BRAIN ORGANOIDS AND ITS ETHICAL IMPLICATIONS

Posted by Jorge Urresti on December 10, 2020 in ethics, Neuroscience | 1 Comment

We have already talked previously in this blog about stem cells, their applications in research and therapies, and how the field is advancing to produce organoids that resemble their ‘original’ counterparts more and more with every new discovery. However, we have not discussed the ethical implications that come with experimenting with human tissue.

This is especially important when we talk about brain organoids. The brain is a complicated organ to access and study, and therefore stem cell approaches that allow us to investigate brain functions and disease are essential. Brain organoids are structures of brain cells that self-organize in a way that mimics parts of early brain development. They respond to drugs and other treatments in a similar way to real brains, so therefore they have the potential to be used for screening in diseases such as Parkinson’s, Alzheimer’s and brain cancer ¹. Brain organoids have been transplanted into rat and mouse brains ², where they can survive for long periods of time, and several strategies have been developed to produce brain organoids that resemble different parts of the brain, such as hypothalamus (which is involved in regulating daily activities like eating and drinking, among others), brain cortex, etc.

But one main question arises from this kind of research: how similar are these brain organoids to the real thing? Can they develop thought processes or even consciousness? In this article we are going to answer these questions and delve a bit into important ethical considerations when working with these new, exciting stem cell models!

NEW EXPERIMENTS LEAD TO NEW CONCERNS

Even if the notions of ethical boundaries applied to cerebral organoids were already on the minds of neuroscientists, it wasn’t until last year that those concerns became more prominent in the field. This is because a study was published in which investigators demonstrated that cerebral organoids produced coordinated waves of electric activity, similar to those observed in pre-term infants ³. This kind of coordinated activity is one of the many properties of the conscious brain.

Another study came around the same time that involved whole brains of pigs instead of human organoids ⁴. In this paper, investigators were able to ‘revive’ brains of pigs that were recently killed. After removing the brains from the skull, and using a combination of chemical factors, they observed how the neurons restored their ability to communicate through electric signals.

It is clear to see how these two groundbreaking experiments led to several ethical concerns. Are we treading too close to creating consciousness in the lab? That is an important question because if this is the case, it raises a multitude of issues about how we experiment with these models. If we find that brain organoids are conscious individuals, this would warrant rigorous conversations about the creation of life in the lab or the commercialization of organoid technologies, among many others.

However, the question itself is difficult to answer, as there is no clear definition on what exactly consciousness is, or how it can be measured. In the case of the pig brains, it is easier to imagine how they could regain or maintain a degree of their previous consciousness after being ‘revived’ during the experiment. But brain organoids lack many of the anatomical features of the real human brain, and they have no sensory input that would allow them to process outside information. For many, this feature is an important one to define consciousness and therefore, many neuroscientists argue that it is still too soon to ask these questions for our current models. But as these cerebral organoid methodologies improve, these questions will become increasingly relevant.

WHAT EVEN IS CONSCIOUSNESS?

To understand the ethical concerns raised here, it’s important to understand how to define consciousness. There are several competing theories ⁵. One such theory is called Integrated Information Theory (IIT). It posits that consciousness is a product of how densely neurons are connected within the brain. According to this theory, consciousness is directly tied to the idea of experience. Any system that is experiencing any effect, whether it’s yourself laying on the beach or your dog taking a nap, has a degree of consciousness. It feels like something inside them. If the system possesses enough complexity, it will be aware of it, and therefore we can declare it conscious. In short, this theory suggests that consciousness is a function of the brain itself, an intrinsic characteristic of highly complex systems.

IIT derives that depending on the level of complexity of the system studied, we can quantify the degree of consciousness. This has been observed using a technique similar to electroencephalograms (EEG), in which we can measure the brain activity by connecting electrodes to the skull of subjects and measuring the electrical activity. In experiments performed using patients who were either minimally conscious or in vegetative state, it was observed that the level of complexity of the signals observed was always higher in the case of the conscious subjects. These are very important observations that suggest that consciousness can be graded between different organisms, and because it postulates that consciousness can be generated without any sensory input, if the system under investigation is complex enough to integrate information.

Another theory that is gaining more traction in the last decade, is the Global Workspace Theory (GWT). It is opposite to IIT, in the sense that it establishes that consciousness arises in the prefrontal cortex – which is the region of the brain that makes up the frontal area and it is involved in higher cognition – after the processing of sensory inputs, which ultimately will form a sense of being. This theory was formulated in response to observations that showed big differences between conscious and unconscious responses to different stimuli. For example, while it is known that unconscious visual stimuli can evoke high electrical activity in different areas of the brain, identically visual stimuli but in a conscious state elicits a bigger electrical response that not only expands to different areas of the brain, but also appears to be more coordinated.

In this model, it is the fact that information is relayed to different parts of the brain to generate an action and that the subject becomes aware of that information that ultimately leads to consciousness. Therefore, it is possible that other non-biological systems, such as Artificial Intelligence, will gain consciousness when sufficiently developed if this theory is true.

CAN BRAIN ORGANOIDS BECOME CONSCIOUS?

How do these theories reconcile with our initial question about brain organoids? If we accept IIT theory, we have to come to terms that organoids may become conscious by themselves when sufficiently developed, and scientists may be creating this in the lab without even being aware. However, the methods to analyze the degree of consciousness as suggested by the IIT are still not fully developed, and they cannot be used on cerebral organoids yet. Moreover, some ‘benchmark’ must be established in order to rate the degree of consciousness generated, by first studying other subjects such as conscious and unconscious human patients and animals. 

If we consider GWT, which is the most agreed upon view by neuroscientists, then it is still way too early to consider the current brain organoids conscious. As mentioned before, brain organoids not only lack very important functional and anatomical features of real human brains, but they also don’t have any mechanism that allows them to receive sensory inputs. Looking at the matter this way, we can affirm that while the neurons in the organoids are certainly active and communicating with each other, that doesn’t mean it is anything close to human thought.

In summary, while questions about ethical concerns using these new cellular models are being asked (see ⁶ for more information), we are still far from having concise and reliable answers. Despite this, the discussion is still worth having because it allows scientists to proceed with caution when pushing the limits of scientific research. While our current understanding on both the nature of consciousness and the functional properties of brain organoids is expanded, eventually the picture will become clearer and guidelines will be put in place, in the same way we already have them for research involving human and animal subjects.

References

1.            Grenier, K., Kao, J. & Diamandis, P. Three-dimensional modeling of human neurodegeneration: brain organoids coming of age. Mol Psychiatry 25, 254-274 (2020).

2.            Mansour, A.A. et al. An in vivo model of functional and vascularized human brain organoids. Nat Biotechnol 36, 432-441 (2018).

3.            Trujillo, C.A. et al. Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development. Cell Stem Cell 25, 558-569.e557 (2019).

4.            Vrselja, Z. et al. Restoration of brain circulation and cellular functions hours post-mortem. Nature 568, 336-343 (2019).

5.            Koch, C. What Is Consciousness? Nature 557, S8-s12 (2018).6.            Farahany, N.A. et al. The ethics of experimenting with human brain tissue. Nature556, 429-432 (2018).