“Science says the first word on everything, and the last word on nothing.”
- Victor Hugo
The recent fervor surrounding Yale’s research system, BrainEx (a system to perfuse ex vivo pig brain in order to maintain a functional ex-vivo brain model), raises important questions for neurosurgeons and neurosurgeon scientists. First and foremost, can we really keep a brain alive in a bucket? Second, what does keeping a brain alive outside of the body mean from a surgical ethics perspective?
BrainEx is one of several methods to keep brain tissue functional outside of its host for the purpose of research. BrainEx is an explanted brain connected to tubes for the purpose of perfusion. Yale scientists were recently able to see billions of neurons with normal activity present in this model. This is a large feat as it provides potential for a larger system to study than formerly possible. Other methods for ex-vivo brain tissue study include: organoids, tissues slices, and chimeras. Organoids (the coolest sounding) are miniature, simplified versions of brain tissue that are derived from pluripotent stem cells. Tissue slices are exactly as they sound and from the post-mortem brain, useful for the study of circuitry. Chimeras are transplants across species to form mixed brain tissue. These four technologies have been in place in some form since the 1990s. They are ways to study small areas of the brain and are primarily used as models for disease states or normal neuronal function.
Researchers derive several benefits from studying brain circuits outside the body. Ex-vivo tissue can be used as a type of “assembloid” or several brain regions functioning together for the purpose of study. An example of studying a pathway ex-vivo is that researchers were able to activate a response to light by stimulating ex-vivo retinal cells.1 Therefore, they can serve as a potential “surrogate” brain or at least pathways to study. These models have been used in studies of microcephaly from zika, schizophrenia, and autism for example. Use of a surrogate avoids human experimentation. Ex-vivo brain tissue also has the potential to stay viable for study longer than 2D neural sheets.
There are scientific limitations to ex-vivo perfused brain. It is difficult to maintain adequate perfusion to the tissue without the presence of complicated blood vessel networks. This means that predominantly hypoxia-resistant brain regions such as portions of the brainstem and cerebellum may be functional but cortical regions likely are not. While ex-vivo models represent a large population of neurons for study, they fall short of the 100 billion neurons present in the human brain.
The simplicity of the ex-vivo model limits the potential for consciousness at this point. As Dr. Dennis Turner, Duke University Professor of Neurosurgery and expert in the field of functional neurosurgery and research, points out “Almost by definition, any ex vivo brain would not have significant sensory input or motor output, particularly the porcine brains described by Sestan et al informally at the Brain meeting. This would limit the degree of ‘consciousness’ and indeed the EEGs on these ‘reanimated’ brains were flat (after eliminating artifacts).” However, even with the lack of consciousness of the current model and unlikely ability to create a model with consciousness in the near future, when hearing about the ex-vivo brain, the public raised several concerns.
Dr. Sestan unintentionally launched a modern neuroethics debate. In an interview he states that the results were not intended for the mainstream media.2 The group is still working on scholarly publication of their system. This story was picked up after the work was presented at an international meeting. Neurosurgeons are getting a leak much like we’ve become accustomed to seeing on the news! Immediate public knowledge provides a window into how those outside the medical system will view the technology. Their imaginations raise questions that may not seem immediately obvious to a neurosurgeon reviewing a system that currently seems light years from a conscious brain.
If we take notes from other technologies suffering the public hysteria incited by information becoming public, we will learn to proactively address potential ethical questions that BrainEx and systems like it pose. To avoid getting behind the technological eight ball, we should understand technologies like BrainEx: their current uses and limitations as well as their potential.
In current form, BrainEx raises the question of how we should protect and regulate ex-vivo brain tissue. In particular, if researchers can create brain tissue in the lab that might have conscious experience, does that warrant additional protection than human and animal research? The concern comes from the potential for the brain tissue to eventually experience inputs such as pain or have memory. Dr. Turner feels that this warrants regulatory attention. He states:
“There are separate regulations for veterinary ethics than humans, including such examples as whole animal cloning, viewed with great trepidation in humans, but now performed almost routinely for various species, including dogs. Like any animal studies, however, in a research sense the constant worry is that the animal may feel pain or suffer, hence the necessary use of anesthesia for all in vivo experiments beyond behavioral testing. Thus, similar animal regulations should definitely be applied to ex vivo studies, but not including tissue slices. Tissue slices are only taken from a cadaver once euthanized, but quickly preserved in cold, oxygenated saline. Similarly, human embryonic tissue for transplant has been only acquired from cadaveric specimens where there is no possibility of sentience/sapience.”3
We should also allow ourselves to be imaginative in possibilities for ethical challenges new neuro-technologies may create in the future. We probably shouldn’t spend a ton of time addressing the out of this world, sci-fi-esque possibility of a brain-in-bucket-robotic takeover, but that doesn’t mean we can’t be creative when considering potential future applications. Most neuroethicists agree that developing guidelines as we advance neuroscience is a good idea.1
Neuroethics is a quickly growing field that addresses issues at the intersection of bioethics and neuroscience. There will naturally be ethical issues as we develop technologies surrounding advancement or alteration of the mind and behavior.4 With recent and constantly developing innovations in neuroscience, neurosurgeons need to be aware of the field and consider ways of collaborating with neuroethicists early.
In the case of ex-vivo brain tissue, what are the questions neurosurgeons should be asking ethicists? In thinking about the possibilities that may evolve from tissue specimen donation for research, how should a neurosurgeon go about informed consent? Who would own a small piece of brain tissue if it was maintained ex-vivo? What happens if eventually this brain assembloid has the capability for consciousness — how do we address disclosing EEG findings to families? What are the boundaries around transplantation and implantation? Of course these questions range from ridiculous to sublime but I’d argue that the possibilities raised are not impossible.
With a rapidly adapting field of neuroscience, I don’t think it’s possible to predict and prepare for all potential scenarios. Instead, I recommend an informed and collaborative approach in which we take the advice of neuroethicists and begin to form guidelines and frameworks to dynamically address the ethical questions of tomorrow.
Theresa Williamson, MD is a Doximity Scholar, Neurosurgical Resident at Duke University Hospital and Researcher at the Duke Margolis Health Policy Center. She focuses on decision-making and physician-patient communication in neurosurgery. Recognizing that neurosurgery is a complex and stressful field, she aims to advocate for both patients and physicians in her writing. For more, follow her on twitter @twilli7 or at medium.com.
1. Farahany, N., Greely, Henry T, Hyman Steven et al, The Ethics of Experimenting with Human Brain Tissue. Nature International Journal of Science, 2018. 556: p. 429–432.
2. Regalado, A., Researchers are keeping pig brains alive outside the body. MIT Technology Review, 2018.
3. W, T.D.a.K., Scientific and ethical concerns in neural fetal tissue transplantation. Neurosurgery, 1993. 33: p. 1031–1037.
4. Illes, J., Bird, Stephanie, Neuroethics: a modern context for ethics in neuroscience. Trends Neuroscience, 2006. 29(9): p. 511–517.
Acknowledgment: Dr. Dennis Turner for providing an interview and background information.