November 2011 | VOL. 10, NO. 11 | www.McGowan.pitt.edu
McGowan Institute for Regenerative Medicine Affiliated Faculty Member Dr. Ron Shapiro Celebrates Transplantation
"Our goal in life is really not to avoid death — that's not possible — but to try to cheat death as much as possible," said McGowan Institute for Regenerative Medicine affiliated faculty member and professor of surgery Ron Shapiro, MD, as he celebrated his appointment as the Robert J. Corry Chair in Transplantation Surgery. Dr. Shapiro presented his talk, "A Life in Transplantation," which was presented as part of the Provost's Inaugural Lecture series.
As reported by Kimberly K. Barlow in the University Times, Dr. Shapiro came to Pitt in 1986 as a clinical fellow in transplant surgery under Thomas E. Starzl. He now directs the kidney, pancreas and islet transplant programs at the Thomas E. Starzl Transplantation Institute. Dr. Shapiro, whose career has focused in particular on the development of improved immunosuppression protocols, credited the collective efforts of many scientists and medical professionals as he outlined advances in the field over recent decades.
Before the development of the first anti-rejection regimens, successful transplants were limited to identical twins, Dr. Shapiro said. "Sixty years ago if you had end-stage renal disease it was pretty easy — you just died. There was no dialysis; there was no transplantation."
As anti-rejection treatments were developed, they came at a price.
"The history of immunosuppression is to a large extent the history of all the terrible things we've done to our patients in terms of infections, weight gain, and growth retardation in children as a result of steroids," Dr. Shapiro noted. In spite of their value, many immunosuppressant drugs are toxic.
In the 1960s and 1970s the first anti-rejection regimes used azathioprine — a failed cancer drug — with steroids and anti-lymphocyte preparations, Dr. Shapiro recounted.
In the 1980s, cyclosporine — discovered by researchers seeking a new antifungal agent — "revolutionized transplantation," Dr. Shapiro said. It improved survival in kidney transplant recipients and made liver and heart transplantation possible. It also brought about the start of successful pancreas and lung transplants. However, cyclosporine is toxic to the kidneys and comes with side effects including hypertension and cosmetic and metabolic problems, Dr. Shapiro noted.
The first immunosuppressive agent not discovered by accident was tacrolimus, or FK506, which was discovered in 1982 and found its first clinical use in 1989 in liver and kidney recipients. The new drug improved survival and resulted in fewer side effects, although it too was toxic to the kidneys.
It enabled doctors to withdraw or nearly withdraw the steroid prednisone in a large number of patients. "This was a new phenomenon," Dr. Shapiro said, noting that tacrolimus and mycophenolate mofetil — a successor to azathia-prine — have become the dominant immunosuppressants over the years in kidney transplants.
Newer treatments — including the use of bone marrow infusions — have enabled doctors to wean some patients off steroids, but work in that area continues as doctors and scientists seek new ways of avoiding or reducing complications in transplant recipients.
In addition to being instrumental in the development of tacrolimus, Dr. Shapiro said his group's work over the past 2 decades has included reducing and avoiding complications such as infections and lymphoma. Another area Dr. Shapiro said his group has been involved in is finding matches for patients who need transplants via paired donations and donor chains.
Dr. Shapiro said the University's progress in the field was a "huge group effort," crediting close relations between nephrologists and surgeons, the dedication of pathologists and scientists, team members including nurses and research coordinators, and fellows of the Starzl Institute program.
"And at the end of the day, it kind of doesn't matter how many papers you wrote or how many talks you gave, but what really matters is who did you train and how did they do?" he said, adding that many former fellows now are running transplant programs all over the world. "It's been a privilege to be involved in their training," he said.
Dr. Shapiro credited his own mentors, including former chief of surgery Richard Simmons, who was recruited to Pitt by Dr. Starzl and was chief of surgery when Dr. Shapiro was a young faculty member.
In addition to being "a great surgeon and a very thoughtful and analytical individual," Dr. Shapiro said, "he was one of the greatest mentors that one could possibly have." He added that Drs. Simmons and Starzl formed a formidable team.
Dr. Starzl's list of accomplishments is lengthy but his most interesting aspect as a mentor is that he is never satisfied, Dr. Shapiro said. "We can always do it better, we can always come up with some sort of better way of taking care of patients, better immunosuppression," is what Dr. Starzl insists. "This lack of complacency, I think, is perhaps his most enduring legacy to us so that we are taught never to really be satisfied with what we've accomplished in the care of our patients and are always trying to improve what it is we are trying to do," Dr. Shapiro said.
