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STEM CELL PRIMER
Explanation
This
primer presents background information on stem cells. It includes an
explanation of what stem cells are; what
pluripotent stem cells are;
how pluripotent stem cells are derived; why pluripotent stem cells are
important to science;
why they hold such great promise for advances in
health care; and what adult stem cells are.
Recent
published reports on the isolation and successful culturing of the
first human pluripotent stem cell lines have
generated great excitement
and have brought biomedical research to the edge of a new frontier. The
development
of these human pluripotent stem cell lines deserves close
scientific examination, evaluation of the promise for new
therapies,
and prevention strategies, and open discussion of the ethical issues.
In
order to understand the importance of this discovery as well as the
related scientific, medical, and ethical issues,
it is absolutely
essential to first clarify the terms and definitions.
DNA - abbreviation for
deoxyribonucleic acid which makes up genes.
Gene
- a functional unit of heredity which is a segment of DNA located in a
specific site on a chromosome. A gene
directs the formation of an
enzyme or other protein.
Somatic cell - cell of the body other than egg or
sperm.
Somatic cell nuclear transfer - the transfer of a cell
nucleus from a somatic cell into an egg from which the nucleus
has been removed.
Stem cells - cells that have the ability to divide for
indefinite periods in culture and to give rise to specialized cells.
Pluripotent - capable of giving rise to most tissues
of an organism.
Totipotent - having unlimited capability to produce
all the cells and tissues in the body.
Multipotent - stem
cells that can give rise to several other cell types, but those types
are limited in number.
An example of a multipotent stem cell is a
hematopoietic cell — a blood stem cell that can develop into several
types
of blood cells, but cannot develop into brain cells or other
types of cells. At the end of the long series of cell divisions
that
form the embryo are cells that are terminally differentiated, or that
are considered to be permanently committed
to a specific function.
What is a stem cell?
Stem
cells have the ability to divide for indefinite periods in culture and
to give rise to specialized cells. They are
best described in the
context of normal human development. Human development begins when a
sperm fertilizes
an egg and creates a single cell that has the
potential to form an entire organism. This fertilized egg is
totipotent,
meaning that its potential is total. In the first hours
after fertilization, this cell divides into identical totipotent cells.
This means that these cells, if placed
into a woman's uterus, have
the potential to develop into a fetus. In fact,
identical twins develop
when two totipotent cells separate and develop into two individual,
genetically identical
human beings. Approximately four days after
fertilization and after several cycles of cell division, these
totipotent cells begin to specialize, forming a hollow sphere of cells,
called a blastocyst. The blastocyst has an
outer layer of cells and
inside the hollow sphere, there is a cluster of cells called the inner
cell mass.
The outer layer of cells will go on to
form the
placenta and other supporting tissues needed for fetal development
in
the uterus. The inner cell mass cells will go on to form virtually all
of the tissues of the human body. Although
the inner cell mass cells
can form virtually every type of cell found in the human body, they
cannot form an
organism because they are unable to give rise to the
placenta and supporting tissues necessary for development
in the human
uterus. These inner cell mass cells are pluripotent - they can give
rise to many types of cells but not
all types of cells necessary for
fetal development. Because their potential is not total, they are not
totipotent and
they are not embryos. In fact, if an inner cell mass
cell were placed into a woman's uterus, it would not develop
into a
fetus.
The pluripotent stem cells undergo
further
specialization into stem cells that are committed to give rise to cells
that have a particular function. Examples of this include blood stem
cells which give rise to red blood cells, white
blood cells and
platelets; and skin stem cells that give rise to the various types of
skin cells. These more specialized
stem cells are called multipotent.
While stem cells are extraordinarily
important in early human
development, multipotent stem cells are also found
in children and
adults. For example, consider one of the best understood stem cells,
the blood stem cell. Blood
stem cells reside in the bone marrow of
every child and adult, and in fact, they can be found in very small
numbers
circulating in the blood stream. Blood stem cells perform the
critical role of continually replenishing our supply of
blood cells -
red blood cells, white blood cells, and platelets - throughout life. A
person cannot survive without
blood stem cells.
How are pluripotent stem cells derived?
At
present, human pluripotent cell lines have been developed from two
sources with methods previously developed
in work with animal models.
The use of somatic cell nuclear transfer (SCNT) may be another way that
pluripotent stem cells could
be isolated. In studies with animals using
SCNT, researchers take a normal animal egg cell and remove
the nucleus
(cell structure containing the chromosomes). The material left behind
in the egg cell contains
nutrients and other energy-producing materials
that are essential for embryo development. Then, using
carefully worked
out laboratory conditions, a somatic cell - any cell other than an egg
or a sperm
cell - is placed next to the egg from which the nucleus had
been removed, and the two are fused. The
resulting fused cell, and its
immediate descendants, are believed to have the full potential to
develop
into an entire animal, and hence are totipotent. As described
in Figure I, these totipotent cells will soon
form a blastocyst. Cells
from the inner cell mass of this blastocyst could, in theory, be used
to develop
pluripotent stem cell lines. Indeed, any method by which a
human blastocyst is formed could potentially
serve as a source of human
pluripotent stem cells.
