Figure 1 -

How can stem cells be used to treat neurodegenerative diseases such as Dementia and do the advantages of using stem cells outweigh the complications, ethical issues and other associated disadvantages involved? By Jennifer Holden Grade awarded: Pass This research paper will evaluate the issues of Neurodegeneration and how possible new treatments for Dementia a particularly prevalent Neurodegenerative disease can be found using stem cells. It is thought that Dementia is caused by the death of cells in the Brain, which is why the introduction of stem cells can provide such a useful treatment for this disease. However, like with any new treatment on the market, it comes with advantages and disadvantages. For example, advantages of stem cell treatment can include the wide availability of stem cells in the body and the ability to use stem cells as a research mechanism to find out more about the disease and possible treatments. Disadvantages could range from costs and availability of the treatment internationally, to major ethical issues associated with using stem cells. However, ultimately this paper will conclude whether stem cells are a viable treatment or a research mechanism, dependant on whether the advantages outweigh the practical issues and controversial areas. Dementia is a degenerative disease of the Brain. The most common symptom of Dementia is memory loss. This is largely because Dementia is a disease that affects the Hippocampus a part of the Brain that provides us with our memories. The most common form of Dementia is Alzheimer s disease. Dementia is caused by the death of cells in the Hippocampus affecting the cell s ability to send and receive messages from other parts of the Brain thus resulting in the memory loss. This means that very often a Dementia patient will struggle with normal every-day tasks such as how to move, what we are seeing, how to speak (f) and their emotions such as laughing and crying (f). Dementia is most common in the elderly population because as a human grows older, these cells in the hippocampus are more likely to become damaged and eventually get killed. In the UK, around 750,000 people (f) are living with Dementia of which only 16,000 are under the age of 65 (f). These statistics show that although the majority of people living with Dementia are over 65, there are also many who are much younger coping with this disease. However, the causes of Dementia are not limited to Programmed Cell Death (the death of cells due to their age). Causes can range from lifestyle and diet to alcohol abuse or accidents that have involved that particular area of the Head being physically damaged in some way, such as in a car accident. Stem cells are undifferentiated cells that are able to differentiate into other types of stem cells and specialised cells. Stem cells are undifferentiated because they have not yet received the instructions from the DNA to turn certain genes on or off, and so they have the ability to become any type of cell in the body. When a stem cell undergoes cellular division, each new cell has the potential to remain a stem cell or become another type of cell with a more specialized function (h). Adult stem cells are most commonly found in many organs and tissues, including the brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis (g). However, it is possible to extract stem cells from places other than in adult tissues (somatic stem cells). For example, the embryo is considered a useful source of stem cells despite the area of controversy surrounding their use. Embryonic stem cells were first used 30 years ago (h) and since then scientific

research has advanced to use embryonic stem cells in In Vitro Fertilisation (IVF) amongst other things. However, it is only within the last 10 years that Scientists have been able to extract human embryonic stem cells for use in research or even in treatments such as possible cures or treatments for Dementia. Embryonic stem cells are first grown and cultured in a lab using in vitro i.e. eggs that have been fertilized (i) and have then been donated to research with the informed consent of the donors (i). Embryonic stem cells and somatic stem cells differ because embryonic stem cells are referred to as Pluripotent they can become almost any type of cell in the body. However, somatic stem cells are mostly referred to as multipotent because although they are able to differentiate into more than one type of cell in the body, they are limited to differentiating (j) into the cells that are present in their tissues of origin (j). Other differences between the two main types of stem cells found are that embryonic stem cells are easier to culture (j) probably because they are easier to access in a lab or on a culture plate whereas with adult somatic stem cells, the human body has to be entered and the stem cells have to be located and extracted, which is a much more complex and difficult procedure. It is also more difficult to grow adult somatic cells rapidly in culturing than it is with embryonic stem cells as the various methods have not yet been worked out (j). This is particularly important when considering using stem cell treatment for nerve transplants into the Hippocampus to treat dementia: a large number of stem cells would need to be cultured which is clearly more difficult using adult stem cells. As with any transplant into the human body, there are always risks of rejection and it is the same with stem cells. Transplanting embryonic stem cells has had relatively few (j) clinical trials, therefore the success of such transplants are not yet known. Adult stem cells on the other hand, are not thought to react in the same way with the immune response because the patient s own cells are being cultured, differentiated and then re-introduced back into the patient. However, it is possible that the immunosuppressive drugs the patient would be on may cause deteriorating side effects (j) of their own. The Hippocampus is a part of the Brain that is located in the medial temporal lobe of the brain (k). The Hippocampus is divided into two separate structures located on the left and right sides of the Brain shown in Figure 1. The organ is vital in processing long term memories and co-ordinating spatial navigation and therefore plays a significant role in Dementia. For example, in Alzheimer s disease - one of the more common forms of Dementia the Hippocampus is the first organ to experience tissue failure and the death of necessary cells such as neurons, leading to the memory loss and disorientation associated with this condition (k). Furthermore, the Hippocampus is also important in learning new things and more specifically converting short term memory to more permanent memory (l). Therefore, should the Hippocampus tissue cells become damaged by degenerative conditions such as age, the ability to convert short term memories to permanent memories is taken away or significantly reduced; this is one of the reasons why many Dementia sufferers will have the ability to recall memories from their childhood or very old memories as opposed to remembering what they had for breakfast that morning or their activities of the day before. The Hippocampus is located in the Limbic system in the Brain which links the brain stem and the cerebral hemispheres (m) and controls memory and emotions through the Hippocampus and the Amygdala respectively. This links the Hippocampus closely with emotions resulting in many Dementia sufferers to become over-emotional or lacking in feelings (m). However, in forms of Dementia such as Alzheimer s, the Amygdala is generally affected later than the hippocampus (m) and so the person may well be able to feel the emotions of a memory they aren t able to recall. Figure 1 - http://en.wikipedia.org/wiki/henry_molaison#/media/file:hippolobes.gif 2

