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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