One critical step that may one day lead to developing therapies that employ stem cells is diagramming the journey the stem cells make once introduced into damaged tissue. At the medical school, Dr. Jerry Glickson, research professor in the Department of Radiology, tags molecules with substances visible by modern imaging techniques. Working with stem-cell researchers, Glickson labels myoblasts and bone-marrow stem cells with iron-oxide particles“a glorified version of rust,” he saysprior to injecting them into diseased mouse hearts. Under MRI, he then follows the labeled particles to monitor their integration into damaged heart muscle, and their differentiation patterns.
Associate Professor of Radiology Harish Poptani uses a similar technique to observe the fate of stem cells injected into the brain tissue of animals with lysosomal storage disorders. He and the lead investigator, pediatric pathobiologist John Wolfe, hope that the procedure, which prolongs the lives of affected mice by about a year, can one day be used to help children, in whom these disorders are also lethal. An understanding of the mechanisms by which stem cells repair diseased neural tissue might one day lead to therapeutic cloning techniques using embryonic stem cellswhich, Wolfe explains, are more likely than adult stem cells to propagate in sufficient numbers to benefit patients suffering from lysosomal storage disorders, and even strokes and tumors.
Dr. George Cotsarelis, the Albert M. Kligman Associate Professor of Dermatology at the medical school, who runs one of the world’s leading laboratories investigating epithelial (skin) stem cells, looks at the molecular signals responsible for the four major changes the skin undergoes: alopecia (baldness), wound healing, aging, and cancer formation. This, in hopes of eventually targeting pathways that regrow hair, repair wounds, rejuvenate old skin and prevent uncontrolled cell growth, or cancer.
“The stem cells really are the common denominator in all of these seemingly different processes,” he explains.
Cotsarelis showed that all cutaneous cell linesfrom hair to the skin surface, or epidermisare generated by special stem cells in the “bulge,” or outer layer, of the hair follicle. He also defined a group of genes expressed in follicular stem cells, including specialized receptors and signaling molecules, that are upregulated in the follicle. Cotsarelis hopes to unravel the convoluted cascade of molecular events responsible for hair follicle cycling, which is at the heart of most cases of hair loss. “What are the signals telling the stem cells which fate to take?” he asks.
His research opens the door to new therapies that target the genes responsible for controlling follicular stem cells, “so they would make a hair where they normally would not have.” Cotsarelis might also one day be able to duplicate these molecular events in vitro in order to clone hair follicles for transplantation into patients suffering from hair loss. He thinks human trials using stem cells to treat alopecia will take place in the next five years, and he predicts that his team’s latest finding could lead to treatments aimed at enhancing the flow of cells from the hair follicle to the epidermis, thereby accelerating the mending of broken skin.
The field of oncology may be one of the biggest beneficiaries of stem-cell work. When doctors diagnose colon cancer or lymphoma, for instance, they are detecting what hematologist-oncologist Emerson calls “the tip of the lethal iceberg,” a minute population of stem cells gone awry.
Dr. Anil Rustgi, the T. Grier Miller Professor of Medicine and Genetics at the medical school and chief of the Gastroenterology Division, studies the molecular machinations of gastrointestinal (GI) cancers, with a special focus on esophageal cancer. One of the most prevalent malignancies in the world, esophageal cancer is also among the deadliest because it produces rapid growth yet subtle symptoms.
In the lab, Rustgi identifies and characterizes normal esophageal stem cells, and hunts down stem cells in diseased tissue from his patients’ surgical biopsies, aiming to formulate new treatment ideas by observing and manipulating the very stem cells that sicken his patients.
While the adult stem cells he studies help him piece together the mysteries of esophageal cancer, he says “the Holy Grail would be to figure out how human embryonic stem cells transdifferentiate into other tissue types, and then use these cells to develop new and exciting strategies to treat cancers.”
In his lab, Emerson studies the pathways for regulating the maturation and output of bone-marrow stem cells. “The bone marrow is the nursery school of blood cells,” he explains. These stem cells sometimes churn out progeny in abnormal proportions, resulting in leukemias. Emerson’s research team recently identified the protein NF-Ya as prime candidate for a master regulatory gene governing hematopoiesis, or blood-cell production. He wants to find a way of controlling the directives that NF-Ya issues to its stem cell subjects, forcing them either to self-renew or to differentiate into daughter cells.
But Emerson is growing impatient with bone-marrow stem cells because, he says, they don’t grow quickly enough, or infinitely. “Our 25 years of studying adult [bone-marrow] stem cells have still not given us these answers,” he laments.
In considering the future of medicine, Gaulton makes a distinction between the school’s priorities for attacking near-epidemic conditions like cardiovascular disease and diabetes and obesity, and research on stem cells. “The priorities in the other areas are imperative because we know more about those individual diseases. We have exciting things to target in those diseases. We have patients we can study directly and really make dramatic, short-termmeaning one-to-three yeardifferences,” he says. “Stem cells is a longer trajectory. We don’t know nearly enough about the basic biology as we need to, so basic biology is needed for both adult stem cells and embryonic stem cells. Therefore, the application of those stem cells to disease is also way behind other disease areas.”
But the view from 20 years on is likely to be different. “The upside future potential for stem-cell research and the application of that to a number of specific diseases, cancer maybe being the most clear-cut one, are enormous, absolutely enormous,” he says. “So it’s a little lower [priority] right now, but just a little.”
Funding remains the dominant factor impeding progress. “You’ve got to have the talented people who can identify great questions and propose great experiments; then you’ve got to have the money and the facilities to support them to do it. Otherwise, they’ll just migrate to other areas. Right now, it’s just very, very difficult.”
What little research money there is in the field is mostly in adult stem-cells, “which are technically very demanding,” he says. “There are very, very few talented stem-cell researchers, here at Penn and nationally. We’d love to recruit more.”
If, as seems at least plausible, the next presidential administration (Republican or Democratic) takes a more supportive position on federal funding for embryonic stem-cell research, then Penn and other institutions will be able to shift their attention and resources more in that direction, says Gaulton. Then the actual sciencethe hard intellectual business of unlocking the secrets of stem cells, and adapting that knowledge to help patientscan begin to overtake the politics and the promises.
Joan Capuzzi Giresi C’86 V’98 is a journalist and a veterinarian in the Philadelphia area.
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©2006 The Pennsylvania Gazette
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FEATURE: Promise and Politics