Authors, Andrea Lavazza *, Marcello Massimini **
(*Centro Universitario Internazionale, Arezzo, Italy; **Department of Biomedical and Clinical Sciences “Luigi Sacco”, University of Milan, Italy; Fondazione Don Carlo Gnocchi, Milan, Italy).
Paper: Cerebral organoids: ethical issues and consciousness assessment (http://dx.doi.org/10.1136/medethics-2017-104555)

Can we grow a sentient human organism in a dish? The answer may depend on how we evaluate few days or weeks-old embryos resulting from artificial fertilization, but it generally seems negative (the debate on the moral status of embryos is open, but it does not seem that they can have feelings at that stage of development). However, the question may find a different answer in unexpected places. In fact, a new line of biological research, also aimed at avoiding the use of animal models and potentially providing parts for human transplants, is leading to a revolution in dishes that could produce unforeseen consequences.

Organoids are three-dimensional biological structures grown in vitro from different kinds of stem cells that self-organize mimicking real organs with organ-specific cell types. Recently, researchers have managed to produce human organoids which have structural and functional properties very similar to different organs, such as the retina, the intestines, the kidneys, the pancreas, the liver, and the inner ear. Organoids are considered a great resource for biomedical research, as they allow for a detailed study of human cells’ development processes and pathologies, as well as for the testing of new molecules on human tissue. Organoids have also helped research take a step forward in the field of personalized medicine and transplants.

However, some ethical issues have arisen concerning the origin of the cells that are used to produce organoids (human embryos) and their properties (donors, researchers, biobanks and transplant recipients). Also, and more importantly, there are new, relevant and so far overlooked ethical questions concerning cerebral organoids. Scientists have created so-called mini-brains corresponding to the development level of a few months foetus, albeit with smaller dimensions and many structural and functional differences. Current cerebral organoids lack vascularity, as well as being devoid of surrounding embryonic tissues, glial cells, meninges and immune cells. Nevertheless, mini-brains exhibit neural connections and electrical activity, raising the question whether they might one day host a covert capacity for a rudimentary form of experience. The problem, of course, is that these brains in a dish would be completely devoid of behaviour, communication, sensory inputs and motor outputs through which an external observer may detect signs of consciousness.

Intriguingly, a similar problem has been recently tackled by the doctors in charge of patients who survive devastating brain injury. Indeed, intensive care medicine is artificially producing, as a by-product of saving many lives, thousands of brains that may remain isolated, split or fragmented; in the extreme case, cortical islands, or an archipelago of islands, may survive that are totally disconnected from the world outside. To address this urgent clinical problem, much attention has been recently devoted to the development of objective brain-based indices of consciousness that are independent of sensory processing, executive functions, and motor outputs.

A recent attempt in this direction is represented by the so-called Perturbational Complexity Index (PCI). This is a novel metric directly inspired by the Integrated Information Theory of consciousness, which measures directly the internal complexity of brain networks. Put simply, PCI involves perturbing directly the brain and characterizing the “echo” it produces, an approach very similar to what we would do with any unknown object; we knock on it with our knuckles and deduce what it might contain based on the sound it makes. Per theoretical postulates, a conscious cortical island should “sound” very different from an unconscious one. When consciousness is lost, the “echo” will either be local, because neurons are unable to engage in reciprocal causal interactions (low integration), or it will be global but stereotypical, because all elements engage in the same pattern (low information). The echo produced by the underlying circuits will be both global and information-rich, that is complex, only if many elements interact through specific mechanisms (integrated information). This theory-driven approach worked quite well at the bedside, allowing to detect a capacity for consciousness in brain-injured patients who were otherwise fully unresponsive. The open question is whether a similar approach may be adapted and calibrated to assess the complexity of organoid circuits in a principled manner.

Given that research and progress in the development of organoids are quite fast-paced, one might wonder if future mini-brains will be endowed with a minimal form of sensitivity, that is, capable of experiencing pain, for example. This may not be the scientists’ primary objective, but it may come as a by-product of achieving the set research goals. Currently, there are still very strong limitations in place, including the almost complete lack of interaction with the environment, which prevents cerebral organoids from developing the sensitivity of a few-months-old brain. But if mini-brains were to show levels of complexity that are somehow comparable with the ones detected in the residual cortex of a minimally conscious patient, it would be necessary to start an ethical debate on their use in clinical research and practice. Could we produce a sentient mini-brain and use it for destructive experiments? Would it be better to use a minimally “sentient” human “brain” or an animal model, for example, a mammal? Such questions are premature today, but may not be so in the future.