Untitled - Interdisciplinary Stem Cell Institute - University of Miami

At the Interdisciplinary Stem Cell
Institute, the ability to fix diseased
organs and cure debilitating illness
stems from tiny tools in the body’s
own repair system.
BODYSHOP
Technicians in ISCI’s FDA-certified Good Manufacturing
Practice lab follow stringent protocols to
grow and prepare the stem cells researchers are
using to heal damaged hearts and other maladies.
The giant picture window reveals what you’d expect of
a “clean room” at a modern manufacturing facility: stainless steel
tables, spotless floors, air handlers that wipe out nearly every
airborne particle, workers dressed like astronauts in protective
suits. But instead of microchips or other high-tech widgets, this
facility churns out lifesaving stem cells.
The Cellular Manufacturing Laboratory is one of many interlocking
parts at the Miller School of Medicine’s Interdisciplinary
Stem Cell Institute (ISCI). Launched in 2008 under the direction
of Joshua Hare, Louis Lemberg Professor of Medicine, ISCI is
an efficient machine designed to realize the vast potential of
regenerative medicine.
By Meredith Danton Camel
Photos by Donna Victor
14 Miami magazine Fall 2011
Fall 2011 Miami magazine 15

Tour this FDA-certified Good Manufacturing
Practice facility and you’ll see
flasks of cells in growth-factor cocktails
being expanded or differentiated for
upcoming transplants, cryogenic tanks
that store isolated cells, and stacks of
binders documenting every detail of
every study recorded on paper.
“Stem cells will change everything
about the practice of medicine, just like
antibiotics did in the last century,” says
Hare, who came to the Miller School
from The Johns Hopkins University,
where he ran a cellular therapeutics
program and the cardiobiology section
of the Institute for Cell Engineering.
“Until now, we’ve had two methods
of treating disease—surgical procedures
and chemicals,” he explains. “Now we’re
using a living cell as a therapeutic. Soon
every specialty and every physician will
need to have some knowledge of stem
cells. That’s why we formed ISCI.”
Stem cell therapy has been
around for more than 50 years
in the form of bone marrow
transplants for patients with leukemia
and other blood diseases. Today bone
marrow is just one of several sources of
stem cells used at ISCI.
ISCI made international headlines
this year when Hare, along with Alan
Heldman, professor of medicine, and
Juan Zambrano, assistant professor of
medicine, published a study of eight
men who received an injection with a
corkscrew-shaped catheter of stem cells
cultured from their own bone marrow.
The pilot’s main purpose was to
demonstrate the safety of injecting
either bone marrow or a type of stem
cell found in bone marrow called mesenchymal
cells into the heart, but it
also revealed a surprising outcome—up
to a 20 percent decrease in the swelling
and scar tissue that typically occurs
recalls of the day she suffered her heart
attack in 2003. Following double-bypass
surgery in 2005, her quality of life
quickly declined.
“The saddest part is that we take a
lot for granted,” she says. “I couldn’t lie
flat on my back because I felt like I was
suffocating. I couldn’t go shopping with
my friends. I was dead weight, dragging
everybody back. I once tried to take a
bubble bath, then realized I couldn’t
pull myself out of the tub. I was stuck
there until my daughter got home.”
Wilson’s cardiologist first suggested
a heart transplant. Reluctant to endure
surgery again, Wilson replied, “Doc,
when I die, I want to have my own heart.
You do what you do, I’ll do what I do,
and God will do the rest.” Then he told
her about the TAC-HFT trial at ISCI.
“I gave my family the pros and cons,”
Wilson says. “We decided that even if
it doesn’t work for me, it may work for
ISCI director Joshua Hare, right, consults with
associate scientist Jose Da Silva in Hare’s lab, located
amid an open plan of 15 such labs designed to kindle
cross-disciplinary collaboration.
Pascal J. Goldschmidt, senior vice
president for medical affairs and dean of
the Miller School, knew Hare was the
best person to lead the Stem Cell Institute
when he first envisioned it. “The
field of stem cell research is one of the
most exciting in medicine right now,
and Josh is taking it into an entirely new
realm,” says Goldschmidt. “Not only are
his trials breaking new ground, but his
teams are laying the scientific groundwork
behind these therapies.”
“Wedecidedthatevenifit
doesn’tworkforme,itmay
workforsomeoneelse
downtheline.” —Deborah Wilson, TAC-HFT study patient
after a heart attack (three times better
than what current treatments offer).
Results of the study, called TAC-
HFT, were published in the March 17,
2011 issue of Circulation Research. But
Miami native Deborah Wilson didn’t
have to read the article to believe the
injections could work. She was the first
woman treated in a follow-up TAC-
HFT study of 60 patients.
“I was at home moving furniture
when I felt the pain,” Wilson, 59,
someone else down the line.”
