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.
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.
|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 Cellular Manufacturing Laboratory is one of many inter-locking 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.
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.”
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.”
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 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, 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 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.”
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.
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.
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.
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.
“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 (blood-forming) cells from healthy donors are necessary, but they introduce a serious rejection risk called graft-versus-host disease, even when the donor is a close HLA match.
“We can always shut down graft-versus-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 infection-fighting T cells finally repopulate, they introduce the potential for graft-versus-host disease.
It turns out that not all T cells are created equal: Some can cause graft-
versus-host disease, and some can reverse it. Komanduri developed a novel technique that uses flow cytometry to 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-versus-host 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—tissue-specific 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 break-dancing 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.”
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.
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.
Omaida Velazquez, vice chair of research surgery and David Kimmelman Endowed Chair of Vascular and Endovascular Surgery, is principal investigator of a 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.
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.
Meredith danton camel is an editorial director at the University of Miami.
For more on clinical trials and stem cell research at ISCI, visit isci.med.miami.edu. To watch UHealth’s Suncoast Emmy Award-winning episode of Breakthrough Medicine, “Stem Cell Therapy: Healing Force of the Future,” go to uhealthsystem.com/breakthrough/stem-cell-therapy.