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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.


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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Cerebral hemispheres from the same brain treated without lysophosphatidic acid (LPA; top) versus with LPA (bottom). LPA exposure alters cerebral cortical growth and anatomy by rapidly inducing folds and widening of the cerebral wall.