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11/18/2004 7:55 AMBy Rich Broderick
Christopher Reeves died waiting for a practical miracle. n Injured in a 1995 horse-riding accident that left him paralyzed from the neck down, the star of the Superman movies was an outspoken advocate for stem cell research. Reeves hoped that scientists would find the key to repairing damaged nerve tissue and make it possible for him and other victims of spinal cord injuries to walk and breathe on their own again. n That breakthrough, if and when it happens, will come too late for Reeves. But researchers and clinicians tirelessly continue to seek ways to transform discoveries made in the lab into treatments in the clinic for a wide array of devastating diseases and disorders. n This search for practical clinical applications for discoveries made in the lab is called translational research, and the process from bench to bedside can take decades. It requires retaining top scientists, acquiring sophisticated equipment, and long-term investment and commitment.
With breakthroughs in transplant surgery, open-heart surgery, and bone and blood marrow transplantation, translational research has long been a strong suit at the University of Minnesota. But now translational research is stepping into the limelight. University of Minnesota President Bob Bruininks has identified Translational Research in Human Health as one of eight interdisciplinary academic priorities for the University. And a translational research facility, which could accelerate the transfer of lab findings to clinical treatments, is slated to open its doors on the Twin Cities campus in June 2005. (Another element of the initiative is a partnership between the University and the Mayo Clinic formed to bring together researchers to develop biomedical inventions and create biotechnology companies.)
"We need a major investment in two things: faculty and facilities," says Dr. Frank Cerra, senior vice president of the University’s Academic Health Center. "These reflect the two elements needed for translational research to succeed by connecting basic research to a disease and then performing the clinical studies that can turn an idea into a new drug, therapy, or medical device."
Minnesota is the obvious place for this kind of research, says Cerra. "We are only one of four universities in the entire nation that has all the health professional leadership schools located in one place, all collaborating in research and education," he says. "Medicine, nursing, pharmacy, dentistry, public health, and veterinary medicine are all part of one Academic Health Center."
The interdisciplinary nature of the translational research initiative—and the physical environment in which clinicians and scientists in various professions will work in close proximity, learning from each other and finding creative solutions—means the time it takes to develop treatments and new technologies should be shortened. And the University’s ability to play a leading role in the health sciences should be strengthened.
Meanwhile, physicians and scientists at the University continue to make advances in finding treatments for the world’s most troubling diseases.
Decoding muscular dystrophy
"There’s oftentimes a confusion about the term translational," says John Day (M.D. ’77), professor of neurology at the University. "The simple view is that basic scientists sit in the lab and come up with a new gene and then gives it to clinicians who stick it into patients and it makes them better."
But translational research is not a one-way street, from research scientist to physician. "For translational research to work it takes a lot of back and forth between the clinic and the lab," Day continues. "You begin with a clinical observation and try to come up with the basic science to explain it and then go back to the clinic where people are suffering and see if the basic science really makes sense in that setting and so on and so forth."
As director of the University’s Muscular Dystrophy Clinic and the Muscular Dystrophy Center, Day has a foot in both worlds—the clinic and the lab. Muscular dystrophy actually is not a single disease but a closely related family of diseases that share certain similarities, most notably a degeneration of muscle fiber. Together, Day and Laura Ranum (Ph.D. ’89), a professor of genetics, cell biology, and development who serves as research director of the Muscular Dystrophy Center, have made breakthrough studies in the genetic origins and disease process of this vexing disorder.
"Translational research is what John and I specialize in," says Ranum. "Bringing [discoveries] from the clinic to the lab and developing tools to understand how genes work so we can bring it back to the clinic."
Day’s and Ranum’s work stems from clinical observations made more than a dozen years ago when a predecessor of Day’s at the Muscular Dystrophy Clinic diagnosed several members of a Minnesota family with a form of the disease known as myotonic muscular dystrophy (MMD), which has an incidence of approximately 1 case in every 10,000 people. Though other forms of muscular dystrophy are more common in children, MMD is most common in adults.
At first, scientists believed a single genetic mutation was the cause of all forms of MMD and thus held out promise of a cure based upon simple gene therapy. But when Day tested the Minnesota family, the results proved negative for the presence of the mutation. "By anybody’s clinical definition, this family had MMD," Day recalls, "but they didn’t have the genetic change that had been identified as the cause of the disease."
The genetic change discovered in the family was an abnormal repetition of the four nucleotides, or letters, of the genetic code in a portion of the gene known as an "intron," which is usually thought of as "silent"—that is, not implicated directly in turning on or turning off a gene or altering the protein that is produced. Until then, mutations that were known to affect human health were located in places where they either turned off a gene—as in cystic fibrosis, whose victims suffer from the lack of a protein essential to proper cell formation in the lungs—or that altered a protein, as in the case of sickle cell anemia.
