Neuroscience research, with the ultimate goal of deepening our knowledge of the human brain, about which we still know so little, is advancing rapidly (see HERE). Thus, major projects such as the “BRAIN Initiative” in the United States and the Human Brain Project (HBP) in Europe have been set up in order to encourage this research.

These experiments also have great potential for application in medicine, for example, to treat neurodegenerative diseases, reverse addictions or act on chronic pain without having to use opioids. Nevertheless, they raise several bioethical issues that need to be addressed to regulate this research.

Neuroscience and Neuroethics

In response to the “BRAIN Initiative”, in 2014 the North American National Institutes of Health (NIH) published a report[1] (see HERE) that gathered together the scientific history to date and gave a series of recommendations to regulate future experimental development in this field. However, it also stated that this research entails “special ethical considerations. brain experiments rekindlel debateBecause the brain gives rise to consciousness, our innermost thoughts and our most basic human needs, mechanistic studies of the brain have already resulted in new social and ethical questions. Can research on brain development be used to enhance cognitive development in our schools? Under what circumstances should mechanistic understanding of addiction and other neuropsychiatric disorders be used to judge accountability in our legal system? Can civil litigation involving damages for pain and suffering be informed by objective measurements of central pain states in the brain? Can studies of decision-making be legitimately used to tailor advertising campaigns and determine which products are more attractive to specific consumer bases?”

At the end of that same year, the NIH convened a workshop entitled “Ethical Issues in Neuroscience Research” (see HERE), in which three dozen researchers, clinicians, bioethicists and patient organization representatives took part, along with leadership from the National Science Foundation, the Food and Drug Administration and the NIH. The aim was to identify high priority areas for this type of research that can inform policies pertaining to either the ethical conduct of neuroscience research or its ethical use. Some of the issues raised were related with: data collection in research versus clinical contexts; data sharing and ownership issues; obligations to research participants; unintended consequences of neural stimulation devices; informed consent; protection for vulnerable populations; neuroenhancement; cultural differences in ethics of neural device research; the development of appropriate definitions for “spectrum disorders”; or with research in animal models, both in the sense that they can become “humanized” and in the issues that surround the translation of findings into effective diagnostic and treatment tools.

In relation to this, Obama tasked the Presidential Commission for the Study of Bioethical Issues (PCSBI) with the bioethical study of these and other issues, which gave rise to two reports. The first, published in 2014 (see HERE) focuses on the explicit and systematic integration of ethics into neuroscience research from the start[2]. The second, published in 2015 (see HERE), refers to three topics: cognitive enhancement, consent capacity and neuroscience and the legal system[3]. For its part, the NIH has established a Neuroethics Division (see HERE) responsible for informing the BRAIN Initiative in the handling of bioethical questions and issues related with their research.

As well as all these issues raised by research practice in neuroscience and by the advance of our knowledge of the brain and its functioning, there is a sub-area of neuroscience that raises specific ethical issues: Experiments with human brain tissue. 

Experiments with ex vivo brain tissue, human brain organoids or chimeras.

Our inability to gain access to the physical study of the brain during the life of an individual is a barrier to understanding its functioning. For this reason, several approaches are being developed to shed light on brain function and the disorders associated with this major organ: research with ex vivo brain tissue, human brain organoids and human-animal chimeras.

The study of ex vivo brain tissue, or even of complete animal brains, provides an insight into certain aspects of this organ, such as some intact brain circuits. Nevertheless, important changes occur in the biophysical properties of the brain after death, so developing other research methods continues to be a challenge. However, technical advances in this field could increase the usefulness of this approach. For example, several media have recently reported that researchers from Yale University managed to keep pig brains alive outside their bodies (see HERE)). To that end, the researchers collected around 200 pigs’ brains obtained from a slaughterhouse and brought them to their laboratory, where they kept them medically active (although not conscious) for 36 hours using a system of pumps, heaters and oxygen transport fluid. Although it appears that it would be possible to keep them working indefinitely, and even to restore the electrical activity that gives rise to the animal “mind”, this was not done as a precaution.