McGowan Institute for Regenerative Medicine affiliated faculty member Douglas Kondziolka, MD, Peter J. Jannetta professor and vice chairman of neurological surgery at the University of Pittsburgh Medical Center (UPMC), is the principal investigator of the Phase 1/2a clinical trial testing a novel cell therapy product, SB623, in patients suffering from disability resulting from ischemic stroke. SB623 is a proprietary regenerative cell therapy from SanBio, Inc. consisting of cells derived from genetically engineered bone marrow stromal cells obtained from healthy adult donors. SB623 functions by producing proteins that aid the healing process.
SB623 has been shown to improve neurological behavior in preclinical models of stroke. In this study, safety and efficacy parameters will be evaluated, including improvements in motor function and cognitive status. The trial will evaluate 18 patients who have suffered an ischemic stroke within the past 6 to 24 months and have a motor neurological deficit.
"We are excited to be a part of this important new study offering a novel approach to therapy for patients suffering from ischemic stroke disability," said Dr. Kondziolka.
"Preclinical models have shown that SB623 restores function in animal models of stroke. With over 7 million stroke victims in the U.S. today, we are eager to explore the potential of SB623 in patients who may otherwise be permanently disabled," said Lawrence Wechsler, MD, chair, department of neurology at UPMC.
McGowan Institute for Regenerative Medicine affiliated faculty member Kang Kim, PhD, assistant professor of medicine and bioengineering at the University of Pittsburgh and the Cardiovascular Institute, was a member of the team of researchers conducting a study of a new imaging method which helps doctors tell whether a patient with Crohn's disease has intestinal fibrosis, which requires surgery, or inflammation, which can be treated with medicine.
According to the University of Michigan-led study, ultrasound elasticity imaging, or UEI, could allow doctors to noninvasively make the distinction between inflammation and fibrosis, allowing patients to receive more appropriate and timely care. The study was recently published in the journal, Gastroenterology.
Crohn's disease patients suffer from chronic inflammation of the intestines, which over time can cause scar tissue to form, resulting in intestinal fibrosis.
Patients with intestinal inflammation usually are treated with medicines that suppress their immune system, while patients with fibrosis are treated surgically. Because current diagnostic tests, including CT scans and MRIs, cannot detect the difference between the two conditions, many patients with fibrosis are often initially treated with immune system-suppressing drugs, which are expensive and are unlikely to help.
Inflamed intestinal tissue is softer than fibrotic tissue, which is hard and thick. The new method uses ultrasound to measure the relative hardness and thickness of tissue inside the body, potentially allowing doctors to differentiate between the two conditions without performing surgery. In animal models, UEI was able to accurately tell the difference between inflamed tissue and scar tissue.
The researchers also found that UEI was capable of differentiating between fibrotic and unaffected intestine in a pilot human study. Patients already scheduled for surgical treatment underwent UEI assessment prior to surgery, and fibrotic strictures were identified in each case.
The next step in the group's research is a long-term human clinical trial, beginning this winter. If UEI is able to accurately assess a patient's condition, doctors will be able to more efficiently treat Crohn's disease patients suffering from inflammation or fibrosis.
The McGowan Institute for Regenerative Medicine is named after the late William G. McGowan, who as chief executive officer at MCI Communications underwent a successful heart transplant at the University of Pittsburgh Medical Center in 1987. Three years ago production of a documentary on his life and contributions began.
Bill was a legendary entrepreneur who was instrumental in the deregulation of the telecommunications industry. His years of work opened the door to industry competition and innovation, and ultimately resulted in cheaper long distance calling rates and the delivery of new technologies for consumers. He took on the most powerful monopoly of his time - AT&T and its Bell System of local phone companies - and won against all odds.
The documentary, "Long Distance Warrior," by renowned producer Sarah Holt is being carried by over 82% of all PBS stations across the country. In the Pittsburgh area, it will be shown on WQED on January 29, 2012, at 5 p.m. Watch the program's trailer here.
McGowan Institute for Regenerative Medicine affiliated faculty member Philip LeDuc, PhD, Carnegie Mellon University (CMU) professor of mechanical engineering, and Mary Beth Wilson, a CMU PhD candidate in biomedical engineering, have won an extremely competitive Grand Challenges Explorations Award from the Bill & Melinda Gates Foundation to explore nutrition for healthy growth of infants and children in underdeveloped countries.
