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REGENERATIVE MEDICINE-­‐ CONTROVERSIAL, PROGRESSIVE, THE FUTURE. IS STEM CELL THERAPY THE KEY TO CRACKING DEMENTIA? BY MATTHEW BILLINGTON HARRY CRAIG ALEXANDER HALL Grade awarded: Pass RESEARCH PAPER BASED ON PATHOLOGY LECTURES AT MEDLINK and VET-­‐MEDLINK 2014 Abstract
“Dementia affects over 830,000 people in the UK.” [1]
Alzheimer’s disease is the most common form of dementia. It doesn’t discriminate on the age of its victims, with
Early Onset Alzheimer’s, affecting people in their 30’s and 40’s, accounting for 5% of its victims. It is distressing
for the sufferer and heartbreaking for the family surrounding the sufferer.
Neurodegenerative diseases, such as Alzheimer’s are becoming more prevalent in our society as our aging
population increases. The current dementia drugs available only suppress the symptoms in the short term. The
race is on to halt Alzheimer’s in its tracks. Current research using stem cells to crack dementia is gathering pace. Is
it possible that we could be on the brink of shackling the full potential of stem cells to finally find a cure for
dementia?
Introduction
Our paper will be exploring the developments in embryonic stem cell research, alongside other
types of stem cells such as adult, and induced pluripotent (iPS). Looking at their significance
and relevance to medicine; in particular, their potential in finding a cure for Alzheimer’s
disease.
We will firstly be investigating present cases, where the use of stem cell therapy has been
successful in humans and why these are significant in our efforts to fully harness the potential
of stem cells, to find cures for neurodegenerative diseases and the related ethical concerns.
We will continue our investigation looking into stem cell pathology research on animals, in our
effort to find a cure for Alzheimer’s.
Finally, we aim to scrutinize to what extend human stem cell research has progressed over
recent years and how close we are to finding a cure.
Embryonic stem cells are derived from the inner cell mass of an embryo up to 5 days old (a
blastocyst). Embryonic stem cells are said to be pluripotent- they are able to differentiate in to
all the different types of cells in the body.
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In 2006, Shinya Yamanaka made a groundbreaking discovery; he discovered a third type of stem cell, Induced Pluripotent Stem Cells, these are somatic, adult stem cells and have been reprogrammed, taking them back in to a pluripotent state. The following video explains Yamanaka’s discovery.
https://www.youtube.com/watch?v=0pXea2D_9OU&feature=player_embedded [2] Scientists are currently experimenting with both iPS and embryonic stem cells to gain an understanding of how specialised cells are formed from pluripotent cells; they are working towards an understanding of how to produce an unlimited supply of replacement cells, to treat people with currently untreatable diseases, such as Alzheimer’s. Figure 1 illustrates the process in which iPS can be used to reprogramme certain cells and hopefully find a cure for certain medical conditions. 3
Figure 1. Alzheimer’s is a neurodegenerative disease, affecting cells in many parts of the brain. One of
the main causes is down to an abnormal build up of certain proteins in the brain, mainly
amyloid beta and tau. This clump together forming plaques and gets twisted into protein
‘tangles’. The plaques prevent nerve cells inside the body communicating properly and the
tangles make it challenging for the cells to get the nutrients they need. The consequences of
having Alzheimer’s are distressing, it causes the sufferer to lose their ability to learn, remember
things, make reasoned judgements, communicate, and carry out their normal daily routine. [3]
Regenerative medicine that use stem cell-based therapies, seek to regulate the innate process by
which new nerve cells are generated. Neurogenesis, although most active during pre-natal
development and considered a rather inactive process in most areas of the human brain, has
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been shown to continue in several small areas, including the hippocampus and the subventricular zone, suggesting the potential to reverse cognitive damage, such as that which
occurs in Alzheimer’s.
This was initially revealed by Professor Perry Bartlett [3], in his laboratory's discovery in 1992,
that the presence of stem cells in the adult brain had the capacity to produce new neurons.
