1st Place Essay

Induced pluripotent stem cells (iPSCs) are a type of pluripotent cells that can be obtained by reprogramming animal and human differentiated cells. Give your opinion on what opportunities this technology should be used for, and what potential applications should be avoided. Support your reasoning with examples.

Dushan Gunawardena, Claire Smith
The Perse Upper School, Cambridge, United Kingdom

Induced pluripotent stem cells (iPSCs) are a type of adult somatic stem cells that have been reprogrammed back into an embryonic-like pluripotent state [1], facilitating the differentiation into any desired human cell. iPSCs represent a revolutionary technology that can open the door to a realm of boundless opportunities.
iPSCs present a versatile platform for the basis of disease modelling. iPSCs originating from humans (hiPSCs) with a genetic disease are known as disease-specific hiPSCs. Disease-specific hiPSCs contain identical genetic information to that of the patient [2], hence they will carry the identical disease-causing genetic anomalies [3]. Alternative methods for disease modelling often use genetically engineered animal models. However, there are contrasting physiological characteristics, such as ion channel expression, between the cells of humans and those seen in animal models. Moreover, animal models are seen as relatively expensive and time-consuming to produce [4]. Thus showing the utility of disease-specific hiPSCs, as they act as enhanced representations of the disease. The use of hiPSCs for disease modelling is particularly advantageous for replicating cells that would otherwise require an invasive extraction process. Hence they would be beneficial for cardiovascular research, due to the current challenges of obtaining a sufficient supply of cardiomyocytes (specialised heart cells). Examples of hiPSC-generated disease models include the modelling of hypertrophic cardiomyopathy. Rodent models for the hereditary disease are restricted due to fundamental differences from humans in their electrophysiology and calcium handling, seen through cardiac action potential lasting ten times longer in humans than in mice [5]. This shows the superiority of hiPSC-generated disease models over animal models, as they allow for a more precise diagnosis of the disease.
The field of regenerative medicine could be greatly enhanced by the use of iPSCs, specifically for cell replacement therapy. The combination of the pluripotency and immunocompatibility of iPSCs makes them particularly useful for cell replacement therapy for the purpose of disease treatment. This would entail isolating and extracting somatic cells from the patient and reprogramming them into iPSCs, through viral/non-viral mediated gene transfer techniques [6]. These iPSCs can then be cultured and resultantly differentiated into the disease-affected cell type. The resulting iPSCs can then be infused back into the patient, enabling the replacement of the diseased cells with functioning cells. The pluripotency of iPSCs would allow for the treatment of disease of every cell type. Furthermore, as this approach uses autologous transplantation it would eliminate the risk of graft rejection, as the immune system would recognise the self-produced antigens on the iPSCs. In comparison, other cell replacement therapies may use allogenic transplantation which involves the transplantation of donor cells which raises the issue of graft rejection. A potential application for iPSC-based cell replacement therapy could be the treatment of Parkinson’s Disease. This would require the introduction of iPSCs differentiated into dopamine-producing neurons into the substantia nigra region of the brain, to replace the diseased neurons.
iPSCs have offered the prospect of generating patient-specific organs suitable for transplantation [7]. The ever-growing demand for compatible donors has left thousands of individuals desperately requiring life-saving transplants. Therefore the emergence of an innovative method for organogenesis using iPSCs would be instrumental for the future of organ transplantation. This autologous approach will eliminate the detrimental effects of lifelong immunosuppression after most allogenic human transplants [7]. Advancements towards organogenesis using iPSCs can be seen through the development of kidney organoids, this is particularly notable as kidneys are the most coveted organ.
Although iPSCs offer a plethora of opportunities if misused they could have a detrimental societal effect. Potential applications of iPSCs to avoid include human germline engineering, as this topic brings about major ethical concerns. The concerns arise from modified genes spreading within the human gene pool with yet unforeseeable consequences [8], this is due to a current lack of understanding of the long-term consequences of genetic modification. A theoretical approach for the use of iPSCs for human germline engineering would involve the reprogramming of cells to differentiate into gametes. They could then be genetically modified, using CRISPR-Cas9 technology, and an embryo could be produced following in vitro fertilisation. The genetic modification of human gametes raises further concerns, as it could lead to modifications for discriminatory reasons.
In summary, iPSCs offer a diverse array of opportunities, with disease modelling, regenerative medicine and organogenesis serving as the optimal applications. I have highlighted these particular applications as there are deficiencies in all their alternative methods which iPSC approaches would improve on. In contrast, the use of iPSCs in germline engineering should be avoided due to substantial ethical concerns.

