"The Basics
About Stem Cells."
by Maureen L. Condic
In August of last year, President Bush approved
the use of federal funds to support research on a limited number
of existing human embryonic stem cell lines. The decision met
with notably mixed reactions. Proponents of embryonic stem cell
research argue that restricting federal funding to a limited number
of cell lines will hamper the progress of science, while those
opposed insist that any use of cells derived from human embryos
constitutes a significant breach of moral principles. It is clear
that pressure to expand the limits established by the President
will continue. It is equally clear that the ethical positions
of those opposed to this research are unlikely to change.
Regrettably, much of the debate on this issue
has taken place on emotional grounds, pitting the hope of curing
heartrending medical conditions against the deeply held moral
convictions of many Americans. Such arguments frequently ignore
or mischaracterize the scientific facts. To arrive at an informed
opinion on human embryonic stem cell research, it is important
to have a clear understanding of precisely what embryonic stem
cells are, whether embryonic stem cells are likely to be useful
for medical treatments, and whether there are viable alternatives
to the use of embryonic stem cells in scientific research.
Embryonic development is one of the most fascinating
of all biological processes. A newly fertilized egg faces the
daunting challenge of not only generating all of the tissues of
the mature animal but organizing them into a functionally integrated
whole. Generating a wide range of adult cell types is not an ability
unique to embryos. Certain types of tumors called teratomas are
extraordinarily adept at generating adult tissues, but unlike
embryos, they do so without the benefit of an organizing principle
or blueprint. Such tumors rapidly produce skin, bone, muscle,
and even hair and teeth, all massed together in a chaotic lump
of tissue. Many of the signals required to induce formation of
specialized adult cells must be present in these tumors, but unlike
embryos, tumors generate adult cell types in a hopelessly undirected
manner.
If a developing embryo is not to end up a mass
of disorganized tissues, it must do more than generate adult cell
types. Embryos must orchestrate and choreograph an elaborate stage
production that gives rise to a functional organism. They must
direct intricate cell movements that bring together populations
of cells only to separate them again, mold and shape organs through
the birth of some cells and the death of others, and build ever
more elaborate interacting systems while destroying others that
serve only transient, embryonic functions. Throughout the ceaseless
building, moving, and remodeling of embryonic development, new
cells with unique characteristics are constantly being generated
and integrated into the overall structure of the developing embryo.
Science has only the most rudimentary understanding of the nature
of the blueprint that orders embryonic development. Yet, recent
research has begun to illuminate both how specific adult cells
are made as well as the central role of stem cells in this process.
The term "stem cell" is a general one
for any cell that has the ability to divide, generating two progeny
(or "daughter cells"), one of which is destined to become
something new and one of which replaces the original stem cell.
In this sense, the term "stem" identifies these cells
as the source or origin of other, more specialized cells. There
are many stem cell populations in the body at different stages
of development. For example, all of the cells of the brain arise
from a neural stem cell population in which each cell produces
one brain cell and another copy of itself every time it divides.
The very earliest stem cells, the immediate descendants of the
fertilized egg, are termed embryonic stem cells, to distinguish
them from populations that arise later and can be found in specific
tissues (such as neural stem cells). These early embryonic stem
cells give rise to all the tissues in the body, and are therefore
considered "totipotent" or capable of generating all
things.
While the existence of early embryonic stem cells
has been appreciated for some time, the potential medical applications
of these cells have only recently become apparent. More than a
dozen years ago, scientists discovered that if the normal connections
between the early cellular progeny of the fertilized egg were
disrupted, the cells would fall apart into a single cell suspension
that could be maintained in culture. These dissociated cells (or
embryonic stem cell "lines") continue to divide indefinitely
in culture. A single stem cell line can produce enormous numbers
of cells very rapidly. For example, one small flask of cells that
is maximally expanded will generate a quantity of stem cells roughly
equivalent in weight to the entire human population of the earth
in less than sixty days. Yet despite their rapid proliferation,
embryonic stem cells in culture lose the coordinated activity
that distinguishes embryonic development from the growth of a
teratoma. In fact, these early embryonic cells in culture initially
appeared to be quite unremarkable: a pool of identical, relatively
uninteresting cells.
First impressions, however, can be deceiving.
