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Marathon of the Mind
This week, Professor Jerold Chun of the Department of Molecular Biology at The Scripps Research Institute is taking a break from running his new laboratory on the east side of campus to participate in a different sort of run—the 31st Honolulu marathon. Chun will be one of more than 30,000 runners competing in the grueling 26-mile race through Hawaii's capitol, Honolulu, on the island of Oahu. Chun spent most of his young life running around the islands. He is a fifth generation Hawaiian, and he grew up in a family of runners. When the first Honolulu marathon was held in 1973, Chun was one of several members of his family who participated (his brother set a world's record for fastest marathon time by a nine-year-old). Chun still returns once a year to run in this marathon. In fact, he is one of three people who have run the marathon every year since its inception in 1973. Chun also has academic ties to the islands. He did his undergraduate work at the University of Hawaii, majoring in English literature and biology and spending his days working in the laboratory of biologist Ian Gibbons and his evenings studying the works of 18th century poet and artist William Blake. It was during this time in his life, in those days spent going between the bench and the Blake that he first began to think about the problems that were to consume him even today. He grew interested in trying to understand on the most basic level how the brain works—an endeavor that is perhaps more grueling and more enduring than 30 marathons. How the Brain WorksIn the most reductionist view, the brain is simply a collection of specialized cells like any other organ. Like any other organ, the brain has a variety of specialized functions (everything from higher reasoning to controlling autonomic activities), and its specialized structure allows it to accomplish these functions. Looking at the brain as simply a collection of cells, however, does not provide a great deal of insight into how the brain works. The organization of the cells in the brain is vastly complex. A single neuron in the cerebral cortex might make connections with thousands of other neurons. And there are roughly a hundred billion neurons in the brain. The real secret to understanding the brain, Chun says, seems to be not in identifying the parts but in understanding how they are put together. For this reason, Chun studies the developing brain. "We would like to understand how the brain develops and how it functions," says Chun. This has implications for everything from basic philosophical and psychological questions, such as what makes a person unique, to pressing medical and social ones, such as how to therapeutically address neurodegenerative diseases and other problems with the brain. One of the big questions that Chun and his laboratory are working on is how the DNA within the cells in the brain may vary as a result of early development. "Are all the neurons in your brain genetically identical?" asks Chun. In fact, he says, the answer is "no." And since his postdoctoral days in the laboratory of Nobel laureate David Baltimore, he has been looking at how the genomes of different neurons differ from cell to cell, from person to person, and from one developmental stage to another. Pieces of GenomeA genome is simply the sum total of all the DNA in a cell. Genomes are organized into discrete chromosomes, which are like giant cassettes of genes that are unique in number and composition for any given species. Humans have 46 chromosomes, for instance, whereas mice have 40. This unique chromosome composition is one of the things that makes species unique. It is why, for instance, one cannot sexually cross animals with one another to make a new viable species. But chromosomes may differ within a species as well, and these differences may account for some of the underlying psychology that makes each individual unique: why some medicines like antidepressants work for some people but not for others; why one person might develop severe schizophrenia and not his/her identical twin; and why some people can live through an earthquake and be perfectly fine while others suffer from post-traumatic stress disorder after the event. Differences in a cell's genome, says Chun, might be one of the organizational principles that controls gene expression within neurons. And one radical way the human body alters the genome of its cell may be by altering the chromosome composition. If this alteration occurs during development of a neuron, then it could potentially have effects over a person's entire life. Even subtle changes in the expression of a single gene can affect the output of a neuron, and controlling the chromosome composition of a cell may be a not-so-subtle way of controlling gene expression. After all, if you lose an entire chromosome, that is two or three percent of your DNA—you have potentially lost a thousand genes, not just one. Such changes might explain why identical twins may be genetically identical but may vary drastically in terms of behavior. Perhaps it could also explain why diseases of the brain manifest so differently in different individuals, and why so many diseases of the brain are sporadic, and cannot be traced to a single gene. In several papers, most recently in November's Journal of Neuroscience, Chun and his colleagues have identified numerous neurons and glial cells in the brain that undergo mitosis (cell division) during development and become aneuploid—they differ from one another in that they don't have the same number of chromosomes. The What and Why of AneuploidyThink of aneuploidy in terms of Beatles recordings. If Beatles songs were genes, then the chromosomes would be the albums they are on, and the Beatles genome would be the complete box set of every Beatles recording. An aneuploid Beatles collection would be one without all the albums—for instance, all albums but Abbey Road and Revolver. That, surprisingly, is what happens to at least some neurons during development. "Cells within the brain had been thought to all have the same complement of chromosomes," says Chun. "It turns out they don't. We have aneuploid cells during development and later in life." The loss and gain of chromosomes is actually a well-known phenomenon in cancer, and many cancers have long been observed to contain aneuploid cells. Most brain tumors, in fact, show some type of aneuploidy, but it is not clear exactly when brain cancer cells become this way. What normal aneuploidy means exactly is not yet known, and right now Chun and his colleagues are trying to understand what the implications of aneuoploidy are for developing and mature brains. "We think that [aneuploidy] contributes to the diversity of different types of cells," says Chun. And, he adds, this knowledge may have implications for therapy. If people have different genomes in their brain cells, then they may be responding to medications or experiences differently. Chun and his laboratory would like to take some of this information and extend it to a drug discovery platform, though he admits that he is at a very early stage. Still, Chun has a lot of experience in drug discovery, as he was formerly the head biologist of Merck Research Laboratories in San Diego, where he created a department of molecular neuroscience that aimed to come up with new strategies for drug discovery in the neurosciences. This is, of course, a difficult problem. "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 MindOne 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. AlohaSeveral 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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