Regenerative Medicine: A Future Healing Art

William A. Haseltine
Bill Haseltine
William A. Haseltine Chair and CEO - ACCESS Health International, Trustee - The Brookings Institution

December 1, 2003

The era of regenerative medicine is upon us. Rapidly advancing medical knowledge is leading to the development of powerful new gene-based therapies that will transform medical practice, allowing most people to live much longer and healthier lives.

Unlike most medicines today, regenerative medicines use human cells and substances to regrow tissue. Early forms are already in use. Some 30 drugs based on human proteins are approved for sale in the United States, as are several therapies that contain human cells. But today’s protein and cell-based drugs are merely the harbingers of what is to come.

Over the past decade, the new science of genomics has made it possible to identify thousands of previously unknown human proteins. Thanks to high-speed, high-capacity laboratory robots, we can make those proteins in pure form, using standard biotechnology techniques. We can test their effects on human cells with relative ease and then evaluate the proteins that have potentially useful medical properties as possible cures. Today, many human-protein drugs identified through genomics are being evaluated in clinical trials.

There are four broad types of regenerative medicine: human substances (proteins and genes), cells and tissues, embryonic stem cells, and novel materials.

Human Substances

The first type of regenerative medicine involves the use of human proteins and genes as drugs. The proteins are generally made using recombinant DNA technology, sometimes known as gene splicing. Genes are chemical instructions that enable a cell to make a specific substance. If we transfer a functioning human gene into a cell that we can easily culture in large numbers, those cells will produce the desired human substance, often a hormone, in industrial quantities. Proteins made this way, unlike those extracted from human tissues, will not transmit infectious agents from a donor.

Current type 1 regenerative medicines include such important recombinant drugs as human insulin, interferon, human growth hormone, and erythropoietin, a substance that stimulates the formation of red blood cells. Because the body readily accepts another person’s purified substances, protein drugs made from one person’s gene can treat anyone. No major technical barriers remain to developing new human-protein drugs.

Some therapeutic proteins substitute for ones that patients cannot make themselves. Most patients with insulin-dependent diabetes, for example, now use recombinant human insulin to compensate for their inability to make insulin, thereby regaining control over the amount of sugar in their blood. Other therapeutic proteins supplement the body’s own inadequate production. Extra erythropoietin, for example, stimulates production of red blood cells in people undergoing chemotherapy for cancer and in people with kidney disease. Several types of supplemental recombinant interferon are now major pharmaceutical products. Interferon alpha is used to treat hepatitis and cancer; it stimulates the immune system to fight disease. Interferon beta treats multiple sclerosis, a disease in which a patient’s immune system erroneously attacks his or her brain and spinal cord. It blunts the immune system’s attack on the nervous system, easing patients’ symptoms and probably lengthening lives.

Many more of the thousands of human proteins revealed by genomics are likely to have profound medical effects. The Human Genome Project, an international effort funded by governments and private organizations, recently produced a map and a draft text of the entirety of our human genetic information, known as the genome. Although much work remains before a definitive version is available, the effort will in time place all human substances within our grasp.

The Human Genome Project produces data about genes in their stored form in our chromosomes. Recognizing genes in this stored form is difficult, and many thousands of genes, known to exist through independent investigations, have thus far eluded the project. Researchers at my company, Human Genome Sciences, focus on isolating the active form of genes—so-called messenger RNA—that is produced only in a cell that is using the gene. They then convert the messenger RNA to a stable chemical copy, called a cDNA, which they examine to learn which genes are active in a variety of healthy and diseased tissues. The approach offers a rapid route to regenerative medicines. Our cDNAs have already yielded genes and proteins that function as active therapeutics.

Having identified, for example, chemical signals that the body uses to stimulate the formation of new skin, we now manufacture one of those signal substances as a healing protein drug called repifermin. Repifermin’s demonstrated ability to heal leg ulcers is being further tested, and the drug is being evaluated as a treatment for chemotherapy-induced ulcers in the mouth and intestines.

Another Human Genome Sciences protein drug, called BLyS (pronounced “Bliss”), is an important, natural hormone that boosts blood levels of antibodies, specialized proteins that bind exceedingly tightly to a specific molecular target. We are testing BLyS as a treatment for diseases in which patients produce too few antibodies, making them more susceptible to disease.

