����

Written by: Anahita Khorashahi

Embryonic stem cell (ESC) research holds the potential to completely revolutionize the world of regenerative medicine, yet it is often met with ethical resistance. Why is that? It seems that to many, the cause for concern with ESC research is rooted in the intersection of emotion and ethicality colliding with misinformation and a lack of knowledge. While some believe ESC research is the future, others are unsettled by the use of embryos, shedding light on the intersections between scientific breakthroughs, ethics, and the role emotion plays in it all. In this paper, I argue that embryonic stem cell research is both ethically permissible on rational grounds and ethically essential due to its scientific, economic, and social benefits. This means that objections based on the ethical status of embryos are outweighed by the overwhelming potential to alleviate human suffering and advance medical science.

What exactly binds some people to the idea that utilizing an embryo before it has any ability to feel pain, for the betterment of research, is so inherently wrong despite its benefits to society? In some cases, the answer is religious or spiritual beliefs. In a religious sense, life is viewed as a sacred gift from a divine source, imbued with purpose and meaning, with the soul understood to begin at conception[1]. For example, the Christian Institute “affirms that human personhood begins at conception and that the human embryo is precisely that – a human embryo”.[2] Therefore, from this point of view any practice which deliberately destroys human embryos is inherently wrong.

With this information, it is important to note that the point of this paper is not to argue for or against religious beliefs in science, but instead to provide a rational argument for ESC research. With these religious frameworks comes an emphasis on the lives of these embryos as opposed to the welfare of those living in debilitating pain, raising an important question; how can we effectively communicate the significance and necessity of ESC research to those who hold these views, and do we, as engineers, have an ethical or professional obligation to do so? It is important to include and respect diverse viewpoints and thought processes in the world of regenerative medicine and innovation, however, it cannot reasonably be argued that an individual's personal religious belief should interfere with the transformative potential ESC research has. As an example, knowing whether the soul enters the body at conception is solely a matter of belief as no solution will be acceptable to everyone. As a matter for all of us as a society, and for scientists in particular, these individual beliefs cannot dictate the welfare of everyone.

Ultimately, it is not the responsibility of engineers and scientists to try to persuade religious individuals to abandon their convictions, but instead to articulate a rational and ethical stance with clarity and integrity.

Given this, addressing misinformation is an essential first step; without a clear understanding of embryonic stem cell research, from what it entails to its potential impacts, many form opinions based on misconceptions rather than facts. ESC research is the study of stem cells from the inner mass of human embryos due to the regenerative properties of these pluripotent cells[3]. ESCs have the potential to develop into any cell type in the body as they continuously undergo cell division[4], offering the potential to replace damaged or diseased tissues and organs. In turn, these ESCs provide an opportunity to understand human and disease development, all while aiding in the development of new therapies.

Understanding ESC research involves recognizing the significance of regulations, such as the 14-day rule, which is essential to the ethical framework of the field. The 14-day rule is an ethical limit that restricts in-vitro research on human embryos to the first 14 days after fertilization[5], meaning this embryo is no larger than a poppy seed when ESC research is conducted[6]. This rule exists to be a compromise between ethical considerations, scientific progress, and public opinion, specifically concerning the ethical status of early embryos, in turn, facilitating ethical embryo research.