2nd Place Essay

Induced pluripotent stem cells (iPSCs) are a type of pluripotent cells that can be obtained by reprogramming animal and human differentiated cells. Give your opinion on what opportunities this technology should be used for, and what potential applications should be avoided. Support your reasoning with examples.

Rachel George, Nicole Copeland
The Perse School, Cambridge, United Kingdom

The discovery that somatic cells can be reprogrammed using transcription factors into induced pluripotent stem cells (iPSCs) was first made by Yamanaka and Takahashi in 2006 [1]. Pluripotency refers to the ability of a cell to differentiate into any cell type [2] and was first reported in 1998 in embryonic stem cells (ESCs) [3]. iPSCs reprogramme accessible cells such as skin fibroblasts and blood cells and hence mitigate the ethical issues concerning the use of ESCs derived from human embryos [4][5][6]. The ability of iPSCs to differentiate into cells of all three germ layers provides unprecedented opportunities in regenerative medicine with the treatment of a number of conditions including neurodegenerative diseases and spinal cord injuries [5]. A cure for sickle cell anaemia (a blood disorder caused by a defect in the ?-globin gene) has been demonstrated in a mouse model is an example of the use of iPSC-mediated therapy [6]. iPSC technology has the ability to overcome the obstacle of immune rejection in transplantation as the host’s own cells are used to generate patient-specific iPSCs that can be reprogrammed into desired cells and tissues [7][8]. This use of iPSCs can also overcome the reliance on organ donors [9]. Remarkable progress has been achieved in disease modelling (in vitro reconstruction of disease state) and drug screening based on iPSCs. More recently, iPSC-derived organoids (3D models) such as neural, cardiac, lung, kidney and gastrointestinal have been developed [7]. Organoids can model molecular mechanisms in diseases and provide important platforms to improve understanding in disease conditions. Better understanding of disease mechanisms can accelerate the development of disease specific treatment and minimise disease progression [9]. This use of iPSC technology allows in vitro modelling of complex genetic diseases such as Down syndrome [9][10] and neurodegenerative diseases such as Parkinson’s Disease[5][8]. In such conditions where there is limited treatment, these models would facilitate advances in therapy and drug discovery. Current animal models provide limited representation of human pathophysiology. Mouse models do not accurately mimic human diseases especially complex genetic diseases such as Down syndrome (DS) as they fail to replicate genetic defects including cranial abnormalities associated with DS [11]. For these cases where mouse and human physiology differ, iPSCs can potentially provide better understanding of diseases and drug development [8]. Despite early promise with drug screening using iPSCs in mouse models, there has been no success in translation to human trials to date [7]. There are clear limitations concerning the implementation of iPSCs in a clinical setting. Firstly, more than three months are required to generate iPSCs therefore it is not possible to meet the deadline for effective treatments of some disorders and injuries. Secondly, the preparation of iPSCs carry a high medical cost [6]. Finally, the formation of teratomas is a reported obstacle concerning the use of both iPSCs and ESCs. Even a small number of undifferentiated cells can result in the formation of teratomas [5]. There are many applications of iPSCs that should be avoided. Cloning and creation of human embryos is a major concern regarding the future development of iPSCs. Since the cloning of Dolly, the sheep [12] [13], the concern of possible human cloning has been a prevalent issue. There have been debates on whether cloning should be banned, however in 2005, the United Nations adopted the Declaration Human Cloning which prohibits “all forms of human cloning inasmuch as they are incompatible with human dignity and the protection of human life” [14]. There are ethical concerns regarding the ability to choose desirable traits in embryos produced using iPSCs via gene editing. In 2018 human germline gene editing without authorisation has sparked ethical controversies and debates. This technology has been seen in gene-edited twins to prevent HIV infection in Hong Kong. Though gene-editing human embryos has the ability to prevent diseases the application of this technology without strict regulation not only raises ethical concerns worldwide but is also dangerous to society[13]. iPSC technology should be used to further develop stem cell transplantation, disease modelling and drug discovery. iPSCs have the potential to overcome high rates of immune rejection in transplantation and organoids can be used to model complex diseases with currently limited treatment options. Currently there are many limitations including preparation time, cost and formation of teratomas so iPSCs should be used in a realistic approach. However, for further development in this field strict governmental and scientific regulations are required to prevent ethical controversies regarding the use of iPSCs.

