|The Waiting Game
Organ Transplant Controversy
January 2, 1998
in this forum:
Is one way to avoid the ethical mess is to have a "National" society of organ donations? What is the difference between heart and brain death? Is it necessary to use Regitine to preserve organs, and what are its dangers? What is the research/clinical status of alternatives such as artificial organs, animal organs, etc.? Is there something wrong with this constant prolonging of life? Jan Andersen of Kalamazoo, MI asks: We have a family friend in the hospital waiting for a liver as I type this, so a timely topic for me.
For a number of reasons, I am skeptical that human organ donation is going to see a significant increase anytime soon. So what is the research/clinical status of alternatives such as artificial organs, animal organs, etc.? Perhaps more important, what is the latest regarding immune system recognition and/or suppression drugs, which allow a human body to more easily accept a "foreign" organ?
Over-arching all of this, of course, is our confused, emotionally charged inability to deal with death as just another fact of life.....
Dr. William Ritchie responds:Jan Andersen:
It is believed under the most optimum of circumstances and the maximizing of the potential donor pool, the supply of transplantable organs will never meet the demand. Several approaches are underway to address the problem.
First is community education on health matters with a focus on healthy living styles. The goal is to decrease the demand by modifying the behavior of those whose unhealthy lifestyles results in the need for a transplant.
Second, a variety of studies are underway regarding the use of animal organs in humans. Limited availability of human organs and tissues, coupled with recent biotechnical advances, has increasingly led to implantations of living cells from other species when human donors are not available, when a bridge organ is needed, or when animal cells may provide a unique benefit. Xenotransplantation is the use of live nonhuman animal cells, tissues and organs in human patients. These cells can be implanted or enclosed in a device that is used outside the body ("ex vivo perfusion"). One area of concern with xenotransplantation is the transmission of diseases. Zoonoses are defined as diseases of animals that can be transmitted to humans under natural conditions (e.g., toxoplasmosis, Salmonella infections). A xenogeneic infection is a transmissible disease introduced from animals into humans through xenotransplantation. The National Centers for Disease Control and Prevention, and the National Institutes of Health are working on recommendations for researchers doing xenotransplant experiments.
Transplant physicians try to suppress the immune system with powerful drugs. While these drugs are often successful, they leave the patient vulnerable to many infections. FDA-approved immunosuppressive drugs include Sandimmune (cyclosporine), Imuran (azathioprine), Atgam (lymphocyte immune globulin), Prograf (tarolimus), and Orthoclone (muromonab-CD3). New drugs are also being researched, including some "designer" immune suppressants. These drugs may enable doctors to suppress the immune system from rejecting a particular organ, but leave the rest of the body's immune system intact.
Drugs designed to help transplant patients may end up also aiding those who are stricken with diseases such as arthritis, multiple sclerosis and diabetes, because these involve problems with the human immune system. For example, Imuran is approved to treat severe rheumatoid arthritis, and Prograf has already shown some promise to MS patients. A large study is under way to determine if it is effective.
Genetic engineering is the next step in battling organ rejection. Researchers have begun experimenting with ways to insert human genes into animal organs, so that the organs will produce proteins the body will recognize as "human." FDA is active in basic research that may lead to better gene therapies and ways of manipulating animal organs. Recently publicized efforts in animal cloning may also prove to be beneficial in the future.
Dr. Michael DeVita responds:
I am skeptical for a different reason. I think donors will increase, however, as our ability to treat more disorders with transplanted organs advances, the need will expand. The net effect will be an ever rising gap between availability and demand. Therefore, advancing the frontiers of science using artificial organs, or animal organs is essential. Artificial organs do not require immune suppressing drugs, but have other problems, while animal organs are a immune nightmare because they are so different from human organs. Rejection is currently inevitable despite our best drugs. However the number of organs from these sources is practically unlimited. You can either build as many as you need or grow as many animals as you need. While some exciting research has occurred recently, it will still be probably 10 years before such technology becomes useable.