Professor Samuel Weiss also, “In 1992 discovered neural stem cells in the brains of adult
mammals. The groundbreaking discovery that dispelled dogmas that the brain cannot
regenerate, has led to new approaches for brain cell replacement and repair”. [4].
Our paper will investigate at what stage we are at in using regenerative medicine, to combat
Alzheimer’s disease, and how far we still have to go. Ethical concerns will be addressed
throughout.
Successes in Regenerative medicine.
In 2008, the first tissue-engineered trachea (windpipe), utilizing the patient's own stem cells,
was successfully transplanted into a young woman with a failing airway. The bioengineered
trachea immediately provided the patient with a normally functioning airway. Professor
Macchiarini, lead author on the paper, said: "We are terribly excited by these results. Just four
days after transplantation the graft was almost indistinguishable from adjacent normal bronchi.
After one month, a biopsy elicited local bleeding, indicating that the blood vessels had already
grown back successfully" [5].
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A team of three eye specialists lead by Yasuo Kurimoto of the Kobe City Medical Center General Hospital, transplanted a 1.3 by 3.0 millimetre sheet of retinal pigment epithelium cells into a lady who suffered from age-­‐related macular degeneration. Ophthalmologist Masayo Takahashi had derived them from the patient's own skin cells, after producing induced pluripotent stem (iPS) cells and then getting them to differentiate into retinal cells. Afterwards, the patient experienced no serious problems. [6] Cases such as these give us great hope for eventually finding a regenerative therapy cure for
Alzheimer’s disease.
The greatest related ethical issues are, preventing suffering and preserving the sanctity of life.
A recent survey by the PEW Research Centre uncovered that 22% of US Citizens [7] believe
that using embryonic stem cells for research is morally wrong. This is due to the method used
to derive embryonic stem cells, they are attained from the undifferentiated inner cells of a very
early human embryo and thus destroying the embryo. “ The human embryo… is not to be
destroyed or seen as disposable tissue that can be used in research” Thomas A.Shannon [8].
However, the advantage of using embryonic stem cells, is that they are pluripotent and can
differentiate into all types of the three primary germ layers- See figure [2] below:
Ectoderm-­‐ the development of the ectoderm is called neurulation as it gives rise to the central nervous system and all related. • Endoderm-­‐ is the inner part of all the germ layers and gives rise to the epithelial linings of organs such as the liver. • Mesoderm-­‐ is the middle part of the three germ layers and gives rise to bone, connective tissue and muscle. As a result they can become more than 220 cell types.
•
Figure 2
Taking this into account The UK Human Fertilisation and Embryology act of 2008 stated that
research was allowed on embryos for up to 14 days given that in future it may benefit other
embryos and improve our future quality of life.
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In comparison, adult stem cells are less problematic as they do not involve the destruction of
embryos in their derivation. They can be derived from multiple organs and tissues in a specific
area called ‘the stem cell niche’. As a result of this they are more widely accepted as a means for
research. Although there are practical disadvantages, unlike embryonic stem cells they are often
restricted to certain lineages and are therefore not pluripotent. If, however, we use the certain
adult stem cell for the lineage needed then there is no need for the stem cell to be able to
transdifferentiate For example, in the 1990s scientist were in agreement that the adult brain
does contain stem cells which can differentiate into the brains major three cell types:
Astrocytes Oligodendrocytes Neurons Neural stem cells can also be derived from hair follicles (see figure 3 below) and as they can
rise to give brain tissue it is believed that in future we can apply this to cure neurodegenerative
disease such as Alzheimer’s. This is currently being tested for by Eva Feldman, M.D. after the
tests that she conducted for ALS (amyotrophic lateral sclerosis) [9]. Furthermore as the brain
can be injected with more stem cells she strongly believes that the benefits will come faster and
be greater. We believe this is possible as the hair follicle is dynamic, and therefore throughout
its life, it cycles through the stages of anagen, catagen and telogen. During the anagen phase a
nestin-expressing hair follicle stem cell can differentiate into neurons and therefore with future
development there is the possibility for this to be used in regenerative medicine. However, this
leads on to another difficulty with using adult stem cells. When using adult stem cell therapy it
requires a stem cell source of the specific lineage needed, which makes harvesting enough stem
cells for the treatment to work difficult.