3rd Place Essay

iPCs: possible uses and risks

Giulia Tocci, Paola Costa
Liceo Da Vigo-Nicoloso, Rapallo, Italy

In 2012, the developmental scientist Sir John B. Gurdon and the stem cell researcher Shinya Yamanaka were awarded the Nobel Prize in Medicine for discovering that mature and specialized cells could be reprogrammed to become pluripotent stem cells. They used fibroblast from the skin tissue and introduced four specific genes coding for transcription factors able to induce the conversion in pluripotent stem cells, known as induced Pluripotent Stem Cells (iPSCs) (1). “Thanks to their undifferentiated features, they are highly versatile: under specific culture conditions, iPSCs can turn into any differentiated cell type” (2). This feature, called potency, is common to every stem cell, but during the embryo’s development stem cells progressively start to lose this potential and can only differentiate into a single type of cell. The discovery of Yamanaka and Gurdon was revolutionary because they reprogrammed cells to a state in which potency is at its peak. Implementing this method could completely transform the way of doing cell research and introduce new potential therapeutic strategies. The benefits of using iPSCs are several. They are pluripotent and can self-renew (2), in the sense that they can undergo several cycles of cell division and maintain their genetic and phenotypic features. Therefore, they can be obtained starting from only a few non-invasive skin biopsies. In addition, iPSCs solve some ethical problems related to the use of human embryonic stem cells (ESCs), which are extracted from embryos at the blastocyst stage, and then in-vitro cultured. The extraction process destroys the blastocyst, hence sacrificing the embryo (3). For this reason, in some countries, it’s illegal to use these cells, although they have great potential, both in basic and clinical research. Using iPSCs could put an end to this debate and substitute ESCs, however, today’s research shows that they are not as effective and could be dangerous. During the reprogramming process, iPSCs acquire a higher risk of accumulation of genetic mutations, due to the culture conditions and the reprogramming protocol used (4). If these cells are then injected into a patient, he could acquire a higher risk of developing cancer. This could be solved by more restrictive culture and reprogramming protocols (4). The discovery of iPSCs is relatively recent, therefore, if more studies were conducted, these risks could significantly decrease soon.iPSCs could have several applications, and some are already developing now, such as drug testing. A problem with the development of drugs is the use of animal models, which is not always an ethical choice and sometimes these models do not respond to a drug while humans do and vice-versa. For this reason, researchers are implementing the use of human cell models. Despite being reliable and having successful outcomes, some patients do not respond to a drug at all. Using iPSCs for drug modelling could completely innovate therapeutic strategy, if not medicine, by making it more personal. In addition, they could be used to find new drugs and therapies for rare forms of diseases (2).“Pluripotent stem cells could also be used to study disease mechanisms, by creating organoids, artificially 3D-grown masses of cells or tissue that resemble the functioning organ” (5). This technique could be used to study neurological degenerative diseases, such as Alzheimer’s (5,6). So far, animal models have been used, especially rodents, because their DNA organization and the expression of their genes are human-like (7), however, not reliable enough to study this disease (6). By using iPCs researchers can obtain small brain organoids relevant to a better understanding of cellular mechanisms involved in Alzheimer’s (6). There are some downsides to the use of iPSCs, mainly ethical problems, strictly connected with the possible harmful applications, since there isn’t a strict code of conduct surrounding them.A group of researchers from Kyoto University, using both ESCs and iPSCs generated mouse sperm, with a pre-existing protocol (8), and oocytes (9). The oocytes were fertilized and implanted in surrogate mothers. The gestation proceeded without complications and the offspring was healthy (9). Without a code of conduct, this could be applied to humans to generate new individuals.
Creating a human baby from stem cells is unnatural and unethical, not only because it defeats the purpose of humankind, but also because “certain gametes could be selected to create superhumans, with enhanced physical and cognitive qualities” (10).In conclusion, in my opinion, iPSCs have brought and probably will bring several advantages to research and medicine, nevertheless, the ethical problems raised by their use should undergo serious consideration.

