The Future of Brain Organoids

The Future of Brain Organoids
May 5, 2022 No Comments Global Bioethics Ishani Wadhwa

Brain Organoids: Revolutionizing the Future of Neuro Experimentation

By Ishani Wadhwa

The technological advancement of human brain organoids, tissue designed to simulate the structure and function of the human brain, has raised many ethical concerns. Their creation, experimentation, and application is being heavily debated by physicians and neurologists alike. I use the values of respect, safety, and identity to weigh how and if brain organoids should be interacted with. Then, I use the frameworks of consequentialism and utilitarianism to further analyze this issue. Finally, I conclude by providing personal recommendations for how to navigate this topic.

Table of Contents

Abstract

Brains organoids, or simplified miniature versions of organisms’ brains, are now being grown in laboratories. Since the first brain organoid development in 2012, its applications have been providing mind-blowing implications for the human race. Brain organoids are grown artificially in labs using many types of stem cells such as ESCs (embryonic stem cells), IPSCs (induced pluripotent stem cells), and ASCs (adult stem cells). Through access to these organoids, scientists have made advancements in studying neurological disorders, testing drugs, providing tissue for brain transplants, and even making strides in autism and Alzheimer’s research. Though these organoids have been overall beneficial to medical achievements, their future is much more uncertain. Scientists predict that as the brain organoids become more neurologically complex, they will become fully sentient beings; signs of this have already been shown, as these brain organoids release brain waves, similar to those emitted in premature babies (Reardon). This has sparked ethical concern over whether any sort of experimentation on these organoids is permissible, given that they may be able advance their cognitive abilities. Application of this technology is also heading in a direction that was barely fathomable 10 years ago; we are on the brink of transplanting these brain organoids into animals (animal-human hybrids) and creating an organoid market to commercially sell these brains. I will explore these pressing issues using the ethical values of respect, autonomy, and identity, along with the frameworks of utilitarianism, consequentialism, and deontology. 

First, this paper will clarify background information and practices related to brain organoids. Then, I will examine the ethicality of their creation, experimentation, and application using the values of respect, autonomy, and identity. Then, I will judge these actions based on the ethical frameworks of utilitarianism, consequentialism, and deontology. Finally, I will propose alternatives and give my own insight as to how we should navigate the ethical issues that arise.

Background Information

The idea of brain organoids seems implausible, especially for a society like ours that is in the emerging stages of brain and neurological research. The future of brain organoids is uncertain; we may find that the potential outcomes of these technologies are fraught with ethical dilemmas. 

Before I describe what a brain organoid is, I will explain the concept of a general organoid. An organoid is an artificially created, simplified, version of an organ, purposed to mimic the structure and function of a real organ. (STEMCELL)

Brain Chip” by NIH-NCATS is marked with Public Domain Mark 1.0.

By this definition, brain organoids are systems that resemble processes and organization of the human brain. They provide an accurate representation of organisms’ brains, whose structures can be modified to study their neurological functions/nervous system.

Though brain organoids are a relatively new development, the foundation for their emergence has been building since 1998, when the scientific breakthrough of stem cell harvesting emerged. Stem cells are a specific type of cells from which specialized cells are created (Stem Cell Program Research). While stem cells had been derived from other organisms before (they were isolated from mouse embryos in 1981), it wasn’t until 1998 that they were able to be derived from humans. Scientists created these stem cells from human blastocysts, also known as embryos. Later in this paper, I will go over the types of stem cells and how they differ in source and abilities. 

Yoshiki Sasai, Japanese biologist, used the breakthrough of iPSC (induced pluripotent stem cells) to aggregate stem cells into a 3D structure, as opposed to earlier methods which adopted a 2D structure to create organoids. Eventually, Sasai found that when stem cells were put under the proper conditions, they could independently form into their own structures.  Flora Vaccarino at the Yale Department of Neuroscience applied this technique in 2012, and her laboratory became the first to create 3D brain organoids. Vaccarino later, using this discovery, created brain organoids meant to model the brain structure of people with autism (Zagorski).  The research of 3D brain organoids was furthered in 2013, when the organoids could be created to display representations of multiple regions of the brain (Corró). This allowed researchers to accurately model more complex brain structures. In 2019, Alysson Muotri of University of California in San Diego and his laboratory found that the brain organoids emitted brain waves, similar to those seen in premature babies (Nature). After the discovery, the experiment was discontinued, likely because of ethical concerns regarding experimenting on a mass of cells capable of this degree of neurological activity. A team of scientists and ethicists discussed whether generating this level of activity could lead to consciousness, if it should be allowed, and whether the organoids should receive special treatment. Since then, other brain organoid institutions have confirmed the emission of these brain waves. 

