Dr. William Haseltine on Regenerative Medicine, Aging and Human ImmortalityJuly 2002
LEF: Did you coin the term "regenerative medicine?"
WH: I did. I meant it to describe an exciting and emerging field. Phase One of regenerative medicine is the use of natural human substances such as proteins and antibodies as drugs. Medicine has in the past been dependent upon plants. More recently, synthetic chemicals have become important. We now have in our hands the information and the genes to change medicine again. In the future, many new medicines will be human substances. Those substances, as I mentioned previously, are mostly interchangeable among the members of our species. We can take one gene, make one protein, then distribute it as a drug.
Human substances used as drugs have the ability to repair, rebuild and restore injured, diseased or worn-out tissues. It is conceivable that over time we will gain enough information to control the behavior of every cell in our bodies. Once we have achieved such mastery, we will be able to heal any disease. We will be able to cause tissues to rebuild themselves. On the other hand, when our natural tissues run amok-for example, when they produce too much of a growth factor or of a necrosis factor-we will short-circuit the destruction process.
Growth hormone is an interesting example of a human protein used as a drug. Too little is not healthy, nor is too much. A deficit can be overcome by injection of recombinant protein. A surfeit can be amended with antibodies against growth hormone.
Another such example is the B-Lymphocyte Stimulator referred to earlier. Too little results in patients developing immune deficiencies. This may be corrected by supplying the protein. Too much induces patients to develop autoimmune diseases, such as systemic lupus erythematosus and some forms of rheumatoid arthritis. We have begun trials of an antibody drug based on this work.
In summary, we are attempting to create a new type of medicine in which our organs and tissues are restored to normal function with exogenous but natural factors.
LEF: If you want to lower levels of TNF (Tumor Necrosis Factor) or growth hormone, don't you think the best way to do it would be to reduce transcription [conversion to the mRNA form] of the offending gene, rather than to try to clean it up with antibodies?
WH: Yes, but we cannot do that yet. I am not a fan of drugs that perturb regulation of transcription [control of the process whereby mRNA forms of genes are produced]. Signal transduction [transfer of a signal from the outside of a cell to the interior of a cell] and transcription initiation are typically mediated by a combination of proteins acting in concert, not by one protein with unique specificity. It is much harder to disrupt such multi-protein (combinatorial) systems than it is to disrupt one-to-one cause-and-effect systems, such as signals on the outside of cells.
LEF: There is a company called Sangamo (ticker symbol: SGMO) that claims it can turn on or turn off genes. Do you disagree with their approach?
WH: It is possible to achieve some degree of control. There will always be exceptions. In general I think that route is much harder than ours.
LEF: You said signaling proteins can tell cells to live or to die. Can you discuss this aspect of regenerative medicine?
WH: In addition to stimulating repair and growth, regenerative medicine may also be used to bring about the regression of unwanted cells, or in some cases, their death. One might want to kill cells that are growing inappropriately. Some of our drugs stop cells from growing. Others are monoclonal antibodies that inhibit specific disease-causing activities.
LEF: So, for example, instead of using tamoxifen to kill breast cancer cells, you might use an antibody to the estrogen receptors in the breast?
WH: Herceptin is such an antibody. It can be used in addition to tamoxifen. One great advantage of drugs that are natural substances is that they seem to have additive anticancer effects without additive toxicities.
LEF: Very good.
WH: Phase Two of regenerative medicine is tissue engineering. When an organ cannot be restored to normal health through the use of natural substances, it must be replaced. Currently, the only means to replace an organ is by transplantation. A new field is now developing in which organs are grown for implantation. This field is an outgrowth of reconstructive surgery. It is now possible to build new bladder and to grow cartilage and bone for implantation. Blood vessels, heart valves and trachea are on the way. I recently wrote an introduction for a new book in the field (Methods of Tissue Engineering, 2nd Ed., Ed. by Anthony Atala and Robert Lanza, Academic Press, 2001). It is a fascinating compendium of what can be achieved today with tissue engineering.