Essays Honourable Mention 1

The World of Induced Pluripotent Stem Cells

Dea Marku, Olgena Thoma
New York High School, Tirane, Albania

Day by day, genetic research is progressing in order to introduce new solutions to diseases. An example are iPSCs or induced pluripotent stem cells, derived from adult somatic cells, which are similar to embryonic stem (ES) cells in many aspects.i The potential for iPSC applications is vast, spanning from basic research to drug discovery to regenerative medicine and the development of disease therapies.ii For example, iPSC are used to study the molecular mechanisms and pathways important for differentiation of tissues during embryonic development.ii But are they entirely safe for human application? iPSC are derived from skin or blood cells that have been reprogrammed back into an embryonic-like pluripotent state that enables the development of an unlimited source of any type of human cell needed for therapeutic purposes.ii They were first generated by Shinya Yamanaka and Kazutoshi Takahashi at Kyoto University in 2006.iii The similarities they have to ES cells along with the fact that they are identical to the cell donor are a plus in disease modeling.iv For example, iPSC can be prodded into becoming beta islet cells to treat diabetes, blood cells to create new blood free of cancer cells for a leukemia patient, or neurons to treat neurological disorders.ivBeing self-renewing and pluripotent, human iPSCs represent a theoretically unlimited source of patient-derived cells which can be turned into any type of cell in the body.iv This leads to many ways of use, one being iPSC-derived cardiomyocytes.iv These iPSC-cardiomyocytes can recapitulate genetic arrhythmias and cardiac drug responses.v I believe this is a beneficial method since these iPSC-cardiomyocytes exhibit the same genetic background as the patient from which they were derived.vi Conversely, the need for blood transfusion is overwhelming. In 2014, type 0 blood cells were synthesized at the Scottish National Blood Transfusion Service from iPSCs.vii After the cells were induced to become red blood cells, they matured properly.vii Thirdly, induced pluripotent stem cells (iPSCs) are used to generate human organs for transplantation.vii Human liver buds grown from three kinds of cells represented the ability of iPSCs to mimic the process of fetal development, thus connecting quickly with the host blood vessels and continued to grow after being transplanted into mice.viii All this whilst performing regular liver functions.viiiUnfortunately this new advancement comes with quite the disadvantages. The main issue is the use of retroviruses to generate iPSCs as they subsequently trigger cancer-causing gene expression.viii Furthermore, the c-Myc (one of the genes used in reprogramming) is a known oncogene, and its overexpression can cause cancer.ix Moreover, in certain non-dividing cell types (such as PBMCs or elderly skin fibroblasts) the reprogramming rate of somatic cells to iPSCs is very low (less than 0.02 %).ix There is also a need to assess the quality and variability of the reprogramming process because iPSCs often have a tendency not to fully differentiate.ix In conclusion, iPSCs are a step towards the future of genetic evolution, yet there is much to learn. Steps should be taken to first provide fully stable organ synthesis and tissue replacement. Non-integrative approaches such as the use of small molecules and microRNAs with less reprogramming efficiency, should be improved.ix Let’s hope that in the near future iPSC technology will help to better understand disease mechanisms or to screen candidate drugs.x In addition, iPSC-based therapies are continually being explored for their potential to treat diseases related to aging like Parkinson’s, macular degeneration and heart disease.xi

Essays Honourable Mention 2

Induced Pluripotent Stem Cells: The Opportunities and Ramifications of a Revolutionary Technology