There are three different types of memory involved in completing daily tasks from remembering people s faces to how to get dressed. The individual degeneration of the different neuron pathways that provide the network for the different memory types cause different symptoms in Dementia patients and can even allow the progression of the Dementia to be diagnosed depending on what stage of memory loss the patient has. The different types of memory are episodic memory, Semantic memory and Procedural memory. Episodic memory is the recollection of an event (m) and involves the different senses. When we experience the event, the information from the senses initially goes into the hippocampus (m) and a short term memory is created by the Hippocampus and stored in the Cerebral Cortex in the form of a network of nerve cells (m). Once the memory is stored in the Cerebral Cortex, it becomes a long term memory. However, memories that have only just entered into the Cerebral Cortex still need the hippocampus to retrieve them (m). In contrast, long term memories such as those from a childhood are more firmly established in the Cerebral Cortex and therefore do not require the Hippocampus to be retrieved as much. This is why Dementia patients who have damage in the Hippocampus region particularly will be much more able to recall long term memories from the Cerebral Cortex as they can be retrieved using less of the Hippocampus, compared to recent memories which require the use of the damaged Hippocampus to be retrieved. Semantic memory also requires the use of the Hippocampus. However, Semantic memory differs from Episodic memory because Semantic memory recalls the general knowledge about objects, word meanings, facts and people (m). Despite these differences, the memories are stored in the same way episodic memories are: by the information entering the Hippocampus and a network of nerve cells being formed which can then be sent to the Cerebral Cortex for long term storage. In this way, a Dementia patient who suffers damage to the Hippocampus will also suffer recent Semantic memory loss. However, as the severity of the disease gradually increases and more of the Brain Cells are affected, the Cerebral Cortex will overall become thinner and therefore long term memories will eventually be lost as well as the short term memories. The Procedural memory type is different to the Episodic and Semantic memory types as it does not require the use of the Hippocampus. Procedural memory is the memory for skills (m), such as learning to ride a bike or tie shoelaces. Procedural memories require the use of the frontal lobes to concentrate (m) allowing a skill to be learnt. Once the skill is learnt, instead of being stored in the Cerebral Cortex, it is stored in the Basal Ganglia (a group of structures between the cerebrum and brain stem (m), the Motor Cortex and the Cerebellum. This is why Dementia sufferers with damage to the Hippocampus will often remember how to complete such practical tasks very well as the Hippocampus is not required for the Procedural 3

