Today's date:
  Fall 2004

Regenerative Medicine: Where the Genetic and Info Revolutions Converge

William Haseltine, one of America's leading molecular biologists, is chairman and chief executive officer of Human Genome Sciences, the firm that is developing a variety of gene-based pharmaceutical products. He is also editor in chief of E-BIOMED: The Journal of Regenerative Medicine.

Rockville, Md.--The completed mapping of the human genome is an historic feat comparable to sending men to the moon. But the actual feat will have little practical impact on our lives unless we can characterize and isolate the useful genetic information in the genome. After all, there was little utility in the moonlanding itself; so far that has come from the associated advances which enabled today's satellite communications.

Genes are stored in fragmentary form in the human genome. Three percent of the genome is genetic information; 97 percent is packaging. The cell is smart enough to assemble that 3 percent for you to build and maintain your body.

When we know, in effect, what our cells know, health care will be revolutionized, giving birth to "regenerative" medicine--ultimately including the prolongation of life by regenerating our aging bodies with younger cells.

Thanks to the convergence of the information and genome sciences revolution, we are already on the threshold of isolating and characterizing virtually all useful genes. The enormous advances during the last decade of the 20th century in molecular biology, laboratory instrumentation and computational capacity have made this possible.

In molecular biology we have learned how to utilize genes by moving them from one organism to another, by altering them and changing the effect of their protein products. Instrumentation advances have allowed us to manipulate genes in parallel and then to create assembly lines, speeding up the rate of biological discovery 10,000 times. Finally, the advances in both computer software and hardware have enabled the storage, retrieval and quick interface of very large amounts of data--essentially what the Internet does for information at large.

Already under way for about four years is the development of new and more efficient drugs to treat disease based on genetic knowledge. Up to this point, pharmaceutical treatment had been a little like wild cat oil prospecting--digging hopefully for knowledge about migraine headaches or cholesterol based on the extant medical literature. Finding a starting point for drug development was always a hit and miss proposition.

Now, by isolating and characterizing human genes and the way they are actually used in different states of cancer or heart disease or schizophrenia, a systematic means to identify where and when to intervene with drug treatment has been opened up.

This does not mean curative drugs will be available over the counter tomorrow. The process is long and difficult. First, the gene and what it does have to be identified. Then, it has to be shown that, when you perturb that gene, you get the desired effect and only the desired effect. The drug has to be compatible with your body, it has to get in, get around and get out of your body and only stay for the right amount of time. We have to cope with the complication that the body metabolizes the drug you take in, like a rocket that bursts into fireworks, and spreads it all around.

All this has to be taken into account and tested through trials that prove the drug safe and effective. But the experience so far is positive. Within six to seven years, we will see a whole range of new drugs for diseases that have no other treatment today.

Our company, to take one exciting example, has discovered a "receptor" on a protein on the surface of cells that is important for the functioning of the immune system. If you don't have this receptor, it appears you are less susceptible to inflammation and viral infections. Based on our discovery, a study by the National Institutes of Health has shown that people who are defective--that is, who lack this receptor--not only don't seem to have any adverse health consequence but, indeed, are not infectible by HIV. A further study in 1999 showed that an unusual form of the herpes virus, like AIDS and probably other viruses, uses this handle to infect a cell.

With this new information in hand, drugs can be developed to inhibit inflammation for viral infection--possibly even to stop AIDS.

It is the action of genes on a single cell and within that cell that leads to the fertilized egg's production of every organ and tissue in our whole body. We are formed by the action of our genes and, as a mature organism, we maintain ourselves for a long time. Under ideal circumstances, that would be 120 years or more.

And we don't do this statically, but by replacing our parts. Everyone knows that the skin we have today is different than our skin tomorrow. And that is true for almost all parts of our bodies, including, we now realize, the brain as well.

Though there are defects, such as among those who can't clot their blood, our bodies are reasonably effective at repairing themselves.

This understanding is key to the regenerative medicine of the future. Once we have full knowledge of the signals that make this process work, we can create a new medicine.

I see four phases of the development of regenerative medicine:

1 GENE DRUGS. The use of our genes, proteins and antibodies--human components themselves--as the new pharmaceuticals. In this way we will be able to use our body's own substances to rebuild, repair and permanently restore ourselves rather than rely on some chemical crutch.

If you now take a pill every day to lower your cholesterol, wouldn't it be much better to have a treatment of your own proteins that permanently lowers the cholesterol level?

