BIOLOGY & MEDICINE

The Case for Adult Stem Cell Research

by Wolfgang Lillge, M.D.

(Full text of article from Winter 2001-2002 21st Century)
What Are Stem Cells, Exactly?

Problems of ‘Therapeutic Cloning’

Whoever Would Cure, Must Use Adult Stem Cells

Human Treatments

For more articles on biology and medicine, check the
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Headline collageThe question of stem cells is currently the
dominant subject in the debate over biotechnology and human
genetics: Should we use embryonic stem cells or adult stem
cells for future medical therapies? Embryonic stem cells
are taken from a developing embryo at the blastocyst stage,
destroying the embryo, a developing human life. Adult stem
cells, on the other hand, are found in all tissues of the
growing human being and, according to latest reports, also
have the potential to transform themselves into practically
all other cell types, or revert to being stem cells with
greater reproductive capacity. Embryonic stem cells have
not yet been used for even one therapy, while adult stem
cells have already been successfully used in numerous
patients, including for cardiac infarction (death of some
of the heart tissue).

Stem cells are of wide interest for medicine, because they
have the potential, under suitable conditions, to develop
into almost all of the different types of cells. They
should therefore be able to repair damaged or defective
tissues (for example, destroyed insulin-producing cells in
the pancreas). Many of the so-called degenerative diseases,
for which there are as yet no effective therapies, could
then be alleviated or healed.

It is remarkable that in the debate–often carried on with
little competence–the potential of embryonic stem cells is
exaggerated in a one-sided way, while important moral
questions and issues of research strategy are passed over
in silence. Generally, advocates of research with embryonic
stem cells use as their main argument that such research
will enable us to cure all of the diseases that are
incurable today–cancer, AIDS, Alzheimers, multiple
sclerosis, and so forth. Faced with such a prospect, it is
supposed to be "acceptable" to "overlook" a few moral
problems.

On closer inspection, however, the much extolled vision of
the future turns out to be a case of completely empty
promises: Given the elementary state of research today, it
is by no means yet foreseeable, whether even one of the
hoped-for treatments can be realized. Basically, such
promised cures are a deliberate deception, for behind the
mirage of a coming medical wonderland, promoted by
interested parties, completely other research objectives
will be pursued that are to be kept out of public
discussion as much as possible.

Perfect candor should rule in stem cell research. This
requires that the scientist himself clearly establish the
moral limits of his activity and declare what the
consequences of research with embryonic stem cells really
are. In the process, no one can escape the fact that,
should one wish to use embryonic stem cells for
"therapeutic purposes," the very techniques will be
developed that will also be used for the cloning of human
beings, the making of human-animal hybrids, the
manipulation of germ lines, and the like–thus for
everything other than therapeutic purposes. Any coverup or
hypocrisy in this matter will very quickly reflect upon the
research as a whole.

What Are Stem Cells, Exactly? It is appropriate here to
sketch the characteristics of stem cells, and the overthrow
of some dogmas of developmental biology. Broadly speaking,
a stem cell is one that–in the course of cell division and
increase in the numbers of cells–is able to reproduce
itself and also mature into various specialized types of
cells. The stem cell with the greatest potential
(totipotential) is the fertilized egg cell, which is
capable of developing into a complete organism.

According to the usual–but actually very
doubtful–explanation, the fertilized egg cell has
totipotential up to the stage of division into eight cells,
and in later stages the cells retain only "pluripotential."
That is, they can form many different types of tissues, but
not the complete organism. Embryonic stem cells–that is,
those 50 cells within a blastocyst, which then continue to
develop into the embryo proper–have this pluripotential. In
the course of further specialization, stem cells of
individual tissues are formed, such as that of the bone
marrow, from which all the other kinds of blood cells
develop.

Behind this description lies the conception that a linear
process of differentiation is played out, in the
development of the individual, toward increasingly
"mature," specialized cells in the individual tissues, from
totipotentiality to tissue specificity. This process is
supposed to run only forward, but never backward. That is,
as soon as a cell has reached a certain degree of
"maturity," the way back to earlier stages of development
is closed off. So it is evident that a stem cell’s capacity
to perform is increasingly limited to specific functions,
and it loses, correspondingly, the manifold capabilities
still present in earlier developmental stages.