Memories to be retrieved. Now that it is recognised that there are different forms of Dementia, it is easier to understand why someone with Dementia might behave in a certain way (m). With the latest technological developments, it is also possible to identify the type of Dementia someone has by using Magnetic Resonance Imaging (MRI) scans which can show areas of reduced activity or loss of brain tissue (m). There are many different forms of Dementia other than Alzheimer s such as Atypical Alzheimer s - a rarer form of the disease, Vascular Dementia and Fronto-temporal Dementia. In Atypical Alzheimer s, the damaged tissues and neurons are not located near the Hippocampus and so the earlier symptoms are different to the more common form of Alzheimer s. For example, in Posterior cortical atrophy (m) (one form of Atypical Alzheimer s), the damage occurs in the Occipital Lobes and parts of the parietal lobes (m) (shown in Figure 2) which process visual information and spatial awareness. Early symptoms of this disease can include difficulty in identifying objects and reading. Depth perception and co-ordination may also be affected. Another form of Dementia is Vascular Dementia which often occurs after a stroke or a series of mini strokes. Vascular Dementia occurs when the blood supply to certain tissues is cut off such as those in a stroke. Fronto-temporal Dementia specifically affects the Frontal lobes and or either the Temporal Lobes. The most common symptoms of Fronto-Temporal Dementia are changes in behaviour and language. Figure 2 - http://www.alzheimers.org.uk/site/scripts/documents_info.php?documentid=114 There are very few case studies of people who have directly benefitted from stem cells being used to directly treat types of Dementia mainly because no stem cell treatments for Alzheimer s disease are yet available (q). However, one case study that has been vital in learning more about Dementia and how the brain is affected by it is Henry Molaison. Molaison s case played a very important role (o) in the developments of such scientific research as the links between Brain function and memory and the development of cognitive neuropsychology (o). For example, studies of Molaison s behaviour led scientists to believe that certain types of memory were more fragile and vulnerable than others, as Molaison was frequently able to draw the whole first floor of his retirement home and yet he lost many of his more recent memories. This allowed scientists to develop the theory that in Dementia, the most recent memories are affected first particularly in Alzheimer s. Henry Molaison suffered from many 4

incurable diseases of the Brain such as Dementia and severe Epilepsy. In an attempt to cure his Epilepsy, surgeons removed the anterior two thirds of his hippocampi, parahippocampal cortices, entorhinal cortices, piriform cortices, and amygdalae (o). Many of the scientists who studied Molaison s case now believe that with the growing evidence from stem cells research, had his diseases not been so complex and been diagnosed much earlier, stem cells could have provided Henry Molaison with a treatment and possible cure, which is why it is so important to invest in stem cell research for the future - to prevent people suffering the way Henry Molaison did throughout his life. There are several different possible approaches to using stem cells to treat Dementia. One possible approach is to directly implant neural stem cells into the affected areas of the Brain in the hope that they would make new, healthy neurons. However this poses several difficulties, as there are numerous neurons in the Brain with so many different neurological pathways that are complex and frequently merge with each other and cross each other. In addition, the neural stem cells would have to be able to travel into the multiple areas of the brain (q) that have been affected (provided they are on the correct neurological pathway), produce the many different types of neurons (q) that would be required to replace all of the cells that have been damaged or killed and they must have the ability to integrate themselves with the brain so they are working efficiently; making connections to replace the lost parts of a complex network (q). Despite these obstacles scientists have been successfully able to implant stem cells into the brains of mice and successfully record significant improvements in memory function. For example a team of scientists made a successful breakthrough in stem cell implantation in mice by using human embryonic stem cells cultured into neural progenitor cells. The scientists first destroyed an area of the brain known as the medial septum in mice (p) and then used the neural progenitor cells to implant into the hippocampus. The neural progenitor cells were then programmed to become cholinergic and GABA neurons (p). According to the scientists, the cholinergic neurons immediately began to "synaptically connect with endogenous neurons" (p) reconnecting the septum and the hippocampus through a short cut. The experiment was successful as the mice scored better in traditional memory tests, suggesting the function of the medial septum had been restored, along with improved hippocampus function (p). However, one of the author s stated that the cells must be pure otherwise tumour growth is possible (shown by previous injections of early progenitor cells). One of the main disadvantages with this type of treatment was that in order to obtain pure progenitor cells, embryonic stem cells are preferred over adult stem cells; unfortunately the usage of embryonic stem cells comes with major ethical issues. Other possible approaches of using stem cells to treat Dementia is using certain types of stem cells to deliver proteins called neurotrophins into the brain. In a fully functioning brain, neurotrophins help the neurons to grow and support them with essential nutrients; however in the brain of a Dementia patient neurotrophic production is much lower allowing the neurons to become more susceptible to damage. Despite having had successful results with mice, like the direct translation route this method must undergo a lot of research and improvements before it can be tested on humans. In the immediate future, a more viable option for using stem cell therapy to treat Dementia is culturing stem cells in a lab where they can be developed into neural stem cells and tested to try and find possible treatments for Dementia. Current research uses induced pluripotent stem cells to do this. These induced pluripotent stem cells are grown by reprogramming specialised cells such as skin cells (r) to produce cells that have the ability to become any type of cell in the human body. An example of using these induced pluripotent stem cells in research is that scientists can develop them into neurons and allow them to develop the key features of Alzheimer s disease (r). Scientists were able to take a sample of cells from an Alzheimer s patient and develop them into induced pluripotent stem cells where they could then grow them into neurons. Scientists discovered these neurons produced beta 5

