PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. The Emergence of Regenerative Medicine: A New Field and a New Society by William A. Haseltine Ph.D. Chairman and CEO of Human Genome Sciences Introduction We are embarking on a great enterprise: the formation of a new field of medicine that will improve the lives of people everywhere by curing disease. It will spawn academic departments as well as companies. I hope our efforts will stimulate progress by encouraging scientific collaborations and government funding. We who are active in this area must also ensure that the potential of regenerative medicine is understood by reimbursement authorities. The seeds of regenerative medicine were planted by researchers in disparate disciplines. Yet there is also a unity to regenerative medicine, which stems from a common need. Bodies eventually wear out and need components to be restored or replaced. The key insight of regenerative medicine is that every human being was once a single cell with the potential to transform into an adult body. Each of our cells retains that remarkable potential in a latent form. We have over the past decade learned how to identify the molecules that our bodies use to direct that great unfolding. We can now isolate, study and produce those substances in virtually unlimited quantities and use them to regenerate our tissues and organs. Non-living components can also restore functions within the body. Materials engineered to atomic-scale precision hold immense promise for this application. Physicians already commonly treat patients by implanting artificial hip joints, heart valves, blood vessels and even intricate parts of the inner ear. Today such devices perform poorly in comparison with nature, but within the foreseeable future they will function almost as well as our natural components. We will restore organs and tissues that have been injured by trauma, damaged by disease, or worn by time. The medical use of natural human components, together with high-technology non-living materials, could thus alleviate much human suffering. This medicine will be transforming. It can help everyone who ages: that is, all of us. It can also address pressing social, political and economic issues, contributing to a healthy, active, productive older population. One such issue is the demographic transition. As a country becomes richer, security in old age depends less on having children and more on the durability of social arrangements. As a result, the species no longer replaces its numbers, and the average age of the population increases. This trend portends enormous economic and social difficulties in coming decades. It has been termed an "aging crisis." Western Europe and the Pacific rim feel the crisis especially strongly. Spain affords a dramatic example. In 1960, the average number of children per family was 2.9, considerably more than the replacement rate. Today, the figure is about 1.2, which is less than half the replacement rate. The birth rate throughout the area encompassed by one view of Europe -- from the Urals to the Atlantic and from the Baltic to the Mediterranean -- is low enough to bring about severe demographic problems. Fifty years from now, the native-born population of Italy will be half its current size. The same will be true of Japan. North America would face similar problems save for immigration. People commonly retire when they reach 60 or 65 years of age. Yet many of them live for decades beyond that age. As the average age of the population increases, therefore, a dwindling number of young people supports the retirement of a growing number of older ones. One consequence will be a huge premium on medicines that can extend working lives. Our students are likely to see the extension of a working lifetime become a dominant political goal. Our systems of social support are already coming under stress, and all the signs indicate that the situation will worsen. Developing new medicines is, however, expensive. Therein lies another of our goals. We are not just scientists. We provide leadership in the worlds of science and medicine. That role implies a responsibility to ensure that our specialized knowledge is properly utilized. We are pioneers who must blaze a safe trail for others to follow. We must ensure that our politicians and our health care administrators understand the powerful capabilities we have developed. If decision-makers appreciate the potential of this new field, they will be able to garner enough support to give it a healthy birth, a strong childhood and a rich maturity. Our innovative technologies will then allow many people to live more active, healthier lives. The First Thread What are the technological changes that have made regenerative medicine possible? At the most fundamental level, recent years have seen a remarkable increase in knowledge about genomes (a term that means simply "all genes"). The past year, in particular, has seen the culmination of a decade of research that has lead to a reasonably comprehensive description of the human genome. Independently, companies, including Human Genome Sciences Inc., have used advanced technologies to establish collections of nearly all human genes in the form the body uses. This is the most useful form for medicine. New, automated, computer-driven machines reveal the function of these genes. These techniques have identified genes that produce signaling proteins that control how cells function. Some of these substances we are now using to create drugs that will treat diseases from cancer to heart disease. This is possible because substances found naturally in the body are actually small, interchangeable body components. For example, insulin is a signaling substance that helps the body use sugar. Insulin is the product of one gene, and insulin made from a gene originating in one individual can be given to any other person. Furthermore, genes from one organism can often function in other organisms. Thus genetically engineered bacteria containing the human insulin gene now manufacture this valuable, human-gene-based drug. Signaling proteins constitute the first thread of what will become a rich tapestry of regenerative medicine. We are learning where the genes encoding these proteins are active and how they are controlled. We are also learning how they are associated with health and disease. One speaker at our December 2000 conference related how experiments are now done not with just one human substance, but with ten thousand simultaneously. Moreover, the information provided by these experiments is more detailed than the information being learned about single substances ten years ago. This is a remarkable