The stem cells that the brain organoids are composed of are called iPSCs, also known as induced pluripotent stem cells. iPSCs are in a pluripotent state, which means that they have the ability to give rise to specialized cells in the body, such as muscle cells and bone cells. iPSC are taken from skin and blood cells and converted back into a pluripotent state (Williams). Therefore, the iPSC can now provide a source for all types of cells for the organism from which they were derived.  iPSCs come in two common forms, known as ESCs and ASCs. ESCs, also known as embryonic stem cells, are a type of pluripotent stem cells derived from pre-implanted embryos. These ESCs are taken from the inside of an embryo, usually 3-5 days after fertilization (the period before an embryo can be implanted via IVF) (Science Direct). The other type of iPSCs are known as ASCs (adult stem cells). ASCs are most commonly found in adults, and their purpose is to renew damaged tissue, and replenish dying cells in the body. Though we extract and harvest ESCs and use them to create brain organoids, we must obtain ASCs through stem cell donations (Nature). 

All organoids are created in labs with the aid of technology. They usually consist of a mix of ESCs and ASCs. The different types of iPSCs are first embedded together to form embryoid bodies. They are then encased in Matrigel, which prevents the bodies from differentiating into specialized cells for the time being (Shou). The structures are then placed within a rotating bioreactor, providing them with a controlled environment to promote tissue and neuronal growth. During this process, the cultures are supplemented with nutrients that push them to form certain structures, in this case, regions of the brain. When not being observed or researched, the organoids are preserved at low temperatures, also known as cryopreservation.

Brains v. Other Organs

Brain” by grapefruitmoon is licensed under CC BY-NC-ND 2.0.

What makes the brain so different from the rest of the organs in our body? What makes cultivation of brain organoids so different from creating other types of organoids? Neurology is a highly specialized field, and brain organoid research within neurology is even more specialized. One of the main causes of this is the distinct purposes of our brains versus our other organs. Other organs in our body, such as the heart, lungs, and liver, serve to execute the basic bodily functions of the human body. If one of these functions is impaired, there is a possibility that the function can be restored if the damage is not too severe. Our brains, on the other hand, control our thoughts, memory, and emotions, all abilities that affect the way we experience life. If any of these functions were to be impaired, it is unlikely that it can be restored to its full capacity without time or extensive intervention, and thus the way we experience life would be forever altered. Another justification for the differences between the brain and other organs is the value we assign to the brain, and how it plays into our sense of individuality. The fact that we are able to undergo and provide for other organ transplants with relative ease but more complex issues arise when we discuss brain transplants, is a sign that we must be careful when manipulating brains. Our brains give us this sense of individuality, since each person’s psychological makeup determines how they think and feel. It is this phenomenon that determines how we go through life, which is what makes the brain stand out from the rest of the organs throughout our bodies. Additionally, the brain is considered to be the most complex organ in our body. This is apparent because so much is unknown when it comes to brain disorders, brain function, and brain organoids. Because of our current lack of understanding of it, we are limited in the ways we can experiment and apply its uses. For example, full brain transplants are unable to happen with today’s technology. The differences between brains and other organs mandate more consideration for safety and protecting identity when working with brain organoids.

Current Applications

Image by Gerd Altmann from Pixabay

Currently, brain organoids are being used to gather knowledge about disorders and diseases that are related to brain function. Scientists do this by manipulating and experimenting on the organoids. For example, a team of researchers at the University of California in San Diego (UCSD) has been utilizing these brain organoids to “mimic brain size differences in people with autism.” Studying the effects of these variations could help us learn more about how autism develops from conception to birth, and eventually how to accurately diagnose and effectively support those with autism. Brain organoids are also helping us learn more about Parkinson’s disease, one of the most common neurodegenerative disorders. Parkinson’s often manifests as tremors, spastic movement, and loss of balance. A patient-derived brain organoid has helped model Parkinson’s disease and enable examination of the physiological processes associated with it. Brain organoids derived from schizophrenia patients have helped us learn about its effects, such as decreased generation of neurons and reduced expression of proteins.