For their part, human brain organoids are 3D multicellular structures derived from stem cells that resemble different brain regions[4]. Brain organoids have already been developed to investigate diseases, such as autism spectrum disorders[5], schizophrenia[6], brain cancer[7] and the microencephaly suffered by babies infected with the Zika virus before birth[8], as well as drug development[9]. Although this research line is at a very early stage, these systems could be used as a model to predict brain disorders specific to certain genetic mutations and even to individual patients, as well as to model microbe-host interactions[10]. Different brain organoids can be combined in vitro to study the formation of neural circuits and the cell interactions between different regions[11].

Brain experiments rekindle debate that includes chimeras

Finally, chimeras involve the transplant of human cells, derived in vitro from pluripotent stem cells, into animal brains, such as those of rodents. One of the challenges for developing brain organoids that are more complex than those obtained to date is the lack of blood supply, for which it has been proposed to implant human brain organoids into the brain of a host animal. For example, human brain organoids have already been transplanted into rodents, where they have been irrigated by blood vessels (vascularized)[12]. Thus, attempts are being made to obtain better modeling of human brain diseases in a physiological setting or to test drug treatments.

Brain experiments rekindle debate. Current bioethical panorama

However, these experiments raise important bioethical questions that are being addressed by different experts. An overview of the current bioethical panorama in this field is outlined below.

Brain experiments rekindle debate in bioethical issues on experimentation with human brain tissue, organoids or chimeras

In March this year, the BRAIN Initiative convened a workshop entitled “Workshop on Research with Human Neural Tissue”, in which two dozen participants with backgrounds including neuroscience, neurology, bioethics, philosophy and theology discussed the state of the science and the ethical implications in relation to these experiments, identifying different ethical aspects related with this scientific area.

Then, in April 2018, the journal Nature published an article[13] entitled “The ethics of experimenting with human brain tissue”, subtitled: “Difficult questions will be raised as models of the human brain get closer to replicating its functions”. In the paper, the investigators laid out some of the issues that they thought should be addressed as a first step to regulate these experiments, many of which coincide with those suggested in the abovementioned workshop.

Brain experiments rekindle debate. That could be classified into twelve items:

  1. Scientific promise: the participants discussed the “ethical imperative” of leveraging these models of the human brain to advance our understanding of brain diseases and disorders. In the article in Nature, the authors say that “the promise of brain surrogates is such that abandoning them seems itself unethical, given the vast amount of human suffering caused by neurological and psychiatric disorders, and given that most therapies for these diseases developed in animal models fail to work in people.”
  2. Humanness: “The brain confers on us certain abilities that make us human, while simultaneously making each of us unique”. In the workshop, the participants debated about which characteristics, specifically, make us human, and discussed topics related to identity, such as memory. They also emphasized the fact that the brain itself is not a human being, it should be functioning in a living body, of a human being, which in turn exists within a social context, which is critical for the development of human identity. There was a discussion on the integration of human cells into the brains of non-human mammals, concluding that it is unlikely to make the animal more human-like and that careful consideration of the societal benefit and animal welfare is needed. Nevertheless, it was suggested as a central question to consider: “what kind of functional modification of the animal brain would matter morally and why?” For their part, the authors of the Nature article say that “decisions about which kinds of chimaera are permitted, or about whether certain human organs grown in animals make animals ‘too human-like’, should ultimately be made on a case-by-case basis — taking into account the risks, benefits and people’s diverse sensitivities.”
  3. Moral status: The group discussed which moral category was more appropriate for human brain models and why a human brain organoid might have a moral consideration. The capacity for sentience was identified as a critical moral marker.
  4. Metrics for assessing sentience or consciousness (or the capacity for either): A key question discussed in the workshop was how to know if a human brain organoid had developed sentience, so it was suggested that this might be an area of research to inform revisiting these questions in the future. In relation to this, in the article in Nature, the authors noted that, as well as the problem of deciding which capacities of the brain model would be morally relevant, with our current understanding of what consciousness is and what building blocks it requires, it is hard to even know what signals to look for.
  5. Informed consent: It may be worthwhile considering the incorporation of information and options in the informed consent process for donating stem cells if these are to be used to derive brain organoids or to produce human-animal chimeras.
  6. Stewardship: Aspects were discussed such as the duration and conclusion of studies and disposal of tissues, suggesting that in the future it might be necessary to establish specific measures for human brain models. In the article in Nature, for example, they ask: “if researchers develop mice, say, with some advanced cognitive capacities, should those animals be destroyed or given special treatment at the end of a study? Already certain animals, such as chimpanzees, enter sanctuaries to live out the remainder of their lives after researchers have finished working with them in laboratories”, and they propose the figure of the “guardian”, someone other than the researchers, to ensure the welfare of brain surrogates or chimeras.
  7. Ownership: The question arose of who should “own” brain models if these had greater moral status in the future.
  8. Brain death: So far, the diagnosis of brain death has been used to declare that a person is dead. Nevertheless, both groups expressed the possibility that technology could be developed in the future that could restore brain functionality in ex vivo brains, so that brain damage was no longer irreversible, which would require this diagnosis to be reconsidered.
  9. Oversight: Participants of the workshop assessed whether existing oversight infrastructures can address these various ethical considerations, highlighting the California model, where research with all kinds of stem cells is overseen, not just embryonic stem cells.
  10. Data and privacy: Data obtained from studying the human brain, for example regarding memory, could require special treatment, similar to the case of genetic information.
  11. Avoiding hype: It is “in the best interest of all stakeholders to discuss both the science and the ethics as clearly and accurately as possible – and to avoid sensationalizing either.”
  12. Collaborative ethics as a model: Collaborative ethics was presented as a model to consider, to encourage ongoing dialogue between scientists and ethicists, and thus respond to the dynamics of research. It “can include both philosophical and practical ethics, with the emphasis shifting dynamically in response to the science”.