Annabelle McKenzie, Sam laing
Wellington College, Crowthorne, United Kingdom

Since the discovery of the Yamanaka factors in 2006, induced pluripotent stem cells (ISPCs) have both enthused and alarmed the scientific community in equal measure. They offer hope of revolutionary advancements, including new cancer treatments, expanded reasearch and repair of previously irreparable organs using organoids all while overcoming the moral controversies of using foetal stem cells. Conversely, IPSC treatments can have devastating side effects, meaning that there are applications of IPSCs that should be avoided.
IPSC research is creating ground breaking opportunities and contributing to breakthroughs in the medical field. For example, IPSCs are used to test the patient specific reactions to drugs, for patients with rare genetic disorders (8). IPSCs are also being used to increase the understanding of a variety of diseases, for instance, IPSCs derived from the cells of patients with adulthood diseases are observed as they mature in order to better understand the development of these illnesses. IPSCs have been used to model disorders of the liver, pancreas, blood, heart, lungs, neurons and immune system (9)(10)(11)(12)(13). Using IPSCs in these ways overcomes the controversial ethical issues of sourcing pluripotent stem cells from embryos, making research using pluripotent stem cells more widely accessible and acceptable. (27)
Post sufficient research IPSCs could also be used in the fight against cancer (1). Due to cancer’s similarities to foetal growth, IPSCs share resemblances with cancer stem cells (CSCs). They share, for example, transcriptomic and genetic signatures, altered metabolism, and over one-hundred tumour associated antigens (TAAs), all of which traits help the body recognise IPSCs as antigens (2). Therefore, patient specific IPSC vaccines, treated with radiation to stop replication, can effectively and safely expose the immune system to cancer specific targets to familiarise it with cancer antigens (3). In one promising study, mice were injected with irradiated human IPSCs and exposed to pancreatic cancer cells. Astoundingly, 75% of the IPSC vaccinated mice rejected the cancer cells entirely while all mice in the control group developed tumours (5). Similarly promising experiments have been conducted using skin and breast cancer with more reasearch in the pipeline(4). Cancer vaccines show great potential and, by being irradiated to halt replication, can avoid cancer risks associated with IPSCs(3).
However, there are also treatments using live IPSCs that are currently unsafe and should be avoided.For example, in 2013 scientists transplanted human liver buds into mice making them the first organisms to receive IPSC grown organoids(20). On being injected, the buds attached themselves to the mice’s blood supply (21) and began carrying out normal function whereby the human liver buds were observed creating uniquely human metabolites (22). These promising results are leading some researchers to prematurely push ISPC organoid transplants, despite no successful human trials (26), with some scientists suggesting that the use of liver organoids could be on the market within a decade (24). However, this experiment is only a ‘proof of concept’ (24), with sceptics arguing that trillions of liver buds would require implanting in order to be effective in humans(22).
Additionally and potentially more importantly, using IPSC organoid treatments poses many graver problems then the mere technical feasibility issues. Even syngeneic (genetically compatible) IPSCs can be immunogenic in some tissues, illustrating how little understood IPSCs are and indicating yet unknown risks inherent to IPSC treatments (15). Studies have identified chromosomal abnormalities in IPSCs suggesting that the prosess creating IPSCs can foster genetic instability (16). For example, genomic hybridisation analysis has revealed genomic deletions and amplifications in IPSCs (17), while other studies have discovered (epi-)genetic memory retention of IPSCs original cell types (19). Moreover, experiments introducing ISPCs often result in teratomas due to insufficient precision in controlling stem cells differentiation (16). Therefore, due to numerous risks and uncertainties,
treatments involving live ISPC derived cells (such as IPSC organoids) are best avoided until more is known.
It is clear that ISPCs carry both opportunities and risks. Considering current uncertainties, the risks of introducing live ISPCs into human bodies outweigh the benefits of these early treatments and so should be avoided. However, ISPCs are also being used safely in cancer vaccines and are invaluable to research where they can play a major role in developing revolutionary treatments while circumventing difficult moral issues. These uses evade risks commonly associated with IPSCs and so should be strongly supported. Further investigation into IPSCs will enhance our understanding of them thereby enabling us to expand their uses safely. Therefore continued work on IPSC therapies is critical to exploit the revolutionary potential induced pluripotent stem cell harbour.

Essays Honourable Mention 3

iPSC’s are a type of pluripotent cells that can be obtained by reprogramming animal and human differentiated cells. Give your opinion on what opportunities this tech should be used for, and what potential applications should be avoided. Support your reasoning with examples.

Izzy Rumsby, Josephine Woodbridge
The Perse, Cambridge, United Kingdom

Technology has improved immensely over the last decade and stem cells are beginning to be used more regularly in the medicinal world. For example, they have been successfully used in treatments for; heart disease, diabetes, cancer, liver disease and lung disease as well as being used to reprogramme reproductive cells to treat infertility. Breakthroughs with iPSCs have allowed scientists to hope for developing treatments for currently untreatable conditions. [1] IPS cells have significant potential because they create endless opportunities for repairing damage in the body caused by trauma or disease due to their division patterns. Additionally, they are ethically preferable to embryonic stem cells because they come from adult cells and do not require human embryos. They have strong immunogenic properties that are able to provoke a cancer specific immune response [2]. The mechanics of an iPS cell provide doctors with a new branch of research for producing vaccinations.
Currently labs use animals to carry out drug screening. This is less than ideal, particularly because the animal organ system is significantly different to that of the human body. As a result of the different anatomies, on average 27% of drugs fail clinical trials due to extreme effects on organs in the human body. If iPS cells were used in place of animal models, it would reduce the number of animals used in drug screening and increase the chances of success for the drug in clinical trials. [3] Stanford University School of Medicine has taken iPS cell research into its own hands with their experiments on mice to explore the potential for the cells serving as a cancer vaccine. [4]. iPS cells have similar characteristics to tumour cells which inspires hope that by injecting a patient with the foreign iPS cells their immune system will produce antibodies to fight them and therefore, when the cancer invades, the body will have memory lymphocytes ready to attack the cancerous cells. Stanford Scientists Nigel Kooreman and Joseph Wu have looked into the similarities between iPS cells and cancer cells and believe they hold “exciting clinical potential.” The mice experiment carried out at Stanford in 2018 helped prove the effectiveness of iPS cells when treating cancerous tumours. Specifically pancreatic cancer, which is the 5thbiggest cancer killer in the UK causing over 9,000 deaths every year. Only 3% of patients who are diagnosed with pancreatic cancer survive beyond five years.
Whilst iPS cells hold great potential for the future of cancer vaccines and research trials, there remain concerns over using iPS cells to clone living animals. The first mammal to be successfully cloned from an adult cell was Dolly the sheep in 1996 [5]. While this was a huge breakthrough in the world of genetic manipulation and a step that lead to the popularisation of animal cloning around the world, animal cloning remains unpredictable. Animal cloning is unreliable as we cannot foretell the placement of the genes until they have been copied. Furthermore, it would have to be a tightly controlled scheme in order to protect native species and ecosystem. [6] Pluripotent stem cells bring fresh promise to the future of medicine. I believe that we owe it to future generations to capitalise on every opportunity to research deeper into these stem cells.The unique qualities of these cells should be appreciated and extensively researched so as not to overlook any consequences of their use, namely the unfortunate risk of iPS cells uncontrollably dividing like that of a cancer cell, but at the same time their astounding potential should not be wasted. The focus to date on cancer vaccines is very important work but I believe that we should continue to maintain a wider view of the potential of these cells by applying this newfound technology into research trials to enhance our chance of developing new life changing vaccines and medicines.

