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Using replacement cells to cure disease
may prove to be one of the most significant advances in medicine. Unlike
all current treatments that rely on surgical intervention or drugs that
modulate activities, stem cells provide a replacement for dysfunctional
or degenerating tissue. Since an overwhelming number of diseases result
from the death of critical cells in the body, millions of Americans may
benefit from advances in this field. As a novel treatment, cell replacement
therapy could dramatically change the treatment of many diseases and cure
many for the first time. Further in the future, stem cells could provide
the means to create entire new organs to replace those that fail due to
aging or disease.
Stem Cells Defined
Stem cells are undifferentiated cells capable of
producing a wide variety of different cell types. In other words, they
are primitive cell types from which you can create a broad array of other
cell types. Stem cells exist in different forms in both the embryo and
the adult. Embryonic stem cells are taken from blastocyst stage embryos
(embryos that are several days old and composed of just a few cells) of
which there are about 200,000 in cryopreservation at in vitro fertilization
(IVF) clinics. Once removed, they are cultured to produce cell lines that
can be grown in the lab. These cells are able to produce all the different
cell types of the adult body, but cannot form a fetus because they have
lost the capability to produce extraembryonic membranes (placenta). These
cells are the pluripotent stem cells that are often discussed in the news
and literature.
In addition to these embryonic stem cells, there
are other stem cells found during other stages of development. Some examples
include embryonic germ cells obtained from medically aborted fetuses at
weeks 5-11 and cord blood stem cells obtained from umbilical cord. However,
even in the grown person there are stem cell populations. Importantly,
these stem cells are restricted in their potential and seem to only produce
a relatively small number of cell types under normal physiologic conditions.
The primary example, hematopoeitic or blood stem cells, were found 40
years ago. These cells can now be purified and can produce all the different
cells of the blood system.
Just 3 years ago, stem cells were found in the
adult brain that seem capable of producing the major types of neurons.
Additional work in the field is challenging the potential of adult stem
cells and asking the important question of whether you can deprogram or
reprogram these stem cells to produce other cell types. For instance,
there is accumulating evidence that you can get neuronal cell types from
blood stem cells.
Diseases Targeted
Currently, adult blood stem cells are used in the
treatment of a wide variety of hematologic cancers such as CML, ALL, AML,
non hodgkin’s lymphoma and multiple myeloma. Establishes uses include
autologous and allogeneic bone marrow stem cell transplants. The procedure
involves purifying stem cells from the bone marrow or peripheral blood
from the patient (autologous) or HLA matched (allogeneic) donors. The
patient’s marrow is then destroyed by radiation and reconstituted with
the stem cell graft.
While this has been an exciting development in
the bone marrow transplant field, people hope for a wide variety of other
uses of stem cells:
Heart. Several groups have been working on animal
models in which pluripotent stem cells are grafted into damaged hearts.
The stem cells were shown to incorporate into the heart and form gap junctions
and beat with the surrounding cells.
Brain. There is widespread interest in using pluripotent
or adult stem cells to repair a wide variety of damage to the nervous
system such as spinal cord injury, Parkinson’s Disease, ALS, Huntington’s,
stroke, and Alzheimer’s. There are animal and early human trials underway
for several of these diseases.
Pancreas. Although type 1 diabetes in which patients
lack pancreatic beta cells is only a small portion of the diabetic population,
it is also a large market that the stem cell field hopes to address. This
work is probably the least advanced since people are still working to
isolate or produce pancreatic stem cells for use in model systems.
Companies
Nexell
The bulk of their current product line focuses
on tools that allow clinicians and researchers to use automated or large
scale means to purify hematopoeitic stem cells from circulating (peripheral)
blood and then to grow those cells in the lab to larger numbers for return
to the patient. As such, they only work on adult stem cells. The foundation
of this technology is a machine called the Isolex 300i Magnetic Cell Selection
System. It enjoys the position of being the only commercially available,
FDA approved device of its kind for the purification of stem cells from
human blood
Autologous bone marrow transplants using the Nexell
device have FDA approval for multiple myeloma, non hodgkin’s lymphoma,
and advanced breast cancer.