"What we are doing is studying how to alter a plant's cellular and molecular structures to optimize release of nutrients during digestion," said Dr. LeDuc, who has courtesy appointments in the Biomedical Engineering, Biological Sciences and Computational Biology departments at CMU. "The idea originated when we became interested in how structural mechanics affect the taste of food. We built off this idea in thinking about how we could apply it in an innovative and meaningful way to tackle global challenges especially for the health of children in poor regions of the world."
Both Dr. LeDuc and Ms. Wilson believe that generating widespread acceptance and consumption of nutrient rich plants like African leafy vegetables could significantly improve infant and child nutrition while curbing rising food costs. Global food prices hit record highs in February 2011 and are expected to become even more volatile. The United Nations reports that more than 900 million people in the world suffer from hunger on a daily basis.
"We have chosen to focus initially on amaranth, a plant indigenous to Sub-Saharan Africa, due to its high content of provitamin A and other micronutrients. We hope that integrating amaranth leaves into feeding strategies as infants transition from breast milk to solid foods could contribute to a reduction in vitamin A deficiency," said Ms. Wilson, a CMU Dowd-ICES (Institute for Complex Engineered Systems) fellow from Bridgeport, WV.
Dr. LeDuc said the work involves significantly changing the palatability of the end food product. "These African leafy vegetables are perceived as 'poor man's food' with a bitter taste," Dr. LeDuc said. "We aim to change both taste and perception by reengineering the plant's cellular structure using traditional principles of cell mechanics that have been used for decades in areas such as heart disease and cancer."
CMU researchers say they also are tapping into the modern and cutting-edge methodology of "molecular gastronomy," the study of physical and chemical processes that occur while cooking. Their culinary curiosity will be showcased next year in a new academic course titled "Culinary Mechanics," designed to explore the application of engineering principles to the science of food.
AWARDS AND RECOGNITIONS
McGowan Institute for Regenerative Medicine faculty member Donna Stolz, PhD, associate director of the Center for Biologic Imaging (CBI) and associate professor in the Department of Cell Biology and Physiology at the University of Pittsburgh, is also an award-winning photomicrographer. Dr. Stolz's entry, "A Blade of Grass," won 2nd place in the 2011 Nikon Small World Competition. This annual competition honors top photomicrographs from around the world. Dr. Stolz's technique included confocal stack reconstruction and autofluorescence.
The CBI is one of the largest optical imaging centers in the country. The CBI is a leading center in the application of cellular imaging from the single molecule to the whole animal. Dr. Stolz runs the electron microscopy component of the CBI and is the contact for planning experiments which involve electron microscopy. Her research interests are primarily in the biology of internal organs (liver, kidney, gut).
Small World is regarded as the leading forum for showcasing the beauty and complexity of life as seen through the light microscope. For over 30 years, Nikon has rewarded the world's best photomicrographers who make critically important scientific contributions to life sciences, bio-research, and materials science.
Top images from the 2011 Nikon Small World Competition will be exhibited in a full-color calendar and through a national museum tour. For additional information, please visit Nikon Small World.
Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.
Fang PA, Conway JF, Margolis HC, Simmer JP, Beniash E.
Hierarchical self-assembly of amelogenin and the regulation of biomineralization at the nanoscale.
Enamel is a highly organized hierarchical nanocomposite, which consists of parallel arrays of elongated apatitic crystallites forming an intricate three-dimensional microstructure. Amelogenin, the major extracellular matrix protein of dental enamel, regulates the formation of these crystalline arrays via cooperative interactions with forming mineral phase. Using cryoelectron microscopy, we demonstrate that amelogenin undergoes stepwise hierarchical self-assembly. Furthermore, our results indicate that interactions between amelogenin hydrophilic C-terminal telopeptides are essential for oligomer formation and for subsequent steps of hierarchical self-assembly. We further show that amelogenin assemblies stabilize mineral prenucleation clusters and guide their arrangement into linear chains that organize as parallel arrays. The prenucleation clusters subsequently fuse together to form needle-shaped mineral particles, leading to the formation of bundles of crystallites, the hallmark structural organization of the forming enamel at the nanoscale. These findings provide unique insight into the regulation of biological mineralization by specialized macromolecules and an inspiration for bottom-up strategies for the materials design.
Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):14097-102. Epub 2011 Aug 8.
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