Indeed, antibodies, an essential arm of the immune system, are themselves used as a form of type 1 regenerative medicine. Their ability to bind to a target tightly allows them to inactivate harmful substances in the body and makes them valuable for treating autoimmune illnesses like rheumatoid arthritis and Crohn’s disease, which are triggered by an overreaction of the immune system. Medicine can also create antibodies that bind to and activate specific receptors on cells. That binding property makes it possible to activate a receptor without using the natural protein that would normally bind to it. This is a sound strategy when the natural protein is unsuitable for use as a drug. For example, Human Genome Sciences has been approved to test in patients an antibody that binds to the so-called Trail 1 “death receptor” found on cancer cells. When a natural protein called Trail binds to the receptor, the cancer cells die. Trail itself cannot be used as a drug, but our antibody mimics its effects; it may become an important medicine for several types of cancer.

For some conditions, regenerative medicine will use genes themselves as medicines. Genes last indefinitely in cells, meaning that once a therapeutic extra gene is in place in a cell, the effects should last as long as the cell does—months or even years—thus eliminating the need for frequent medication. Several perplexing problems, however, still bedevil gene therapy, making its future somewhat uncertain. For example, it is a challenge to protect genes, once they are inserted, from the body’s defenses, and to direct them to the place in the body where they would do the most good. Although gene therapies have produced good results in clinical tests with a small number of patients, it could be many years before they are widely used.

Conventional, chemically-based drugs serve mostly as temporary supports for the body’s failing chemistry. They usually do not repair what is wrong. If a patient with a tendency to depression stops taking medication, for example, the depression returns. Nor do chemically-based drugs regenerate injured or worn tissues. Regenerative medicine, by contrast, has the potential to cure disease, because it can bring about long-lasting changes in the body that are tailored to a particular ailment. Regenerative medicines generally also have less toxic effects than chemical drugs, because they are based on natural substances. They are also less likely to cause dangerous side effects when used in combination with other drugs.

The many drugs based on human substances such as hormones, antibodies, and genes that are now being tested are only the beginning of what will become a far-reaching revolution.

Cells and Tissues

As we become comfortable using human substances as medicines, we are also starting to use human cells as medicine. In type 2 regenerative medicine, cells will be removed from the body, grown in culture, then reintroduced into patients.

Type 2 regenerative medicine is often referred to as a form of tissue engineering. The field evolved from reconstructive surgery, the rebuilding of damaged body parts. Tissue engineering takes two forms. One involves building an organ or tissue outside the body by combining human cells with appropriate materials, often a scaffold-like structure to provide support. The other involves growing suitable cells in laboratory flasks, then injecting them into a tissue needing repair. The cells can often find their own way to the sites where they are needed. Some of the human substances discovered in type 1 help in type 2, because they can direct cells to change, migrate, and divide.

Progress in tissue engineering is accelerating dramatically. The need for replacement organs and tissues is growing, driven in part by the aging of the population. Among older people, diseased or worn-out muscle, bone, cartilage, nerves, digestive systems, skin, and brain cells may all benefit from cell-based interventions. We can already culture many human cells, including elusive but powerful adult stem cells, outside the body. Adult stem cells have prized potential for healing, because they can renew themselves indefinitely.

The secret of growing many replacement tissues seems to lie in providing intricate scaffolds, foundations on which cells may grow. Several natural and synthetic substances are proving valuable for creating structures that mimic natural scaffolds, and we are rapidly learning how to use such structures to create working tissues.

Companies now use human cells to make artificial skin, a product that has considerably improved care of burn victims. Another firm prepares a cell-based therapy for joint repair from patients’ own cultured cells. Scientists can also grow new blood vessels in the laboratory, as well as cardiac muscle, corneas, and parts of the alimentary canal, the urogenital system, liver, and kidney. Clinicians are starting to implant these new tissues into patients.

Bone marrow transplants have for decades been used to regenerate marrow tissue destroyed by chemotherapy and radiotherapy. Surgeons rescue patients by transplanting replacement bone marrow stem cells, which migrate to suitable sites in the bones and permanently spawn new blood cells. This therapy gives hope that we will be able to develop many more adult stem cell therapies.

Indeed, bone marrow stem cells appear to have greater potential than anyone suspected, for they can apparently turn into other types of stem cells. Stem cells of various kinds are under investigation for repairing injuries to the spinal cord, bone, brain, and other organs. Brain stem cells are showing particular promise. Isolating enough stem cells is often a challenge, so bone marrow stem cells may play an important role as progenitors of multiple stem cell types.

Patients who receive medicines derived from cells that are not their own must sometimes be given immunosuppressive drugs to prevent rejection of the foreign cells. Yet not all types of tissue prompt immune rejection, so for some tissue transplants immunosuppressive drugs are unnecessary. Furthermore, banks of tissues with diverse immune characteristics will likely be established, making it possible to select a close match for any given patient’s tissue. Type 2 regenerative medicine therapies may well find widespread application within the next decade. Brain stem cells may find broad uses even sooner.