Switching our focus to embryonic capabilities, some may understandably feel a sense of discomfort with the reality of embryonic stem cell research utilizing embryos, as arguments that these embryos do indeed have the ability to feel pain arise. However, embryos used in ESC research do not have the capacity to experience pain, are not considered sentient beings, nor are they able to maintain homeostasis on their own. Returning to our previous question regarding the ethicality of using an embryo for scientific research, it is important to define the meaning of life through a biological lens. In biology, life is generally defined as a system capable of performing complex yet self-sustaining functions such as homeostasis, growth, metabolism, adaptation, response to stimuli, and finally, reproduction. These are a few of the many characteristics of human life that embryos lack. When these ESC lines or blastocysts are obtained, the embryo itself is around five days old, long before it has fully developed any cognitive abilities, sentience, pain receptors, or even a cerebral cortex. Embryos are unable to feel pain until at least 24-25 weeks of gestation[7] due to the lack of key bodily systems and functions. The cerebral cortex, which produces vital reflexes such as continuous breathing movements in the embryo[8] and is necessary for pain experience, forms, at its earliest during the second month of pregnancy[9]. Embryos are unable to maintain and typically achieve complete homeostasis around the second trimester, from week 13 to week 27[10]. In addition, embryos are not considered sentient, as the necessary brain structures and neural connections for experiencing pain or consciousness are not yet developed[11]. Therefore, in each of these instances, these embryos are nowhere near having developed any of these cognitive abilities or pain reception during the allotted 14-day rule. This is not to say that the embryo should be disregarded entirely; however, instead the ethical values of the two parties should be reasonably weighed against the potential benefits that could come from using it for research.

Through understanding these embryonic capabilities, another common ethical concern arises; using embryos in research denies them a potential future. An NIH article brings up a perspective surrounding the ethics of killing, stating that “we should not kill a being when doing so will deprive it of a valuable future”[12]. However, this position overlooks the practical realities surrounding unused embryos, which are rarely destined for a lived existence. This can be seen when it is argued that “if they are not destroyed in the process of research, they are instead destined to languish in freezers until they are destroyed for some other reason”[13]. Given that “it is not clear what is wrong with depriving something of the possibility of a valuable future when we know that this future will not be realized”[14] the use of such embryos in scientific research may be ethically justified. Thus, their application represents a valuable contribution to scientific progress at a minimal and arguably hypothetical ethical cost. Addressing the concern that using embryos in research denies them a potential future, it is important to establish where these embryos are sourced. Embryos being used in embryonic stem cell research come from eggs that were lab-formed and fertilized at in vitro fertilization clinics but never implanted in women's uteruses; therefore the gametes used are donated with informed consent from donors. Therefore, given that these embryos are ethically sourced via informed consent and lack a viable future beyond cryopreservation, it can be reasonably argued that their use in research is reasonably justified.

ESC research shows great promise in improving understanding of disease development and mechanisms due to the pluripotency of these cells, allowing scientists to model disease processes, study cellular mechanisms, and identify potential therapeutic targets, therefore improving human development[15]. ESCs can be used to create disease models by introducing genetic mutations or exposing them to environmental stressors, mimicking the conditions that lead to disease[16]. If we are able to understand how and why diseases develop, we can have a better idea of how to treat them. Not only do ESCs allow for an understanding of how diseases develop, they also provide key insights in tissue and organ formation by providing a genetic model system for studying the early development of these cells. Their ability to differentiate into any cell type allows scientists to examine how specific gene expressions influence the formation of various tissues and organs[17]. Understanding disease development allows us to promote new breakthroughs in the field of medicine and further advance human development. Human development can be defined as: "the process of enlarging people’s freedoms and opportunities and improving their well-being. Human development is about the real freedom ordinary people have to decide who to be, what to do, and how to live."[18] One core issue that hinders one's well-being, negatively impacting human development, are disease-induced premature deaths. Cardiovascular diseases (CVDs) are the “leading cause of death globally with an estimated 19.8 million deaths in 2022, representing approximately 32% of all global deaths.” In addition, “out of the 18 million premature deaths due to noncommunicable diseases in 2021, at least 38% were caused by CVDs,” meaning roughly 6.84 million of those premature deaths were a result of heart disease and stroke. Stem cell therapy, specifically ESC research offers transformative potential for cardiac repair and “treating ischemic heart disease by fostering

new cardiac tissue and improving heart function.”[19] However, it is important to note that aside from ESCs being associated with significant ethical concerns, their use also comes with a higher risk of teratoma formation[ 20[. On the other hand, “cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020”[21]. In addition, cancer is a leading cause of premature mortality globally with “a global total of 5.28 million deaths from cancer occurring prematurely in 2020, of which 3.63 million were preventable and 1.65 million were treatable”[22]. Stem cell therapy has provided a hopeful option in the fight against cancer, however preclinical trials utilizing stem cells have sown both great promises and challenges for cancer treatment[23]. Finally, for type 1 diabetes “premature deaths are estimated at 174,000, with 17.2 % of these due to non-diagnosis soon after clinical onset”[24]. The medical progress from ESCs holds the most promise for transplantation therapy to treat type 1 diabetes as stated by the NIH[25].

