Human brain organoids: Between hype and reality

Human brain organoid research offers immense promise for biomedicine but many uncertainties surround the ethical status of organoids and whether existing guidelines are sufficient to ensure responsible innovation in this field.

Brain organoids offer a novel way of visualizing and understanding the human brain in laboratory settings. Photo credit: Andrew Brookes/Getty

The complex and intricate nature of the human brain in health and disease is an enigma that science has been trying to solve for centuries. This has proven difficult given that it cannot easily or ethically be investigated in a living human. As a result, in order to better understand how the brain develops and how it responds or succumbs to disease, research has traditionally used animal and cell culture models. Recently, research using a new type of model, brain organoids, has garnered both immense excitement and scrutiny. Is all of this hype warranted? Although brain organoids come with an undeniable and unprecedented potential for biomedicine, the field remains in its infancy and actual brain organoids are a far cry from misconstrued visions in science-fiction movies. However, rather than waiting for brain organoid research to advance to the point of an ethical gray zone, immediate development of clear research priorities and boundaries is imperative for safe and optimal use of this new technology.

Harnessing the power of stem cells

Human embryonic stem cells have the fascinating ability to turn into almost any cell of the body. However, the neural stem cells that are found in the human brain, are difficult to access and of limited number, which has prevented scientists from fully harnessing their power. Incredibly in 2007, work by the Japanese stem cell researchers Takahashi and Yamanaka showed that they could take mature human cells, such as skin cells, and reprogram them back to a stem cell state, called human induced pluripotent stem cells (hiPSCs). From there, researchers could use specific factors to create an environment for the hiPSCs that would push them to differentiate into a mature cell, like a human brain cell. The newly generated human brain cells could then be used for research. This discovery was a paradigm shift for stem cell research and the field of neuroscience, as it resulted in the ability to obtain high volumes of specific cell types that may not have been easily accessible otherwise.

A second groundbreaking discovery in the field was made in 2013, when Madeline Lancaster and colleagues found that, if given just the right conditions, hiPSCs could spontaneously assemble and build into brain organoids. These functional 3D structures mimic the architecture of the brain and overcome many of the limitations encountered with traditional animal or cell culture models. Organoids bring about a seemingly limitless potential for modelling the brain, yet at what point does this human cell model become too advanced and similar to an actual human brain? The ability to recapitulate components of the human brain is exciting but it comes with a number of potential implications, given the deeply intimate connection of the brain to the self.

The promise of brain organoid research

The information scientists can gain with brain organoid technology is of incredible value for biomedicine. As explained in a report from Harvard University, organoids not only help scientists examine interactions between cells, learn about development, and observe what goes wrong in disease, but also allow for rapid and tailored screening of potential new therapies. Furthermore, organoid research avoids having to extrapolate findings from animal studies where the underlying genetics or anatomy may not perfectly match that of humans. In addition, many neurodegenerative diseases are complex, and arise from changes in many genes and cells. Organoids built from stem cells or hiPSCs of patients with these ailments allow scientists to generate much more precise models of the disorder to better understand how they develop. For example, researchers have generated brain organoids that can model components of Alzheimer’s disease, allowing them to observe the cellular response to disease progression in real time. To date, organoid models of a number of important brain structures such as the hippocampus, which is involved in memory formation, the brain stem, the retina, and the cortex, which is the outer layer of the brain, have been reported. Robust functionality of these brain organoids has been proposed based on recordings of active neuronal networks and the finding that they can connect to mouse spinal cords and induce movement in muscle.

Microscopic image of a cortical brain organoid with different cell types pictured in different colors. Photo Credit: Arlotta Lab, Department of Stem Cell and Regenerative Biology, Harvard University.

If brain organoids can recapitulate so many physical aspects of the human brain, what then of higher order components that are more intimately tied to human experience? Although consciousness or emotions have yet to be achieved, a 2019 study reported the ability of brain organoids to generate brain waves that were comparable to those of a preterm infant. This discovery sparked widespread concern and intense philosophical and ethical discussions about the moral status of brain organoids. Controversy has also arisen with regards to the transplantation of human brain organoids into animals and the subsequent creation of chimeric animals. University of California-San Francisco researcher Dr. Arnold Kriegstein has explained that the benefit of doing so is that the environment of the animal helps with the survival and maturation of the brain organoid, making it more conducive to examine the research question at hand. Nonetheless, this has prompted questions about brain enhancement and possible humanization of animals.