•
•
•
Figure 3
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Pathology Research on Animals Alzheimer's is identified by two abnormal protein deposits in the brain. The deposition inside nerve cells of abnormal tau proteins into structures called tangles; along with the accumulation outside abnormally folded amyloid protein into plaques. Researchers working on cures for Alzheimer’s have observed plaque and tangle pathology within model organisms such as fruit flies, mice and primates. This section will summarise the progress made in recent years. “Recent progress shows that neurons suitable for transplantation can be generated from stem cells in culture, and that the adult brain produces new neurons from its own stem cells in response to injury.” [10] These findings have spurred on the campaign to use stem cell therapy to find a solution to neurodegenerative disorders. However, it is not always possible to research the use of new potential cures using computer simulations, as symptoms need to be seen, accessed and monitored. Therefore, before researchers can begin clinical trials on humans there is a need to test their laboratory cultured cells on animals. “We need to know much more about how to control stem cell proliferation and differentiation into specific phenotypes, induce their integration into existing neural and synaptic circuits, and optimize functional recovery in animal models closely resembling the human disease.” [11] Animals have been used for testing and trialling medical procedures for generations. However, opponents of animal research argue that it is unethical to cause suffering to animals for the benefit of humans. This opposition has led to laws being created setting down guidelines which medical researchers must adhere to, “The law covers any scientific procedure which might cause an animal pain, suffering, distress or lasting harm. A procedure is only permitted when its likely benefits outweigh any pain or distress to the animals, and where there are no alternatives.” [12] Keeping within the boundaries laid down researchers have conducted research on: fruit flies, as there is no restriction on their use; monkeys, as their brains are the most similar in memory and cognitive functions as human brains; and also mice. In 2007, Yamanaka reprogrammed the skin cells of mice to produce, Induced Pluripotent Stem Cells (IPS). This work was developed further in 2012 by a Spanish research team who reprogrammed adult cells in live mice, to revert to stem cells, which are as potent as embryonic stem cells (ES). Maria Abad, from the Spanish team said, “The team believes the achievement brings the potential to use stem cell technology in regenerative medicine a step closer.”[13] “The development of human pluripotent stem cells has opened up the possibility to analyse the function of human cells and tissues in animal hosts, thus generating chimeras. Although such lines of research have great potential for both basic and translational science, they also raise unique ethical issues that must be considered.” [14] Summary of recent stem cell therapy studies on animal models of Alzheimer’s.
[15]
Study
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Types of stem
Animal
Transplant site
Outcome
cells transplanted
Babaei et al.
(2012)
Murine- bone
marrow
mesenchymal
stem cell
1. Aged rats (30
months)
Hippocampus
(CA-1 region)
2. Ibo-induced
memory
impairment
group—
significant
reduction in
latency to find
platform in
Morris Water
Maze
2. Ibotenic
acid-induced
NBM lesion rats
Kim et al. (2012)
Park et al. (2012)
Human adiposederived stem cell
human neural
stem cell
Transgenic ADmodel mice
(Tg2576)
1. Aged rats—
learn more
rapidly
1. Intravenous
Both intravenous
and intracerebral
transplantation
rescued memory
impairment and
improved spatial
learning;
2.
