THE FUTURE OF STEM CELLS IN MEDICINE BY AGNES MILNER KATIE CLARK. Pass with Merit

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1 THE FUTURE OF STEM CELLS IN MEDICINE BY AGNES MILNER KATIE CLARK Pass with Merit RESEARCH PAPER BASED ON PATHOLOGY LECTURES AT MEDLINK

2 Abstract Embryonic stem cell research offers great promise for understanding basic mechanisms of human development and differentiation, as well as the hope for new treatments for diseases such as diabetes, spinal cord injury, Parkinson's disease, and myocardial infarction. However, embryonic stem cell research also raises severe ethical and political controversies. The reprogramming of human adult cells to produce induced pluripotent stem cells (ips) avoids the ethical problems specific to embryonic stem cell research. In any stem cell research, however, difficult dilemmas arise regarding consent to donate materials for research, early clinical trials of therapies, and oversight of research. These ethical issues need to be discussed along with scientific challenges to ensure that stem cell research is carried out in an ethically appropriate manner. This paper provides a critical analysis of these issues and how they are addressed in current policies. Discussion Since 1908, when the term stem cell was first proposed for scientific use by the Russian histologist Alexander Maksimov at congress of hematologic society in Berlin, there has been a copious amount of research carried out on stem cells and in particular embryonic stem cells for medical purposes. Stem cells are undifferentiated cells that can, with the right stimuli, transform into many other cell types found in the human body, serving as a possible repair system for the body. They can theoretically divide without limit to replenish other cells. When a stem cell divides, each new cell has the potential to either remain a stem cell or become another type of cell with a more specialised function, such as a muscle cell, a red blood cell or a brain cell. In 1998, Dr. James Thomson at the University of Wisconsin, isolated cells from blastocysts and developed the first embryonic stem cell lines, this was one of the first major steps into the scientific research of embryonic stem cells. Much of the research carried out since 1908 has led scientists to deduce that stem cells, if grown in the correct conditions, can be used to treat such diseases as leukaemia and other malignant illnesses, as well as repair spinal chord and brain tissue. Figure 1: The human embryonic stem cells cultured at the University of Wisconsin - Madison have been observed to randomly differentiate in culture into a variety of different cell types, including (A) gut, (B) neural cells, (C) bone marrow cells, (D) cartilage, (E) muscle and (F) kidney cells 2

3 In October 2010 the first clinical trial on humans with recent spinal cord damage was carried out, the company Geron had injected stem cells into the spines of a small number of patients with spinal cord injuries, in the hope that these stem cells would differentiate into specialised nerve cells. However these trials were halted in October 2011 due to insufficient funding, therefore the outcome of these investigations is unknown. Prior to these clinical trials on humans the same experiment was conducted on paralysed rats. These rats regained some movement due to improvement in their locomoter recovery, which suggests that similar outcomes may be achieved in humans. In 2008 researchers in Kyoto (Japan), Wisconsin and California (USA) recorded that they had successfully reprogrammed human skin cells to become pluripotent, almost identical to embryonic stem cells. In this process, the researchers identified four essential regulator genes and have called the cells induced pluripotent stem cells (ips cells). If such cells can be safely developed from any individuals own skin cells and used to generate the 200+ different cell types found in a human, the technique could replace the more controversial nuclear transfer method used by scientists working on therapeutic cloning, in which a differentiated cell from an adult animal can be taken, and its nucleus placed in an egg cell which has had its own nucleus removed. The egg then goes through the stages of development using genetic information from the inserted nucleus; the first animal cloned by this method was Dolly the sheep in Using genetic reprogramming with protein transcription factors, pluripotent stem cells become equivalent to embryonic stem cells, which have been derived from human adult skin tissue. 3

