failed for many reasons, but, remarkably, we
were able to use chimeric channels to identify two amino acids that were
critical for drug action on these channels. Even more remarkable, the
arrangement of these amino acids suggested that they could form a pocket or
cavity that might bind small drugs.
Where have you taken this work since the 1997
paper?
We have worked on addressing the key questions raised by the 1997 paper. Do
these amino acids actually form a cavity? Are there other amino acids that
are important? Why does binding of a small molecule in this cavity change
the function of the channel? We have made good progress in answering each
of these questions.
An even more important question is whether the modulation of these channels
observed in our simple models is actually important for anesthesia or other
actions of these drugs. This can be approached by introducing the mutations
we found to eliminate alcohol or anesthetic action in our models into mice.
We are fortunate to collaborate with Dr. Gregg Homanics on this project and
have published results from a few mutant mice currently testing several
additional mutations.
Where do you see this research going in five to ten
years?
The questions that must now be explored relate to the actions of these
drugs on brain mechanisms. We do not know how many different brain proteins
have binding cavities for these drugs, or which proteins are required for a
particular action of the drug. Are different proteins required for the
rewarding and sedative effects of these drugs? Can we design an antagonist
that will block actions of the drugs and prevent alcohol abuse? Can any of
this be understood by reductionist approaches (examining individual
synapses or channels) or will it require more of a systems, neuronal
network analysis? The work we have done will provide tools which hopefully
can answer these critical, elusive, and exciting
questions.
R. Adron Harris, Ph.D.
Waggoner Center for Alcohol and Addiction Research
University of Texas
Austin, TX, USA