Wilson’s first inkling that the stem
cells worked was during a quiet moment
alone in bed, reading the newspaper
on her back, a simple pleasure
formerly too painful to enjoy. “I pulled
myself up and said, talking to myself,
‘Wow, did you see that?’”
Before the injection, she couldn’t
walk her dogs more than two blocks.
“Now we walk for blocks and blocks,
and I say to them, ‘Who’s in charge?’”
In addition to TAC-HFT, Hare’s
cardiovascular team is running two
other clinical trials. The Poseidon
study compares outcomes of patients
with heart damage who receive their
own (autologous) mesenchymal cells
versus those who receive donor (allogeneic)
mesenchymal cells. Mesenchymal
cells, which are multipotent and
can generate a variety of cell types, are
used because they don’t trigger an immune
response. Other types of stem
cells require a match between donor
and recipient through a process called
HLA typing.
“A key advantage of autologous is that
it’s your own,” Hare explains. “The disadvantage
is that you have to take a biopsy
of your bone marrow, then there’s
a delay to expand [the cells], and there’s
a chance they won’t grow. Allogeneic
cells are from young, healthy donors, off
the shelf and ready to go.”
The other cardiovascular trial under
way is Prometheus, a collaboration
with investigators at Johns Hopkins
following patients who receive either a
high or low dose of mesenchymal stem
cells injected into the heart during bypass
surgery.
“Having research laboratories, a cell
manufacturing lab, an animal lab, a
unit that can work on FDA approvals,
and a unit that can administer clinical
trials—and having it all run like clockwork—that’s
what really makes ISCI
translational,” Hare says. “That’s what
really lets us go from the bench to the
bedside.”
Led by Hare, ISCI’s cardiac clinical
trials account for the largest cohort
of patients injected with stem cells in
the United States. But cardiovascular
research is just one of eight platforms
at ISCI. Housed in the Biomedical Research
Building at the Miller School,
ISCI maintains lab space for about 15
investigators in disciplines such as basic
cell biology, blood, bone and skin, cancer,
diabetes, ethics and science policy,
and the nervous system. There are an
additional 45 ISCI members located in
schools throughout the University.
ISCI’s primary investigators have
received $10.3 million in extramural
funding. But it will take more than
government grants to broaden preclinical
and clinical trial research, establish
an endowment, and expand research
facilities. At least $50 million is being
sought in gifts and pledges over the
next five to seven years, says Hare. Such
funding would speed the translational
pipeline for a host of incurable diseases
and dire medical conditions such
as pulmonary fibrosis, burns, stroke,
macular degeneration, glaucoma, hearing
loss, chronic kidney and gastrointestinal
diseases, and heart disease.
16 Miami magazine Fall 2011 Fall 2011 Miami magazine 17

In its bone and skin division, associate
professor of dermatology Evangelos
Badiavas is using cells that have been
expanded and optimized at ISCI’s Cell
Manufacturing Laboratory to continue
the groundbreaking work he began ten
years ago at Brown University.
“We were the first with the idea
of taking a stem cell population and
putting it into a chronic wound,” says
Badiavas, director of ISCI’s Laboratory
on Cutaneous Wound Healing and
Regeneration. He and his team at
Brown applied bone marrow cells topically
to a surgical wound that had been
open for several years. The cells rebuilt
skin tissue, healing thoroughly rather
than simply scarring.
“It was one of those worth-it
moments—all those nights in the lab,
my wife being angry with me for being
home late,” Badiavas recalls. “It’s a situation
where you made a difference with
your own hands, your own ideas.”
Since arriving at ISCI in 2008,
Badiavas, who did his residency and
fellowship at the Miller School, has
had several “worth-it” moments. He
describes one patient with bilateral leg
ulcers from severe veinous disease who
was dependent on narcotics for pain
management. Injection of the patient’s
own bone marrow cells closed his
wounds, restored his ability to walk,
and got him off of narcotics.
Mesenchymal cells show
widespread therapeutic
promise because of their
ability to fly under the immune system’s
radar. But they alone cannot regenerate
blood destroyed by chemotherapy
or radiation treatment for cancer or
other diseases. Hematapoietic (bloodforming)
cells from healthy donors are
necessary, but they introduce a serious
rejection risk called graft-versus-host
Through their work with stem cells, Evangelos Badiavas, associate professor of dermatology and cutaneous surgery, and research
associate Marcela Salgado have been able to close chronic wounds and restore patients’ independence and quality of life.
disease, even when the donor is a close
HLA match.
“We can always shut down graftversus-host
disease with steroids or other
lines of immunosuppressants,” explains
Krishna Komanduri, the Kalish Family
Endowed Chair in Stem Cell Transplantation
and director of the UM/Sylvester
Stem Cell Transplant Program. “But the
problem is that patients end up so profoundly
immunodeficient they often
die of infection.”
