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LE Magazine July 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.
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| We do analyses for one disease at a
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. |
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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?
WH: No.
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.
LEF: Right.
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.
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