Beyond Transplantation

Regenerative biology attempts to address organ failure in innovative ways through research into replacing or supplementing the function of damaged organs. For Jeffrey Platt, M.D., head of the Mayo Clinic Transplantation Biology Program, regenerative biology and new approaches to organ replacement promise to transform the practice of medicine and to improve public health worldwide.

"Our goal is to revolutionize patient care and the scientific approach to treating organ failure," he says. "We believe we have the leading vision in the world for what the future of replacing organs will be."

Dr. Platt's team senses the urgency to move technology from the laboratory bench to patients' bedsides. In the year 2002 alone, the group originated at least six patents and 50 publications. (See also: Publications and Technology Commercialization.) Patent awards indicate the depth and breadth of regenerative biology research topics. For example, collaboration between Marilia Cascalho, M.D., Ph.D., and Dr. Platt resulted in a patent for a new vaccine technology that could be applied for hepatitis C, SARS and HIV. The technology stems from a fundamental understanding of how microorganisms evade the immune system and how immune cells try sometimes futilely to catch up with these organisms.

Another patent uses two genetic techniques the regenerative biology team devised to probe how the immune system is able to recognize so many different germs. This has led to new technology that may someday be applied to rebuilding the immune systems that are devastated by AIDS, or aging, or cancer.

Patient Needs

Organ failure is an increasingly common root of illness and there is a drastic shortage of donor organs. As a result, the societal need for research into regenerative biology is growing. Beyond the current problem there looms a greater crisis: new research will enable physicians to be able to diagnose diseases such as cancer years before the disease causes symptoms. Then, of course, physicians will be tempted to try to replace the affected organ, exacerbating the existing organ shortage. The upshot: physicians will be even more helpless to save the vast majority of those patients they know will develop life-threatening diseases.

As a world leader in this field, Mayo Clinic and its investigators attempt to meet this need through cutting-edge research into:

• Organogenesis - This experimental technology explores the idea of generating new organs to grow within the body to replace a damaged or ailing organ. "Let's say I had failure of a kidney or a lung. Would it be possible to actually grow a kidney or a lung that could be within me?" asks Dr. Platt, adding: "This technique is for the future, but we're making what we hope are the initial steps in the present."
• Immune Reconstitution - This approach involves a similar idea to organogenesis. But instead of encouraging growth of new organs, Dr. Platt's team endeavors to rebuild the immune system. This is something that needs to be done for patients whose immune systems are destroyed by AIDS, or by aging or by cancer. Says Dr. Platt: "We've made some key insights, and have actually launched a program to apply our ideas, which have potential for the patient."
• Xenotransplantation - This is the concept in which organs or tissues from specially-bred animals might be transplanted into human beings. Today, this technology is still in the experimental stage. But Mayo Clinic researchers are among the leaders worldwide in successfully transplanting pig hearts into non-human primates for at least 90 days, and transplanting cells from pigs into non-human primates for hundreds of days.
• Tissue Engineering - This approach involves coaxing cells to grow into tissues that could be used to replace or enlarge damaged tissues. Tissue engineering is already being applied for repairing defects in skin, bone and bladder. New technologies, however, will be needed if tissue engineering is to be applied to the replacement of whole organs. Dr. Platt hopes Mayo scientists will provide those technologies.
• Stem Cell Transplant - This approach enlists the regenerative properties of stem cells, "primitive" cells found in large numbers in a fetus and in smaller numbers throughout life. Stem cells can develop into a variety of tissues. The idea here is to actually generate stem cells for a patient that could be used to rebuild damaged organs. Stem cells are already being studied at Mayo Clinic and elsewhere as building blocks for repairing the heart, and for replacing the insulin producing cells in the pancreas. Key to future applications, however, is the development of technologies that will allow those cells to replace more complex organs such as kidney and lungs.
  The overarching goal of Mayo Clinic regenerative biology research is discovery of foundational concepts that underlie the very workings of human organ and immune function. But the discovery process actually begins with patients' needs not with the laboratory world of possibilities. "The problems that the clinicians and patients face together at the medical center are a major resource for us: they are our primary motivation for the work we do, and a base of information about a given medical condition," Dr. Platt says.
  Too often in traditional settings technology is developed in a vacuum, out of the context of patient care. Not so at Mayo Clinic. Because of the collaborative nature of the Mayo Clinic regenerative biology research, its programs are well poised to address the most basic problems patients face. The research agenda does this through major commitments to investigations in heart, lung, liver, kidney, pancreas and orthopedics.

