606 Lavazza A, Massimini M. J Med Ethics 2018;44:606–610. doi:10.1136/medethics-2017-104555 PAPER Cerebral organoids: ethical issues and consciousness assessment Andrea Lavazza, 1 Marcello Massimini 2,3 Neuroethics To cite: Lavazza A, Massimini M. J Med Ethics 2018;44:606–610. 1 Centro Universitario Internazionale, Arezzo, Italy 2 Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy 3 IRCCS Fondazione Don Gnocchi Onlus, Milan, Italy Correspondence to Dr Andrea Lavazza, Centro Universitario Internazionale, via Garbasso 42, Arezzo 52100, Italy; lavazza67@gmail.com Received 2 September 2017 Revised 8 January 2018 Accepted 5 February 2018 Published Online First 28 February 2018 ► http://dx.doi.org/10.1136/ medethics-2018-104778 ► http://dx.doi.org/10.1136/ medethics-2018-104976 ABSTRACT Organoids are three-dimensional biological structures grown in vitro from different kinds of stem cells that self- organise mimicking real organs with organ-specifc cell types. Recently, researchers have managed to produce human organoids which have structural and functional properties very similar to those of 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 the development and pathologies of human cells; they also make it possible to test new molecules on human tissue. Furthermore, organoids have helped research take a step forward in the feld of personalised medicine and transplants. However, some ethical issues have arisen concerning the origin of the cells that are used to produce organoids (ie, human embryos) and their properties. In particular, there are new, relevant and so-far overlooked ethical questions concerning cerebral organoids. Scientists have created so-called mini-brains as developed as a few-months- old fetus, albeit smaller and with many structural and functional differences. However, cerebral organoids exhibit neural connections and electrical activity, raising the question whether they are or (which is more likely) will one day be somewhat sentient. In principle, this can be measured with some techniques that are already available (the Perturbational Complexity Index, a metric that is directly inspired by the main postulate of the Integrated Information Theory of consciousness), which are used for brain-injured non-communicating patients. If brain organoids were to show a glimpse of sensibility, an ethical discussion on their use in clinical research and practice would be necessary. INTRODUCTION: FROM THOUGHT TO LAB EXPERIMENTS In a famous mental experiment, philosopher Hilary Putnam imagined a cruel scientist able to dislodge the brain from one's body and immerse it in a vat of nutrient fluid to keep it alive. 1 The nerve terminals are then connected to a supercomputer, so that the brain's owner is under the illusion that everything is perfectly normal. The person will think that there are objects and people in an environment and will have feelings and perceptions that correspond to the actions that he or she will conceive. But all that the person (the brain) feels is the result of the pulses transmitted by the computer to the nerve terminals. This scenario was of course constructed by a philosopher, under no claim of being real- istic, in order to theoretically discuss the themes of scepticism and knowledge. For some years, however, the idea of a brain in a vat has no longer been just a mental experiment, but also a labora- tory experiment. For a decade now, scientists have been trying to build mammal and human organs starting from single cells: the so-called organoids. 2 Recently, scientists have also tried to produce cere- bral organoids. 3 The latter are by no means similar to adult brains, nor is technology able, for now, to simulate an external reality and a body, transmitting it to the brain with the relative perceptions and feelings. However, the rapid progress that is being made suggests that one should begin to reason on the ethical aspects of organoids in general, and cere- bral organoids in particular. 4–6 After a discussion of what cerebral organoids are, in this paper we will address some new, relevant ethical issues related to the (today still remote) possibility of creating a sentient system in a dish. Then we will discuss the need to find shared criteria (which is not easy) and to establish a threshold beyond which simple biolog- ical material becomes something that should not be manipulated or destroyed, at least not without having a serious ethical discussion on the matter. Specifically, we want to focus on the developmental states in which a cerebral organoid may begin to be capable of experience, potentially including pain sensations. To do this, we need a general theory of conscious- ness that attempts to explain what experience is and what type of physical systems can have it. 7 The Inte- grated Information Theory (IIT) does so starting from phenomenological axioms to derive postulates about the properties required of physical mecha- nisms to support consciousness. The fundamental phenomenological axioms are (i) that conscious experience is informative (each conscious experi- ence differs in its own specific way from countless other possible experiences) and (ii) that conscious experience is integrated (each conscious experience cannot be split). The corresponding fundamental postulate is that a system has subjective experi- ence to the extent that it is capable of integrating information. The ability to experience depends on an optimal balance between diversity (information) and unity (integration), a non-trivial condition for a phys- ical systems. 8 9 Importantly, the theory proposes a theoretical measure (PHI), as well as related empirical metrics, to quantify a system’s capacity for integrating information. Although there is general consensus on the idea that consciousness is tied to the capacity of different cortical areas to on May 31, 2020 by guest. 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