It was rapidly discovered that dissociated early embryonic cells
retain the ability to generate an astounding number of mature
cell types in culture if they are provided with appropriate molecular
signals. Discovering the signals that induce the formation of
specific cell types has been an arduous task that is still ongoing.
Determining the precise nature of the cells generated from embryonic
stem cells has turned out to be a matter of considerable debate.
It is not at all clear, for example, whether a cell that expresses
some of the characteristics of a normal brain cell in culture
is indeed "normal"—that is, if it is fully functional
and capable of integrating into the architecture of the brain
without exhibiting any undesirable properties (such as malignant
growth). Nonetheless, tremendous excitement accompanied the discovery
of dissociated cells’ generative power, because it was widely
believed that cultured embryonic stem cells would retain their
totipotency and could therefore be induced to generate all of
the mature cell types in the body. The totipotency of cultured
embryonic stem cells has not been demonstrated and would, in fact,
be difficult to prove. Nonetheless, because it is reasonable to
assume embryonic stem cells in culture retain the totipotency
they exhibit in embryos, this belief is held by many as an article
of faith until proven otherwise.
Much of the debate surrounding embryonic stem
cells has centered on the ethical and moral questions raised by
the use of human embryos in medical research. In contrast to the
widely divergent public opinions regarding this research, it is
largely assumed that from the perspective of science there is
little or no debate on the matter. The scientific merit of stem
cell research is most commonly characterized as "indisputable"
and the support of the scientific community as "unanimous."
Nothing could be further from the truth. While the scientific
advantages and potential medical application of embryonic stem
cells have received considerable attention in the public media,
the equally compelling scientific and medical disadvantages of
transplanting embryonic stem cells or their derivatives into patients
have been ignored.
There are at least three compelling scientific
arguments against the use of embryonic stem cells as a treatment
for disease and injury. First and foremost, there are profound
immunological issues associated with putting cells derived from
one human being into the body of another. The same compromises
and complications associated with organ transplant hold true for
embryonic stem cells. The rejection of transplanted cells and
tissues can be slowed to some extent by a good "match"
of the donor to the patient, but except in cases of identical
twins (a perfect match), transplanted cells will eventually be
targeted by the immune system for destruction. Stem cell transplants,
like organ transplants, would not buy you a "cure";
they would merely buy you time. In most cases, this time can only
be purchased at the dire price of permanently suppressing the
immune system.
The proposed solutions to the problem of immune
rejection are either scientifically dubious, socially unacceptable,
or both. Scientists have proposed large scale genetic engineering
of embryonic stem cells to alter their immune characteristics
and provide a better match for the patient. Such a manipulation
would not be trivial; there is no current evidence that it can
be accomplished at all, much less as a safe and routine procedure
for every patient. The risk that genetic mutations would be introduced
into embryonic stem cells by genetic engineering is quite real,
and such mutations would be difficult to detect prior to transplant.
Alternatively, the use of "therapeutic cloning"
has been proposed. In this scenario, the genetic information of
the original stem cell would be replaced with that of the patient,
producing an embryonic copy or "clone" of the patient.
This human clone would then be grown as a source of stem cells
for transplant. The best scientific information to date from animal
cloning experiments indicates that such "therapeutic"
clones are highly likely to be abnormal and would not give rise
to healthy replacement tissue.
The final proposed resolution has been to generate
a large bank of embryos for use in transplants. This would almost
certainly involve the creation of human embryos with specific
immune characteristics ("Wanted: sperm donor with AB+ blood
type") to fill in the "holes" in our collection.
Intentionally producing large numbers of human embryos solely
for scientific and medical use is not an option most people would
be willing to accept. The three proposed solutions to the immune
problem are thus no solution at all.
The second scientific argument against the use
of embryonic stem cells is based on what we know about embryology.
In an opinion piece published in the New York Times ("The
Alchemy of Stem Cell Research," July 15, 2001) a noted stem
cell researcher, Dr. David Anderson, relates how a seemingly insignificant
change in "a boring compound" that allows cells to stick
to the petri dish proved to be critical for inducing stem cells
to differentiate as neurons. There is good scientific reason to
believe the experience Dr. Anderson describes is likely to be
the norm rather than a frustrating exception. Many of the factors
required for the correct differentiation of embryonic cells are
not chemicals that can be readily "thrown into the bubbling
cauldron of our petri dishes." Instead, they are structural
or mechanical elements uniquely associated with the complex environment
of the embryo.