Essays Honourable Mention 4

What should iPSCs be used for and what applications should be avoided

Guang Xu, Clare McKinnel
Eton College, Windsor, United Kingdom

First demonstrated by Yamanaka and Takahashi’s ground-breaking work on reprogramming adult mouse somatic cells back into a pluripotent state1, induced pluripotent stem cells (iPSCs) have offered an alternative to embryonic stem cells (ESCs) for disease modelling, drug screening and regenerative medicine whilst avoiding the ethical issues of working with ESCs. Although the process of induction is still not fully understood, iPSC technology has progressed enough to reproduce the cellular phenotypes that are desired. When compared to ESCs, both express the same pluripotent markers (e.g Oct4, Sox2) and can differentiate into all 3 germ layers2. iPSCs even pass the most stringent test of pluripotency: the tetraploid complementation assay which tests if the iPSCs can form viable offspring by injecting them into tetraploid blastocysts3. These characteristics make iPSCs useful in answering particular scientific questions for example by modelling diseases. For example, iPSCs can directly differentiate into the dopaminergic cells affected in Parkinson’s disease (PD), providing many more disease-relevant cells than post-mortem samples, and even encapsulating all the genetic risk factors from an actual PD patient4. This has led to the discovery of specific mutations such as LRRK2 and pathways like ERK in PD which can point us in the right direction for developing therapeutics5. iPSCs can also be elaborated into self-organising tissues in a 3D culture, better replicating in vivo conditions, disease phenotypes and aggregation like the amyloid plaques in Alzheimer’s disease2. Furthermore, iPSC models of blood vessels can evaluate vascular toxicity, involving blood vessel damage by drugs or toxins, essential to the safety studies during a pharmaceutical’s development. Not only are iPSC models of blood vessels more accurate and clinically relevant than animal models, but they can also be used to emulate a patient’s genetic predisposition to certain risks, allowing for personalised assessments of which drugs to prescribe6. There is very promising preliminary evidence that iPSCs could be used in autologous stem-cell based therapies, with several reports of positive clinical outcomes. For example, the treatment of a patient with age-related macular degeneration by transplanting iPSC-derived retinal pigment epithelial cells has been trialed as well as injecting healthy dopaminergic neurons for PD and platelets for thrombocytopenia7. In these clinical applications though, safety is paramount; creating additional challenges to overcome. iPSC genomic stability and reduced tumorigenecity will entail a non-integrating reprogramming technique such as sendai virus2. Additionally, alternative xeno-free feeder cells such as clinical-grade human foreskin fibroblast cells must be used to prevent contamination from animal-derived products8. This compromise for safety drastically affects the cost (around $800,000 per treatment) and time required to manufacture the clinical iPSC products (up to a year)9. One alternative is creating “haplobanks” of ready-made iPSCs from various donors with the most common Human Leukocyte Antigens (HLA) to provide HLA matched transplants, reducing the risk of rejection7. Although these allogeneic transplants will solve the wait time, they still require immunosuppressive therapy and so should be used only as an intermediary until further development has made autologous treatment viable. Eventually it may be possible to grow far more complex tissues like whole organs for a transplant with no fear of rejection,
no need for donors, and no need to bear the risks associated with taking immunosuppressants for the patient’s entire life. However, some uses of iPSCs should be avoided such as experimental or clinical trials where the background knowledge has not been built up, as well as the abuse of iPSCs for unethical practices. Topics such as creating germ cells or “organoid intelligence” (3D models of neurons) from iPSCs are grey areas. Although, iPSC derived germ cells may be promising for infertility treatments10, they allow the cloning of human beings and genetic manipulation to create “designer babies” which must be avoided11. “Organoid intelligence” may lead to breakthroughs in computing12 but, like cloning, it raises ethical questions on consciousness and identity. Furthermore, “haplobanks” may exacerbate issues of healthcare inequality due to the increased genetic diversity of ethnic minorities causing HLA matching to be less likely in those groups. Unless action is taken globally to create a “haplobank” with the required genetic diversity, there will be a discrepancy in allogenic treatments which must be avoided13. IPSC technology should be widely available to all and used to their fullest extent, but scientists have to be careful around issues of safety and ethics. Nevertheless, with a strict regulatory and ethical framework in place, the promise of iPSCs to drive a generation of new research and treatments, and to improve countless lives makes them an incredibly worthwhile venture which is still in its infancy.