4 Figure 2: Induced Pluripotent Stem Cell (ips) Pathway As the researchers in Kyoto, Wisconsin and California have successfully reprogrammed specialised adult cells to give rise to cells with pluripotent capabilities we therefore are potentially able to manipulate the signals of a differentiated cell into a pluripotent cell. This pluripotent cell can then become specialised and there is the capability of ultimately developing tissues and possibly organs from an individual s own skin cells therefore providing an alternative to organ transplants. ips cells retain a memory of their tissue of origin, for example ips cells made from blood are easier to turn back into blood. This can become problematic when using ips cells made from skin cells in transplants for other cell types. It may be possible to fade the memory of the ips cells, but only through many rounds of cell division. Today, donated organs and tissues are often used to replace those that are diseased or destroyed. Unfortunately, the number of people needing a transplant far exceeds the number of organs available for transplantation. The ips method is also believed to eliminate the implications of organ donor transplants as there is no possibility for organ rejection due to immunogenic responses as the organ is grown from the recipient s own cells. Every day, 18 people die while waiting for a transplant of a vital organ. Therefore hopefully, with the introduction of the ips method, this number of deaths due to the lack of organ donors will be greatly reduced. Current research is being carried out by Dr. Thanassi Athanassopoulos at the Stem Cell Research Laboratory and National Blood Service, Oxford, on whether tissue engineered skin created with endothelial progenitor cells can provide the solution to many of the limitations associated with the use of skin grafts particularly in patients with major burns. Although stem cells are rare in the peripheral blood, there is strong evidence that suggests that endothelial progenitor cells are present in the circulation. In laboratory-controlled investigations, blood was cultured over a period of eight weeks and colonies of endothelial precursors were grown from the umbilical chord and adult peripheral blood samples. The stem cell nature of these endothelial progenitor cells was confirmed by a technique named flow cytometry, which allows accurate determination of the expression of a cells surface markers. These progenitor cells were able to integrate into mature capillaries, mimicking the process of vascular repair and the progenitor cells were capable of forming capillary like tubes in artificial skin substitutes. This research is continuing with the assessment of the safety of these cells for human use and further development of the microcirculation in skin substitutes. Burn injuries are devastating for the victims and living artificial skin offers improved reconstruction and quality of life stated Dr. Athanassopoulos. Skin grafts are one of the many conditions that embryonic stem cells have the potential of treating. In the USA alone, stem cell research offers hope for 2 million diabetics, 1.5 million Parkinson disease sufferers and 250,000 people with spinal cord injuries. 4

5 Figure 3: The development of capillaries over two weeks from stem cells derived from blood samples However there are many major ethical implications of using embryonic stem cells to treat any medical human conditions. The foremost issue is that the process of obtaining the cells destroys the human embryo. Many patients may object to receiving treatment due to the fact that they believe that life begins at conception and the destruction of the embryo is the termination of a human life. In an address to an international congress in September 2006, Pope Benedict XVI stated: The destruction of human embryos to harvest stem cells is "not only devoid of the light of God but is also devoid of humanity" and "does not truly serve humanity." The notion that an embryo in a petri dish has the same moral status as a person can be challenged on further grounds. Taking the stance that the embryo is regarded on the same grounds as a human life rules out all possibilities for artificial conception and other embryonic stem cell research. For instance, defenders of in vitro fertilization point out that embryo loss in assisted reproduction is less frequent than in natural pregnancy and therefore, the natural loss of embryos can be seen as no worse than the obliteration in the aid of future medical advancements. It can be viewed that the loss of the human embryo is far outweighed by the much-needed developments in medical treatments. Already, there are companies who currently specialise in culturing and engineering stem cells, which scientists use in an array of therapies from wound healing to reconstructive surgeries. Dr. Zain Kadri, a plastic surgeon and medical director of Invitrx Therapeutics, has explained that, the stem cells are programmed to look for damaged tissue. They come and attach to the damaged area, divide and multiply, and they repair the area. However, a danger of embryonic stem cell research into the repairing of damaged skin cells is that the results of a successful technique could be exploited and abused for cosmetic reasons. For instance, stem cells could be injected into the skin of the aged to revitalise and rejuvenate their face and body. The cells injected are able to self-renew and differentiate into mature adipocytes (a type of fat cell, also known as lipocytes). These cells act as soft-tissue filler and this provides the appearance of more youthful skin. This new method has been highly successful in animal trials and avoids the drawbacks of current technology. However as these trials have only been conducted on animals, it is 5

6 too early to establish whether they would make the perfect tissue filler. The use of embryonic stem cells in cosmetic techniques is regarded as an extremely narcissistic justification for the discarding of human embryos by a large collection of individuals. Figure 4: The specific focus of stem cell research in New York State in 2008 Another future possibility of using embryonic stem cells, is in sex reassignment surgery, in which the sex organs can be reconstructed, providing people with the opportunity to become transsexual. If the use of embryonic stem cells to construct the exterior sex organs artificially becomes successful, then it may also be possible to grow the interior sex organs such as the uterus, enabling transsexuals to conceive a child and allow the pregnancy to become full term, with no need for immunosuppressant drugs. However, in many religious views, sex reassignment surgery is seen as defiling the wishes of God. In Abrahamic religions there are creation stories in which God creates people, male and female. This is sometimes interpreted as the fact that each gender is a divine mandate and gender variance is strictly prohibited. Although the ethical implications are extensive, the scientific implications are also as devastating and potentially fatal. These implications include the unregulated differentiation of cells, thus leading to the formation of teratomas and teratocarcinomas, these are tumours composed of tissues that are not normally present at the site of formation and consist of all three germ layers, unlike most cancerous tumours, the embryonic stem cell tumours originate from a group of apparently normal cells. Teratomas are potentially dangerous as the cells from which they arise are pluripotent and so can differentiate into a number of different types of tissue, such a teeth, bone and hair. These dangers of developing a teratoma from embryonic stem cell treatments in clinical trials, implicates the extent to which research can be carried out. Conclusion To conclude, the colossal advances in embryonic stem cell research since their discovery in 1908, has led to the development of critical medical achievements, which have the capability to save many human lives and improve the quality of living for countless patients. The use of embryonic stem cells in the treatment of leukaemia, spinal chord damage and other malignant conditions has only been made possible through the 6

