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STEM CELLS:
THEIR APPLICATION IN DIABETES AND ERECTILE DYSFUNCTION AND
THEIR SURROUNDING ETHICAL ISSUES
BY
NEIL THAKRAR
Pass with Merit
&
VISHNU MENON
Pass with Merit
RESEARCH PAPER
BASED ON
PATHOLOGY LECTURES
AT MEDLINK 2011
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ABSTRACT
The following paper is a study into the modern and future developments of stem cell research and the
ethical controversies and systems related to the subject. The introduction explores an overview of
what stem cells actually are, their current uses in regenerative medicine and the different types of
stem cells such as ‘totipotent’ and ‘pluripotent’. We evaluate the feasibility of embryonic, adult and
foetal stem cells in the possible advancements in medicine. After, there is a discussion into the further
routes we could take with the research, such as curing diabetes and helping males with erectile
dysfunction. The advantages and disadvantages of these particular applications will also be touched
on and a conclusion on whether it is pragmatic and justified will be made. The justification will come
from a look into the ethical aspects of the stem cell debate. Different systems of ethics will be looked
into such as a consequentialist’s, a natural law deontologist’s and a Kantian’s views.
INTRODUCTION
Stem cells are undifferentiated cells. This means they are yet to become specialised and
adapted for specific functions. Stem cells have two main defining properties1: firstly the
ability to divide indefinitely by mitosis, making exact copies (clones) of themselves – this is
known as self-renewal or self-regeneration – and secondly the ability to differentiate, which
is the potential to develop into other cell types and so become specialised and adapted for
specific functions.
Stem cells are categorised by their potency –their potential to differentiate into different
cell types. At the top of the hierarchy, a totipotent stem cell can develop into all cell types,
for example, pancreatic cells, bone cells and so on. Pluripotent cells, derived from totipotent
cells, have the ability to differentiate into several different types of cells in any of the three
germ layers2. [See Figure 1] However, pluripotent cells, unlike totipotent cells, cannot form
extra embryonic membranes, such as the placenta.
Figure 1. The three germ layers and the structures they form
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Multipotent cells, however, can only differentiate into a closely related family of cells. An
example of a multipotent stem cell is a hematopoietic cell, which has the ability to
differentiate into different blood cells, such as red blood cells or B lymphocytes, but not any
other cell type, such as a neuron. [See Figure 2]
Figure 2. Differentiation of a hematopoietic stem cell
There are many more types of stem cells, categorised by their potency, but based on their
source, there are three broad sorts of stem cells: embryonic stem cells (ESCs), adult or
somatic stem cells (ASCs), and foetal stem cells (including cord blood).
Embryonic stem cells are derived from a human embryo, four or five days old. “Spare”
embryos from In Vitro Fertilisation are used, where eggs are fertilised in a test tube. When a
male’s sperm fertilises a female’s ovum, a single cell is formed, called a zygote. The zygote
divides by mitosis to form two, four, eight, and then sixteen cells and so forth. After four
days, the mass of cells is called a
blastocyst3, before it is implanted
into the mother’s uterus. [See
Figure 3] The blastocyst has an
outer cell mass, a trophoblast,
comprising of totipotent cells that
go on to form part of the placenta.
The blastocyst also has an inner cell
mass (embryoblast) – comprised of
the pluripotent cells that go on to
Figure 3. Culturing Embryonic
become the structures of a
Stem cells from a Blastocyst
developed adult, and it is this
pluripotency that is a major
advantage to researchers.
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It was James Thomson (1998)4, a cell biologist, who isolated the first human ESCs from the
inner cell mass of a blastocyst, at the University of Wisconsin in Madison. As demonstrated
by Thomson (2007)4, human skin cells can be converted into cells similar to human ESCs,
known as induced pluripotent stem cell lines. These ESCs are at the forefront of
regenerative Medicine because of their possible uses in tissue repair and regeneration.
Current research involves the use of ESCs in cancer therapies and according to the Journal of
Immunology (2005)5, one of these cancer therapies involves generating natural killer cells
from human ESCs which destroy some cancer cells.
Adult stem cells, or somatic stem cells (cells of the body), are stem cells found in blood,
blood vessels, bone marrow, skeletal muscles, brain, skin, liver, intestines3 – all after
embryonic development. This means ASCs are found amongst differentiated cells
specialised for the functions of that tissue or organ. The role of ASCs is thus to maintain and
repair the tissue in which they originate. The hematopoietic stem cell is an example to
demonstrate this: most red blood cells only live for one hundred and twenty days and so the
hematopoietic stem cell is to differentiate into red blood cells, replenishing them once they
die. Until needed, though, ASCs remain in a quiescent state, where they do not divide3.