Eventually, many more types of stem cells will be in medical use. And developments in materials science suggest we will be able to use cells in more varied ways before long. Evolving fabrication techniques could soon make it possible to engineer scaffolds to a precision of a few atomic diameters. Materials made with such precision—comparable to that of the body itself—will offer much greater control over the growth of cells, and so will expand the range of conditions that cell-based medicine can treat.

Despite its promise, type 2 regenerative medicine remains limited by the difficulty of isolating and activating adult stem cells. To repair some tissues for which bone marrow or other adult stem cells are inapplicable or unavailable, we may have to turn to a more powerful type of cell, the embryonic stem cell.

Embryonic Stem Cells

The third type of regenerative medicine, which will be distinct both from the use of human substances as drugs and from tissue engineering as described so far, does not yet exist. Yet the key discoveries that will enable it to develop have already been made, so it will arrive in due course—if society permits.

The defining feature of type 3 regenerative medicine is embryonic stem cells, special cells obtained from very early-stage human embryos. These cells can develop into every major kind of cell in the body (more than 200 cell types exist in the body). They have already been coaxed into establishing cultures of many different kinds of potentially healing cells, including several types of nerve cells, heart muscle, skin cells, and certain immune-system cells. That virtuoso flexibility stands in contrast to the much more limited potential of most adult stem cells, which will probably be limited to only certain cell types.

Cultures of embryonic stem cells can be maintained for years, thus in principle overcoming the main obstacle slowing development of type 2 regenerative medicine—isolating and growing enough adult stem cells. Embryonic stem cells have extraordinary potential for repairing and regenerating damaged or worn-out organs.

Although mouse embryonic stem cells have long been known, the human version was found only in 1998. Which type of tissue these cells give rise to depends on which specific human substances they are exposed to as they grow. Researchers, however, have not yet established precisely how to make them turn efficiently and predictably into many of the specific cell types needed. This must be the key research goal for the future.

Embryonic stem cells have been used successfully to treat injury and illness in animals, including spinal cord injuries in rats. They have also shown promise treating rodents with conditions that mimic Alzheimer’s disease and Parkinson’s disease. Potential benefits are not restricted to the brain and nerve cells. Cells made from embryonic stem cells can survive in the pancreas and secrete insulin and even withstand attack by the mouse immune system well enough to reverse diabetes. Naturally, the hope is that the equivalent human cells will do the same for human patients.

Embryonic stem cells, like many adult stem cells, trigger an immune reaction when injected into an organism that is not a genetic match. Their use thus might depend, as a practical matter, on a powerful new biological technique known as nuclear transplantation, which was used in 1997 to produce Dolly, the cloned sheep.

Nuclear transplantation should in principle be able to produce early-stage embryos that are genetically identical to any patient’s cell sample, thus eliminating the difficulty of obtaining genetically compatible cells. In cloning animals, the nucleus from one cell of the creature is removed and transferred to an egg of the same species from which the nucleus has been removed. An electric shock causes the egg to start developing into an early embryo. Implanted in a womb, the embryo will sometimes develop into a cloned offspring genetically identical to the animal that supplied the original nucleus. But if the objective is to derive stem cells, the cells are extracted from the very early-stage embryo, which is not implanted into a womb.

The Dolly experiment proved two important points. One was that we can “reprogram” an adult cell so that its descendants can turn into any other type of cell in the body. Dolly also showed that nuclear transplantation can rejuvenate aging cells, setting back their internal “clock” so that they act like young cells once again—a process that might be used to rejuvenate aging human cells.

The idea of exploiting rejuvenation in medicine is not as remote as it might at first appear. Bone marrow transplant recipients are routinely given cells from a much younger person, and the cells thrive. Type 3 regenerative medicine that uses nuclear transplantation to produce matched embryonic stem cells could become an important part of the medical scene.

However, it is uncertain whether society will fully assist research into embryonic stem cells and nuclear transplantation any time soon. The Bush administration has restricted federal support for research on embryonic stem cells to a small set of established cell lines, which may or may not be medically useful. Because nuclear transplantation could be used to make a copy of a human being, some people oppose any use of that technique, including the therapeutic, not reproductive, uses that the vast majority of scientists envision for it. The Bush administration has supported attempts to ban any use of nuclear transplantation to create tissues that match those of a patient. Unless these positions are reversed, the United States will fall behind the rest of the world in these exceptionally promising areas.

Opposition to using embryonic stem cells derives from their origin in embryos, which are destroyed as cells are retrieved. Yet at this early stage of development the microscopic human embryo, consisting of perhaps less than 100 cells, has no heart, no brain, and no nervous system to feel pain. In vitro fertilization programs produce—and dispose of—thousands of such embryos every year in excess of those that women can carry to term. Often donors would be willing to volunteer an embryo otherwise destined for disposal to supply stem cells for healing the sick.