It took almost 10 years of work in the lab and the clinic—during which Day and Ranum and Dr. Kenneth Ricker, a collaborator from Germany who had collected two hundred families with the same disease, pooled their clinical observations—while Ranum and members of her lab sifted through the patient DNA to identify the mutation.
It turned out that, rather than altering the production of proteins, the genetic mutation they’d identified altered the production of RNA, the intermediary molecule that forms the link between DNA and its genetic expression in the production of proteins. The fact that the mutation did not directly change proteins explains why MMD presents such a complex clinical picture with a wide range of symptoms affecting different kinds of tissue located throughout the body. For example, because of their work, it’s now understood that type-2 diabetes, a common symptom of MMD, is caused by changes in the RNA responsible for translating the DNA code into the creation of insulin receptors.
With further research, this progress could lead to ways to treat, if not cure, MMD. For example, Ranum is working to genetically "cure" muscular dystrophy in a mouse model by switching off the genetic mutation that causes MMD. In the meantime, says Day, "If we can identify downstream genes that are abnormally regulated by the affected RNA, as with the insulin receptor gene, those could be potential targets for treatment even before we come up with an overall treatment for the disease."
Day says the new translational research facility will greatly improve the understanding of diseases and the development of treatments for them. "The priority the president has given to the Muscular Dystrophy Center has allowed us to attract the local, regional, national, and international resources and collaborations necessary for us to create and administer effective treatments and ultimately cures for fatal diseases," says Day.
Striking back at stroke
While cancer, AIDS, and heart disease may receive more press, a silent killer—stroke—is the number one cause of death in the world. While strides have been made in reducing the risk of stroke in some patients, there is no cure for the debilitating effects of stroke on its victims. But that may change in the next few years, in large part because of the work of Dr. Walter Low, a professor in the University’s Department of Neurosurgery.
About 18 months ago, Low acquired stem cells developed at the University’s Stem Cell Institute by a team working under the Institute’s director, Dr. Catherine Verfaillie. Low wanted these particular stem cells because they had developed in unexpected ways. Stem cells are unspecialized cells that develop into specific cells, such as for a particular organ or for blood cells, as assigned.
"When the institute was trying to make bone cells [from stem cells], it turned out that their morphology resembled neurons. They were not self-contained, like bone cells, but had elaborated processes similar to axials and dendrites [parts of the nervous system]," Low explains.
Low knew that, in the wake of stroke, stem cells in the brain begin to divide and migrate to the site of the injury but don’t multiply in sufficient numbers to completely repair the damage. This explains the degree of spontaneous recovery stroke victims tend to exhibit in the weeks after a cerebral incident. But what would happen, he wondered, if those stem cells he’d acquired were injected into the brains of laboratory animals that had suffered strokes, not at the actual site of the cerebral injury, but nearby?
In a study involving stem cells injected near the site of a stroke, Low discovered that the animals regained the use of their limbs as well as sensation in their forepaws. When he examined the brain tissue, Low discovered that not only had the stem cells survived, they had begun to take on the form of the three main kinds of neural cells found in the brain.
"These results proved to us that the grafted cells can differentiate and migrate to the site of injury and then go on to restore neurologic function," he says. "All of the animals recovered to some degree and all have recovered beyond what would occur without intervention."
At the same time, Low found that the number of surviving stem cells injected into the brain was not as great as he’d expected, and so the dramatic recovery displayed by the mice must involve some other mechanism—a "rewiring" of the brain itself. In newer experiments, transplanted cells have been injected along with a tracer dye on the opposite the side of the brain from where a stroke has been induced. The result of those experiments show that the stem cells not only help replace cells at the site of the injury but also stimulate an upsurge in the density of nerve fibers elsewhere in the brain—part of the process by which the brain reapportions functions previously governed by the injured part of the organ.
"Ultimately, we would like to take this into the clinic and try it on patients who have not been able to recover the use of limbs or speech," he says.
Encouraged by his work with stroke, Low has now turned his attention to using stem cell therapy for the treatment of Parkinson’s disease. By exposing stem cells to chemicals released naturally by the body during the development of the nervous system, he is "pushing" these cells to grow into forms resembling the neurons that produce dopamine. Now he is trying to produce enough of these dopamine-producing nerve cells to transplant them into animals with Parkinson’s.
Regenerative medicine, such as using stem cells to treat diseases like Parkinson’s, is one of promising areas targeted by the U’s initiative on translational research.
