Marathon of the Mind

By Jason Socrates Bardi

Tyger Tyger burning bright,
In the forests of the night
What immortal hand or eye,
Dare frame thy fearful symmetry?

—William Blake, Songs of Innocence and of Experience, 1789

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 Works

In 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 Genome

A 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 Aneuploidy

Think 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.


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"We would like to understand how the brain develops and how it functions," says Professor Jerold Chun, who is an investigator in the Helen L. Dorris Child and Adolescent Neurological and Psychiatric Disorder Institute at Scripps Research. Photo by Jason S. Bardi.