Future Applications

Organ transplant” by theglobalpanorama is licensed under CC BY-SA 2.0.

The future of brain organoids is uncertain, mainly because of the emerging ethical issues that arise. However, because of an organoid’s inherent purpose to mimic the functions of its organ counterpart, it seems reasonable to think that scientists may wish to implant or transplant brain organoids in the future. Brain transplants themselves at this point are purely hypothetical. Brain organoid transplants would involve the transfer of tissue of a brain organoid onto the brain of a patient, also known as a graft. The possibilities of these have become more likely due to recent advances in stem cell research. One example of brain transplantation in the near future is of a brain organoid derived from human iPSCs, to a human recipient, or Human-to-Human transplantations. Though brain organoid research has not yet been applied to human subjects, these transplants have been executed on animals. This means that there are animals who are in possession of brains constructed entirely by human stem cells. An animal who undergoes this type of transplantation is known as an animal-human hybrid or chimera: an organism that is composed of cells that are genetically not from the same species (Britannica). In this case, the animal that received the brain organoid transplant would be considered a chimera, because the source of its brain tissue (human iPSCs) is different from that of the rest of its organs. In 2018, an experiment was conducted where mouse chimeras were created when they had a human brain organoid transplanted into them. This resulted in some benefits for the mice; for example, they had greater cell survival and better neuronal differentiation (neurons are created) (Chen). This shows that we are making efforts toward the benefits of human brain organoid transplantation.

Ethical Analysis

Because of  the recent rapid advances in human brain organoid research, is creation, experimentation, or application of them permissible now or in the future?

Stakeholders

On some level, everyone is a stakeholder when we consider the ethics of creating, experimenting on and transplanting human brain organoids.  However, in this paper, I would like to focus on the scientists, patients with brain disorders, stem cell donors, experimentation animals, and the general public. Scientists are at the forefront of stem cell and brain organoid research, and their discoveries will set standards for how these new organoids might be used. Patients with brain disorders stand to benefit from this research. Potential cures and medicines can be derived from brain organoid research, which could help to soothe the conditions of the brain-ill. The individuals who donated their stem cells in the name of science will likely have their cells used for the purpose of creating brain organoids. As of now, stem cell donors waive their rights to any decision regarding their cells after donation, however: should this principle change because of the new possible uses of their material? Now, the consequences of donating stem cells could result in one’s genetic material being used for the formation of the organoids, which could potentially be transplanted into other people and animals. The animals who undergo human-animal transplantation (become chimeras) are stakeholders in this situation. After the transplant, they live their continued lives with brain cells of another being, thus experiencing life with the aid of  brain tissue belonging to another species. The public gains benefit from brain organoids because of the information they can provide. Their taxes also support publicly-funded research projects, so they are directly involved in the advancements of these topics. This goes to show that though we may not have a personal connection with the topic at hand, everyone will be affected by the impacts of brain organoids.

Respect for Stem Cell Donors

The ESCs and ASCs used to create human brain organoids must be harvested from embryos and healthy adults respectively. Does using the stem cells provided by these embryos and adults undermine our respect for them?

Thank you, anonymous donor.” by makelessnoise is licensed under CC BY 2.0.

I believe that harvesting ESCs from embryos does not threaten the value of respect because the embryos cannot be identified as humans who can think and process their surroundings. To obtain embryonic stem cells, the embryo must be created and destroyed, which is where controversy arises. This procedure is compared to taking a human life, which raises the question, are these embryos “living”? Embryos used in this research present few qualities of human life, such as a cardiac activity at 6 weeks, viability (ability to survive outside the womb) at about 22 weeks, and physical resemblance to human infants. However, embryos lack the most vital characteristic that makes us human: thought. It is thought that gives us our emotional, intuitive, and intellectual qualities, and embryos simply don’t possess that. Because we cannot equate the lived experience of a post-birth human with an embryo, extracting ESCs from embryos should not be considered unethical.

When discussing the respect to which stem cell donors are entitled,, we can look to the case of Henrietta Lacks. Henrietta Lacks’ cancer cells (HeLa cells) are a type of immortal cell, meaning they can reproduce indefinitely in the correct environment. Her cells made it possible to conduct certain research experiments involving drugs, toxins and viruses in vitro (in the laboratory). However, not only were the cells collected without her knowledge or consent, but she passed away from cancer before the breakthroughs involving her cells were acheived. We can use this example to examine how/if the respect for human donors is undermined when their cells are used for research.