However, an implication of their role is that ASCs are limited to developing into a cell of the
tissue in which they reside i.e. they are multipotent. For example, it is believed a stem cell
found in the liver can only develop into a liver cell, but newer investigations, such as those
by Murrell et al, are trying to prove otherwise. Moreover, there are only very few ASCs in
each tissue and once extracted their ability to divide is somewhat limited, meaning large
quantities are harder to culture. This raises doubts over the versatility in their use in
Medicine. Nevertheless, they play a vital role in many treatments today, an example of
which is a bone marrow transplant, where it is the stem cells that rebuild the damaged
immune system of patients with leukaemia6.[See Figure 4]
Figure 4. Hematopoietic Stem Cell Transplant
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Foetal stem cells are the stem cells found in the organs of a foetus but also include cord
blood stem cells. Cord blood is the residual blood in the umbilical cord and the placenta
after birth and is a rich source of stem cells, with the potential to develop into blood cells
and cells of the immune system7. Cord blood can be collected by syringing blood out of the
placenta and the umbilical cord for storage in a public cord blood bank. The stored cord
blood can then be used for hematopoietic stem cell transplants in babies with severe
combined immunodeficiency, who would otherwise die from an increased susceptibility to
recurrent infections, as a result of defective genes in B and T cells of the immune system8. A
disadvantage of cord blood stem cells is that there are not enough in a single collection of
cord blood to support an adult transplantation. However, it is now thought that cord blood
stem cells have the potential to differentiate into cells beyond the blood and immune
system, opening up new avenues of treatment for other diseases.
DISCUSSION: FUTURE DEVELOPMENTS IN MEDICINE
A relatively new method for culturing stem cells is therapeutic cloning, or somatic cell
nuclear transfer (SCNT). For this process, women donate unfertilised eggs, from which
researchers remove the nucleus containing the woman’s genetic material, leaving a
deprogrammed egg cell9. The scientists then take any somatic cell and extract its nucleus
containing the patient’s genetic coding. The rest of this somatic cell is discarded but the
nucleus is kept and is inserted into the empty egg. By means of an electric shock, the fused
cell is stimulated to undergo mitotic divisions, much like a zygote self-regenerating after
conception10. [See figure 5] After several divisions a blastocyst is formed, with the
embryoblast being a rich source of pluripotent ESCs. With the genes in these cells matching
those of the patient, the ESCs produced from therapeutic cloning can be used to treat many
diseases, such as diabetes mellitus, and it is this particular notion we wish to explore in this
section.
Figure 5. Process of Therapeutic Cloning
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Before we can propose our ideas of stem cell
treatment for diabetes, we need to consider
what the disease is. Diabetes mellitus is a
condition characterised by abnormally high
levels of glucose in the blood, due to a lack of
insulin
production
and/or
insulin
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resistance . Insulin is a hormone produced
in the pancreas, a gland located behind the
stomach. The pancreas contains endocrine
(hormone producing) regions, known as
islets of Langerhans. [See figure 6] The islets
of Langerhans consist of several types of cell
Figure 6. Histology
– one of these is beta cells12, which produce
of the Pancreas
and secrete the hormone insulin. Insulin is
needed to regulate blood glucose levels by encouraging the uptake of glucose in body cells
for use in metabolic reactions i.e. respiration. Type one diabetes is when the body’s immune
system no longer recognises beta cells as self, destroying them. Consequently, insufficient
insulin is produced and glucose cannot be assimilated, thus accumulating in the blood. Type
two diabetes is a result of body cells responding ineffectively to insulin. This is known as
insulin resistance, and sometimes this is combined with a deficiency in insulin production
and secretion (perhaps due to a decrease in beta cell mass) leading to raised blood glucose
levels.
One possible application of stem cells to treat
diabetes is the use of “spare” embryos obtained
from In Vitro Fertilisation. The zygote should be
allowed to divide by mitosis until the blastocyst is
formed. ESCs should then be extracted and isolated
from the embryoblast of the blastocyst and placed
in a culture dish. The medium in which they are
placed in would stimulate their division, but not
differentiation at this stage, forming clusters of
cells, known as embryoid bodies [See figure 7.]
