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A decade of research has led me to rediscover a profoundly simple truth - the human body
is the product of a multi-billion year long evolutionary experiment. While some of our
ancestors stayed as they were, others multiplied and mutated, eventually swimming, walking,
developing organs and the first glimmers of complex thought. One of many basic cellular
processes that evolved in those single-cell ancestors was vesicle formation, which has
been elaborated by evolution into the human synapse. So what does this mean for medicine
and the search for new drugs? Surprisingly, many drugs affect human tissues in a number
of complicated ways that existing pharmacology doesn?t even begin to explain. And that?s
where yeast come in. Using an approach I've dubbed Evolutionary Pharmacology, my lab studies
living fossils and their connections to complex diseases, in particular brain diseases, like
depression, which are still poorly understood at the cellular level. Over the last 5 years,
my lab at Princeton University has studied the yeast cell reaction to the antidepressant
Zoloft. Zoloft increases levels of serotonin between nerve cells by jamming serotonin reuptake
transporter proteins, thereby -- so goes the prevailing wisdom -- boosting well being.
However, the hypothesis that depression is caused by a chemical imbalance is an over-simplification.
It cannot explain why the effects of antidepressants on serotonin are fast (minutes to hours),
yet antidepressants don't kick in for weeks or months. In a recent paper in the journal
PLoS ONE, we found that Zoloft accumulates in yeast cell membrane -- a bit startling,
since yeast cells lack serotonin all together. This accumulation changed the shape of specific
vesicle-forming membranes. Might the gradual accumulation of Zoloft in human brain cell
membranes explain the time lag in antidepressant effects? Might it be involved in the growth
of new neurons, as has been found in lab rats chronically exposed to antidepressants? By
comparing drug responses between us and our very distant cousins, we can discover novel,
medically actionable drug targets. THIS is Evolutionary Pharmacology. It's a new way
of thinking, studying the very small and very old to develop very large and very new ideas.
But, like all science, it needs creativity and collaboration. That?s why I?ve opened
my lab to the Internet. To participate and learn more about Evolutionary Pharmacology,
visit my new modular Open Science platform at perlsteinlab.com, where I share data, discuss
results and ideas, and engage with colleagues, collaborators and the public.