Intrinsically, disease-induced premature deaths rob one's freedom and opportunity to live a fulfilling life, significantly decreasing well-being, quality of life, and gradually diminishing human development.

However, ESC research has the potential, and in some cases, has already demonstrated its ability to improve human development by targeting the root problem: disease-induced premature deaths. By manipulating the environment of ESCs, scientists can observe how these cells respond and differentiate into desired cell types, revealing the mechanisms behind tissue development.

Embryonic stem cell research can additionally be used in drug testing by utilizing these cells’ pluripotent characteristics to mimic human tissues and organs. This allows scientists to test drug efficacy, therapeutic effects, and potential toxicity on these ESC models before moving onto clinical trials, accelerating the drug development process and improving safety. For example, if a drug is meant to target a specific type of nerve cell, stem cells can be differentiated into those nerve cells for testing. ESCs can additionally be differentiated into 3D structures called organoids, which mimic the structure and function of specific human organs (like the heart, brain, or liver)[26]. These organoids provide a more accurate representation of the human body and the drug's specific effects in a particular organ compared to animal models or simple 2D cell cultures. Currently, pluripotent stem cells such as ESCs have been used to produce hollow organs such as vessels, upper airways, urethras, and bladders in which reconnection to the systemic vascular system is not necessary[27]. Through the formation of organoids, scientists can directly test a drug’s potential effects on specific cell types or organs, aiding in the production of drugs that target different aspects or stages of a certain disease[28]. Furthermore, through ESC research, we find that ESCs have the potential to provide a source of cells for organ transplantation, addressing the organ donor shortage as well as providing a means to expedite the drug development process. By exposing ESC models to developing drugs, researchers can assess if the drug causes any harmful effects such as cardiotoxicity or damage to other organs[29].

Through organoid construction, ESC research offers patients with incurable and debilitating diseases a promising alternative to lifelong and often painful treatments by providing regenerative therapies that reduce the need for constant medical interventions. For example, individuals with type 1 diabetes who endure multiple daily insulin injections or finger pokes could instead undergo a limited number of stem cell treatments to restore natural insulin production, achieving long-term insulin independence[30]. Researchers have made a breakthrough in diabetes treatments, demonstrating the potential of stem cell-derived islet cells to restore insulin production in patients with type 1 diabetes. “A dozen people with type 1 diabetes received islet cells made from donated embryonic stem cells, injected into their livers. After three months, all participants began producing insulin, and some no longer needed insulin injections.”[31] By reducing the need for constant medical interventions, ESC treatments not only alleviate physical symptoms but also enhance mental well-being, offering patients relief from chronic pain and a significantly improved quality of life. This research presents a leading life-saving alternative to those living with debilitating diseases such as cancer, diabetes, tissue damage, spinal cord injuries, and neurodegenerative diseases[32]. In summary, embryonic stem cell research has the potential to eradicate incurable and debilitating diseases, assess drug efficacy and toxicity, and potentially accelerate drug development, in turn improving the lives of millions.

Some may argue that while ESC research has brought plenty of promising results, it can also be done by using non-embryonic adult stem cells taken from other, less ethically controversial parts of the body such as the umbilical cord, placenta, adult tissues (such as bone marrow), blood[33], or even from deceased donors[34], offering a viable alternative to living donor stem cells. Another form of non-embryonic stem cells called induced pluripotent stem cells (iPSCs) are reprogrammed adult somatic cells which have similar qualities to ESCs[35] while also eliminating ethical concerns associated with them. Additionally, due to the fact that these non-embryonic stem cells have already been used to treat medical conditions, including leukemia, lymphoma, neuroblastoma[36] and is less taboo, it is understandable why one would see this as a promising alternative.