Figure 7. Embryoid Bodies
With the addition of the appropriate chemical substances and signalling13, these clusters can
form endodermal (precursor) cells and then pancreatic progenitor cells i.e. multipotent
pancreatic cells. The differentiation of these cells would then have to be further directed to
form insulin producing beta cells, by adding the correct growth factors. It could then be
possible to perform stem cell transplants, in which the dysfunctional beta cells of a diabetic
are replaced with functioning beta cells from an embryonic stem cell line. The beta cells
would now secrete insulin to regulate glucose levels in the blood. However, a drawback of
this would be a risk of rejection of the new cells, although this might be controllable by
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immunosuppressive drugs – but these have their own detriments, such as increasing
susceptibility to infection.
An alternative method which may overcome this risk of rejection would involve the use of
therapeutic cloning. To do this, one would have to fuse the genes of a patient, obtained
from the nucleus of a beta cell, with a donated egg, from which its nucleus has been
removed. The fused cell would then be placed in a culture medium and stimulated to divide,
much in the same way as the preceding method. In theory, however, no further directed
differentiation of the cells would be required, as the genetic material obtained from the
patient is from a beta cell, which (although it has the same DNA as any other cell) has the
gene, Insulin promoter factor 1 (Ipf1), expressed for the coding of insulin production14. This
means that the genes of the new beta cells match those of the patient and the risk of
rejection is minimised. However, the question mark lies over whether, by using the patient’s
genes from a beta cell, a defect in insulin production is carried forward.
So, a way to bypass this possible complication would be to fuse the genes of any somatic cell
taken from the patient with a donated egg, from which its nucleus has been removed. This
still maintains the benefit of producing beta cells with matching genes to the patient, but
overcomes a potential reproduction of beta cells that secrete insufficient insulin. Despite
this, extra steps may be required to direct the differentiation of the embryonic stem cells
into beta cells.
A further alternative to any of these methods would be to turn our focus on stimulating
somatic stem cells to become beta cells15. One would have to find and extract stem cells
from the pancreas of the patient and then stimulate these to divide and differentiate. An
advantage of this method is that the stem cells found are highly likely to be multipotent –
that is they can only differentiate into pancreatic cells. Whether there are many somatic
stem cells in the pancreas, and their viability to be extracted, is questionable however.
A more advanced technique would incorporate the use of induced pluripotent stem cell
lines, by exposing adult cells to the correct genetic factors, returning them to a pluripotent
stem cell like state. This creates possibilities of regenerating an entire gland, such as the
pancreas, for transplantation.
Not only could it be possible to treat diabetes directly using stem cells, but it may be
possible to treat associated symptoms, such as erectile dysfunction in male diabetics.
Erectile dysfunction, or impotency, is the repeated inability to develop or maintain an
erection, caused by damage to the controlling nerves (neuropathy) and blood vessels, and is
likely to occur ten to fifteen years earlier in males with diabetes16. A possible utilisation of
stem cells could be to direct the differentiation of embryoid bodies into the appropriate
nerve cells and endothelial cells of blood vessels, to replace those that are damaged. This
restoration of endothelial cells could be expanded to treat diabetic retinopathy and
maculopathy.
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Although our proposed uses of stem cell research may revolutionise treatment for diabetes,
they carry several ethical implications. Before we explore these, let us define ethics:
(Used with a singular or plural verb) a system of moral principles: the ethics of a culture.
The rules of conduct recognised in respect to a particular class of human actions or a
particular group, culture, etc.: medical ethics; Christian ethics.
Moral principles, as of an individual: His ethics forbade betrayal of a confidence.
(Usually used with a singular verb) the branch of philosophy dealing with values relating to
human conduct, with respect to the rightness and wrongness of certain actions and to the
goodness and badness of the motives and ends of such actions.
(oxforddictionary.com)
To demonstrate the severity of this particular part of the argument for stem cell research,
we have discovered an article that shows how much consideration has been put into this by
world leaders.
The Senate Vote and presidential veto, July 2006
On July 18, 2006, the US Senate voted to expand federal funding of embryonic stem cell
research, passing a bill that had passed the House the year before. The next day President
Bush, as he promised to do, vetoed the bill, the first of his administration. President Bush, at
a news conference at the White House explaining his veto, said the bill would be ‘crossing a
moral line and would support the taking of innocent human life’. He was surrounded by
dozens of Snowflake children, born from embryo-adoption programs, and by their parents.
‘These boys and girls are not spare parts’, the President affirmed.
