Institute of Mental Health
of Medicine and Biomedical Sciences
The Azores Islands
the ecstasy & the agony
Two UB researchers seek the genetic key to bipolar disorder
Story by Scott Thomas Photos
by Frank Miller
a wooden bookshelf in the laboratory that Carlos N. and Michele
T. Pato run on the ground floor of Farber Hall, hard by two years'
worth of the American Journal of Psychiatry, is a glossy coffee-table
book: Cultural Atlas of Spain & Portugal.
It's not what you'd expect in the
Laboratory of Psychiatric and Molecular Genetics ... until, that
is, you get to know this husband-and-wife team of psychiatrists.
For the Patos, the genetics of psychiatric maladies-most recently
bipolar disorder-and the country of Portugal-specifically its
island group called the Azores, a thousand miles into the Atlantic
off the Portuguese coast-are intimately tied together.
doctors are celebrating a $4.2 million grant from the National
Institute of Mental Health (NIMH), announced in November. It will
enable their research team to search methodically, in the Azores
and at other sites, for the gene or genes responsible for bipolar
disorder, commonly known as manic-depressive illness. The disorder
is a cruel one, afflicting the sufferer with cycles of uncontrollable
energy punctuated by severe and debilitating periods of depression.
Those affected may be talking incessantly and acting out bizarre,
egotistical fantasies one week, and the next be unable to climb
out of bed because they're paralyzed by hope lessness and self-loathing.
The condition affects about seven of every 1,000 people-imagine
560 sufferers in a sold-out Ralph Wilson Stadium, and you get
an idea of its prevalence.
Current treatments involve mood-stabilizing
drugs like lithium carbonate and depakoate for the manic (high)
phase, and antidepressants for the bottom of the roller coaster.
But the treatments aren't 100 percent effective, come with serious
side effects, and certainly are not a cure.
Enter gene therapy, which offers
the distant but tantalizing possibility of alleviating the group
of conditions known as bipolar disorder.
"We're pretty sure these disorders
don't have a single genetic factor, like cystic fibrosis does,"
says Michele Pato. "It's probably the case that there is
more than one gene interacting that allows the disorder to be
expressed. It's not sweet peas, like [early geneticist Gregor]
"It's a very complex interaction
that we're looking for," says Carlos Pato. "In each
family (of subjects) we are asking the question, ‘Are there any
single genes or groups of genes that seem to be inherited in a
way that can cause this illness?'"
the Azores? Setting their study on the subtropical island group
was a happy accident of genetics and heritage. Carlos Pato was
born in Portugal, and the couple has visited there many times.
On one of those visits they became more aware of the Azores, which
were first settled in the 15th century by the Portuguese. That's
where genetics comes into play: Because they're so remote, the
island population has seen very little intermarriage with "outsiders."
Thus the genetic code of the inhabitants shows much less variability
than it would in, say, New York City. It's like looking for an
imperfection in a roll of wallpaper-much easier to thumb through
roll after roll of the same pattern, rather than an assortment
of patterns that just obscure the target.
photo by: Tim Stegner
"There's some benefit to studying
an ethnically similar population," says Michele Pato. "We
can eliminate a whole bunch of the genome [an individual's genetic
material], because we know that the whole culture shares that
part of the genome."
The study itself is at once tedious
and thrilling. Researchers-including all of the islands' psychiatrists-are
identifying individuals among the islands' 250,000 people who
have some variety of bipolar disorder. They now have close to
2,000 subjects and family members, and may end up with 5,000.
The researchers collect very detailed psychiatric histories from
those individuals-in interviews that can take up to six hours
per patient-and identify other family members with the disorder
and interview them, as well.
The researchers also draw blood
samples from the subjects, then culture and multiply the white
blood cells and extract the DNA from their nuclei to begin the
exacting process of searching for chromosomal "markers"
for manic depression. It's not the A-G-C-T sequencing done in,
for example, the Human Genome Project; rather, the researchers
will scan the samples for segments, maybe 100 genes long, that
seem to have been passed from parent to offspring with bipolar
disorder. Once those "marker" segments are identified-no
easy task in itself-the goal becomes to narrow the focus until
the specific genes responsible for the disorder are identified.
Complicating the process is that
bipolar disorders, like many men tal illnesses, are not entirely
a genetic condition: Having the gene doesn't mean that a person
will definitely develop the disorder; it merely predisposes him
or her to developing it. Stressful life events and childhood traumas
have been identified as "triggers" that can increase
a genetically predisposed person's probability of developing a
bipolar disorder in adulthood.
enetics holds the possibility of teasing out what's nature and
what's nurture," says Michele Pato. "There has been
some suspicion of this kind of research, because some people worry
that it could be used against people by insurance companies, for
example. But I'm of the ‘knowledge-is-good' school. The more we
know, the more we can be preventative."
The Patos' study of bipolar disorder
comes even as they continue another massive project along similar
lines, searching among the Azores population for genetic markers
for schizophrenia. That $2.6 million project, also funded by the
NIMH, is in its third year. Michele Pato also has a major research
interest in obsessive-compulsive disorders.
These projects are the latest in
a productive personal and professional collaboration that began
when the doctors met as undergraduate students at Brown University.
She was studying cognitive psychology; he was majoring in biochemistry
and comparative literature. The Patos were the first residents
accepted as a couple for psychiatry residencies at Massachusetts
General Hospital; this was followed by fellowships-hers in obsessive-compulsive
disorder, his in schizophrenia.
"We both came to the realization
that we loved psychiatry, and what we loved most about it was
that so much was undiscovered," Michele Pato says.
When they came to the University
at Buffalo in 1996, that happy intersection of family and science
happened again. They have two adolescent children, and Carlos
Pato's parents happen to live in nearby Fredonia. Professionally,
Michele Pato notes, the university was willing to invest in their
work by building the Laboratory of Psychiatric and Molecular Genetics-an
investment that has paid off handsomely in grant money that employs
a team of six people in Buffalo and about 50 worldwide. (The bipolar
disorders study also includes collaborative research teams in
Toronto, Brazil, Portugal and Fall River, Massachusetts-all locations
where significant populations of Portuguese emigrants have settled.)
That grant money also supports their research-related travels.
There are two ways to get from Buffalo to the Azores by air: a
weekly direct flight out of Boston, or a longer route that goes
from Newark to Lisbon and then on to the islands. The Patos make
three or four quick trips per year; they also take their children
for a longer stay in the summer.
All this in addition to their teaching (both are associate professors),
scholarly writing and other professional responsibilities. Carlos
Pato serves as associate dean for clinical affairs in the School
of Medicine and Biomedical Sciences, working on programs within
UB's affiliated clinical sites, including clinical research and
space-allocation issues in the university's health-care affiliates;
he also heads the Division of Psychiatry for Kaleida Health. Michele
Pato directs UB's psychiatry residency program. She also has a
special interest in mentoring young investigators, and teaches
a course for young residents on how to enter the research field.
"Carlos and Michele Pato have made major contributions to
undergraduate and postgraduate education during their relatively
short tenure at the UB medical school," says medical school
dean John Wright. "We are all very proud of their accomplishments."
Scott Thomas is copyediting coordinator
of the Buffalo News.