I believe that the use of donors’ stem cells in brain organoid research does not threaten the value of respect. People donating stem cells to research often are unaware of what becomes of their stem cells, but I believe that using their stem cells for brain research does not infringe on the value of donor respect, though they may be unaware of the stem cells’ use. It may be disturbing that a brain organoid is an entity that shares cell origins with the stem cells it was derived from, though it was created apart from the person. However, stem cell donors should be well informed of the paths that their stem cells can take, so respect for the owner should not be a consideration when determining ethicality of brain organoid creation.

One nuance to go over is the difference between the cultivation of HeLa cells and the stem cells, and why I believe that using the HeLa cells infringed upon respect while donating stem cells does not. This is because Lacks did not consent to her cells being used in this manner, nor was she able to approve the use later on because she had already passed away due to cervical cancer. In contrast, the stem cell donors are willingly giving away their cells to science, which gives researchers the autonomy to perform on them in a given manner.

Safety in Brain Organoid Experiments

As Alysson Muotri discovered in 2019, brain organoids can develop the ability to generate brain waves, which signify neural activity. Neural activity is often the first step to gaining cognitive abilities. The ability to think and process information is unique to animals, including humans. This blurs the line between brain organoid research and human experimentation, so does this mean that we can equate them? First I will draw conclusions about human experimentation with and without consent. Then, I will determine if brain organoids’ cognitive capabilities are comparable to those of humans.

Human experimentation comes in many forms. Clinical trials and data sampling are common forms of human experimentation that are deemed as ethical practices. (It’s important to note that the subjects in the experiments noted above consented to being experimented upon). However, more invasive forms of human experimentation, such as the Cold War experiments, are deemed unethical due to their infringement on safety and autonomy. The Cold War experiments were a series of radiation experiments, where researchers would expose their patients, including but not limited to pregnant women and inmates, to radiation in order to study its effects. This practice infringed on safety, by putting the patients at risk for radiation poisoning, and autonomy, as the patients were not fully informed about the effects of the experiment, and therefore couldn’t make a fully formed decision on whether or not to participate, because of the forced nature of the experiments. In all, invasive human experimentation is unethical and does more harm than good if the experimentees do not consent to the process. If brain organoid experimentation were to veer toward human experimentation without informed consent, it would be considered unethical as well.

However, we commonly see examples of human experimentation with fully informed consent in today’s world. During the COVID-19 pandemic, clinical vaccine trials took place in order to learn about the disease itself, and ultimately create an effective vaccine available for public distribution. In a current trial, volunteers are either prescribed the SARS-CoV-2 vaccine, or a placebo. The participant are fully aware that the test is a “randomized, double-blinded, and placebo controlled phase III clinical trial of the SARS-CoV-2 inactivated vaccine manufactured by Sinovac Research & Development” and serves to “evaluate the efficacy, safety and immunogenicity of the experimental vaccine in healthy adults aged 18~59 Years.” Because volunteers are fully informed about the processes, goals, and risks of the experiment, human experimentation with informed consent is ethical. If brain organoid experimentation were to tend toward human experimentation with informed consent, it would be considered ethical as well.

Though brain organoids can eventually gain consciousness, they lack many other qualifications that are unique to humans and animals. For example, ability to express thought/emotions. Because of this apparent intellectual gap between brain organoids and humans, their respective experimentations are not comparable. Because of the lack of moral ties that come with brain organoid experimentation, it can now be used for good, such as scientific research advancements and creation of treatments. Therefore, experimentation directly on brain organoids is ethical because cognitive capacity cannot be compared to that of humans and animals.

Experimental implantation of brain organoids into humans has not been executed yet, but experimental insertion of brain organoids into animals is currently underway-as exemplified by the brain organoid-implanted chimeras mentioned previously in the paper. Is animal experimentation involving human brain organoids ethical? As in the mouse experiment I explained previously, the mice were subjected to living the rest of their lives through the neurological processes of humans. This disregards the value of respect because the lives of the chimera mice were biologically altered, with no respect to their consent, deeming this type of experimentation unethical. 

The experimentation with brain organoids and mice could have been said to improve the quality of life of the subjects because of how it altered their neurological functions. As a result of the experiment, the mice had greater cell survival and neuronal differentiation, which led to greater life expectancy and a more active nervous system. The results of the experiment as well, provided more knowledge about the functions of the brain organoids themselves, which can help researchers understand more about applications of brain organoids. However, the bottom line is that the mice did not consent to the experimentation, making the experimentation of brain organoids on animal subjects without informed consent unethical.