transformation. The substances that serve as signals can convey any of several messages to cells, but the number of possibilities is not large. They can drive cells to remain at rest or to grow; to stay alive or to commit suicide; to differentiate or remain undifferentiated; and to remain attached to a substrate or to detach. These messages thus have powerful medical potential. We have also learned over the past decade how to make fully human antibodies that inactivate or mimic almost any human substance. Antibodies can oppose a signal already present in the body and so greatly extend therapeutic possibilities. As founders of regenerative medicine, our task is to use signaling substances and antibodies to create medicines that will grow wounded tissue, stop cancer cells from growing, activate cells to produce needed substances, or even recreate tissue that is damaged or diseased. We are confident of this future, because there are now few technical barriers to the medical use of these human substances and antibodies. Moreover, we know that provision of appropriate micro-environments can re-grow tissue. The current situation is analogous to that of the space program in 1961, when President Kennedy announced the goal of putting a man on the moon. Achieving it was a matter of resources, because no fundamental scientific discoveries were needed. Likewise, we now know how to turn human substances and antibodies into drugs. Of course, it is probable that some important new substances are still to be discovered. Moreover, mimics of these will in some cases be optimal for use as drugs, rather than the substances themselves. Yet the fundamental technology is understood. Discovering genes is no longer an obstacle. The rate-limiting step in the development of genomic-based pharmaceuticals is, rather, determining a gene's natural functions and medical uses. This means that the weak link in the chain from the desire to cure to a successful treatment is now our weak institutional base. A few years ago we could often study only highly specialized cell lines. Advances in cell biology mean we can now study the behavior of many natural human cell types in culture. It follows that we can relatively easily modify their behavior and calibrate their responses. A commercial enterprise needs to be confident, however, that success treating an animal disease will translate into success treating an equivalent human disease. If a good animal model exists we can move with extraordinary speed. Progress is much slower when no animal model is available. Unfortunately, medical schools now often lack the resources to develop animal models. Despite this difficulty, I believe the promise of genomics will be realized, in part, within five years. Within this period we will see new drugs become available. We at Human Genome Sciences Inc. already have several human-substance-based medicines in phase two clinical trials. We maintain active partnerships with a growing number of biotechnology companies that have expertise in the development of antibodies and in drug formulation and delivery. Within ten years, a rapidly expanding range of genomics-derived human substances and antibodies will be on the market. Twenty years from now, I believe that at least a half of all new medicines will be of this type. Innovative chemical drugs that influence molecules discovered through genomics will also by then be marketed. Eventually, regenerative medicine will make use of human cells as therapies. This development will take longer to arrive. Nevertheless, it is reasonable to suppose that within ten years, several cell-based therapies will find widespread use. Within twenty years, such therapies will constitute a major field within medicine. The Second Thread The second thread of regenerative medicine is tissue engineering. Many of those who attended our conference are leaders in this field, an area of medicine that did not exist five years ago. Tissue engineering is based on the insight that it should be possible to build an entire organ outside the body, by bringing together specialized bio-compatible materials, signaling molecules and human cells. Enormous progress has occurred in the field of tissue engineering, which seems to be accelerating. Several reasons are apparent. The need for replacement organs and tissues is growing. The increasing demand stems in part from the increasing number of congenital defects, injuries and diseases that can now be treated. Demand is also growing because of demographic changes. Among older people, muscle, bone, cartilage, nerves, the digestive system, the skin, and the brain may all need help. Implanting new components created from a patient's own tissue will become an important way to restore function to these systems. Medical science is currently just beginning to acquire that capability. It seems likely that in time we will be able to replace most, if not all, the tissues in the body. We have some impressive developments to build on. Materials science has given rise to bio-compatible structures fabricated with unprecedented precision. Such advances are the result of progress in information science as well as progress in developing new materials. High-performance information systems are needed to assemble the detailed knowledge employed in the creation of complex structures. Our species has learned how to alter our material world by placing atoms in specific configurations and positions in space. This capability means that we can start to build molecular machines and structures to the same precision as our proteins. Engineering at this scale, which usually goes by the name of nanotechnology, has far-reaching implications for medicine. An alternative term would be "atomic-scale engineering," which reminds us of our ability to put atoms in specific places. We are about to witness this new ability drive rapid developments in chemistry and materials science. Radical societal change is in prospect whether or not we apply these advances to medicine. If medical applications are developed, however, the implications will be profound: materials designed and built at the same scale as the organelles within our cells will be used as the basis for new organs and tissues. Another reason for optimism about the prospects in tissue engineering is a growing awareness that we will all be its beneficiaries. Yet dramatic change will not ensue if we simply create these structures in a test tube. The new discipline must be recognized in hospitals, which are the obvious home for this work. Surgeons, cell biologists and materials scientists will have to work together to provide these new tissues and organs. They will constitute new