Nuclear transplantation is likewise a technique that people ought to be able to choose. Current attempts to prevent nuclear transplantation to produce human embryonic stem cells are retarding the development of medicines that could greatly enhance the quality of life, or save the lives, of potentially millions of people.

Novel Materials

Rapid progress in materials science underlies type 4 regenerative medicine, in which novel materials engineered to atomic-scale precision will integrate seamlessly with our own cells. Functioning microscopic devices and other structures produced by atomic-scale engineering will be able to meld with the body without causing rejection. In becoming part of us, these creations will provide the aged and sick with restored capabilities unthinkable with cells and human substances alone. Indeed, we can expect that they will surpass the body’s natural capabilities. The implications of atomic-scale engineering, or nanotechnology, are far-reaching. Medical applications will boost regenerative medicine far beyond anything we can achieve today.

The field will take time to mature, but its earliest beginnings can already be discerned. Physicians commonly implant steel or plastic hip joints, synthetic heart valves, and dacron blood vessels. Thousands of people hear with artificial cochleas within their inner ears.

What sort of substance can be made to fuse with the body? The answer is surprisingly simple: any material that persists in the body and does not attract the attention of the immune system. That defensive system, composed of specialized blood cells as well as antibodies, will reject materials that it recognizes as chemically different from the body’s natural components. Yet it will accept those that are chemically similar and will even accept some materials that do not resemble our components, provided they carry no chemical red flags to attract attention.

Devices and prostheses that can fuse with the body must be made of carefully selected materials. Experiments have identified several that are suitable, including certain minerals and the alloyed metals used in shoulder and hip replacements, as well as some plastic-like substances that eventually dissolve in the body, such as those used during surgery as temporary fastenings.

Recent achievements in micromechanical engineering, electronics, and materials science hold much promise for the future of implanted devices. For example, at the heart of spy satellites are coin-sized devices that contain more than a million individual detectors. In medical applications, they could be used, and are being tested, as artificial retinas.

Although society has been slow to put its best efforts into helping the disabled, new avenues appear promising. Researchers have amplified signals in the brains of patients and translated them into movements of a mechanical arm. This progress suggests that signals from a paralyzed patient’s brain could, with appropriate feedback, achieve fine control over muscles, thereby bypassing injuries of the spinal cord.

It has been speculated that more refined implants could, in time, enhance our mental capacities. Prostheses that integrate with the nervous system might even bolster our memory and our analytical abilities. By connecting to external computers, such prostheses could fundamentally change our relationship to the material world. The ethical and philosophical implications of such changes are profound, although society has yet to pay much attention to such possibilities.

Given the advanced nature of such revolutionary technologies, it may be many years before prostheses engineered to atomic accuracy can take a crucial role in treating damage to the nervous system and other body systems. In the meantime, however, advances in atomic-scale engineering will accelerate type 2 and 3 regenerative medicine.

From Regeneration to Rejuvenation

Chemical drugs have no effect on aging. Remarkably, however, regenerative medicines may very well be able to check the changes of aging. After all, they are the very substances and cells that steer our development and maintain and repair our bodies. They can stimulate the regrowth of aging tissues.

Regenerative medicine can already restore complex tissues. Repifermin, as noted, forms new skin. Recombinant human growth hormone promotes muscle growth. Drugs to regenerate skin and muscles could make an enormous difference to many of us as we age.

No single drug will treat all aspects of aging. But we can envisage a range of regenerative medicines for different symptoms. Human substances are now in testing for boosting the immune system, strengthening bones, repairing cartilage, and a variety of other purposes. As regenerative medicine advances, we will learn how to restore an ever-widening range of worn-out organs and tissues.

The choices society makes could speed—or slow—the arrival of these revolutionary therapies. Attempts to limit health care costs, in particular to contain the cost of pharmaceuticals, could strangle the emerging biotechnology industry, with disastrous effects for regenerative medicine.

Society faces difficult decisions about how to pay to translate advances in scientific knowledge into regenerative medicine. My own view is that we must move forward with maximum vigor to develop therapies that minimize human suffering. In the end, people will want to, and should be allowed to, make the choices that will give them happier, more productive, and longer lives.

Regenerative medicine may become the most powerful tool available to improve the human condition. Science has shown it can achieve the goal of using the body’s own substances and cells to repair, restore, and rejuvenate it. Once society is fully aware of the staggering potential of regenerative medicine, it is unlikely to decline the promise that it offers.