Potential Applications of Pluripotent Stem Cells
There
are several important reasons why the isolation of human pluripotent
stem cells is important to
science and to advances in health care. At
the most fundamental level, pluripotent stem cells could help
us to
understand the complex events that occur during human development. A
primary goal of this work
would be the identification of the factors
involved in the cellular decision-making process that results in
cell
specialization. We know that turning genes on and off is central to
this process, but we do not know
much about these "decision-making"
genes or what turns them on or off. Some of our most serious
medical
conditions, such as cancer and birth defects, are due to abnormal cell
specialization and cell
division. A better understanding of normal cell
processes will allow us to further delineate the fundamental
errors
that cause these often deadly illnesses.
Human pluripotent stem cell research
could also dramatically change
the way we develop
drugs and test them for safety. For example, new
medications could be initially tested using
human cell lines. Cell
lines are currently used in this way (for example cancer cells).
Pluripotent
stem cells would allow testing in more cell types. This
would not replace testing in whole
animals and testing in human beings,
but it would streamline the process of drug development.
Only the drugs
that are both safe and appear to have a beneficial effect in cell line
testing would
graduate to further testing in laboratory animals and
human subjects.
Perhaps the most far-reaching potential
application of human pluripotent stem cells is the
generation of cells
and tissue that could be used for so-called "cell therapies." Many
diseases
and disorders result from disruption of cellular function or
destruction of tissues of the body.
Today, donated organs and tissues
are often used to replace ailing or destroyed tissue. Unfortunately,
the number of people suffering from these disorders far outstrips the
number of organs available
for transplantation. Pluripotent stem cells,
stimulated to develop into specialized cells, offer the
possibility of
a renewable source of replacement cells and tissue to treat a myriad of
diseases,
conditions, and disabilities including Parkinson's and
Alzheimer's diseases, spinal cord injury,
stroke, burns, heart disease,
diabetes, osteoarthritis and rheumatoid arthritis. There is almost no
realm of medicine that might not be touched by this innovation. Some
details of two of these
examples follow.
Transplant of
healthy heart muscle cells could provide new hope for patients with
chronic heart
disease whose hearts can no longer pump adequately. The
hope is to develop heart muscle cells
from human pluripotent stem cells
and transplant them into the failing heart muscle in order to
augment
the function of the failing heart. Preliminary work in mice and other
animals has
demonstrated that healthy heart muscle cells transplanted
into the heart successfully repopulate
the heart tissue and work
together with the host cells. These experiments show that this type of
transplantation is feasible.
In the many individuals who
suffer from Type I diabetes, the production of insulin by specialized
pancreatic cells, called islet cells, is disrupted. There is evidence
that transplantation of either the
entire pancreas or isolated islet
cells could mitigate the need for insulin injections. Islet cell lines
derived from human pluripotent stem cells could be used for diabetes
research and, ultimately,
for transplantation.
While this
research shows extraordinary promise, there is much to be done before
we can realize
these innovations. Technological challenges remain
before these discoveries can be incorporated
into clinical practice.
These challenges, though significant, are not insurmountable.
First,
we must do the basic research to understand the cellular events that
lead to cell specialization
in the human, so that we can direct these
pluripotent stem cells to become the type(s) of tissue
needed for
transplantation.
Second, before we can use these cells
for
transplantation, we must overcome the well-known
problem of immune
rejection. Because human pluripotent stem cells derived from embryos or
fetal tissue would be genetically different from the recipient, future
research would need to focus
on modifying human pluripotent stem cells
to minimize tissue incompatibility or to create tissue banks
with the
most common tissue-type profiles.
The use of somatic cell
nuclear transfer (SCNT) would be another way to overcome the problem
of
tissue incompatibility for some patients. For example, consider a
person with progressive heart
failure. Using SCNT, the nucleus of
virtually any somatic cell from that patient could be fused with
a
donor egg cell from which the nucleus had been removed. With proper
stimulation the cell would
develop into a blastocyst: cells from the
inner cell mass could be taken to create a culture of
pluripotent
cells. These cells could then be stimulated to develop into heart
muscle cells. Because
the vast majority of genetic information is
contained in the nucleus, these cells would be essentially
identical
genetically to the person with the failing heart. When these heart
muscle cells were transplanted
back into the patient, there would
likely be no rejection and no need to expose the patient to
immune-suppressing drugs, which can have toxic effects.
Adult Stem Cells
As
noted earlier, multipotent stem cells can be found in some types of
adult tissue. In fact, stem cells
are needed to replenish the supply
cells in our body that normally wear out. An example, which was
mentioned previously, is the blood stem cell.