According to latest reports, however, this dogma of
developmental biology does not hold. Evidently,
tissue-specific stem cells have the ability–as has been
impressively demonstrated in experiments with animals–to
"transdifferentiate" themselves when in a different
environment–that is, to take on the cell functions of the
new tissue. Thus, neuronal stem cells of mice have
transformed themselves into blood stem cells and produced
blood cells. Indeed, there are indications of another
capability of adult stem cells: Apparently they have the
potential to be "reprogrammed." Not only can they adjust to
the specific conditions of a new tissue environment, but
they can even assume more generalized, earlier levels of
development, so that it even appears possible that they
become totipotent again.

in vitro mouse bone marrowLaboratory Virola in Ukraine has
demonstrated that bone marrow stromal cells in culture are
pluripotent–that is, they are able to differentiate into
cells of liver, bone, fat, cartilage, and so on.
Researchers at this laboratory have developed techniques to
differentiate in vitro mouse bone marrow stromal cells into
different types of neuronal and glial cells. The laboratory
is seeking funds to develop similar methods for human bone
marrow stromal cells. Laboratory Virola

Problems of ‘Therapeutic Cloning’ Until now, talk of a
possible source of human replacement tissue has centered on
embryonic stem cells, the production of which has been
extremely controversial. They are a typical product of
"consuming embryonic research," so called, because in
obtaining them from a human embryo produced by artificial
fertilization in vitro, the embryo is destroyed.

The most important research technique for which such
embryos are obtained is "therapeutic cloning." In
principle, a human egg cell is denucleated, that is, the
DNA is removed, and in its place is put the nucleus of a
somatic (body) cell. The egg cell is stimulated with a
short electrical pulse, and it then develops into the
blastocyst, from which stem cells can be removed. These are
identical with those of the donor of the somatic cell
nucleus.

Normally it goes unmentioned, that it is only a small step
from this so-called "therapeutic cloning" (because, it is
claimed, in this way a therapy for diseases can be
developed) to what is called "reproductive cloning." The
only difference is that the development of the embryo is
not interrupted in the early blastocyst stage; instead the
embryo is implanted in a uterus and a complete organism
develops–an exact genetic copy of the donor. "Dolly," the
first cloned sheep, was produced by this method, and here
is the basis for the widespread fear that the same method
that is used for "therapeutic cloning" can also be used for
the selective breeding of humans.

In addition to the obvious moral consideration, there are
still other serious disadvantages that make this path to
the development of human "replacement parts" appear to be
untenable.

The danger of tumors. So far there has been no solution to
the problem of developing in the laboratory an unmistakable
identifier for stem cells that can distinguish them
unequivocally from cancer cells. For this reason, it is
also not possible to produce sufficiently pure cell
cultures from stem cells. So far, with embryonic mouse stem
cells, a purity of only 80 percent has been achieved. That
is in no way sufficient for cell transplantation as a human
therapy. In a cell culture for therapeutic purposes, there
must not be a single undifferentiated cell, since it can
lead to unregulated growth, in this case to the formation
of teratomas, a cancerous tumor derived from the germ
layers. This problem would not be expected with adult stem
cells, because of their greater differentiation.

Genetic instability. Only recently a further problem has
emerged. Fundamental doubt of the suitability of embryonic
stem cells for transplantation has come to the surface
because of the genetic instability of cloned cells.

Cloned animals like Dolly give the outward appearance of
full health, but the probability of their having numerous
genetic defects is very high. Moreover, the entire cloning
procedure is extremely ineffective. Most cloned animals die
before birth, and of those born alive, not even half
survive for three weeks. In the best case, there is a
success rate of 3 to 4 percent.

One of the reasons for this high failure rate has now been
discovered by the German scientist Rudolf Jaenisch at the
Institute for Biomedical Research at the Massachusetts
Institute of Technology, and his colleague, Ryuzo
Yanagimachi. Their conception is that in cloning–that is,
when the nucleus of a somatic cell is inserted into a
denucleated egg cell–the reprogramming of the genes does
not proceed properly, so that not all of the genes that are
necessary to the early phase of embryonic development, are
activated. Even when cloned animals survive at all,
probably every clone would have subtle genetic
abnormalities that would frequently become noticeable only
later in life.

Jaenisch performed his experiments with mice that had been
cloned using embryonic stem cells in place of the somatic
cells, which produces better results. But to his surprise,
the reprogramming of the inserted genetic material by the
embryonic cells proceeded in a very unregulated way. There
were no two clones in which the same pattern of gene
activation was found, and Jaenisch is convinced that the
use of embryonic stem cells was clearly responsible.

What consequences follow from this for the therapeutic use
of human embryonic stem cells–consequences that will in
fact be multiplied through cloning–are not yet foreseeable.
NeuroblastsNeuroblasts differentiated from bone marrow
stromal cells by Laboratory Virola. Laboratory Virola
Whoever Would Cure, Must Use Adult Stem Cells It has been
known for about 30 years that stem cells are present in the
tissue of the adult, but it was assumed that they could
only form cells of a particular tissue. That is,
reprogramming them was considered impossible. In recent
years, however, pluripotent stem cells were discovered in
various human tissues–in the spinal cord, in the brain, in
the mesenchyme (connective tissue) of various organs, and
in the blood of the umbilical cord. These pluripotent stem
cells are capable of forming several cell types–principally
blood, muscle, and nerve cells. It has been possible to
recognize, select, and develop them to the point that they
form mature cell types with the help of growth factors and
regulating proteins.