7 extensive amount of research, which has been carried out in recent years. Barack Obama stated in an address to the congress in 2009 that; "Medical miracles do not happen simply by accident. They result from painstaking and costly research, from years of lonely trial and error, much of which never bears fruit, and from a government willing to support that work, which demonstrates the extreme importance of the continuation of research into key scientific areas such as embryonic stem cells. Although the extreme importance of research into embryonic stem cells is recognised, an alternative to their use has recently been discovered with research into induced pluripotent stem cells (ips). Many scientists are in favour of using these ips cells instead of embryonic stem cells as they bypass many controversial issues, hoping to bridge the gap between science and religion. However two independent teams of scientists have reported that these ips cells do not behave exactly like the stem cells found in early human embryos. These two research teams both effectively found that the ips cells were not completely reprogrammed back to the early embryonic stage of development, which could cause problems if they were to be used in transplant operations. Dr. George Daley of the Children s Hospital in Boston stated that these findings cut across all clinical applications people are pursuing and whatever disease they are modelling Everyone working with these cells has to think about the tissues of origin and how that affects reprogramming. As the large majority of medical treatments using embryonic stem cells are only at a developing stage, precautions must be taken along with numerous clinical trials to ensure our understanding of any possible detrimental side effects. Embryonic stem cell treatments suggest huge advancements in the medical field, however there are arguments that suggest it may be unsuccessful, such as the formation of teratomas. Research into embryonic stem cells is highly controversial and raises many ethical debates, however we believe that the advancements in medicine, which require the continuation of research, far outweigh the resulting disadvantages, hopefully improving the quality of life for many individuals. There is no doubt that embryonic stem cell research is cutting edge and that the benefits are huge, however in the contemporary economic situation many of the stem cell research companies are in competition with each other for funding, resulting in the overhyping of the achievements of each individual company s research. This exaggeration gives false hope to many and provides a false sense of security to those funding the individual research projects. This hype does however give a realistic interpretation of the future achievements in medicine, which can only be made possible through embryonic stem cell research, causing us to ponder the following questions; Will this research discover a cure for cancer? and Could this research extend our lifespan beyond the best interest of our species?. 7

8 References Athanassopoulos, T. (2010) Tissue Engineering with Endothelial Progenitor Cells, in the Surgical Research Report 2011 online, The Royal College of Surgeons of England, RCSENG, page Stem Cells and Diseases, Bethesda, MD. (2012) National Institutes of Health, U.S. Department of Health and Human Services. 8

9 Bowser, BA. Obama Lifts Restrictions on Funding Human Stem Cell Research (2009), report by PBS Newshour. Connor, S. (Tuesday 20 July 2010) Plan for non-embryo stem cell technique suffers setback, The Independent. Devitt, T. (1998) Wisconsin scientists culture elusive embryonic stem cells in a report by University of Wisconsin Stem Cell and Regenerative Medicine Centre. Kennedy, P and Sochacki, F. (2008) AS OCR Biology, Heinemann Publishers. Page Facts About Organ Donation and Transplantation (2012) National Kidney Foundation, Inc. Stem cells for stroke (2012) online report by NewsChannel5. The use of stem cells in innovative research, report by The State of VA Research Committee. Figure on Cover Sheet. Figure 1: Wisconsin scientists culture elusive embryonic stem cells photograph in a report by University of Wisconsin Stem Cell and Regenerative Medicine Centre. Figure 2: Sigma Aldrich online, Embryonic and Induced Pluripotent Stem Cells. 9

10 Figure 3: Athanassopoulos, T. (2010) Tissue Engineering with Endothelial Progenitor Cells, in the Surgical Research Report 2011 online, The Royal College of Surgeons of England, RCSENG, page Figure 4: Stem Cell Research in New York State, (2008), in a report by New York State Stem Cell Science, 10