The early development of tissue engineering is being conducted with adult cells harvested from the patient. The field holds great promise. The difficulty is that, unlike human proteins and antibodies, human cells are individual-specific, and are likely to remain so for many years. That means that tissue engineering is likely to be performed at the hospitals where the patients are. Tissue samples will be harvested from patients and worked on by technicians at a regional hospital. That is a different kind of business from ours.
LEF: Tissue engineering is really the only way to fill in the gap between the supply of the cells, tissues and organs we need for transplant today, and the demand.
WH: That is true. We are still in the early days. When we are able to combine advances in materials science, cell biology, and our knowledge of cell growth and differentiation, the result will be a very exciting area.
LEF: Do you have some direct initiatives in this area?
WH: Human Genome Sciences does not, but I am personally very involved in this field. I am President of the Society for Regenerative Medicine. Anthony Atala, a leading practitioner of tissue engineering, is Vice-President. I am also Editor-in-Chief of a journal called e-Biomed: The Journal of Regenerative Medicine. We hold an annual meeting in Washington, D.C.
LEF: What about the company that's building an artificial heart?
WH: I am also involved in that program. So far, it is more moral encouragement than anything real. Should the organizers need growth factors, however, we are in a position to help them.
LEF: Okay. Let's talk about the third stage of regenerative medicine.
time. In one case, we were interested
in diseases that could be treated by
stimulating the immune system-
either cell-mediated or antibody
immune responses. We examined the
ability of our set of 10,000 proteins
to influence those processes. We
have found several proteins that
influence immune system function,
which then became candidate drugs.
WH: Phase Three of regenerative medicine involves the use of stem cells. This takes us from strictly regenerative to rejuvenative medicine.
Rejuvenative medicine can be done in two ways.
The first is by building younger tissues or organs for implantation. We can replace older tissues and organs with younger versions made from a patient's own cells. That would involve regressing adult cells to an embryonic state, then progressing them to differentiated states suitable for organ regeneration.
Second, rejuvenative medicine can be done by direct implantation of lineage-specific stem cells, or of stem cells capable of becoming lineage-specific or organ-specific. We know this works with hematopoietic [blood-forming] stem cells. There is some preliminary evidence that it may work for brain stem cells as well.
There is a tremendous amount to be learned at a fundamental level before stem-cell-based medicine can become a practical reality. For that reason I think it is not appropriate for most companies to invest in such research. It is appropriate for governments and not-for-profit research foundations to support it. Such research will have its major effect 20 to 30 years from now. In that respect the field resembles the War on Cancer, which the government launched in 1971. For almost 15 years, it remained just a government program. The effects on the biotechnology industry were not felt until the 1980s. I think the same will be true of stem cell research. With a few exceptions, the field is not generally ready for clinical applications.
LEF: Given that perspective, are you disappointed with the Bush Administration's decision about stem cell research?
WH: I think the decision is unfortunate. Any policy that presupposes what is or is not worth pursuing, that limits the potential of research, is likely to be unwise. There are too many unknowns and too many directions that must be pursued. If we had decided in the early 1970s not to pursue the War on Cancer, we would not be enjoying many of the benefits of modern medicine. I hope the Administration's restrictive policy on stem cells will be reconsidered. It could haunt future generations.
The other consequence of the President's approach is that research in Europe, Japan and other countries may jump ahead of research here. That would be unfortunate. The United States has a strong research foundation and strong research leadership. A human tragedy might also result. Our best scientists are eager to work on stem cells. Those scientists might decide to work in some other, less productive field, or leave the United States altogether.
LEF: Do you have any in-house stem cell effort?
LEF: Your approach, as I understand it, is to attack one disease and one
disability at a time. But many of these diseases and disabilities arise from the aging process. Larry Ellison, one of the world's richest men, seems very interested in attacking aging directly, and it seems to me that if he and others succeed in that regard, it might make some of the things that you're trying to do obsolete.
WH: I would be delighted! I agree that many medical treatments might be made obsolete by some general and systematic solution to aging. Many of the conditions that we are working on are consequences of aging. Should the fundamental aging clock be stopped, or indeed reversed, the need for most of these medications would evaporate. That would be a happy day indeed.