Aastrom
This company is working on a "desktop-sized
device" that supports the growth of stem cells. Called a bioreactor,
such a device allows the production of many cells from a small number
harvested from a patient. They address a significant problem. Stem cell
harvests often fail to yield a useful number of cells. Cord blood and
neurons from fetusus perhaps best exemplify such a precious resource.
The harvest procedures are laborious, invasive, and expensive. The general
notion of developing means to expand stem cells in a simple culture system
would be a very important contribution to the field of stem cell transplantation
since it would allow harvested tissue to be used for many more patients.
Their products allow the growth and replication of adult stem cells as
well as stem cells from umbilical cord blood.
They have two phase III trials underway for stem
cell therapies. Both are for hematologic malignancies, but one uses bone
marrow stem cells and the other uses cord blood.
StemCells
This company focuses on using stem cells in central
nervous system (brain) disorders and in the liver and pancreas. This company
fell into the limelight when stem cells were featured as the breakthrough
of the year in the journal Science. Compared to the other stem cell research
companies, this group publishes articles with very high frequency in many
high profile scientific journals. A consequence of this activity that
will be explored in the next few sections is the significant intellectual
property held by this company.
All of their products are in preclinical stages,
but they have programs underway for neural, liver, and pancreatic stem
cells
Geron
This company emphasizes synergy between three separate
technologies. They have patents on telomerase, a gene that produces an
enzyme that allows cells to properly maintain chromosome integrity and
grow in culture. They also are performing work on cloning by way of nuclear
transfer a la Dolly. And of course their last area of interest consists
of stem cells.
Like StemCells, they have no products in clinical
trials. However, of the stem cell companies they are the largest and are
working in the most areas. They have telomerase projects in which they
are producing immortalized cell lines for sale to the research community.
They are also producing several strategies of telomerase inhibition for
cancer treatment including small molecules, gene therapy, and oligonucleotides.
They perform quite a bit of work in stem cells utilizing embryonic stem
cells, embryonic germ cells, and adult stem cells. They own the intellectual
property used to clone Dolly by way of their acquisition of Roslin BioMed.
Finally, they have announced a collaboration with Celera to examine the
genes involved in cellular differnentiation.
Problems
By far, the most talked about issue in the stem
cell field is the current American political climate. Several high ranking
Republicans, including the President, adamantly oppose all embryonic stem
cell research as it requires the destruction of embryos at some stage
of the process. In addition, they have stated in several press releases
that they believe that adult stem cells can fulfill the roles of embryonic
stem cells, making embryonic stem cell research unnecessary. From a scientific
standpoint, there is no basis for this conclusion and the question of
the true potential of adult stem cells remains very open. The major political
threat is maintenance of the status quo, meaning that the NIH will not
be permitted to fund embryonic stem cell research. Given a sharply divided
Congress and prominent admirers of stem cell research such as the new
HHS secretary Tommy Thompson and Senators Arlen Specter (R-Pa) and Strom
Thurmond (R-SC) who have gone on the record several times in support of
embryonic stem cell research, it remains unclear if the political will
is present to block the NIH.
In the scientific arena, the areas of most avid
investigation can be divided into three areas: 1. growing or culturing
stem cells, 2. deriving interesting adult cell types from stem cells,
3. introduction of stem cells or differentiated cells into model organisms
or humans. The first problem is related directly to having a relatively
cheap and reliable source for the large number of cells necessary for
any potential use. Explorations of the second issue have really put stem
cells on the map, perhaps beginning with the cover article in Science
and the other high profile articles suggesting some plasticity in blood
and neural stem cells. Finally, the various attempts underway to transplant
stem cells or differentiated cells into rodents or humans have thus far
been promising, but serious questions remain about efficacy, long term
effects, and immune response.
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