 Conclusion 

As stated, neuroscience in general and studies with brain tissue, organoids or chimeras in particular, raise numerous serious ethical questions that must be addressed before continuing with this type of research. In our opinion, this area of medical research is one of those that poses the greatest bioethical problems, which inevitably must be considered, debated and resolved. Although many questions refer to future scenarios, given the likelihood that many will become a reality in the not too distant future, they must be contemplated and discussed from now on, to ensure that the development of this promising discipline is guided and directed in accordance with the respect that human dignity requires.

Lucia Gomez-Tatay

Bioethics Observatory – Institute of Life Sciences

References

[1]Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Working Group Report to the Advisory Committee to the Director, NIH. (Junio 2014). BRAIN 2025: A Scientific Vision.

[2]Presidential Commission for the Study of Bioethical Issues (PCSBI). (Mayo 2014, May). Gray Matters:

Integrative Approaches for Neuroscience, Ethics, and Society. Washington, DC: PCSBI.

[3]Presidential Commission for the Study of Bioethical Issues (PCSBI). (Marzo 2015). Gray Matters:

Topics at the Intersection of Neuroscience, Ethics, and Society. Washington, DC: PCSBI.

[4] Lancaster MA, Renner M, Martin CA, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013 Sep 19;501(7467):373-9.

[5] Mariani J, Coppola G, Zhang P, et al. FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders. Cell. 2015 Jul 16;162(2):375-390.

[6] Ye F, Kang E, Yu C, et al. DISC1 Regulates Neurogenesis via Modulating Kinetochore Attachment of Ndel1/Nde1 during Mitosis. Neuron. 2017 Dec 6;96(5):1041-1054.e5.

[7]Ogawa J, Pao GM, Shokhirev MN, Verma IM. Glioblastoma Model Using Human Cerebral Organoids. Cell Rep. 2018 Apr 24;23(4):1220-1229.

[8]Qian X, Nguyen HN, Jacob F, Song H, Ming GL. Using brain organoids to understand Zika virus-induced microcephaly. Development. 2017 Mar 15;144(6):952-957.

[9]Watanabe M, Buth JE, Vishlaghi N, et al. Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection. Cell Rep. 2017 Oct 10;21(2):517-532.

[10] Ho BX, Pek NMQ, Soh BS. Disease Modeling Using 3D Organoids Derived from Human Induced Pluripotent Stem Cells. Int J Mol Sci. 2018 Mar 21;19(4). pii: E936.

[11]Birey F, Andersen J, Makinson CD et al. Assembly of functionally integrated human forebrain spheroids. Nature. 2017 May 4;545(7652):54-59.

[12]Mansour AA, Gonçalves JT, Bloyd CW, et al. An in vivo model of functional and vascularized human brain organoids. Nat Biotechnol. 2018 Jun;36(5):432-441.

[13]Farahany NA, Greely HT, Hyman S, et al. (2018). The ethics of experimenting with human brain tissue. Nature, 556(7702):429-432.