LEF: Do you see the possibility that Human Genome Sciences will mount an attack on aging itself anytime soon?
WH: We will not pursue that goal directly for some time. We are engaged in, as you correctly pointed out, treating many of the symptoms of aging, with a series of very specific interventions. That is something real and tangible. Whether we, in our lifetimes, can stop or reverse the fundamental process of aging, other than through understanding the behavior of stem cells, is highly questionable.
I am sure, however, that we will find many new drugs using the methods we have.
LEF: Have you heard of the gene chip experiments that are being done to study changes in gene expression during aging?
WH: Yes, I have.
LEF: I just interviewed Dr. Stephen Spindler of LSG Sciences. His recent paper in the Proceedings Of The National Academy Of Sciences ("Genomic Profiling of Short- and Long-Term Caloric Restriction: Effects in the Liver of Aging Mice" PNAS volume 98, pp. 10630-10635, 2001) showed that, as mice get older, only 46 genes change in expression in the liver, and most of those changes can be reversed with caloric restriction(CR).
WH: I am familiar with that work. The question, however, is, How long will those old mice live?
LEF: Well, we know that CR extends life span quite a bit, including maximum life span.
WH: It does so in mice.
LEF: Not only in mice, but also in rats, fleas, spiders and in all kinds of other creatures, too.
WH: But not necessarily in humans.
LEF: Well, two long-term CR studies in monkeys look as if the maximum life spans of the monkeys may be extended as well.
WH: People are very unlikely to restrict their caloric intake. A practical solution might be to find a gene whose expression, when modified, produces the same effects as caloric restriction. We recently discovered a gene that prevents pre-fat cells from developing into fat cells.
Several years ago, working with Glaxo-SmithKline and their academic partners, we found a receptor involved in appetite called the orexin receptor, and orexin itself, a peptide hormone. Orexin and its receptor control pain and hunger.
LEF: We're very interested in your viewpoint about human immortality. Could you please tell us what your view is on this subject?
WH: In the past few years it has become possible for the first time to construct a scenario in which humans may become immortal: by the systematic replacement of stem cells.
Death is not an intrinsic property of life. Life is intrinsically immortal. Our germ cells are the decedents of a four-billion-year old, unbroken chain of cell divisions. The molecule that determines our structure and function, our DNA, has conveyed the basis of life continuously. There is no reason why DNA
cannot continue to convey the basis of life for another four billion years. Nothing about life necessitates death.
One theory of aging is that the stem cells in an individual age and eventually fail to reproduce. If stem cell death is the predominant driver of aging, then the solution is to replace old stem cells with young. That hypothesis will be tested, first in animals, and if results are positive, in humans.
LEF: Are you familiar with research being done at Advanced Cell Technology?
WH: I am familiar with some of the work that company is doing.
LEF: Are you familiar with their demonstration that they can use therapeutic cloning to reverse the aging clock?
WH: They recently published a paper in the journal I edit showing that this does not yet work in the case of humans.
Development proceeds to a certain point-to about six cells-but not further. Until such time as it can be shown that the cloned embryo can develop past the 6-cell stage to the blastocyst stage, I think the jury is still out. It may be possible some day. That is one of the reasons we need many groups active in this area.
LEF: Going back to how stem cells might be used to eliminate aging, have you considered that there may be old cells around that are not dead, and therefore cannot simply be replaced, but are nevertheless misbehaving?
WH: That is possible. One way to address that possibility would be to introduce drug resistance markers into the new stem cells. Once those stem cells have displaced enough of the previous ones, the old cells could be killed.
LEF: Yes, that could be done.
WH: The strategy would depend on a very thorough and systematic replacement of the existing cells. However, we do not know enough about the fundamental processes of aging. The process of stem cell death may be only part of the answer.
WH: For the first time, though, it is conceptually possible to chart a path to human immortality. Whether that path will lead to success, nobody yet knows.
LEF: Has anyone criticized you for even thinking about things like that?
WH: I do not believe people should be criticized for thinking.
LEF: Very good. Thank you for a refreshing and forthright interview.
WH: Thank you.