Hippocampus
(bilateral dentate
gyrus)
Reduced amyloid
plaque
formation,
upregulated
interleukin-10
and neurotrophic
factors in the
brain of Tg2576
mice
Right lateral
ventricle
Rats receiving
human neural
stem cells
overexpressing
cholineacetyltransferase
showed full
recovery in
learning and
memory
functions,
whereas those
receiving NSCs
AF64A
cholinotoxin
injection in rats
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only remained
memory
impaired
Monkey’s brains are so similar to human brains in memory and cognition, which makes them the ideal primate to use to test possible human reactions on. Monkeys do not appear to suffer from Alzheimer’s however, it is possible to induce memory loss in monkeys and then test stem cell therapies. Drosophila models of human neurodegenerative diseases can make a significant contribution to the unmet need of disease-­‐modifying therapeutic intervention for the treatment of these increasingly common neurodegenerative conditions. [16] The nervous system of a fruit fly, although a great deal smaller, is very similar to the human nervous system. Scientists are able to manipulate stem cells, place them in to the fruit flies and observe the reaction. Fruit flies have a life span of only a few months so the changes can be very rapid. “Basic research, most of it involving animals, is needed to understand: how to get a pure sample of stem cells out of the mixture of cell types in an organ such as a brain; how to persuade new stem cells to go to the areas where they are needed – in most kinds of dementia, the damage in the brain is not limited to one area; how to get the new cells to work with other brain cells; and how to make sure that stem cells don’t keep on making too many cells, causing cancer.” [17] Research using stem cells to replace defective and dead nerve cells in the brain is still at a very early stage. That said, a team of researchers at King's College London have developed a line of human spinal cord neural stem cells that can develop into all types of neurons, they have normal chromosomes and behave normally when introduced into animal models. Will the next step be to attempt to replace human brain nerve cells? In all studies, the assessments of cognitive improvement were performed only shortly after stem cell transplantation without much follow-­‐up. As Alzheimer’s is a progressive disease, longer term studies are needed to look at lasting effects as well as safety profile of the treatments [18] The Application of Current Stem Cell Research in finding a cure for Alzheimer’s disease.
To be able to find a successful cure for Alzheimer’s it is essential that clinical tests on all drugs
which have the potential of curing for the disease are conducted, as no animal truly mimics the
human disease. So far, scientist’s most effective method is disease modeling, which allows
scientists to explore how the disease works in the laboratory rather than directly in the patient.
It also allows us to obtain an accurate representation of the abnormal human biology of brain
cells that occur in the disease. These brain cells can then interact with potential restorative or
healing drugs in a disease dish, where the conditions mimic a human disease. This technology
has improved vastly over recent years, as we can see the effect of the drug in a matter of
minutes in comparison to the previous nine months. This allows researchers to test potential
therapies more accurately and quickly, which in turn means they can conduct many more tests,
therefore improving the validity of the test. This is essential for results to be considered
reliable.
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Dr Selina Wray of University College London was awarded £900,000 in 2014 to conduct a
groundbreaking stem cell study [19] to develop new treatments for dementia. Scientists were
challenged to use the latest stem cell techniques to create a cell model of dementia to be used
for drug screening.
Dr Wray and her team are using skin cells from people with dementia and turning them into
working nerve cells. They have seen that the cells recreate the build up of tau and are working
to find drugs which are able to halt this process.
In February 2012, Mason Israel and his colleagues published an iPS disease modeling. They
created the iPS cells by using skin samples that had been taken from Alzheimer’s patients, as
well as a control group without the disease. Over a period of eight weeks, they made nerve
cells in the lab form the skin cells. They purified the samples and compared the patient’s
results with the control group. The study successfully distinguished between the different cells.