As a result of the first revolution in bioengineering we already have medicines--such as insulin, which is a tiny human part made from the gene of a person and used as a drug--that are essentially body parts. The remarkable fact about insulin--one person's can be used by everyone--is that it shows how humans are essentially interchangeable at the gene and protein level.

Knowing this, the first phase of regenerative science will be to use our own genes, proteins and antibodies as medicines to rebuild our bodies from the inside out. All we are doing, really, is stimulating the body's inherent regenerative capacity.

An example: We are testing methods of using a natural protein to enhance the healing of skin for patients with large open wounds or for chemotherapy patients with ulcers in their mouths. This treatment is based upon the cell signal to repair damaged skin (when cells know they don't have a neighbor, they turn on a receptor that grows new cells). A normal, healthy body doesn't have these receptors; they only appear when there is a problem.

We will see the first set of these new drugs emerging in two to three years. By 10 years, it may be 15 percent of our medicine. In 20 years, it will be at least half of all our medicines.

DRUG DELIVERY | A parallel revolution is taking place in delivering such drugs to our bodies. The full power of modern materials science. Already underway are technologies enabling drug inhalation for large molecules that look like minuscule whiffle balls, enabling the prescribed drugs to reach into the deep recesses of the lungs. And there are microchips implanted in your body that will release the right dose of a given drug on schedule.

2 ORGAN REPLACEMENT. The next phase of regenerative medicine, already with us in early form, involves engineering organs outside the body so they can be implanted. This has already been done for bladders.

If a person has bladder cancer, the bladder can be removed. A matrix made of material similar to cat-gut is used as a kind of scaffolding to which snippets of the cancer patients' own cells are attached. These cells grow into a thin sheet of muscle and lining cells that are stretched over the scaffolding, where they take hold and grow as the cat-gut-like material disintegrates. That new bladder can then be implanted in the patient with out any danger of rejection because it is an "auto-transplantation." In this way arteries, ligaments, new pieces of bone and tracheas are being created.

Within 5 to 10 years replacement kidneys will be possible; within 10 to 15 years liver replacement will be a reality. Eventually, entire hearts can be made for reimplantation. In 20 to 30 years, organ replacement will be a major part of medicine.

3 RESETTING THE GENETIC CLOCK. The ultimate transgenic medical treatment, only now a gleam in the eyes of scientists made possible by the cloning technology begun by Ian Wilmut and Dolly the sheep, is resetting the genetic clock.

This involves supplanting aging adult cells with younger cells grown from "stem cells"--the originating cells for all body functions. There is one stem cell, for example, for blood. Another for the skin, the brain and so on.

It will be possible in the future to take a cell from a person, reset its genetic clock and then move it to stem cell status for brains or muscles--in effect enabling our bodies to rebuild themselves in a younger form. The fundamental process that drives aging is the aging of stem cells that replace tissues worn down by living--reactive oxygen interacting with DNA changing its chemical nature.

The average life of an essential gene in an essential stem cell is about 50 years. But there is nothing intrinsic in that age; it is a result of our body's evolutionary response to its environment. If we can regenerate stem cells--and get rid of the old cells that turn into cancer--then we can prolong life.

The current medical practice of bone marrow transplants shows that this idea is not at all far fetched. In that process, an older person with cancer whose ability to form new blood cells has been damaged by chemotherapy often receives marrow donated from someone younger. In effect that person is an age-hybrid, with 50- to 60-year-old bodies, but with blood-derived tissues that are only 20 or 25 years old.

In short, rather than continually regenerate our body with aging stem cells, in the future we can regenerate them with our own younger cells.

I expect this third wave of regenerative medicine to come into being no sooner than the year 2050.

4 INTEGRATE NON-BIOLOGICAL SUBSTANCES WITH OUR BODIES. Already, an older person is a bit of metal with a joint in his leg, a bit of plastic with a valve in his heart, a bit of nylon with a new blood vessel, a bit of an electronic device with a pacemaker or hearing aid.

Miniaturization and nano-technology (molecular-sized machines) will further enable the creation of prosthetic devices fully compatible with our bodies. One exciting field in rapid development today is neuro-prosthesis where brain implants pick up mental intent and can translate that signal into the movement of muscles independent of the spinal cord.

Already, implants in the brains of monkeys enable them to move robots in the next room--or it could be the next continent. This will make it possible for people to move through bypassing the spinal cord--which may have been ruptured or otherwise injured--altogether.

Though less than a decade in the works, it is already clear that the combination of the genetic and information revolutions will change medicine within the next 50 years more than in the past several centuries.