Multipotent
stem cells have not been found for all types of adult tissue, but
discoveries in this area
of research are increasing. For example, until
recently, it was thought that stem cells were not present
in the adult
nervous system, but, in recent years, neuronal stem cells have been
isolated from the rat
and mouse nervous systems. The experience in
humans is more limited. In humans, neuronal stem
cells have been
isolated from fetal tissue and a kind of cell that may be a neuronal
stem cell has been
isolated from adult brain tissue that was surgically
removed for the treatment of epilepsy.
Do adult stem cells have the same potential as pluripotent stem cells?
Until
recently, there was little evidence in mammals that multipotent cells
such as blood stem cells
could change course and produce skin cells,
liver cells or any cell other than a blood stem cell or a
specific type
of blood cell; however, research in animals is leading scientists to
question this view.
In animals, it has been shown that
some adult stem cells previously thought to be committed to the
development of one line of specialized cells are able to develop into
other types of specialized cells.
For example, recent experiments in
mice suggest that when neural stem cells were placed into the
bone
marrow, they appeared to produce a variety of blood cell types. In
addition, studies with rats
have indicated that stem cells found in the
bone marrow were able to produce liver cells. These
exciting findings
suggest that even after a stem cell has begun to specialize, the stem
cell may, under
certain conditions, be more flexible than first
thought. At this time, demonstration of the flexibility of
adult stem
cells has been only observed in animals and limited to a few tissue
types.
Why not just pursue research with adult stem cells?
Research
on human adult stem cells suggests that these multipotent cells have
great potential for
use in both research and in the development of cell
therapies. For example, there would be many
advantages to using adult
stem cells for transplantation. If we could isolate the adult stem
cells from
a patient, coax them to divide and direct their
specialization and then transplant them back into the
patient, it is
unlikely that such cells would be rejected. The use of adult stem cells
for such cell
therapies would certainly reduce or even avoid the
practice of using stem cells that were derived
from human embryos or
human fetal tissue, sources that trouble many people on ethical
grounds.
While adult stem cells hold real
promise, there
are some significant limitations to what we may or
may not be able to
accomplish with them. First of all, stem cells from adults have not
been isolated
for all tissues of the body. Although many different
kinds of multipotent stem cells have been identified,
adult stem cells
for all cell and tissue types have not yet been found in the adult
human. For example,
we have not located adult cardiac stem cells or
adult pancreatic islet stem cells in humans.
Secondly,
adult stem cells are often present in only minute quantities, are
difficult to isolate and purify,
and their numbers may decrease with
age. For example, brain cells from adults that may be neuronal
stem
cells have only been obtained by removing a portion of the brain of
epileptics, not a trivial procedure.
Any attempt to use
stem cells from a patient's own body for treatment would require that
stem cells
would first have to be isolated from the patient and then
grown in culture in sufficient numbers to
obtain adequate quantities
for treatment. For some acute disorders, there may not be enough time
to grow enough cells to use for treatment. In other disorders, caused
by a genetic defect, the
genetic error would likely be present in the
patient's stem cells. Cells from such a patient may not
be appropriate
for transplantation. There is evidence that stem cells from adults may
have not had
the same capacity to proliferate as younger cells do. In
addition, adult stem cells may contain more
DNA abnormalities, caused
by exposure to daily living, including sunlight, toxins, and by
expected
errors made in DNA replication during the course of a
lifetime. These potential weaknesses could
limit the usefulness of
adult stem cells.
Research on the early stages of cell
specialization may not be possible with adult stem cells since
they
appear to be farther along the specialization pathway than pluripotent
stem cells. In addition,
one adult stem cell line may be able to form
several, perhaps 3 or 4, tissue types, but there is no
clear evidence
that stem cells from adults, human or animal, are pluripotent. In fact,
there is no
evidence that adult stem cells have the broad potential
characteristic of pluripotent stem cells.
In order to determine the
very best source of many of the specialized cells and tissues of the
body
for new treatments and even cures, it will be vitally important to
study the developmental potential
of adult stem cells and compare it to
that of pluripotent stem cells.
Summary
Given
the enormous promise of stem cells to the development of new therapies
for the most
devastating diseases, it is important to simultaneously
pursue all lines of research. Science and
scientists need to search for
the very best sources of these cells. When they are identified,
regardless
of their sources, researchers will use them to pursue the
development of new cell therapies.
The development of stem
cell lines, both pluripotent and multipotent, that may produce many
tissues
of the human body is an important scientific breakthrough. It
is not too unrealistic to say that this
research has the potential to
revolutionize the practice of medicine and improve the quality and
length of life.
1 Michael Shamblott, et al, Derivation
of
pluripotent stem cells from cultured human primordial
germ cells. PNAS,
95: 13726-13731, Nov. 1998.
James Thomson, et al, Embryonic stem cell lines derived from human
blastocysts. Science,