Brain Transplants and Identity

Image by talha khalil from Pixabay

Though purely hypothetical at this point, brain organoid transplants could become a very real possibility for those in need of a brain tissue donation. What is the ethicality and what are the implications of applying these brain organoid transplants? The brain is essential to how we go through life. It controls our actions, emotions, decisions, and thought processes. The most intriguing part – no two brains look, think, or function in the same way. If one were to be transplanted with tissue of a brain organoid (derived from another’s stem cells), their identity would be compromised because their individual thought processes would be combined with that of another. However, I believe that brain organoid transplants have the potential to solidify a sense of identity. Brain organoids, if successfully transplanted, can provide greater cognitive abilities. We can see this with the mouse chimeras; after being transplanted with a human brain organoid (with more neuronal capacity), they were able to produce more neurons. Because more neurons result in a greater ability to interpret information, the mice were left with greater cognitive abilities. A greater sense of consciousness results in more interaction with one’s identity. This could also potentially apply to humans with brain disorders, such as Alzheimer’s and Parkinson’s diseases. Because both of these are neurodegenerative disorders, a person’s cognitive ability can be improved from brain transplantation. Thus, brain organoids can aid in improving one’s self awareness and who they are as a person.

Frameworks

The three frameworks that I will use to evaluate the ethicality of brain organoid research are consequentialism, utilitarianism, and deontology. In consequentialism, we evaluate the ethicality of an action based on the consequences alone. This differs from utilitarianism in the sense that we evaluate the end results, whereas in utilitarianism we evaluate the stakeholders. In this scenario, allowing the creation, experimentation, and application of brain organoids would result in more knowledge of presently unknown medical areas, which has the potential to save future lives, and transplants themselves will improve the quality of life for those who undergo them. Because of these positive consequences, via consequentialism, brain organoids would be deemed ethical. Utilitarianism is an ethical framework, derived from consequentialism, defined as the greatest good for the greatest number of people. While brain organoids can infringe on the value of respect for those whose cells and subjects are used for  research, its findings can be overall beneficial for the rest of humanity. Application of brain organoids can provide us with more knowledge of diseases/disabilities that originate in the brain, which raises the possibility that we may be able to help people with these conditions.

Conclusion

Based on the values of respect, safety, and identity and the ethical frameworks of utilitarianism, consequentialism, and deontology, it is ethically permissible to create, experiment on, and use brain organoids. Research on brain organoids upholds the value of respect because their creation takes into account the consent of the stem cell providers. Brain organoids also comply with the value of safety because they allow experiments to continue to a point where they don’t veer into human experimentation. Finally, brain organoids may help enforce the value of identity because of their ability to help people keep a sound mind and full consciousness. In all, the technology’s potential to do good on so many scales was the biggest factor in my decision to promote its ethicality.

The values of privacy, empathy, and identity can be used against the application of brain organoid technology. Creating brain organoids that resemble brains of specific humans can be an invasion of privacy because they essentially take a unique part of a human’s body, swiftly model it in a lab. To resolve this, I recommend an emphasis on informed consent, being able to know all relevant information regarding a procedure, and then making a free decision. The empathy toward embryonic stem cells is hindered by the creation of brain organoids, because their growth and development is imparied by the cultivation of ESCs. I recommend that an experimentation window be placed on the brain organoids in order to prevent this from veering into human experimentation without informed consent. The line would be drawn at the time/stage when the brain organoid emits human-like brain waves. A 14-day experimentation window already exists for embryonic stem cells. The 15th day is when the embryo begins to transform into a multicellular and multidimensional structure called the gastrula. Identity serves as both a positive and a negative when it comes to the discussion of brain organoids. The identity of people receiving brain transplants could be impacted, because it introduces tissue that belongs to the brain of another human, in possession of their own thoughts, emotions, and neurological processes. Because of lack of knowledge surrounding brain organoid transplants, we don’t know how exactly this could affect the identity and wellbeing of the tissue recipient. I recommend a greater emphasis on doctor-patient transparency, also known as informed consent. This would help prevent misconceptions that surround vastly unknown topics such as brain organoid transplants. Since brain organoids have recently been introduced into the scientific community, regulations for their proper use must be put in place as their applications expand.

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