At what point does a mass of nerve cells growing in a laboratory Petri dish become a brain? That question was first raised seriously in 2013 by the work of Madeline Lancaster, a developmental biologist at the Medical Research Council’s Laboratory of Molecular Biology, in Cambridge, Britain. That year Dr Lancaster and her colleagues grew the first human-derived “cerebral organoid”. They did so using pluripotent human stem cells, which are cells that have the potential to develop into any type of tissue in the human body. The researchers coaxed these cells into becoming nervous tissue that organised itself, albeit crudely, as structures which had some of the cell types and anatomical features of embryonic human brains.
The twitch
Since then, Dr Lancaster’s work has advanced by leaps and bounds. In March, for example, she announced that her organoids, when they are connected to the spinal cord and back-muscle of a mouse, could make that muscle twitch. This means cerebral organoids are generating electrical impulses. And other scientists are joining the fray. One such, Alysson Muotri of the University of California, San Diego, has published this week, in Cell Stem Cell, a study that looks in more detail at cerebral-organoid electrical activity.
To carry out their study, Dr Muotri and his colleagues grew and examined hundreds of organoids, each a mere half-millimetre in diameter, over the course of ten months. To probe individual neurons within these they used tiny, fluid-filled pipettes that acted as electrodes small enough to maintain contact with the surface of an individual cell.
Neurons probed in this way proved electrically active, so the researchers went on to employ arrays of electrodes inserted simultaneously into different parts of an organoid to study its overall activity. They looked in detail, once a week, at each of the organoids that were chosen for examination. This revealed that, by six months of age, the electrical activity in different parts of an individual organoid had become synchronised.
Such synchronicity is also a feature of real brains, including those of preterm human infants of about the same age as Dr Muotri’s organoids. It is regarded as an important part of healthy brain function. So, to check how similar natural and organoid brain waves actually are, the research team ran those waves obtained from their organoids through a computer program that had previously been trained to recognise the electrical activity generated by the brains of premature babies. This algorithm proved able to predict to within a week the ages of laboratory-grown organoids 28 or more weeks old. That suggests those organoids are indeed growing in a manner similar to natural human brains.
Brain work
If further research confirms this opinion, then for medical science that conformity with natural development could be a boon. Neuroscientists have long been held back by the differences between human brains and those of other animals—particularly the brains of rodents, the analogue most commonly employed in medical research. The purpose of the work that Dr Lancaster, Dr Muotri and others involved in the field are engaged in has always been to produce better laboratory models of neurological and psychiatric diseases, so that treatments may be developed.
And, although it may be some time in the future, there is also the possibility that organoids might one day be used as transplant material in people who have had part of their brains destroyed by strokes.
For ethicists, however, work like this raises important issues. A sub-millimetre piece of tissue, even one that displays synchronised electrical pulsing, is unlikely to have anything which a full-grown human being would recognise as consciousness. But if organoids grown from human stem cells start to get bigger than that, then the question that was posed back in 2013 becomes pressing.
