‘Consciousnessoids’: clues and insights from human cerebral organoids for the study of consciousness

Human cerebral organoids (HCOs) are an in vitro three-dimensional model of early neural development, aimed at modelling and understanding brain development and neurological disorders. In just a few years, there has been a rapid and considerable progress in the attempt to create a brain model capable of showcasing the structure and functions of the human brain. There are still strong limitations to address, including the absence of vascularization that makes it difficult to feed the central layers of organoids. Nevertheless, some important features of the nervous system have recently been observed: HCOs manifest electrical activity, are sensitive to light stimulation and are able to connect to a spinal cord by sending impulses that make a muscle contract. Recent data show that cortical organoid network development at 10 months resembles some preterm babies’ electroencephalography (EEG) patterns. In the light of the fast pace of research in this field, one might consider the hypothesis that HCOs might become a living laboratory for studying the emergence of consciousness and investigating its mechanisms and neural correlates. HCOs could be also a benchmark for different neuroscientific theories of consciousness. In this paper, I propose some potential lines of research and offer some clues and insights so as to use HCOs in trying to unveil some puzzles concerning our conscious states. Finally, I consider some relevant ethical issues regarding this specific experimentation on HCOs and conclude that some of them could require strict regulation in this field.

Calcium and muscle contraction: the triumph and tragedy of Lewis Victor Heilbrunn

Lewis Victor Heilbrunn has been called the pioneer of Ca2+ as an intracellular regulator (Campbell AK. Cell Calcium 7: 287–296, 1986; Campbell AK. Intracellular Calcium, 2015). In 1947, he was the first to provide convincing evidence that Ca2+ triggered muscle contraction (Heilbrunn LV, Wiercinski FJ. J Cell Comp Physiol 29: 15–32, 1947). Yet his work was met mostly with silence and neglect. One wonders why. Heilbrunn was a general physiologist who believed in the uniformity of nature with regard to movement. He believed that “. . . the theory of what makes cells divide should not be very different from the theory of what makes muscle contract . . .” (Heilbrunn LV. The Dynamics of Living Protoplasm, 1956). He did not believe that one could understand how the living machine worked by investigating its parts. He believed that, to understand life, one must study the dynamics of living protoplasm. The origin and evolution of Heilbrunn’s thought process regarding the role of Ca2+ as a physiological activator will be traced back to the 1920s. The ways in which he tested the Ca2+ hypothesis in sea urchin eggs in the 1920s and 1930s will be explored. This work shaped Heilbrunn’s thinking about the role of Ca2+ in muscle contraction. Importantly, why he and his results were ignored for years will be examined. It turned out that being right was not enough. Bad luck and a stubborn belief in an outmoded scientific philosophy contributed to the neglect.

Swallowing induces sequential activation of esophageal longitudinal smooth muscle

We examined the mechanical activity of the longitudinal and circular muscles of the esophagus at three different levels (9, 5, and 1 cm above the lower esophageal sphincter) during peristalsis induced by swallows or vagal stimulation in anesthetized opossums with miniature strain gauges applied in the axis of muscle fibers. The onset of longitudinal muscle contraction occurred in an aboral sequence with swallows but simultaneously with vagal stimulation. The speed of longitudinal muscle activation with swallows was 7.6 +/- 1.7 cm/s. Circular muscle contraction occurred in an aboral sequence with vagal stimulation and swallowing with speeds of 4.1 +/- 0.8 and 2.3 +/- 0.1 cm/s, respectively. Longitudinal muscle contracted before the circular muscle at all sites. The duration of longitudinal muscle contraction increased aborally (P less than 0.05) with swallowing or vagal stimulation. These studies show that 1) during swallowing, esophageal longitudinal and circular smooth muscle contract in a sequential fashion, 2) the longitudinal muscle sequential contraction is due to central mechanisms, whereas circular muscle sequential contraction may be due to both central and peripheral mechanisms, and 3) peripheral neuromuscular mechanisms produce regional differences in the duration of longitudinal muscle contraction.

Assays of the metabolic viability of single giant mitochondria. Experiments with intact and impaled mitochondria.

Single giant mitochondria isolated from mice fed cuprizone were assayed for their metabolic viability. Two tests were devised. One test optically detected the accumulation of calcium phosphate within the mitochondria under massive loading conditions (including the presence of succinate and ATP). The accumulation corresponds to a test of energy coupling from either electron transport or the hydrolysis of ATP since it is blocked by either antimycin A or oligomycin. The other assay tested for the production of ATP from ADP and Pi, using myofibrils. Myofibrils prepared from glycerinated rabbit psoas muscle contract only in the presence of ATP and not in the presence of ADP. Myofibrillar contraction is unaffected by the presence of antimycin A or oligomycin. However, myofibrils in the presence of mitochondria that are phosphorylating ADP to ATP do contract. This contraction is blocked by antimycin A and/or oligomycin. Hence, the ATP which causes myofibrillar contraction is produced by oxidative phosphorylation. At low mitochondrial concentration, only the myofibrils in close proximity with mitochondria contract in the presence of ADP. Therefore the assay can be used to test the viability of individual mitochondria. Individual giant mitochondria were found to be viable, using both of these assays. Comparable results were obtained in mitochondria impaled with microelectrodes. The potentials and resistances were unaffected by concomitant calcium phosphate accumulation or oxidative phosphorylation.

Topical treatment of chronic simple glaucoma

In chronic simple (open-angle) glaucoma loss of visual field may be prevented by improving the outflow of aqueous humour from the eye and thus lowering the raised intra-ocular pressure. This is achieved mainly by miotic drugs which constrict the pupil and make the ciliary muscle contract. These either mimic acetylcholine, acting directly on the ciliary muscle, or inhibit cholinesterase and so allow acetylcholine to accumulate.