Ed Botchwey is not a hematologist. He’s very clear about that.
Botchwey runs a tissue-engineering lab at the Parker H. Petit Institute
for Bioengineering and Bioscience, with a focus on regenerative
medicine.
That’s been his professional history – tissue
engineering and regenerative medicine. But there’s a piece of personal
history that carries a bit more influence, and that, perhaps more than
anything else, is what led Botchwey and his research team to publish in
the journal Blood, the most cited peer-reviewed publication in the field
of hematology.
Their research and paper, with the running
title, “Sphingolipid Metabolism in Sickle Cell Disease,” represents a
sharp turn for Botchwey and his colleagues, who shed new light on causes
for some of the disease’s pervasive and devastating symptoms, while
offering new hope for patients who struggle with the disease, people
like his sister.
“As it turns out, my sister has sickle cell
disease, and I have a student, the first author of this paper, Anthony
Awojoodu – his sister has it. So this is something we felt very
passionate about,” says Botchwey, associate professor in the Wallace H.
Coulter Department of Biomedical Engineering (Coulter Department), who
didn’t set out to research sickle cell disease (SCD). It just sort of
happened. He was just following a logical trail of research.
“We’d
been looking at certain classes of signaling lipids and how they
regulate inflammation. Part of our goal was, and still is, exploiting
certain inflammatory responses to help in tissue regeneration,” Botchwey
says. “But along the way, we recognized that some of the enzymes that
are central components in the metabolism and production of these
signaling lipids were responsive to stresses in cell membranes.”
Like,
for example, the stresses that cause the telltale geometric distortion
of red blood cell (RBC) membranes in SCD. It
occurred to Botchwey that SCD would make a great model system in which
to observe the relationship between membrane stresses, inflammation and
the metabolism of these sphingolipids. Turns out, there’s a very close
relationship.
Their findings reveal for the first time that
sphingolipid metabolism is indeed dysregulated, or altered in SCD.
Membrane stresses associated with SCD activate sphingomyelinase (SMase),
an enzyme that contributes to progression of the disease (SMase has
been implicated in vascular inflammation). SMase, in concert with other
enzymes, also causes elevated production of microparticles, which
contribute to what Botchwey calls, “this chronic inflammatory state that
underlies so much of the pathology of sickle cell disease.”
What
encourages Botchwey is the research also illuminates potential new
strategies to regulate inflammation through modulating sphingolipid
metabolism – results that may also be applicable to other red blood cell
disorders, not just SCD. What’s more, a promising therapeutic solution
is already close at hand – the antidepressant, amitriptyline.
“We
wanted to know, can you pharmacologically inhibit SMase in order to
reduce these pro-inflammatory microparticles. And we found that, in
fact, we can, and we’re excited about it. If you can cut off one of the
primary means whereby sickled red blood cells are perpetuating a chronic
inflammatory state in the patient, then you may be cutting off a wide
range of the disease consequences associated with SCD,” says Botchwey.
“Amytriptyline happened to factor quite highly in our survey of
potential inhibitors of SMase. You can find certain papers that will
make an indirect association to what we’ve shown.”
Sure enough,
there are 30-plus year-old research papers that explore the inhibitive
effects of tricyclic antidepressants on SMase in various contexts, and
Botchwey’s team connected the complicated dots. But there has been next
to no research on the role of SMase and sphingolipid dysregulation in
SCD (a disease that affects millions worldwide), and that surprises
Botchwey.
“It’s a mystery to me.” says Botchwey. “When you think
about a disease as prevalent as this one, as well understood as it is,
in terms of what the underlying genetic mutation is, and you consider
all the tools we have at our disposal for correcting such mutations, you
would think this would be a curable disease. I’ve lamented the fact
that it’s not cured, but never considered that I might be part of the
research that might lead to a cure.”
Botchwey, whose work is
supported by the NIH and NSF, as well as the Petit Institute and Coulter
Department, led a research team that included Awojoodu, a native
Nigerian who was responsible for recruiting Petit Scholar, Alicia Lane,
to the team.
“They struck up a very productive working and
mentoring relationship, and this paper is partly the culmination of
that,” says Botchwey, whose collaborators in the study also include
Phillip Keegan, Yuying Zhang, Kevin Lynch from the University of
Virginia, and BME assistant professor Manu Platt.
Botchwey, not a
blood guy, says this research represents a new direction for him, one
he might not have taken if he didn’t make the move several years ago
from the University of Virginia to the Georgia Institute of Technology,
and the Petit Institute.
“Like I said, I’m not a hematology
researcher, but the opportunity to take risks resonated with me. It’s a
risk to go in new directions, and Georgia Tech enabled me to take that
risk,” he says. “The multidisciplinary, interdisciplinary environment
here is one in which I felt comfortable asking what I perceived to be a
frontier question that impacted a disease I felt passionately about. I
don’t know if that would have happened if I’d stayed where I was.”
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