Cells frequently require factors such as mechanical
tension, large scale electric fields, or complex structural environments
provided by their embryonic neighbors in order to activate appropriate
genes and maintain normal gene–expression patterns. Fully
reproducing these nonmolecular components of the embryonic environment
in a petri dish is not within the current capability of experimental
science, nor is it likely to be so in the near future. It is quite
possible that even with "patience, dedication, and financing
to support the work," we will never be able to replicate
in a culture dish the nonmolecular factors required to get embryonic
stem cells "to do what we want them to."
Failing to replicate the full range of normal
developmental signals is likely to have disastrous consequences.
Providing some but not all of the factors required for embryonic
stem cell differentiation could readily generate cells that appear
to be normal (based on the limited knowledge scientists have of
what constitutes a "normal cell type") but are in fact
quite abnormal. Transplanting incompletely differentiated cells
runs the serious risk of introducing cells with abnormal properties
into patients. This is of particular concern in light of the enormous
tumor–forming potential of embryonic stem cells. If only
one out of a million transplanted cells somehow failed to receive
the correct signals for differentiation, patients could be given
a small number of fully undifferentiated embryonic stem cells
as part of a therapeutic treatment. Even in very small numbers,
embryonic stem cells produce teratomas, rapid growing and frequently
lethal tumors. (Indeed, formation of such tumors in animals is
one of the scientific assays for the "multipotency"
of embryonic stem cells.) No currently available level of quality
control would be sufficient to guarantee that we could prevent
this very real and horrific possibility.
The final argument against using human embryonic
stem cells for research is based on sound scientific practice:
we simply do not have sufficient evidence from animal studies
to warrant a move to human experimentation. While there is considerable
debate over the moral and legal status of early human embryos,
this debate in no way constitutes a justification to step outside
the normative practice of science and medicine that requires convincing
and reproducible evidence from animal models prior to initiating
experiments on (or, in this case, with) human beings. While the
"potential promise" of embryonic stem cell research
has been widely touted, the data supporting that promise is largely
nonexistent.
To date there is no evidence that cells generated
from embryonic stem cells can be safely transplanted back into
adult animals to restore the function of damaged or diseased adult
tissues. The level of scientific rigor that is normally applied
(indeed, legally required) in the development of potential medical
treatments would have to be entirely ignored for experiments with
human embryos to proceed. As our largely disappointing experience
with gene therapy should remind us, many highly vaunted scientific
techniques frequently fail to yield the promised results. Arbitrarily
waiving the requirement for scientific evidence out of a naive
faith in "promise" is neither good science nor a good
use of public funds.
Despite the serious limitations to the potential
usefulness of embryonic stem cells, the argument in favor of this
research would be considerably stronger if there were no viable
alternatives. This, however, is decidedly not the case. In the
last few years, tremendous progress has been made in the field
of adult stem cell research. Adult stem cells can be recovered
by tissue biopsy from patients, grown in culture, and induced
to differentiate into a wide range of mature cell types.
The scientific, ethical, and political advantages
of using adult stem cells instead of embryonic ones are significant.
Deriving cells from an adult patient’s own tissues entirely
circumvents the problem of immune rejection. Adult stem cells
do not form teratomas. Therapeutic use of adult stem cells raises
very few ethical issues and completely obviates the highly polarized
and acrimonious political debate associated with the use of human
embryos. The concern that cells derived from diseased patients
may themselves be abnormal is largely unwarranted. Most human
illnesses are caused by injury or by foreign agents (toxins, bacteria,
viruses, etc.) that, if left untreated, would affect adult and
embryonic stem cells equally. Even in the minority of cases where
human illness is caused by genetic factors, the vast majority
of such illnesses occur relatively late in the patient’s
life. The late onset of genetic diseases suggests such disorders
would take years or even decades to reemerge in newly generated
replacement cells.
