November
9, 2001
Sharon
Stranford: Exploring the Mysteries of the Immune System
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FRED
LEBLANC
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Two San Franciscans
are exposed several times to the human immunodeficiency virus
(HIV), but only one becomes infected. Two others, already HIV
positive, show equally puzzling differences over the years; one
rapidly deteriorates and develops acquired immunodeficiency syndrome
(AIDS), while the other lives in excellent health. From 1995 to
1999, Sharon Stranford and Jay Levy of the University of California,
San Francisco (UCSF), studied such cases, trying to uncover why
some individuals resist AIDS while others do not. Levy, among
the first to isolate human strains of HIV in the United States,
continues the investigation at UCSF with a large group of patient
volunteers and research collaborators. Stranford continues it
through research and teaching at Mount Holyoke, where she is now
Clare Boothe Luce Assistant Professor of Biology.
"They
are engaged and curious," said Stranford of the students
enrolled in her fall course Introduction to Immunology. "Many
of them want to go on to medical school or graduate programs in
biomedicine or infectious disease, so they encouraged me to focus
on human diseases. I'm lucky to be able to teach the same subject
of my interest and research."
Stranford's
interest in disease and immunity began even before her undergraduate
days at Pennsylvania's Beaver College (now Arcadia University).
It emerged in high school, when she learned that her friend's
mother suffered from the autoimmune disease lupus, then witnessed
firsthand the potentially strange outcomes of an immune response.
The strange things that Stranford witnessed in her youth she now
understands to be the result of an immune system unable to differentiate
viruses and bacteria from healthy cells and tissues, a system
that no longer protects the body from sickness but actually attacks
it and leads to painful diseases like lupus and multiple sclerosis.
Studying
these diseases in the context of immunology and modern microbiology
was uncommon at the undergraduate level in Stranford's day, but
she remained intrigued by the few immunology lectures offered
in her biology courses. She went on to study immunology, molecular
biology, and genetics at Hahnemann University in Philadelphia,
focusing her doctoral work on the genetic blueprint of two groups
of rats, one susceptible to a disease akin to multiple sclerosis,
the other resistant to it.
The flip
side of that research came next for Stranford, as she spent three
years at Oxford University—focusing not on how to protect
the immune system from disease, but on how to fool it into tolerance
for something it would normally attack: a foreign graft or organ.
"It was a highly practical study," said Stranford, "because
it is very difficult to find an exact match for skin grafts or
organ transplants." We already know about a phenomenon called
"the blood transfusion effect," she said, whereby people
more readily accept transplanted organs if they first receive
blood from the organ donor. Stranford set about studying mice
to see just how this trickery of the immune system worked.
Before transplanting
a foreign heart into a recipient mouse, Stranford mixed new genes
from the donor mouse into cells of the recipient, then let them
spread through the mouse's body so that they might "re-educate"
the immune system to tolerate the foreign heart. The research
not only helped Stranford hone in on which DNA and proteins can
help re-educate the immune system but also led her to a new research
interest— studies of RNA-containing viruses (such as HIV),
called "retroviruses." Having used retroviruses to transfer
new DNA into the cells of host mice, and having seen the way that
retroviruses can sometimes induce a disease that wreaks havoc
on the immune system (and ultimately causes immune deficiency),
Stranford shifted her work from heart transplants and immune tolerance
to HIV and AIDS.
This new
interest first brought Stranford to California for postdoctoral
work with Levy, then on to a teaching position at Amherst College,
where she moved to studying a mouse version of AIDS called MAIDS.
This time, she looked at the genetic differences between two mouse
strains that differ in their vulnerability to MAIDS—similar
in its symptoms to human AIDS.
Stranford
is continuing this research at Mount Holyoke. In particular, she
is studying the white blood cells known as CD8+ T cells; these
cells can be activated to "see" viruses living inside
host cells and either kill those cells or suppress the virus they
carry. This particular ability of CD8+ cells was found to be prevalent
in some high-risk populations in San Francisco, Stranford explains.
In many of the people she studied who had "beat the odds"
of HIV infection, the CD8+ cells appeared to have multiplied and
become very active after a first exposure to the virus. This activity
itself was not surprising—we count on similar immune responses
when we give babies a small dose of mumps and measles in a vaccine—but
just how and why those CD8+ cells worked so well in some people
and not others is unknown.
Stranford
hopes to find out. She hypothesizes that mice proven to be genetically
resistant to MAIDS will have a different type of CD8+ cell response
than susceptible mice. By breaking open the CD8+ cells of virus-resistant
mice, Stranford hopes to learn exactly what proteins they are
producing and secreting and whether those secretions interfere
with the life cycle of the virus. If successful, Stranford hopes
to use this information to help others like Levy pinpoint how
CD8+ cells might be working against HIV infections in some people.
"HIV
mutates rapidly and can put on a different jacket every day, making
it hard for the immune system to recognize and attack it,"
said Stranford. "But HIV can't change all of its most basic
structures. If we can find out how certain cells in some individuals
attack these basic structures of HIV, we may be able to develop
a vaccine to target the virus, regardless of the cloak it is wearing."
Stranford's
research and its potential applications to HIV infection will
provide opportunities for student learning. Inside the CD8+ cells
she examines, Stranford wouldn't be surprised to find many years
of undergraduate research projects in the form of hundreds of
DNA chains, each one requiring study for its specific sequence,
timing of production, secretion patterns, and ultimate function
in the immune response against the virus. To support those student
opportunities, Stranford has secured both College support and
a National Institutes of Health grant to fund her research and
has established a cell and molecular biology laboratory where
she is already hard at work. "I'm loving the overlap between
my teaching and research interests and the obvious enthusiasm
of the students," she said. "I feel really lucky to
be here at MHC."
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