This shows that in tissues of the body, adult stem cells
possess a much greater potential for differentiation than
previously assumed. This knowledge must be brought into the
public consciousness with all possible emphasis. If stem
cell research were really only meant for therapeutic uses,
which it most obviously should be, adult stem cells would
promise a very productive research field–and beyond that, a
possibility, without moral objection, to discover
fundamentals of the dynamics of tissue differentiation.

It has become clear from transplantation experiments with
animals, that stem cells of a particular tissue can develop
into cells of a completely different kind. Thus, bone
marrow stem cells have been induced to become brain cells,
but also liver cells.

Adult stem cells obviously have a universal program for
division that is common to all the kinds of tissue stem
cells, and makes them mutually interchangeable. This was
discovered by Alexei Terskikh at Stanford University School
of Medicine in California. He was able to prove that adult
stem cells of blood-forming tissues, and of the brain,
activate the same genes, in order to preserve their status
as stem cells.

In May 2001, a further, spectacular experiment was
reported, which was carried out on mice by scientists at
Yale University. The researchers obtained stem cells from
the bone marrow of male mice, and injected it into females
whose own marrow had been destroyed by radioactive
irradiation. Eleven months later, the male stem cells
(identifiable through the male Y-chromosome) were found not
only in the females’ bone marrow, but also in their blood,
and in their gut, lung, and skin tissues.

If these observations are correct and are confirmed by
other teams of scientists, science should concentrate on
research with adult stem cells and renounce further
experiments with the embryonic.

Human Treatments Moreover, very promising treatments of
serious diseases with adult stem cells have already been
tried. The special advantage is that there are no rejection
reactions, because the cells are from the same body.

Of longer standing is treatment with bone marrow stem
cells. The treatment comes into play when, for example, a
patient has lost his or her blood-forming tissue through
radiation or high-dose chemotherapy. Previously removed
bone marrow stem cells are then retransplanted, and are
able to resume the formation of blood cells.

In 2001, however, a team of doctors at the Duesseldorf
University Clinic carried out a treatment of very
far-reaching consequences. For the first time, they treated
a cardiac infarct patient with stem cells from his own
body. The cardiologist, Prof. Bodo Eckehard Strauer, is
sure that the stem cells from the patient’s bone marrow,
after injection into the infarct zone, autonomously
converted to heart muscle. The functioning of the severely
damaged heart clearly improved within a few weeks.

Four days after the infarction, the doctors took bone
marrow from the patient’s pelvis using local anesthesia.
The stem cells in the marrow were concentrated outside of
the body and implanted in the infarct area the next day
with a special technique via a coronary artery. However,
the doctors could not yet take cardiac tissue to prove
definitively that the implanted blood stem cells had
converted to heart muscle cells. But, according to Strauer,
there is no other way to explain the marked improvement in
the patient’s condition. After this first successful
operation, six more patients have already been treated with
their own stem cells, with similarly positive results.

There are also reports of successful treatments with adult
stem cells in cases of Crohn’s disease (a chronic infection
of the gut), thalassemia (a blood disease), and a rare skin
disease. And–despite the fact that basic research with
adult stem cells is in its earliest beginnings and is in no
way being promoted with urgency–there have been a growing
number of reports lately of experiments with animals, from
which it emerges that adult stem cells can successfully
transform themselves into differentiated cells of organs of
many kinds.

In contrast, reports of successful conversions of embryonic
stem cells are very infrequent and cautious. Thus, we find
in Science of Dec. 1, 2000 (Vol. 290, pp. 1672-1674): "In
contrast, the human embryonic stem cells and fetal germ
cells that made headlines in November 1998 because they
can, in theory, develop into any cell type have so far
produced relatively modest results. Only a few papers and
meeting reports have emerged from the handful of labs that
work with human pluripotent cells. . . . The work suggests
that it will not be simple to produce the pure populations
of certain cell types that would be required for safe and
reliable cell therapies. . . ."

This is the restrained language used by established science
to describe a truly disastrous set of results.

There are, of course, still substantial problems to be
overcome, even with adult stem cells: They are relatively
rare, and are hard to find with the techniques used so far.
They are also not very easy to culture outside of the body.
It was therefore an important advance that Australian
researchers of the Walter and Eliza Hall Institute of
Medical Research have now found a way to isolate nerve stem
cells with "extreme purity" from the brains of mice. In
Nature of August 16, 2001 (Vol. 412, pp. 736-739), they
reported obtaining a culture of 80 percent purity, compared
to a previous rate of 5 percent at best.

It is now urgently necessary to tackle the research in
precisely this direction, in order to find out the exact
conditions under which the differentiation of stem cells
comes about and how, in detail, it proceeds. Only by this
morally unassailable route will it be possible to develop
new therapies for serious, heretofore incurable diseases,
and beyond that, to improve our understanding of the
development of life itself.

http://www.stemcell-tech.com

Wolfgang Lillge is the Editor-in-Chief of the
German-language Fusion magazine. His article appeared in
the Sept.-October 2001 issue of Fusion, and was translated
into English by David Cherry.