Introduction
Scientists attempting to grow human organs themselves are not an entirely new concept; in fact, scientists have been conducting this process for well over a decade, growing human organs ranging from kidneys to skin. Researchers have now been able to grow a mini-brain with neural activity that mirrors a preterm infant. This is an enormous stride forward as earlier work was unable to demonstrate brain activity that was similar to how the brain actually functions.
This research was largely founded based on neural oscillations, rhythmic brain signals found across species. Neural oscillations are one of the many cellular networks that eventually develop into circuits in the human brain during the maturation process. While this eventual development of neural oscillations into circuits is known, it is unclear when these networks precisely develop. Recent students in mice have demonstrated that oscillations develop immediately after birth. However, due to the fact, there previously were not any adequate models of the human brain in the laboratory setting it is unclear whether the same course of events occurs in humans brains.
Process
The team at the University of California, San Diego first grew human induced pluripotent stem cells (iPSCs), cells that can self renew, in neurons found in the cortex of the brain, which is responsible for controlling thought and behavior. The researchers opted to use iPSCs during this experiment as they have been shown in recent studies that they have the capacity to mimic various development features and the cellular and molecular processes of the human brain. In order to successfully grow the pluripotent stem cells, researchers created a solution that contained a mixture of transcription factors that regulate fetal development. Creating the perfect mixture was pivotal as it allowed for organoids to last long amounts of time. Many of these organoids were still usable after a year since the research was completed. These conditions allowed for the researchers at UCSD to mimic the neural oscillations and electrophysiological network activity.
This process differed from earlier attempts to create mini-brains as the team created the most optimal conditions for mini-brain development at every stage. For example, unlike standard protocols which start with a clump of cells to construct the organoid, the team started from a single cell to build the organoid. In addition, they also changed the timings and concentrations of certain aspects in the mixture. While the process was meticulous, it certainly paid off.
Results
The results of this study revealed that the mini-brains produced neural activity that mirrors a preterm infant; thus, mini-brains have the potential to serve as laboratory models for studying psychiatric conditions. The iPSCs used in the study, like most stem cells, can be differentiated to specialize in any cell; in this case, the iPSCs were directed to specialized into neurons and glia.
Due to the team’s unique way of creating an organoid from scratch, the team was able to identify a particular neuron that has previously never been able to be created in a laboratory setting: the GABAergic neuron. Another example of the team’s diligent process paying off was seen when measuring the electrical activity of the mini-brains using an electroencephalogram (EEG). The test revealed the mini-brains following the new protocol had 300,000 electrical impulse spikes per minute. With the old process, the earlier mini-brains produced a mere 3,000 spikes per minute.
The results are what lead the UCSD to compare their results with the electrical patterns in newborn baby brains. The neural oscillations discussed earlier in the introductions, change according to age. Newborn baby brains tend to be the least active in oscillations. Their brains tend to have almost no waves between spikes of electrical activity. As we get older, these periods with no activity tend to get shorter, and eventually become constant. Other than age, oscillation patterns can also be affected by cognition skills and various diseases.
The team compared their mini-brains with a previously published dataset of 567 EEG recordings from 39 babies born prematurely (between 24 and 38 weeks gestation). This cross-analysis revealed that the organoids revealed similar patterns in their EEG levels for up to 9 months after being developed.
Implications
The successful development of a functional mini-brain has far-reaching applications as it broadens the range of neurologic conditions that could be adequately studied. Further, in most psychiatric conditions the neuronal circuitry is impaired: mini-brains would allow for a better understanding of diseases such as autism and epilepsy. Prior to this study, there were no adequate models in the laboratory to study certain neurological diseases adequately. For example, Alysson R. Muotri, Ph.D., one of the lead scientists of the study, reported sending the brain organoids to the International Space Station, in an attempt to determine the effect microgravity has on brain development. Potentially, the results yielded from this experiment could determine the prospects for human life outside of Earth.
While developing mini-brains further holds the potential to change the way we study neurological diseases, this study exists in a fine line between science and ethics. Critics of this study and other members of the scientific community ask, “Are we getting too close to re-creating the human brain?”. Muotri understands these concerns and responds to these concerns by stating that the mini-brains developed in the lab are far from being functional adult human brains. He points out that the mini-brains are not only much smaller than fully developed brains but also lack hemispheres and blood vessels. Muotri also stated, “They are far from being functionally equivalent to a full cortex, even in a baby… In fact, we don’t yet have a way to even measure consciousness or sentience…”. Muotri asserts that science is far ways from creating a fully functional, developed brain, but as the medical landscape changes faster than ever ethics dilemmas that arise similar to this situation cannot be ignored.
References
1. “Lab-Grown “Mini Brains” Can Now Mimic the Neural Activity of a Preterm Infant.”
Scientific American, 30 Jan 2020 https://www.scientificamerican.com/article/lab-grown-mini-brains-can-now-mimic-the-neural-activity-of-a-preterm-infant/
1. “Machine Learning Algorithm Can’t Distinguish These Lab Mini-Brains from Preemie Babies,” UC San Diego Health, 29 Aug 2019, https://health.ucsd.edu/news/releases/Pages/2019-08-29-algorithm-cant-distinguish-lab-m ini-brains-from-preemie-babies.aspx 2. “Mini Brains” Are Not like the Real Thing,” Scientific American, 30 Jan 2020,
https://www.scientificamerican.com/article/mini-brains-are-not-like-the-real-thing/
3. Cleber A. Trujillo, Richard Gao, Priscilla D. Negraes, Gene W. Yeo, Bradley Voytek,
Alysson R. Muotri. 2019. Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development. Cell Press. Vol. 25; 1-12 https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30337-6?_returnURL=https %3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1934590919303376%3F showall%3Dtrue
Youth Medical Journal 