amyloid proteins (r) that forms plaque in the patient s brain. This allowed the scientists to develop testing on these cells to observe if there were certain materials that reduced the amount of beta amyloid protein produced. Not only could this type of research allow scientists to observe how cells function under Alzheimer s but it also allows scientists to compare the cell biology with the patient s clinical symptoms which could provide key knowledge about how the disease works (r). Areas of controversy surrounding stem cell treatment are still avid today, however it is significantly less due to the abandonment of using embryonic stem cells for research to instead use induced pluripotent stem cells which have much less ethical controversy surrounding their use. However, despite this huge advancement in stem cell research there are still advantages and disadvantages of using such treatments in scientific research. For example advantages include the enormous range of diseases that would benefit stem cell development, such as Parkinson s Diseases, Alzheimer s disease, injuries to the spinal cord, possible treatments of cancer and stem cells could also provide organ repairs and replacements. The treatment of such diseases would provide a better quality of life for individuals and also contribute to economic gains for society (r). There are also significant disadvantages and potential dangers that must be considered in the development of stem cells as a viable treatment and cure for many diseases. For example, many believe that research such as this will lead to the possible cloning of human life in the far future which could be potentially very dangerous should such knowledge get into the wrong hands. As we know with other research programmes, that there can be devastating consequences despite good intentions such as nuclear research (r). It is also impossible to know how far stem cells could be developed in the future, but it is always possible that such research can be misused. In addition to this, there are also the potential problems with funding for the research and the uncertainty that stem cells will be successful in reaching their full potential. To conclude, it is evident from this research that Stem Cells are a clear way forward to developing possible new treatments and even cures for devastating diseases such as Dementia. It is thanks to huge donations and investments from companies that such research can take place. Although, it is clear that Stem Cells have not provided a cure yet, they are essential in their contribution to testing possible treatments on them and culturing them into nerve cells that replicate those in the areas of the Brain affected by Dementia, such as the Hippocampus in the Temporal Lobe, so it is possible to find out more about the Disease and help those living with it. It is perfectly probable that a treatment using direct implantation of cultured undamaged nerve cells into the affected areas of the Brain could become a viable treatment for Dementia, by comparing it with the experiments such as those carried out by the Waisman Centre team. However, the disadvantages of this treatment outweigh the advantages in that in order to obtain a pure sample of stem cells to directly implant, the stem cells must be taken from the Embryo. Also, the procedures involved in this line of treatment are very complicated and require more funding than is required of other methods involving stem cell therapy. In order to overcome this ethical barrier, research would have to take place to try and obtain cells that can be directly implanted into the Hippocampus from adult somatic stem cells without the risk of tumour growth. However, as a result of the research conducted in this paper, the advantages of using stem cells to make induced- pluripotent cells and culture them in the lab massively outweighs the disadvantages: there is very little ethical protest, the funding for such projects looks secure for the future and there are huge advancements to finding treatments for such diseases using this method already showing that it will be successful in the years to come. 6

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8 l) http://serendip.brynmawr.edu/bb/kinser/definitions/def- hippocampus.html m) http://www.alzheimers.org.uk/site/scripts/documents_info.ph p?documentid=114 n) http://en.wikipedia.org/wiki/henry_molaison#/media/file:hip polobes.gif o) http://en.wikipedia.org/wiki/henry_molaison#spatial_memor y p) http://www.wired.co.uk/news/archive/2013-04/22/stem- cells- memory q) http://www.eurostemcell.org/factsheet/alzheimer%e2%80%9 9s- disease- how- could- stem- cells- help r) https://explorable.com/stem- cell- pros- and- cons