Ms. Renee Fox responds:
Like Jan Anderson, I too, doubt whether there will either be a significant increase in human organ donation anytime soon, or whether in the foreseeable future we can expect to come closer to the goal of offering a transplant to much a larger number of suitable patients with organ failure than we currently do. The reasons for this are multiple and complex. One very important contributing factor to what is constantly referred to as the shortage of organs is the tenacity of organ rejection to which Jan Anderson refers – the phenomenon described by the immunologist R.E. Billingham as "the innate and unrelenting intolerance of individuals to grafts of other people's tissues and organs." In spite of the advances in knowledge of the biology of organ and tissue rejection that have occurred during the past several decades, and the development of many new immunosuppressive drugs that attenuate or slow the immune reactions responsible for the rejection of transplanted human organs and that prolong their survival in recipients, it is still not possible indefinitely to prevent or to abolish rejection, which remains an "unrelenting" occurrence. Furthermore, every immunosuppressive drug thus far available carries with it serious side effects. In the Institution of Medicine report on Xenotransplantation: Scientific, Ethics, and Public Policy issued in 1996, transplant surgeon and immunologist Barry Kahan stated that although different combinations of "new generation" immunosuppressive drugs have significantly prolonged graft material, the identification and development of an ideal immunosuppressive medication that is "capable of selectivity, synergy, and specificity," that can "overcome sensitization of the recipient to the transplant," and that does not engender serious toxic side effects is still a research goal rather than an achieved reality. This means that with the exception of those very rare instances when donor and recipient are genetically identical twins, every transplanted organ will eventually be rejected. When their patients undergo organ failure due to rejection, transplant physicians are strongly motivated to seek retransplants for them, because they feel, to use their language, that they are "abandoning" these patients if they do not do so. However, with respect to graft survival and patient mortality, retransplant recipients do not do as well as first-time recipients. Thus, however understandable their desire to wrest patients from death through a succession of retransplants may be, physicians waiting for a first transplant whose chances of benefiting from it are much greater.
A wave of interest in the possibility of renewed clinical trials of Xenotransplantation (the transplantation of organs from animals to humans) has just crested. An informal moratorium had been called in the United States and in numerous European countries during the early 1990s on xenografts. Now, it appears, there is growing support for some well-chosen human Xenotransplantation trials to proceed. Formidable problems of organ xenograft rejection still exist, especially in connection with whole organ grafts between phylogenetically distant species, because they elicit new rejection reactions not previously encountered in human-to-human organ transplantation. But particularly among biologists and immunologists doing cross-species animal studies there is a great deal of optimism – possibly over-optimism – about being "on the brink of overcoming" these problems. Their positive expectancy is reinforced by pharmaceutical and biotechnology companies that have invested heavily in Xenotransplantation- relevant research. In the deliberations about Xenotransplantation held in 1996 by the U.S. Institute of Medicine, on the one hand, and the British Working Party on Xenografts appointed by the Nuffield Council on Bioethics, on the other, the questions regarded as the most weighty and urgent were serious public health issues concerning the possibilities for transmission of infectious, disease-bearing agents from animals to human transplant recipients. These concerns were accentuated by awareness of the global threats to human health that are currently being posed by "emerging" and "re-emerging" infectious diseases. It was agreed that because the most serious and elusive public health hazard that Xenotransplantation in humans might engender would be human infection with animal pathogens not previously known or recognized, special procedures to screen source animals and for lifelong surveillance of patients who undergo Xenotransplantation, their families, and health care workers would have to be established.
As for the alternatives of replacing a failing human organ with an implanted mechanical device intended to permanently assume its functions, the rise and fall of the Jarvik-7 artificial heart experiment during the years 1982-1986 is indicative of how far we still are from achieving this. All five of the patients implanted with permanent Jarvik-7 hearts died of the same complications as the laboratory animals (sheep and calves) on whom it had been previously tried: persistent problems with biomaterials, the durability of some components of the device, and with the pneumatic power supply that resulted in blood clotting, uncontrolled hemorrhaging, strokes, and lethal infections due to penetration of the skin by the device'' air hoses.