units within the ever-growing mazes of our major medical institutions. Establishing such units will be difficult, as we are operating in a highly cost-conscious environment. We will have to show that our therapies can be cost-effective. This can be done, but it will be more than a merely technical challenge. Clinical investigators are now initiating path-breaking experiments in which patients are implanted with new cells and tissues. Currently this work is done on a relatively small scale. Nonetheless, we are likely to see some major successes. Ten years from now this second thread should be a major part of the tapestry of regenerative medicine. We may by then be starting to train young doctors in the field. The Third Thread The third thread of regenerative medicine is the field of human stem cell biology. It has already captured the public imagination, as it is extraordinarily compelling. Stem cells have unmatched potential for healing, because their descendants can adopt different forms depending on which chemical signals they receive. The field was initially controversial, because some key stem cells were derived from human embryos. That origin angered opponents of abortion. Moreover, these cells entered public consciousness soon after a sheep, named Dolly, became the first animal to be cloned from an adult cell. The result was a generalized public apprehension about developments in biology. Yet only a very small number of maverick scientists have announced a desire to clone a human being. Furthermore, we now know that many stem cells are present naturally in adult bodies. These might become an important source of therapeutic cells that have no connection to embryos. Nonetheless, future technologies derived from cloning might play an important role in regenerative medicine. They could provide another source of human stem cells with the potential and vigor of youth that would be untainted by any connection with embryogenesis. For this type of regenerative medicine there are major obstacles to be overcome. Scientific progress must be made, and the future is, famously, unpredictable. Yet the fundamental experiment has been done. Dolly showed that it is possible to reprogram the nucleus of a cell so that its descendants can serve many different functions. It would also appear that cloning resets a genetic clock within cells. Many of the foremost authorities in this area believe it will ultimately be possible to restore tissues with cells that have been rejuvenated in this sense. The power to reset the clock within cells, when combined with the ability to culture specific cells, suggests a very powerful form of medicine. We need to state clearly that research on these subjects is unrelated to abortion and cloning of people. Rather, it is about new and better ways to treat disease. Bone marrow stem cells are already used in medicine, and neural stem cells may be used in the brain in the relatively near future. Surprisingly, the brain seems to be one of the most suitable organs for stem cell transplants. For other tissues, such developments may be still some years away. Still, I believe that a decade from now, we will have established the parameters for how we may be able to use stem cells broadly in medicine. Human signaling proteins will find important applications in controlling the growth and differentiation of such cells, and will allow physicians to produce cells with specific competencies. The Fourth Thread The fourth thread of regenerative medicine is the use of non-living materials to substitute for the living matter of our bodies. Even today, as we age, we acquire non-living components. We may have steel or plastic hip joints, plastic heart valves, or dacron blood vessels implanted in our bodies. We may use a hearing aid. Even our glasses are non-living aids. The history of prosthetic medicine is a sad one. Society has been unwilling to put its best efforts into helping small numbers of patients, so those who need the most help often suffer unnecessarily. Paraplegics, people who are missing a limb and people with hearing difficulties readily describe technologies that exist today and could be beneficial if they had been suitably applied. Progress in the relevant fields is proceeding apace, however. We have only to think about advances in micro-mechanical engineering, the miniaturization of electronics and the creation of new materials to gain an impression of how neuro-mechanical prosthetics might progress. Consider the technology that goes into spy satellites. Imaging devices smaller than a laboratory slide may include more than a million detectors. Similar devices could be used to create artificial retinas. Recent research also suggests avenues that might be explored to help paraplegics. We have been able to detect and amplify signals in the brains of monkeys and translate these into movements of a mechanical arm. We might be able to pick up similar signals from a patient's brain. These could then be used, with appropriate feedbacks, to activate muscles. In this way we may be able to bypass unrepairable injuries to the spinal cord. Neuro-mechanical and neuro-electronic prostheses do not necessarily involve living cells, but they must be fully integrated with living cells. Building an artificial retina, for example, would entail knowing much about how the brain processes visual information. These programs would be expensive. Some might eventually be pursued for military purposes. Giving a pilot the ability to guide a plane by thought, for example, could provide much better control than relying on muscles. Whether such advances will be applied to medicine remains to be seen. The discouraging history of prosthetic medicine suggests developments may be slow to arrive. The aging baby-boom generation may, however, push the area forward. Readers of this volume will find some of the manifold possibilities discussed. Steps to the Future The four threads of regenerative medicine are tightly interwoven. To advance the field broadly, we must agree on a set of actions. In the words of the famous slogan, we must think globally and act locally. At meetings held in association with our conference, participants discussed not only the scientific and technical aspects of regenerative medicine, but also how we should relate to society. We thought particularly about how we should establish links with the political system, the hospital system and insurance companies. As a result of those discussions, it was decided to form a new professional society, the Regenerative Medicine Society. Those attending the conference will be invited to join the Society as charter members. We look forward to making the Society