Therefore, this method can work towards developing an effective treatment. [20]
Researchers are trying to engineer several new methods to improve stem cell function. So far,
the most impressive drug is, Brain Derived Neurotropic Factor (BDNF), this pushes the stem
cells to generate more new nerve cells. (21)
Scientists at The New York Stem Cell Foundation laboratory have developed a cell-­‐based model of Alzheimer’s disease. “In this initiative led by Scott Noggle, PhD, the researchers reprogrammed cells of early-­‐onset patients into induced pluripotent stem cells to create cholinergic basal forebrain neurons (the cells affected in Alzheimer’s). These cells demonstrate the features of the disease on a cellular level, creating a viable disease model that will be critical for drug discovery and testing. Preliminary results have demonstrated differences in cellular function in patients. Alzheimer’s neurons produced more of the toxic form of beta amyloid, the protein found in amyloid plaques, than healthy neurons.” [22] Notwithstanding the current research, there are still many complexities that need to be overcome before we can apply the research of stem cells to humans. Scientists are working with new types of iPS cells all the time. It is essential that more research is needed to develop a greater understanding of the reprogramming process and the effect it has on cells, in order to find out potential uses and risks. It is very difficult to recreate a disease accurately, even though researchers aim to recreate features in the laboratory, by generating cells with the patient’s genetic code, it does not always result in cells that have the exact characteristics of the disease. It is not only mutations in the DNA code that causes the disease, but other biological and environmental influences can have an effect. Researchers must build much more complex structures to display these aspects of disease more completely. The final concern is that we need to find a way for the brain to have the ability to integrate new neurons, once Alzheimer’s has taken hold. We must avoid the transplanted stem cells being damaged by the amyloid and tau proteins building up in the brain, which would result in a transplant of new cells only having a temporary effect. [23] Overall, iPS cells give the most hope for developing future therapies, as researchers can now
study human cells that were previously inaccessible. We can now obtain nerve cells of the
brain and the disease modeling provides a stepping-stone towards a better understanding of
how the disease works. [20]
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This latest findings, hold great promise to the millions of suffers and their families.
Conclusion
It is clear to see that the race to find a cure for Alzheimer’s disease using Stem Cell Therapy is
gaining momentum. Governments have identified Alzheimer’s as disease that must be
combated; with our aging society, more of the population are falling victim to this disabling
and currently incurable disease. It is having a massive global financial impact, both in caring for
sufferers but also due to it prohibiting otherwise healthy people from working and making a
contribution to society. The governments of many countries are providing large grants to
support the research into regenerative therapy to find a cure for Alzheimer’s.
There is no question that we have come a long way since 1963 when self renewing stem cells in
mice were discovered. Stem Cell research has enabled scientists to monitor how diseases
develop and to create treatments for a variety of conditions. The long term aim is to use stem
cell therapy to enhance health, lengthen life, and reduce the burdens of illness and disability.
Notwithstanding these aims, there are many ethical hurdles to jump; many believe that human
life begins at conception and that blastocysts should not be destroyed to extract embryonic
stem cells, even if the embryo is not wanted or needed. In the case of animals there are those
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who campaign against animal cruelty and claim that the degree of suffering and destruction to
large numbers of animals during medical research is so high that the benefits to humanity don't
provide moral justification for their use. The question, “Are we playing God?” Is it wrong for
us to try to prevent the natural course of life and death? Will we eventually try to cheat death
and prolong life unnaturally? Hypothetically if we learn how to regenerate all cells will we be
able to live forever?
Working within the guidelines set out to protect unnecessary animal testing (the 3Rs) Babaei et
al, Kim et al and Park et al in 2012 have had success in transplanting stem cells into the
Hippocampus, intravenously, and into the right ventricle, and have shown aged mice can learn
more, have improved special awareness, and have shown recovery in learning and memory
functions. This research has given us great hope for prospective human trials.
Major issues still to surmount are: how to target stem cells to the areas of the brain which need
regeneration, dementia is not restricted to one area of the brain; scientists also need to learn
how to teach the cells to stop reproducing; finally, how to prevent the new cells falling foul of
developing new plaques and tangles. Additionally, understanding stem cell differentiation
pathways, migration through the body and safety issues are aspects of research that are vital.
The goal of stem cell research is to find a way to regenerate and successfully replace large
numbers of lost cells. Stem cell therapy is an exciting and rapidly developing field of medicine.
Imagine a world where worn out or damaged organs of the body can be routinely replaced and
there is no waiting for donors; where victims of spinal cord injuries can walk again; where
suffers of neurodegenerative diseases can be completely cured using the patient’s own stem
cells, with few risks of negative side effects. It seems like a fantasy, but step by step scientists
are unravelling the potential of stem cells and we are beginning see light at the end of the
tunnel.
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References
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Figures
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http://www.eurostemcell.org/factsheet/reprogramming 2
http://crescentok.com/staff/jaskew/isr/botzo/germlayer.gif
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http://haireng.dmax.kr/img/res5.jpg
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