"Translational research is designed to get therapies into the clinic," Low says. "This kind of research can occur at several different levels. Some of what we do here is close to basic research—studying brain cells and their mechanisms—and some of it is done with the clear idea in mind of getting therapies into the clinic."
Growing new heart cells
As a post-doctoral fellow at the Albert Einstein College of Medicine in New York City, Dr. Doris Taylor was in the midst of studying the genetic differences between the muscle tissues in the heart and the skeletal system when she recalled her mentor pointing out that human beings are born with all the heart cells they are ever going to possess. Heart cells grow and expand, but the body doesn’t make new heart cells throughout life. Unlike skeletal muscle, which is capable of repairing or replacing damaged cells, once the heart is injured with, for example, a myocardial infarction, no new cells develop to replace those cells that have died as a result of the injury.
A few years later, while Taylor was working at Duke University, this distinction led to a flash of insight. "It occurred to me that if skeletal muscle contains cells—which are called myoblasts—that can repair damaged tissue, maybe we could use those cells to get heart muscle to repair itself too."
In 1991, Taylor decided to find out, removing myoblasts from the skeletal muscle of rabbits and injecting them into the hearts of rabbits that had been damaged by myocardial infarctions. The results of her groundbreaking research were startling. By 1998, she was able to demonstrate that the hearts that had received transplanted myoblasts showed a 20 percent improvement in functioning, far better than the post-trauma improvement displayed by the hearts of rabbits that did not receive the cells.
"As you can imagine, that made a big splash," says Taylor, who was appointed Medtronic-Bakken professor of medicine and physiology and director of the University’s Center for Cardiovascular Repair. With nearly 5 million Americans suffering from heart failure at an annual treatment cost of $40 billion, Taylor’s work holds out hope for a nonsurgical cure for this debilitating and often fatal condition.
Initially, Taylor’s findings prompted a certain amount of skepticism, but that has long since faded away. "People said, ‘If it’s so easy, then why hasn’t it been done before?’" she recalls. "But it’s remarkable how well it has worked. Patients treated with these cells improve." Clinical trials of cell replacement therapy in human patients began in Europe in 2000 and a year later in the United States. This summer, Minnesota-based Medtronic announced a joint venture with Massachusetts-based Genzyme Corporation to develop a commercially available cell therapy. Another company, Florida-based Bioheart, with which Taylor has had a consulting relationship, is in the final stages of testing a cell therapy that it says will be released in Europe next year and in the United States as early as 2006.
Meanwhile, Taylor and her team of researchers are also studying the effects of transplanting stem cells along with myoblasts into damaged hearts. The results from this work appear to be even more promising than her earlier discovery.
"We figured that if you were going to put myoblasts into a scarred area of the heart, they would need ‘food,’" Taylor says. Stem cells, she observes, seem especially suited for growing new blood vessels, and combining the two kinds of cells has yielded results that are truly dramatic. The improvement in heart function of 15 to 20 percent with myoblasts alone has jumped to 30 or 40 percent with myoblasts and stem cells. "What that says is that if you want to repair damage to an injured heart, you have to get the cells there and feed them well."
New research focuses on the effects of cell therapy begun shortly after the original heart trauma, before the cascading effect that leads to chronic heart failure. "Most of the clinical trials have been done on patients years after the injury," Taylor explains. "Now some patients are being given stem cells within days of a heart attack and that also has a positive effect. It appears that recovery is the result of re-profusion—the growth of new blood vessels.
"The future is finding the right cell for the right patient at the right time," she continues. "Fortunately, one of our strengths here at the University is in the treatment of heart failure. We are moving forward and designing clinical trials for patients who may have received a VAD [ventricular assist device] but are on the heart transplant list. We have the opportunity to actually study hearts that are being treated.
"On the other hand," she says, "if patients improve so much because of our treatment that they don’t need a new heart, I can live with that."
The University has a long and proud history of translational research in health care. But to maintain that tradition—and to provide the citizens of Minnesota and the world with the treatments and cures for deadly and debilitating diseases—major new investments are needed. President Bruininks naming translational research as one of the eight top priorities at the University is one step in that process. So is the construction of the translational research facility. But that’s not the end of the story for getting cures out of the lab and into the world, according to Dr. Frank Cerra of the Academic Health Center.
"At the University we have made major investments in basic research," says Cerra. "Now we need to implement a major investment into clinical science. This means hiring and retaining faculty members who practice medicine, perform clinical trials, and produce scholarly work that disseminates new knowledge and new practices into the community for all practitioners to use."
Rich Broderick is a freelance writer in St. Paul.