a strong voice for the field. I have argued for the creation of training programs for translational medicine. We in the United States should argue for increased support from the National Institutes of Health, for example. We should also argue for funds that would provide academic paths for physicians, especially new physicians. These are messages we should organize around. If we are going to be healthy, we must have a healthy system. Currently our system largely fails to promote research on new therapies. I have long encouraged scientists to develop medicines or medical devices, because only in this way have I seen scientific knowledge be translated into benefits for patients. Many of the students that I trained at Harvard Medical School are now leaving the university, after very productive careers as professors, because they cannot find either grant support or institutional support for developing medicines at the university. Many of them leave research, and go to direct clinical trials for pharmaceutical companies. There could be no clearer indication of the need for more support for translational research. Practically-oriented research in medical school settings might then become more feasible. Our current system for translating discoveries into therapies is under enormous stress. Those who create predictive animal models of human disease are finding themselves in an increasingly hostile environment. Their years of experience are critical for the advancement of medicine in general. Yet they are facing serious difficulties both here in the United States and in Europe. In the United States we are putting an ever-increasing premium on the doctor who treats patients, rather than the doctor who creates new modes of treatment. In my community, a major academic medical institution was recently taken over by a Health Maintenance Organization. The entire faculty of Georgetown University Hospital was summarily relieved of tenure and given one-year employment contracts. A letter sent to faculty explained that the administration had determined that every dollar spent on research lost ten cents for the medical school, so research would not be encouraged. This takeover ended decades of work by people whose contributions we need to drive regenerative medicine forward. Yet it occurred without significant protest. It is thus clear that although we already have effective tools for creating therapeutic proteins, antibodies and cells, the infrastructure we need to make progress is under threat. Infrastructure is under threat in Europe for a different reason. There, the problem is funding for drug reimbursement. Successive administrations have come to power in Britain, Germany, France, and the Scandinavian countries promising increased support for medicine. They have usually failed to deliver it. Medical science thus finds itself with too few outlets for its great prowess. The bodies that fund our research have difficulty seeing this argument, because basic research funding is increasing. It is common to suppose that there is a direct link between an increasing budget for the National Institutes of Health and consequent medical progress. In reality, that budget is spent chiefly on fundamental research. Medical progress also requires an expansion of translational medical research, to shorten the path to innovative drugs. Professionals involved in hospital organizations must ensure that there will be room for tissue engineering within those institutions. We must make our arguments locally, because many decisions are made at that level. Yet there must also be national-level work. The sooner stem-cell research can be liberated from reliance on embryonic tissue, the sooner we will gain political freedom to pursue this vital area. What could be more compelling than using one's own cells to rebuild a younger version of one's body? Few people would have entertained such a dream twenty or thirty years ago. Yet already some of our conference participants have reprogrammed adult cells for multi-potential differentiation and implanted them in animals. They were then able to observe these cells growing in a new location. The Regenerative Medicine Society should provide an additional voice to articulate our priorities. It might be said that Washington D.C. already has enough organizations pressing for more enlightened public policies. Our answer is: No, regenerative medicine does not yet have enough voices. Many voices have more impact on the political process than one or two. For this reason it is advisable never to do anything alone in Washington. The more help that other societies can offer, the better. Allies can help make arguments to different constituents. They can also provide political protection. The Regenerative Medicine Society will be an important new voice, but we have to make our arguments within all relevant professional societies. Academic scientists and those trying to help patients directly have many problems in common. Both must decide how to pay for translating new knowledge into medicine. Ultimately, that decision will affect the health of much of the world's population. Businesses have to be hard-headed. Companies do not develop treatments they cannot sell. That is why there are few treatments for diseases of the developing world. It is also why the patent system is so important. Economic realities usually ensure that no patent means no drug. Only under a strong system of intellectual property protection can commercial enterprises continue to justify the substantial investment needed to develop new drugs. The health of our economic system is also essential for the development of regenerative medicine. We should not assume that the relatively favorable conditions that exist in the United States today will persist for ever. We have only to look at what happened to our European and Japanese counterparts to see that a good situation can quickly turn into a bad one. Since their economies turned for the worse, they have had increasing difficulties justifying investment. Such difficulties bear on how much we are willing to pay for health. They also relate to how we apportion that amount between preventive care and treatment, and between medical services and pharmaceuticals. These are political issues that are worth fighting for. ### This essay is an edited version of a presentation given at the First Annual Conference on Regenerative Medicine. It is reprinted with permission from William Haseltine, Ph.D., Chairman and CEO of Human Genome Sciences. The conference was held in Washington D.C. in December 2000. ### << Previous Next >> [ View All Perspectives ] |
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