Crossing an ethical line

Have these experiments already begun to blur the line between cell culture, animal and human? It is important to note that many argue that these conclusions have been vastly overstated, as there is still a long way to go in brain organoid research. First and foremost, according to bioethicists, the extent of efficacy and the value of brain organoids must be determined. When is brain organoid research a better choice than traditional models? Are there any instances where brain organoids would not be able to adequately answer research questions? To date, the brain organoids produced have been considered quite immature in comparison to a bonafide human brain. Kriegstein has emphasized that what scientists are currently working with are not the equivalent to a human brain in a dish. For one, their size is minute when compared to a whole adult brain and issues of blood flow and proper connectivity are just beginning to be addressed. Furthermore, reviews by Qian and colleagues and Chen and colleagues have noted that key components of brain structure, such as proper cortex folding and white matter connections are often lacking in current brain organoids.

Brain organoid research warrants intense scrutiny

Just because brain organoids are still in their infancy, does not mean that discussions surrounding their regulation are premature. Rather, this should be an opportunity for comprehensive and careful planning. Stanford law professor Hank Greely has pointed out that brain organoids do not fall into any one category of biomedical regulation but represent more of a grey area. As such, policy makers, scientists and bioethicists must come together to create new research ethics regulations or adjust current procedures in place. Furthermore, we must also establish what exactly prompts concern about these brain organoids. Bioethicists Julian Koplin and Julian Savulescu explain that although public discussions of brain organoids are fraught with fears and questions of potential organoid sentience, traditional animal models that are currently used are sentient and there are well established regulations in place for their use. If sentience is not the main source of ethical concern, what is driving our apprehension and unease with regard to brain organoids? Instead, it is the narrow possibility that these brain organoids could become so advanced that they develop consciousness or a sense of self, making them just as much of a person as you and I.

Human brain organoids growing in a flask. Photo Credit: Mayur Madhavan

Similar controversies have arisen in biomedical research and the moral status of embryos, stem cells and other human tissues has long been debated. Considerations from prior debates on related biomedical research can be used as guidelines as we navigate the ethical and policy issues. In Canada, for many years, research involving human embryonic stem cells and their transplantation into animals was subject not only to standard research and animal ethics reviews, but also had to undergo an additional review by a special stem cell research oversight committee. In the light of this practice, it may be reasonable to adopt heightened ethics oversight on experimentation with human brain organoids to address grey areas until appropriate research ethics procedures are in place. Furthermore, the notion of consent is of utmost importance in biomedical research. Currently, consent for research is required when obtaining human stem cells from donors, as well as when using other donated cell types to generate hiPSCs. Given the potential controversies arising from organoid research, Greely has posed the question of whether organoid specific research would have to be explicitly stated in consent forms or whether it would fall under the realm of “general research use”. It is important to address this concern since donors of human tissues often make decisions for donations based on their ethical principles. For instance, prominent brain organoid researcher Alysson Muotri has found that when told their cells might be used for brain organoid research, some prospective donors decided to opt out from participation in the study.

New committees and measures have been assembled or suggested to navigate the complex ethical landscape of organoid research. The National Institutes of Health (NIH) in the United States implemented the Brainstorm Project, where scientists and ethicists meet to discuss moral issues and important future studies in organoid research. Computer programs that can detect perceptions or awareness have been proposed to ensure no moral boundaries are crossed with the brain organoids generated. However, with the latter, we cannot be naive and simply hope nothing problematic will occur. What happens if an organism created in the lab does become aware or perceptive? Clear protocols and procedures must be in place in the event that a situation like this was to occur. More importantly, however, rather than waiting and assessing situations as they come, committees should be applying the precautionary principle and direct their efforts towards establishing the limits of research in this field with the goal of preventing a situation like this from ever occurring in the first place.

Why we should proceed with caution

Hindsight is always 20/20 but it should not take a scientific mishap or an ethics violation to prompt action. The remarkable power of CRISPR, the gene editing technology, was well understood within the scientific community and the ethical lines that could be crossed with its use were clear. Unlike brain organoids, the relative ease and advancement of this technology meant that its misuse was not a question of if, but when. Accordingly, in December 2018 Chinese geneticist Dr. He Jiankui announced that he had used CRISPR technology to edit the genomes of two embryos prior to their birth in order to confer resistance to HIV. The experiments were met with severe criticism from the scientific community and deemed to have crossed a moral boundary. It was only in response to this controversy that defined regulations and ethics committees were put into place by the World Health Organization and other countries that didn't have strict regulations in place. Although this hopefully prevents future ethical violations, the genetic alterations performed cannot be undone and it is remains to be seen if they have done more good than harm to the two babies. This unethical experiment could have been prevented with early and collective action of scientists, bioethicists, and policymakers.

It is clear that brain organoids offer an unprecedented ability for scientists to study the human brain and understand the mechanisms of neurodegenerative diseases. With any great discovery, comes a duty to be proactive and aware of the power that comes with it. Yet, research and advances in brain organoids are in full swing. Discussion of brain organoid use and appropriate regulation must be prioritized, so that we can realize the potential of brain organoid research in a responsible and ethical way.

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