Molecules on the Mind
By Jason Socrates
Bardi
KING
LEAR:
O, let me not be mad, not mad, sweet heaven
Keep me in temper: I would not be mad!
——William
Shakespeare, King Lear, 1605
The irony of schizophrenia and bipolar disorder is that
we understand how to treat these diseases a lot better than
we understand how they actually work.
We do know that they are both chronic and often devastating
brain disorders that affect a significant portion of the population.
According to the National Institute of Mental Health, more
than two million American adults have bipolar disorder in
any given year, and approximately one percent of our population
will suffer from schizophrenia in their lifetimes.
We know that schizophrenia is a very heterogeneous and complicated
disorder involving many genes and manifesting itself through
many different symptoms. There are whole bodies of literature
describing the symptoms people with these diseases suffer,
and there are established guidelines for diagnosing both conditions.
And while we cannot treat either disease perfectly, there
are numerous anti-psychotics available for treating schizophrenia—some
of which have been around since the mid-1950s. Likewise, there
are numerous anti-depressants and mood stabilizing drugs available
for treating bipolar disorder.
Therapeutic approaches that combine various drugs with individual
and group therapy have helped countless people lead lives
free from the sometimes-debilitating symptoms of schizophrenia
and bipolar disorder.
And yet what is missing is a truly reductionist understanding—a
molecular understanding—of schizophrenia and bipolar
disorder.
We do not know what specific genes predispose people for
these disorders. We do not understand what environmental factors
determine why identical twins often, but not always, have
the same illness. We do not know the factors that determine
whether a schizophrenic patient will have mild symptoms or
full-blown hallucinations. We do not know why some people
with bipolar disorder suffer shifts between depression and
mania a few times a year while others "cycle" more rapidly—several
times a week.
Nor do we have a blood test, a brain scan, or some easy
way to identify whether somebody is afflicted with schizophrenia
or bipolar disorder. Nor can we predict, based on somebody's
symptoms, whether they will be among the 10 percent of people
with schizophrenia who end their lives in suicide.
Towards a Molecular Understanding
These are all questions that motivate scientists at The
Scripps Research Institute (TSRI) who study the molecular
aspects of diseases like schizophrenia and bipolar disorder
so that they can be better diagnosed and treated.
"Everybody here," says Professor J. Gregor Sutcliffe, speaking
of his laboratory in the Department of Molecular Biology,
"has some interest in the molecular biological aspects of
central nervous system problems."
His own interest in such problems goes back to when he first
began to collaborate with TSRI Department of Neuropharmacology
Chair Floyd Bloom, who was then at the Salk Institute for
Biological Studies. Sutcliffe and Bloom decided to make cDNA
clones of various RNAs in the brain and then characterize
the proteins the RNAs made by using recombinant DNA technology
to identify unknown gene products expressed selectively in
the brain. This was accomplished by isolating thousands of
mRNAs from brain tissue and cloning and sequencing the ones
that were not detectable in the liver or kidney.
After identifying some 20,000 to 40,000 sequences in the
mid-1980's, Sutcliffe decided to concentrate his efforts on
only a few of the genes that were expressed. In particular,
he was interested in identifying and characterizing RNAs that
are expressed in limited fashion—in small numbers or
in selected brain tissues—and that has been his guiding
principle for research ever since.
"We thought that if we could find RNAs that were highly
selective in their expression to particular regions," he says,
"then those would give us more insight into the functionality
of those particular regions."
This approach is not unique—it is a way of looking
at nature that is common to all fields of science. And despite
how much "reductionism" has today come to resemble a four-letter
word, this is exactly what is needed to elucidate the molecular
basis of diseases like schizophrenia and bipolar disorder.
The problem is that our definitions and diagnoses of schizophrenia
and bipolar disorder depend upon the symptoms, but the symptoms
can range from mild to severe in both diseases.
"These symptoms may actually represent distinct subtypes
within themselves," says Assistant Professor Elizabeth Thomas,
who works closely with Sutcliffe.
And to even further complicate the situation, the two diseases
can be so similar to each other that someone with one can
be misdiagnosed as having the other. For instance, the flat
emotional affect and social withdrawal that are common among
schizophrenics are similar to symptoms that bipolar people
display during depressive episodes. Likewise, psychotic behaviors
also manifest in both schizophrenic and bipolar patients.
"What we're [closing in on] in the genomic era is what genes
are distinguishing these two disorders," says Thomas, "If
we can identify which genes are making up the sub-types of
these disorders, it would be a huge breakthrough in understanding.
Hopefully, this would help us find cures that would be specifically
tailored towards one [disorder] or the other."
Withdrawals from the Brain Bank
In a recent study, Sutcliffe and Thomas compared the expression
levels of one protein in post-mortem tissue samples taken
from various brain regions in schizophrenic and bipolar subjects
to control subjects matched for age and other variables.
All of the tissue samples came from a "brain bank" maintained
by Thomas and Sutcliffe's collaborators at the Rebecca Cooper
Research Laboratories of the Mental Health Institute in Parkville,
Victoria, Australia. This brain bank maintains the brains
in freezers and has records of the patients so that tissue
samples can be well-matched with controls for such variables
as the age and sex of the patients.
The recent study was actually the third in a series of studies
by Thomas and Sutcliffe in which they addressed the question
of which genes are involved in these diseases.
In the first study, they looked at the effect of "chronic"
dosing of the schizophrenia drug clozapine on gene expression
in the brain. The brain responds to a large dose of the drug
by increasing levels of expression of particular genes. One
thing they noticed right away from this study is that the
levels of expression of a gene coding for a 29,000 Dalton
protein called apolipoprotein D (apoD) increased. This led
them to hypothesize that the protein plays an important role
in the pathology of the disease.
In their second study, they concentrated on the elevated
expression levels of apoD in one particular region in the
brain, the prefrontal cortex, which is the key brain structure
involved in a range of cognitive functions, such as planning,
judgement, decision making, and the mediation of working memory.
Impairment of all of these cognitive functions is a characteristic
of both schizophrenia and bipolar disorder, and the prefrontal
cortex was previously known to be involved in both of these
disorders.
The significance of this second study is that it correlated
elevated apoD expression levels in the prefrontal cortex with
schizophrenia and bipolar disorder. While the prefrontal cortex
was already known to be involved, the apoD gene is one that
perhaps people would not have looked at before. And while
the physiological role apoD is playing in these psychiatric
disorders is not yet clear, its presence in these areas of
the brain implicates its involvement.
"The elevated expression of apoD," says Sutcliffe, simply,
"is a signature of the pathology."
Guilt by Association
In their latest study, to be published this month in the
journal Molecular Psychiatry, Sutcliffe, Thomas, and
their colleagues looked at apoD expression in several other
brain regions of people with schizophrenia or bipolar disorder
as compared to the well-matched control brains. They examined
12 regions of the brain and looked at the apoD expression
in these regions to gauge the differences.
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