Representative Nancy Pelosi of California, the house minority leader, retorted that
Bush’s veto was ‘saying “no” to hope’. And Senator Orrin Hatch agreed, saying the veto ‘sets
back embryonic stem cell research another year or so.’
(Gregory Pence, Classic Cases in MEDICAL ETHICS fifth edition, page 130).
The question here is whether embryonic stem cell research is actually crossing the line. And
even if it is, how are those lines to be decided. Medical ethics has become such an
important factor in modern society concerning multiple issues such as abortion and
euthanasia. Like these, stem cell research also provides a huge source for debates based on
the subjects, where different moral and ethical systems clash or agree over the on-going
research. The use of stem cells in science offers the very great opportunity of treating life
threatening diseases, so people may wonder how in any way some may oppose this.
Instantly we can recognise two main moral problems of using stem cells. Firstly, using
totipotent stem cells means that the actual developing embryo must be destroyed to
harvest the stem cells. Secondly there are risks involved when using these, as the
pluripotent cells are reprogrammed (adult stage) so that they must ‘forget’ their previous
role. The body produces a stem cell for every cell with a defined role but not all adult stage
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cells act in a similar way and some of the reprogrammed stem cells can return to their
earlier state but in an uninhibited way. So, in essence, instead of actually curing a patient’s
defective tissue, the uncontrolled cells end up turning into tumours (teratomas). The actual
challenge for stem cell scientists is to zero adult stem cells to behave like embryonic stage
cells. Azim Surani (Cambridge University) said that ‘it is relatively easy to grow an entire
plant from a small cutting, something which seems inconceivable in humans. Yet this study
brings us tantalisingly close to using types of skin cells to grow many different types of
human tissues’ (The Times, 21 November 2007).
To further our understanding of the ethical issues behind stem cell research, it is important
to look at what different ethical systems think of this matter. Consequentialism is the theory
that moral decisions should be made based on the outcome or consequences of the event.
Therefore it is no doubt that the aim of consequentialists is to find adult stage cells which
are totipotent. Act utilitarian consequentialists consider the likely consequences of actions
and make a decision based on this. They also offer several considerations in the use of stem
cells. They say that the success of using pluripotent cells at the moment is very low (1 in
5,000 cells in one recent case) but it might be worth gambling that in a particular case a
positive outcome might be achieved. Therefore, by the continual use of these cells and
improving the knowledge we have, the chances of success in the long term are vastly
improved. So, as this advancement in science would bring the greatest amount of happiness
for the greatest number of people, the principle of Utilitarianism, then maybe stem cell
research could actually be justified.
Natural law deontologists sustain the view that innocent human life should always be
protected and preserved. In the teachings of the modern Roman Catholic Church, an
innocent life is considered to come into existence right at the moment of conception. They
use the Aristotelian distinction between being an actual and potential person. The embryo
as a potential human being will, considering all things being equal, become a person or
persons and should then be given the respect and dignity of a person. Many would look to
teachings from the bible such as Ecclesiastes 7:13 ‘consider what God has done: Who can
straighten what he has made crooked?’ This is implying that modern day scientists should
not change or partake in altering the creation of God, as he himself intended a person to be
in the state they are in. However some have argued that some blastocysts naturally stop
developing at a few days old. In this case it would be accepted to use embryonic stage cells
as their loss would not be killing an embryo which has no vital organs, no brain and no
potential to become a human being. The Roman Catholic Church rejects this argument
because this only treats the physical aspect of the embryo. To them, an embryo is like all
human beings, psychosomatic (means literally spirit in the body, the soul or spirit is the lifeprinciple of the body) whole and it cannot be said for sure that a body actually has no “soul”
until it is dead. Pope John Paul II said:
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Therefore at no moment in its development can the embryo be the subject of tests that are
not beneficial or of experimentation that would inevitably lead to its destruction or
mutilation or irreversibly damage it, for man’s nature itself would be mocked and wounded.
(John Paul II, Society Must Protect Embryos, address to a
working party on the legal and clinical aspects of the Human Genome Project, 1993)
Paul Ramsey said “Men ought not to play God before they learn to be men, and after they
have learned to be men, they will not play God”, (Fabricated Man, pg 138).
Kantian deontologists are philosophers who follow the teachings of Immanuel Kant, a
German philosopher from the 18th Century. They might argue from two positions. The first
of these might be that they would not want to be experimented on or discarded as an
embryo; they would therefore not wish the same fate upon others. Thus, through the
categorical imperative it now becomes a universal duty to protect all embryonic human life.
