CREDITS: (PHOTO VERONICA SZAREJKO; (GRAPHIC CREATED WITH BIORENDER.COMscience.org SCIENCEINSIGHTSPRIZE ESSAY
INNOVATIONTargeting memories
to treat trauma
Blocking a metabolic enzyme controls the
encoding of memories
ByPhilipp MewsA
re we really what we eat? EpiVario,
cofounded by Shelley L. Berger and
myself, was born of this fundamen-
tal question rooted in an age-old ad-
age. We discovered that we—or more
accurately, our brains—are, in some
respects, the product of what we eat and
drink. Brain functions, including memory
formation, can be affected by metabolism.
We found that metabolic enzymes fed by
what we consume can alter gene expres-
sion in the brain’s learning centers. Our
company, EpiVario, was established to help
bring the benefits of our discoveries to the
fields of psychology and addiction studies—
two areas that can have an outsized effect
on societal health at large.
Through our metabolism, the body turns
what we eat and drink into energy and mo-
lecular building blocks. Neurobiologists
have traditionally viewed these metabolic
processes in the body as wholly separate
from the cognitive functions of the mind.
Our research has helped shift this paradigm
by demonstrating that metabolism directly
affects learning and memory ( 1 ). Metabolicenzymes are emerging as key players in the
nuclei of neurons, where, fueled by food
metabolites, they work as engines to drive
gene expression. It is this enzymatic process
that activates neuronal genes whenever we
learn or create a new memory.
Memories are stored in the connections
between neurons, and forming a memory
requires new proteins at the synapse. These
proteins are encoded by neuronal genes in
the cell nucleus, where the genetic material
is tightly wrapped around histone proteins
to form a complex called chromatin ( 2 ).
When the compact chromatin structure is
unwound, the histones are modified with
chemicals called acetyl groups, leading to
an increase in the production of synapse
proteins ( 3 ).
In relation to those acetyl groups, our re-
search in mouse brains has found a meta-
bolic enzyme responsible for turning on the
production of acetyl coenzyme A (acetyl-
CoA) in memory. This enzyme, acetyl-CoA
synthetase 2 (ACSS2), binds to chromatin
in neurons, fueling the acetylation of his-
tones throughout the hippocampus, the
brain’s memory center ( 1 , 4 ). This process
activates genes that reshape synaptic con-FINALIST
Philipp Mews
Philipp Mews
received an
undergraduate
degree from the
Free University
of Berlin and a
BSc and PhD
from the University of Penn-
sylvania. In 2017 he cofounded
EpiVario, Inc., and is currently an
instructor in the Neuroscience
Department at the Icahn School
of Medicine at Mount Sinai. His
research explores the interplay
between metabolism and epi-
genetics in the adult brain, with
an emphasis on brain circuits
involved in the formation and
maintenance of memory.
http://www.science.org/doi/10.1126/
science.abo4234AcetateAcetateAlcoholHippocampusAcetyl-CoAGut metabolitesMemory
consolidationACSS2Al cohol metabolism affects memory
Alcohol is metabolized in the liver to acetate, which is released into circulation and enters the brain. In the
brain, acetate is used to generate acetyl coenzyme A (acetyl-CoA) by acetyl-CoA synthetase 2 (ACSS2),
boosting histone acetylation and gene expression involved in memory.147-A 8 APRIL 2022 • VOL 376 ISSUE 65890408PrizeEssay_15347997.indd 148 4/1/22 4:36 PM