Essays Honourable Mention 5

Uses and Disadvantages of Induced Pluripotent Stem Cells

Çagatay Yildiz
Çankaya Doga Ananadoulu Lisesi, Ankara, Turkey

1. Introduction Induced pluripotent stem cell is the name given to cells obtained from a non-pluripotent cell as a result of reversal of differentiation by providing some genes or external factors. In other words, they are cells programmed from a somatic cell to the embryonal level. Initiated in 2006 by Shinya Yamanaka, the successful programming of somatic cells into pluripotent stem cells was seen as a turning point in disease research. It is thought that the conversion of a differentiated cell back into a stem cell will mostly be used to develop regenerative medicine and medicine. 2. Areas of Use Regenerative medicine is the branch of science that studies the effect of stem cells and the body’s ability to self-repair damaged cell tissues and organs. Somatic cells taken from the patients themselves can be transformed into pluripotent stem cells under laboratory conditions and can be differentiated into the desired cell type according to the need. With this method, unlimited production of cells is ensured and the possibility of rejection by the immune system is eliminated due to the fact that the cells are taken from the patient’s own body. Gene diseases due to mutations can be treated using induced pluripotent stem cells. The mutation can be corrected by gene targeting in patient-specific induced pluripotent stem cells. After the induced pluripotent stem cells are differentiated into target cells, they are transplanted into the diseased area in order to enable the defective cells to fulfil their functions and to eliminate the symptoms of the disease. The main aim of regenerative medicine is to artificially obtain cells and tissues to be transplanted to patients using induced pluripotent stem cells. One of the most important causes of hearing loss is sensorineural hearing loss, which is characterised by the irreversible loss of hairy cells in the inner ear. Intensive research is ongoing to find a solution to sensorineural hearing loss using induced pluripotent stem cells. For this purpose, research is ongoing to obtain hairy cells using induced pluripotent stem cells, especially for the treatment of hearing loss due to drug toxicity. Another area of use of induced pluripotent stem cells is the pharmaceutical industry. Drug development studies should investigate the treatment efficacy and side effects of a newly developed molecule. For these studies, experiments are usually carried out with suitable animals such as mice, dogs and pigs in the laboratory environment. These studies are both expensive and difficult to standardise due to biological and physiological differences between animals and humans. Therefore, induced pluripotent stem cell studies before animal experiments can provide more accurate selection of the target and prevent unnecessary repetitions in animal experiments. Strict hygiene requirements are imposed by ethics committees in many countries for the acquisition of human-derived materials to be used in scientific research in genetic diseases. This measure of preventing the acquisition of materials in sufficient quantity and at the desired time is one of the most important obstacles. It is a great advantage for a researcher to have access to experimental animals in sufficient quantity and at the appropriate time. Stimulated pluripotent stem constructs are becoming an important argument that needs to be addressed to overcome these constraints. However, specialised analysis models and their use can produce specialised induced pluripotent stem constructs. It is also possible to obtain cell lines using preservatives. Today, this is becoming an important argument that needs to be addressed in order to bring these enclosures under containment. However, specialised analysis models and uses of specialised induced pluripotent stem configurations can be produced. Furthermore, cell lines using preservatives can also be obtained. Today, this is becoming an important argument that needs to be addressed for containment. However, specialised analysis models and uses of specialised induced pluripotent stem configurations can be produced. In addition, cell lines can also be obtained if we use preservatives. today, 3. Disadvantages Among all these benefits there are downsides to this possibility. It has to be very expensive and it takes about a year from the first skin cells to transplantation. It has been a long time since a person was in critical condition and needed an organ at short notice. Apart from this, the remnants of a quality control procedure that may be present everywhere, the risks such as the inability of cells to fully transform or differentiate into induced pluripotent stem cells due to their epigenetic memory suggest that a little more time is needed for this method to be used clinically. Induced pluripotent stem cell technology is today far ahead of the first version designed by Shinya Yamanaka and is as close to cell therapy with improved gene transfer methods and a limited number of factors. However, the molecular mechanism of reprogramming has not been fully elucidated and the role of each of the factors used remains unresolved. The fact that they can be tailored to the patient and are free from the problems of inducing immune responses places induced pluripotent stem cells at the centre of recent scientific research. Therefore, in order for induced pluripotent stem cell applications to be applied in cell therapy;

