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"We do not," says Chun, "understand how a lot of neuroscience
drugs, given to millions of people, work." In fact, this applies
to many of the mechanisms of some of our most common drugs—like
antipsychotics and antidepressants.
Historically, this has not been a prohibitive problem. Many
of the biggest breakthroughs in pharmacology—like morphine—were
discovered prior to our knowledge of how they work. The problem
is how to address the huge medical needs of people who suffer
from neurological and neuropsychiatric diseases for which
there are inadequate or suboptimal therapies.
Several years of grappling with this led Chun to realize
that he wanted to go back to the most basic question—how
the brain works. "If you do not understand how the brain works,
how are you going to make medications for it rationally?"
he asks.
This was the impetus that led him to return to academia,
which he did in joining Scripps Research full-time this year.
Now, he is looking forward to investigating topics that scientists
in industry do not have the luxury to explore.
A Wrinkle in Mind
One of the issues Chun and his colleagues have been looking
at is what controls the formation of the cerebral cortex,
which he has been studying since his days as an MD/PhD student
at Stanford University, working with Carla Shatz. The cortex
is the part of the brain that is believed to be involved in
higher functions, like memory, cognition, and the interpretation
of sensory input. The vast majority of these cerebral cortical
neurons are generated before birth, and Chun and his colleagues,
postdoctoral fellows Marcy Kingsbury and Stevens Rehen, along
with graduate students James Contos and Christine Higgins,
wanted to know what signals controlled this process in early
development.
A few years ago, while at the University of California,
San Diego, they were studying a phospholipid called lysophosphatidic
acid (LPA), and they identified the first cellular receptor
to which LPA binds.
Phospholipids, molecules of fat with a charged head on one
end, are commonly found in biological organisms and are generally
regarded as essential structural components of cells. For
instance, bilayers of phospholipids are the primary component
of cellular membranes, those essential barriers that define
the boundaries of cells and keep the molecules inside a cell
separated from those outside a cell.
But lipids apparently do more than just form barriers.
Chun and his colleagues decided to look at the effect of
LPA on the development of mammalian brains, and they published
their most recent results in this December's issue of the
journal Nature Neuroscience. They found that LPA can
act as a signal that induces neurogenesis—the formation
of new neurons. Previously, scientists believed that growth
factors and other proteins largely controlled neural development
and neurogenesis, but Chun and his colleagues discovered that
when LPA binds to receptors in the embryonic brain, the result
is a brain that shows a vastly increased number of neurons
in the cerebral cortex.
Interestingly, this neuronal increase works not by causing
neuronal progenitor cells in the brain to proliferate and
then become neurons, as one might expect, but by a new mechanism
whereby the neuronal progenitor cells that normally would
die are prevented from dying and other neuronal progenitor
cells are forced to divide prematurely.
Remarkably, LPA also induces folds in the brain. When developing
brains are exposed to LPA, the brains spontaneously form gyrated
structures that are characteristic of higher mammals, like
humans. These gyrations increase the surface area of the cerebral
cortex that is believed to be essential to higher functions
like intelligence and reasoning, which are characteristic
of humans and other primates. Such gyrations are not normally
seen in the brains of lower mammals, like mice.
The work is significant because neural generation in early
development predestines an organism for what happens later
in life. The work may help clinicians and scientists understand
some of the many diseases that arise from developmental defects
that may be related to LPA signaling. Several childhood mental
disorders and certain types of schizophrenia, for instance,
are believed to be developmental in origin. The work may also
help clinicians understand how to control stem cell differentiation—an
important step for stem cell therapy.
This lipid signaling field is still in its infancy, and
there is a whole family of lipids other than LPA that may
also influence how the brain develops and functions. Chun
and his laboratory are interested in understanding this chemical
biology in the nervous system—how it works and whether
it is a possible target for therapeutics.
"Fat [molecules] have new roles that we are only beginning
to understand," says Chun. "I'm really excited about it.
Aloha
Several months ago, when Chun arrived at Scripps Research,
the first thing he did was to carry his books into his new
office. In his boxes were copies of Blake and Shakespeare
next to volumes on biophysics and neuroscience.
He is looking forward to new collaborations with other investigators
throughout Scripps Research—something that his years
in Hawaii have prepared him well for.
"There is something called the Aloha spirit in Hawaii,"
says Chun. "[It means] being helpful and friendly from the
start."
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