Komanduri’s lab at ISCI is working
on ways to prevent graft-versus-host
disease while reducing risk of infection
and relapse. A lot of his work is with
T cells, components of the human immune
system also vulnerable to HIV.
“In many cases, the same pathogens
that cause problems in HIV-infected patients
also cause problems in bone marrow
transplant patients,” says Komanduri,
who first worked with T cells in the
early 1990s at an HIV immunology lab
in San Francisco, the epicenter of the
AIDS epidemic at that time.
When chemotherapy destroys leukemia
cells, it takes T cells with it. Hematopoietic
stem cell transplants also deliver
new T cells from the donor, but they
take time to multiply, leaving the patient
vulnerable to infection. When infectionfighting
T cells finally repopulate, they
introduce the potential for graft-versushost
disease.
It turns out that not all T cells are
created equal: Some can cause graftversus-host
disease, and some can
reverse it. Komanduri developed a
novel technique, called flow cytometry,
that helps isolate different types of
T cells. His team is working on a transplant
protocol that combines these different
T cells in a ratio that can quash
infections and graft-versus-host disease
at the same time.
Komanduri is also exploring how
to improve outcomes in blood cancer
patients who can’t find a donor match.
Cord blood transplants use stem
cells from the small amount of blood
that’s in a baby’s umbilical cord and
placenta, usually discarded after birth.
This blood contains hematapoietic
stem cells, along with immature T cells
that are less likely to cause graft-versushost
disease. Therefore, they can be
used even when they’re not a perfect
HLA match. Komanduri is testing a
new way of growing cord blood cells
on a “feeder” layer of mesenchymal
cells to boost immune recovery after
transplant.
Over the last 20 years, both private
and public cord banks have sprouted
up worldwide. Public banks accept
donations for anyone in need. Private
banks charge a fee to store cord blood
solely for use by the family that deposited
it.
While a federal funding ban on research
involving embryonic stem cells
(those derived from an unused embryo
created through in vitro fertilization)
was lifted in 2009, ISCI trials don’t currently
involve this category of stem cell.
Hare notes that only mesenchymal cells
are used in clinical trials presently under
way at ISCI, but several research teams
are shifting focus to a new area—tissuespecific
stem cells.
“What’s driving progress in the field
is the discovery that every organ has its
own specific stem cell,” Hare explains.
“We’re working very intently now on
cardiac stem cells, and we know from
animal studies that these cells are more
potent than mesenchymal cells.”
He says this discovery, which happened
within the past ten years, is one
example of how quickly the science of
translational medicine is moving. He
also gives props to patients like Deborah
Wilson, who are eager to participate in
the trials.
“If I look back on the last ten years,
I never thought we’d be this far along,”
Hare admits. “I think this is ready for
approval, at least in its first iteration,
by 2015. It doesn’t mean we won’t
improve on it. We didn’t avoid using
penicillin because we were waiting for
the third-generation antibiotics. We
used what we had at the time that we
knew worked. And we’ll do the same
with stem cell therapies.”
In April ISCI hosted an appreciation
luncheon that drew more than 50
clinical trial participants, one of whom
showed his appreciation and energy
level by giving a spontaneous breakdancing
performance during the event.
“They are seeking us out from all
over the country,” Hare says of his
patients. “They understand that we
don’t know whether it’s going to work,
but they stand shoulder to shoulder
with us in the importance of doing this
research.”
meredith danton camel is an
editorial director at the University of Miami.
For more on clinical trials and stem cell
research at ISCI, visit http://isci.med.miami.edu.
To watch UHealth’s Suncoast Emmy Awardwinning
episode of Breakthrough Medicine,
“Stem Cell Therapy: Healing Force of the Future,”
go to www.uhealthsystem.com/breakthrough/
episode4.asp.
MoreCutting-EdgeActivityatISCI
t
Nanette H. Bishopric, recipient of the American College of Cardiology’s 2010
Distinguished Scientist Award, professor of medicine, and director of the Cardiovascular
Genetics Laboratory, led a team of researchers in discovering a factor that can
serve as a predictor of stem cell development into blood vessels, a key finding for
future applications.
t David Seo, director of the Genomic Medicine Registry and associate professor
of medicine, Division of Cardiology, is exploring the use of bone marrow-derived
stem cells to repair artherosclerosis.
t Omaida Velazquez, vice chair of research surgery and David Kimmelman
Endowed Chair of Vascular and Endovascular Surgery, is principal investigator of an
National Institutes of Health-funded grant to study growth factors critical to the
wound-healing process, among several other stem cell-related studies she is leading.
t Karen Young, assistant professor of clinical pediatrics, Division of Neonatology,
is studying how stem cells become lung cells. She received the 2010 Micah
Batchelor Award for Excellence in Children’s Health Research and a $300,000 grant
for research that aims to identify factors leading to impaired lung cell development
in premature infants.
18 Miami magazine Fall 2011 Fall 2011 Miami magazine 19