Training Students

A related goal driving the regenerative biology team is furthering education at the College of Medicine. Investigators do this by teaching medical and graduate students such subjects as immunology, biochemistry, genetics, and developmental biology. Says Dr. Platt: "That's an important aspect of our mission."

In addition to mentoring medical school and graduate research students, Dr. Platt and colleagues reach out to high school students and undergraduates through informal education programs. "In our program, headed by Marlo Bungum, we're hoping we can help students become engaged at all levels," he says. "We want to encourage curious minds to pursue interests and careers in science, to get a taste for research and teaching, because often it happens that students who are very talented are not choosing this path. They pursue other careers based on their daily experiences. We hope to change that. We hope they see what we do, and how much fun we have and how rewarding it can be to make discoveries that impact so profoundly on human health."

Influencing international health policy is another priority of the Mayo Clinic Regenerative Biology research team. As a leader in the field, Dr. Platt frequently interacts with legislative and regulatory agencies. "I do this because I'm an advocate for the importance of organ replacements as a matter of pressing concern for public health, not just for medicine. I can't ever forget the needs I've seen from so many patients."

Collaborating: The Immune System

In addition to the general shortage of donor organs, Dr. Platt says there is a second problem faced by transplant patients: Even if the organ transplant works, the patient needs to be treated with immunosuppressive drugs for the rest of his or her life to keep the body's immune system from attacking and rejecting the organ. These drugs have many undesirable side effects, such as increasing the risk of life-threatening infection.

To change that, Dr. Platt's team has developed a research program that functions as an umbrella for new technologies and new ways of thinking linked through creative collaborations of biomedical disciplines. Members of the program and collaborators come from such diverse fields as basic immunology, genetics, biochemistry, physiology, surgery, medicine and pediatrics, systems biology and transplant surgery. The alliance is necessarily broad because the science is demanding and the applications may be equally broad. Says Dr. Platt: "The immune system is, by some estimates, 1,000-fold more complex than all the genes in the body. Making sense of this complexity is a challenge that we have recently met by wedding genomics and immunology with tissue engineering."

Collaborators include:

Scott Nyberg, M.D., Ph.D., and his team in their efforts to develop a new device for liver failure. Dr. Platt's team is working to understand the body's immune response to this device.

Mark Stegall, M.D., in developing new ways to enable successful kidney transplantation across blood groups The result of this collaboration has greatly expanded the availability of donor organs to meet a dire need.

Yogish Kudva, M.D., in developing a new understanding of how the body destroys insulin-producing cells in diabetes and how to prevent or reverse this process.

Dr. Platt's Contributions

Dr. Platt attributes his drive for pathbreaking research to an experience early in his medical career. "During my internship in pediatrics, I had a newborn patient with renal failure. I was told by my supervisor that renal failure in the newborn could not be treated and that the only course we could taker was to make the baby comfortable and watch him die. It was just not possible in that era to carry out a kidney transplant, and it would make no sense, it seemed then, to undertake dialysis. I was riveted by our impotence." Experiences like that continue to provide the human context for the research Dr. Platt performs. "This baby could have been saved by technology available at that time, but nobody knew it."

Dr. Platt's contributions to both research and practice are deep and wide, with far-reaching effects. For example, Dr. Platt was the first to describe a phenomenon central to the success of an organ transplant called "accommodation". Accommodation is the acquired resistance that an organ develops to survive attacks from the immune system. He has authored/co-authored hundreds of articles and four books. He has achieved the high honor of election to the membership of the Institute of Medicine of the National Academy of Sciences. He has mentored students and trainees who now hold posts around the world in surgery, immunology, pediatrics and medicine.

Dr. Platt's team is now applying the lessons learned from accommodation to help restore damaged organs. "Our vision has always been to see if we can understand what this acquired resistance is, and how to bring it about therapeutically. Then we can potentially use it to treat disease. Or, we can allow organs to repair themselves in the face of disease," Dr. Platt explains.

As another example Dr. Platt cites the discovery he and a graduate student made while studying the body's defense against infection: a new way of regulating body fat and bone density. Notes Dr. Platt: "Sometimes the answer to important questions comes by luck from studies quite remote from that question."

Most recently, Dr. Platt and his colleagues have discovered ways to rebuild the immune system that may be applied in such diverse fields as cancer, chronic infection, AIDS, and transplantation.