“Mini Brains” in the lab show electrical activity similar to a preemie’s brain

By Dr. Ananya Mandal, MDAug 29 2019

Researchers have developed successfully mini brains in the labs which are essentially a cluster of brain cells perfused in fluids. These brain tissues are now showing electrical activity akin to real brain, explain the researchers and this is a path-breaking development in brain research. The brain activity shown by the clumps of cells is same as that shown by brains of premature babies they explain. The results of the latest development were published in the latest issue of the journal Cell Stem Cell and is titled, “Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development.”

UC San Diego Stem Cell Program found complex network signaling developing in human cortical organoids that appear to recapitulate fetal brain development, offering an in-vitro model to study functional development of human neuronal networks. https://www.youtube.com/watch?v=rkpo7R8UOlc

While this is a progress in the field of neurobiology, the appearance of the electrical waves have also raised some ethical questions. The researchers describe these brains grown in labs as organoids. These are three dimensional clumps of tissues that are miniature and are simplified versions of the organs that are grown in the lab for research purposes. They can be sued for testing new drugs and agents for example on the brain tissue. These organoids are also useful for study of neurodegenerative diseases such as Alzheimer’s and Parkinsonism and neurodevelopmental conditions such as autism, write the researchers.

Lead neuroscientist from the study, Alysson Muotri from the University of California, San Diego said in a statement, “The level of neural activity we are seeing is unprecedented in vitro. We are one step closer to have a model that can actually generate these early stages of a sophisticated neural network.” Muotri and his lab colleagues have been developing the organoids for the last few years and this is the first time that their organoids have shown real neuroal activity. “I think they are replicating like crazy at this stage, and so we’re going to have bigger organoids,” he added. “The most incredible thing is that they build themselves,” he said meaning that if the conditions were right the organoids could take charge of their own growth and development.

“We are failing miserably,” Dr. Muotri said. “We can cure animals of some diseases, but it’s not translatable.” He was speaking about the brain diseases such as Schizophrenia, autism, bipolar disorder etc. which are poorly understood and which could be studied using these organoids. They have worked with Zika virus and seen the effects of the virus on the brain orhganoids for example, say the researchers.

Muotri explains that the team developed these organoids or mini brains from a bunch of pluripotent cells or stem cells which were coaxed to become brain cells. Pluripotent cells of the body have the capacity to turn into any type of cell when induced. The team created pluripotent cells from the skin cells of a donor. Then they coaxed these stem cells to turn unto cells of the cerebral cortex. This region of the brain forms the major part of the brain and is responsible for functions such as cognitive thoughts, sensation perception, memories etc. Once the organoids were developed they were allowed to grow in a culture of nutritious broth for a period of nearly 10 months before they were ready for further experiments and testing explains Muotri. All this while, the team kept a close watch on the genetic make-up of the brain as well as on the electrical activity of the brain organoids using electroencephalography (EEG).

By the end of six months in the culture, the organoids started showing some amount of electrical activity. This was significant and recordable says the team. However these activities were random and not organized as is seen in human brains. With time the electrical beats and waves became more synchronized and the patterns were similar to the bursts of brain activity seen in the brains of preterm infants. The team wrote that the cortex organoids have shown, “phase-amplitude coupling during network-synchronous events.” They explained that these oscillations or electrical activities were sustained by the neurotransmitters “glutamate and GABA”.

The researchers wrote, “While network activity from organoids does not exhibit the full temporal complexity seen in adults, the pattern of alternating periods of quiescence and network-synchronised events is similar to electrophysiological signatures present in preterm human infant EEG.” Not all features were same as preterm infants, but certain signatures were seen, they explained adding that over the past 28 weeks the development of the brains in terms of electrical activity was similar to a developing preterm infant.

These organoids were created in a special way so that they would be deficient in a vital protein that allows the neurons to function like in normal brains. They were also isolated tissues and had no other regions of the brains to connect to, write the researchers. This development of electrical activity over the weeks could be a process of how the brain develops in the fetus and in a preterm infant until in matures in to the human brain explains Muotri. The team wrote, “While we do not claim functional equivalence between the organoids and a full neonatal cortex... the current results represent the first step towards an in vitro model that captures some of the complex spatiotemporal oscillatory dynamics of the human brain.”

Further research focuses on working on these organoids to see their development as well as devise ways they could be used to study neurodevelopmental disorders.

However this development is also fraught with ethical concerns. Last year in November this study results were presented at the Allen Institute for Brain Science in Seattle. From this institute, neuroscientist Christof Koch said in a statement, “The closer they get to the preterm infant, the more they should worry.” “The closer we come to his goal, the more likely we will get a brain that is capable of sentience and of feeling pain, agony and distress,” Dr. Koch said. Researchers and experts on bioethics from across the world have lauded the study and also sounded words of caution.

The authors of the study have defended themselves saying that the organoids are engineered to lack a particular protein that could allow the neurons to form networks and connections. They have said that if they detect the organoids showing signs of becoming a conscious human being, the team would shut down the project. “There are some of my colleagues who say, ‘No, these things will never be conscious,’” said Dr. Muotri. “Now I’m not so sure.”