The first position is reinforced by the second position that as it is never right to treat people
as a means to an end, but an end in themselves, then the use of embryonic stage cells
should be rejected as it treats the early embryo as a resource to be cannibalised and not as
a person. However, the fundamental problem with the Kantian position is highlighted by the
third version of the imperative which is that in the kingdom of ends everyone is a law-maker
whose decisions take into account all other human beings as law-makers. But the status of
the early embryo could hardly enable it to be considered to be a rational, even sentient,
member of the kingdom of ends. A Kantian might argue for the protection of all the weak
but, as the early embryo displays no rational features at all, then it ceases to be a matter of
moral concern.
CONCLUSION
Ethics is clearly a very important issue when it comes to stem cell research. Everything that
we do that is in any way related to this topic will consequentially have implications that
have to be dealt with sensitively. There are many different viewpoints from many different
systems of ethics that would determine what route we should take. Clearly with every step
taken in modern science, ethics and morality is as important as the method taken to
progress to a scientific conclusion on the matter.
Should our suggested methods and applications of stem cell research in the treatment of
diabetes be developed, a significant positive impact and improvement in quality of life for
patients with diabetes could be made: the need for insulin injection could be eliminated,
and erectile function in male diabetics could be restored. Conversely, what is to say that,
after having a beta stem cell transplant, the immune system of a type one diabetic will not
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destroy the newly implanted beta cells? And will the muscle cells of a type two diabetic be
resistant to the insulin secreted by new beta cells? Moreover, there are potential risks of
using stem cells, such as the danger of them becoming cancerous in a laboratory. The
induced stem cells could form an insulinoma: a tumour that secretes excessive insulin,
leading to hypoglycaemia. Nevertheless, with rapid advancements in stem cell technology,
the once believed irrevocable diseases could become revocable, and a cure for diabetes
may well be within striking distance.
REFERENCES
1) Properties of stem cells:
http://www.csa.com/discoveryguides/stemcell/overview.php
2) Potency of stem cells:
http://en.wikipedia.org/wiki/Cell_potency
3) Embryonic stem cells:
http://www.medicalnewstoday.com/info/stem_cell/
4) Research by James Thomson (1998) and (2007):
http://stemcells.wisc.edu/faculty/thomson.html
5) Journal of Immunology (2005), stem cells in cancer therapies:
http://www.jimmunol.org/content/182/11/7287.abstract
6) Adult stem cells in bone marrow transplants:
http://www.newscientist.com/article/dn9982-instant-expert-stem-cells.html
7) Cord blood stem cells:
http://www.explorestemcells.co.uk/cordbloodstemcells.html
8) Stem cells in Severe Combined Immunodeficiency Syndrome:
http://www.scid.net/
9) Somatic Cell Nuclear Transfer:
http://en.wikipedia.org/wiki/Somatic-cell_nuclear_transfer
10) Therapeutic Cloning:
http://www.explorestemcells.co.uk/therapeuticcloning.html
11) Information on Diabetes:
Bilous, R. (1996) Understanding Diabetes in association with the BMA
12) Beta cells:
http://www.betacellsindiabetes.org/podcast/beta-cell-pathophysiology-and-itsrelevance-primary-care
13) Directing differentiation towards Beta cells:
http://www.nature.com/nchembio/journal/v5/n4/full/nchembio0409-195.html
14) Insulin promoter factor 1:
http://en.wikipedia.org/wiki/PDX1
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15) Adult stem cells in diabetes:
http://stemcells.nih.gov/info/scireport/chapter7.asp
16) Erectile dysfunction in diabetics:
http://www.diabetes.co.uk/diabetes-erectile-dysfunction.html
17) Sochaki, F and Kennedy P-OCR Biology AS
18) http://en.wikipedia.org/wiki/Stem_cell_controversy
19) http://www.globethics.net/?gclid=CKLRgY7t6a4CFQITfAodi1gbKA
20) http://plato.stanford.edu/entries/stem-cells/
21) http://www.eurostemcell.org/factsheet/embyronic-stem-cell-research-ethicaldilemma
22)http://www.religioustolerance.org/res_stem.htm
23) Wilcockson, M-Medical Ethics
24) Pence, G-Classics Cases in Medical Ethics
25) Surani, A-Cambridge University, The Times
26) Ramsey, P-The Fabricated Man
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