However, simply because these adult stem cells are obtained without the inclusion of embryos doesn't necessarily make this the better option. Embryonic stem cells and adult stem cells differ in their origin, potency, and applications. Adult stem cells are rare, undifferentiated cells present in many adult tissues. In contrast, embryonic stem cells are derived from the inner mass of the blastocyst and can readily differentiate into all bodily cell types due to their pluripotency, therefore exhibiting unique properties, including spontaneous differentiation into three germ layers in vitro[37]. Adult stem cells are limited to differentiating into different cell types of their tissue of origin, and consequently are either multipotent or unipotent cells[38]. Not only are these stem cells rare, but it is difficult to isolate a unique group of adult stem cells in their pure form[39]. Although adult stem cells in humans have been used to treat diseases such as leukemia via transplants, it has proven difficult to use these stem cells to treat a larger range of diseases[40]. For example, stem cell research and transplants have limited clinical applicability despite a vast therapeutic potential due to the multipotency or unipotency of these cells[41]. In short, adult stem cells obtained from these specific procedures are more limited in their ability to differentiate than ESCs, and in turn are less useful.

When it comes to arguing between embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) the argument gets much more complex due to the unique advantages and areas of ethical resistance of each; the inclusion of embryos with ESCs, and concerns surrounding genetic modification with iPSCs as they are man-made stem cells. ESCs offer a vigorous model for early development and disease modeling, while iPSCs provide patient-specific, personalized medicine and disease research. iPSCs have some limitations such as the potential for genetic or epigenetic abnormalities compared to ESCs. For example, the genetic reprogramming that induces somatic cells and reverts them to a pluripotent state, thus creating iPSCs, increases genetic instability which can lead to chromosomal abnormalities and cells becoming tumorigenic[42]. Unlike ESCs, however, iPSCs also have the ability to create patient-specific stem cells in turn allowing “for the production of limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine.”[43] It is reasonable to argue that ESCs and iPSCs should coexist in a scientific setting as they are both essential resources in research and medicine. However, due to their unique advantages and limitations, iPSCs cannot reasonably be considered to be a complete replacement to ESCs, but rather a complementary approach.

Given the promising potential of iPSCs as a complementary resource alongside ESCs, some may argue that a balanced approach to stem cell research may lie in regulating the use of embryonic stem cells as a means of research to a minimum, thus reaching an ethically plausible middle ground. However, limiting embryonic stem cell research could slow down progress and delay potential cures. In addition, realizing the full potential of embryonic stem cell research will likely require many years of dedicated study and development. Therefore, the decision to restrict access to this research, or stem cell research as a whole, could prolong suffering and reduce overall well-being. Supporting broader access to ESC lines is ethically plausible, as the advancements in medical research would justify the use of these otherwise discarded embryos to maximize well-being for the greatest number of people.

California Proposition 71 is essential in understanding the revolutionary nature of ESC research, as it has not only helped reduce stigma but also demonstrated real-world benefits by advancing healthcare, boosting the economy, and improving public welfare. California Proposition 71 is a law that was passed in 2004 and authorized an initial $3 million start-up loan and a limit of $350 million per year up to $3 billion in funding for stem cell research and research facilities in California[44]. This law ultimately established a state constitutional right to conduct stem cell research, creating the California Institute for Regenerative Medicine (CIRM) to fund and oversee this research[45]. The advancement of Proposition 71 has enabled over 90 clinical trials involving over 4,000 patients for over 75 neurodegenerative diseases and various cancers[46], created over 56,000 full-time jobs (with salaries higher than the state average), and generated an estimated $10.7 billion increase in gross revenue for the state's economy by the end of 2018[47]. Meaning, with funding and permission by the government, the CIRM was able to effectively create therapies meant to treat diseases that lack an effective remedy, therefore, reducing medical spending and improving the quality of life for people in the state of California[48]. The success of California Proposition 71 highlights the tangible benefits of ESC research, thus it is imperative to invest in the endeavor of furthering ESC research.