In light of the compelling advantages of adult
stem cells, what is the argument against their use? The first
concern is a practical one: adult stem cells are more difficult
than embryonic ones to grow in culture and may not be able to
produce the very large numbers of cells required to treat large
numbers of patients. This is a relatively trivial objection for
at least two reasons. First, improving the proliferation rate
of cells in culture is a technical problem that science is quite
likely to solve in the future. Indeed, substantial progress has
already been made towards increasing the rate of adult stem cell
proliferation. Second, treating an individual patient using cells
derived from his own tissue ("autologous transplant")
would not require the large numbers of cells needed to treat large
populations of patients. A slower rate of cell proliferation is
unlikely to prevent adult stem cells from generating sufficient
replacement tissue for the treatment of a single patient.
The more serious concern is that scientists don’t
yet know how many mature cell types can be generated from a single
adult stem cell population. Dr. Anderson notes, "Some experiments
suggest these [adult] stem cells have the potential to make mid–career
switches, given the right environment, but in most cases this
is far from conclusive." This bothersome limitation is not
unique to adult stem cells. Dr. Anderson goes on to illustrate
that in most cases the evidence suggesting scientists can induce
embryonic stem cells to follow a specific career path is equally
far from conclusive. In theory, embryonic stem cells appear to
be a more attractive option because they are clearly capable (in
an embryonic environment) of generating all the tissues of the
human body. In practice, however, it is extraordinarily difficult
to get stem cells of any age "to do what you want them to"
in culture.
There are two important counterarguments to the
assertion that the therapeutic potential of adult stem cells is
less than that of embryonic stem cells because adult cells are
"restricted" and therefore unable to generate the full
range of mature cell types. First, it is not clear at this point
whether adult stem cells are more restricted than their embryonic
counterparts. It is important to bear in mind that the field of
adult stem cell research is not nearly as advanced as the field
of embryonic stem cell research. Scientists have been working
on embryonic stem cells for more than a decade, whereas adult
stem cells have only been described within the last few years.
With few exceptions, adult stem cell research has demonstrated
equal or greater promise than embryonic stem cell research at
a comparable stage of investigation. Further research may very
well prove that it is just as easy to teach an old dog new tricks
as it is to train a willful puppy. This would not eliminate the
very real problems associated with teaching any dog to do anything
useful, but it would remove the justification for "age discrimination"
in the realm of stem cells.
The second counterargument is even more fundamental.
Even if adult stem cells are unable to generate the full spectrum
of cell types found in the body, this very fact may turn out to
be a strong scientific and medical advantage. The process of embryonic
development is a continuous trade–off between potential
and specialization. Embryonic stem cells have the potential to
become anything, but are specialized at nothing. For an embryonic
cell to specialize, it must make choices that progressively restrict
what it can become. The greater the number of steps required to
achieve specialization, the greater the scientific challenge it
is to reproduce those steps in culture. Our current understanding
of embryology is nowhere near advanced enough for scientists to
know with confidence that we have gotten all the steps down correctly.
If adult stem cells prove to have restricted rather than unlimited
potential, this would indicate that adult stem cells have proceeded
at least part way towards their final state, thereby reducing
the number of steps scientists are required to replicate in culture.
The fact that adult stem cell development has been directed by
nature rather than by scientists greatly increases our confidence
in the normalcy of the cells being generated.
There may well be multiple adult stem cell populations,
each capable of forming a different subset of adult tissues, but
no one population capable of forming everything. This limitation
would make certain scientific enterprises considerably less convenient.
However, such a restriction in "developmental potential"
would not limit the therapeutic potential of adult stem cells
for treatment of disease and injury. Patients rarely go to the
doctor needing a full body replacement. If a patient with heart
disease can be cured using adult cardiac stem cells, the fact
that these "heart–restricted" stem cells do not
generate kidneys is not a problem for the patient.
The field of stem cell research holds out considerable
promise for the treatment of disease and injury, but this promise
is not unlimited. There are real, possibly insurmountable, scientific
challenges to the use of embryonic stem cells as a medical treatment
for disease and injury. In contrast, adult stem cell research
holds out nearly equal promise while circumventing the enormous
social, ethical, and political issues raised by the use of human
embryos for research. There is clearly much work that needs to
be done before stem cells of any age can be used as a medical
treatment. It seems only practical to put our resources into the
approach that is most likely to be successful in the long run.
In light of the serious problems associated with embryonic stem
cells and the relatively unfettered promise of adult stem cells,
there is no compelling scientific argument for the public support
of research on human embryos.
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