Essays Honourable Mention 6

How iPSCs’ technology can change today’s society

Mishel Zdrava, Olgena Thoma
New York High School, Tirane, Albania

Historically, there have been countless myths and methods proposed for achieving eternity for human beings. But what if there were scientific ways to achieve this seemingly delusional idea?Let’s start with our own bodies, from which human life derives. Pluripotent stem cells are incredibly useful in helping the body repair and create. While maintaining a normal karyotype, these cells can infinitely divide during symmetrical division to produce either identical types of cells or different daughters attained from another differentiated type of cell. The most well-known type of stem cells are ESCs (Embryonic Stem Cells), which are found in the inner cell mass of the human blastocyst at an early stage of embryonic development.[1] They use division as their method of creating new cells that form different tissues in the body, which are intertwined together through different characteristics to form a fully functioning human body. Limitations of ESCs appear during their inability to provide a more diverse production of cardiomyocytes. However, to this day, there is still a lot of uncertainty about whether embryonic stem cells can generate continuous lines, whether they can risk the exposure to genetic diseases such as cancer or teratomas, and the lack of knowledge on the rejection of ESCs by the body during transplants.[2] Even though they still have many medically forward abilities that can help further medical studies, ESCs hold a controversial ethical position. The destruction of the embryo to acquire the mass from the inner cells, as well as the risk to the female donor, make them an unsuitable solution for therapeutic purposes. Another type of stem cells, which have a more limited selection of cells that they can produce, are ASCs (Adult Stem Cells). They have numerous benefits, including no ethical dilemmas and a lower risk of rejection during implantation. However, there is still a vague understanding of these cells, and their rarity of existence prevents further deeper investigation, experimentation, and growth in culture for longer periods of time. Therefore, to attain the heavily important stem cells, a type of production that involves the usage of calculated genes to turn somatic cells into a terminally differentiated state to embryonic ones was needed. Using Oct4, Sox2, Myc, and Klf4 proteins, stem cell researchers Shinya Yamanaka and Kazutoshi Takahashi achieved the creation of a new type of stem cell: iPSCs (Induced Pluripotent Stem Cells).[3] So why are induced pluripotent stem cells so beneficial to advancing human society? iPSCs include most benefits of both ESCs and ASCs while excluding their main concerns and lack of experimentation. By developing the iPSCs technology, many medical and research applications can be provided. Since these cells are incredibly more practical and adaptable, mentioned below are some of the biggest impacts they can have on today’s technology and the health of our society. iPSCs can be a substitute for organ donation by using cells that can be specific to each patient and including every generatable tissue around them.[4] In this way, iPSC-derived organs can ensure the patient’s safety at an incredible rate. By adapting specific body cells to comply with the patient’s needs in genetic manipulation, iPSCs can be a significant step forward in gene therapy. iPSCs are the most helpful technology pushing drug development forward. [5] By using these cells and their ability to explore medicinal reactions without harming beings or even animal or human cells, there can be a vast increase in discoverable cures. In a similar way, these cells can help in disease modeling by continuously monitoring ways and predictions of disease transmissions. Although being a phenomenal ongoing assistance to the evolution of different fields of health studies, iPSCs have several uncertain disadvantages that are best avoided until proper prevention of them. There is still unreliability regarding the maintenance of differentiated tissues. As a type of genetic engineering, the risks regarding exposure to viruses by unprotected modified stem cells still remain. Every fairly new technology and discovery has many difficulties at the beginning of its development to the masses. Advising people to be careful with treatments using iPSCs does not discourage the prevention of further discovery of this advanced method of helping in many fields of genetic engineering. This technology will surely further have an irreplaceable effect on the overall health of us, the beings of our planet.