Let’s Make A Brain: Stem Cells, CRISPR, and Cerebral Organoids

Delving into the depths of newly published science in the field of biotechnology, welcome to Bioscription.

Perfectly mapping and even regrowing parts of a brain have long been something only considered to be a thing in science fiction. The technology has always seemed like it was centuries away from ever becoming a reality. But, day by day, researchers continue to develop new techniques and methods that push the boundaries of what was previously possible.

In this study set to be published in October in the journal Neuroscience, all the current methods in the development of cerebral organoids (cells that make up the brain) are discussed, from using pluripotent stem cells to directly regrow cellular parts found in a brain to using CRISPR to unravel the genetic components that make the brain work as it does. From this research, not only do we expand our understanding of the brain itself, but also open up ways to treat neurological disorders in living patients.

Background

One of the primary problems that has always needed to be confronted in studying the brain is the utter complexity of it. Made up of 80-90 billion neurons that themselves connect to each other in a number of ways, this results in trillions of connections that make up how our consciousness works. Even the best supercomputers today are only just now reaching the computational complexity required to properly attempt to model a single human brain.

The variability between individuals, their genes, and the connections in their brains is also significant, meaning that attempting to find always accurate patterns that apply to all people can only be done in the most general sense. For specific brain functions, each individual is often truly an individual, even within their own lifetime, where a person’s brain in childhood will have large changes by adulthood in regards to neural connections.

Complexity

For researchers involved in human disorders of the brain, whether physiological or genetic, this sort of complexity can prove a challenge in even knowing where to properly start researching. One of the ways to get around this is to just deal with smaller cellular samples in a test tube or culture plate or to research the brains of simpler models, such as a mouse, in order to better understand how brains function in general.

Even with these methods though, there are limitations. A common practice in animal, plant, and bacterial models is to showcase genetic effects by breeding mutant lines that develop differently. This, obviously, is not possible in human models and human brain tissue can’t be made to develop differently than the genetics that already make it up.

That is, until pluripotent stem cells (PSCs) and CRISPR came along. With the former, cell cultures can be grown that mimic the development of brains themselves. These cultures are known in scientific fields as organoids. And with the latter, as readers of Bioscription are well aware, genetic changes can be made on the fly, allowing the growing of mutant organoids much more simply in order to study how genetics affect brain development.

The Study

As a review of an emerging field, there’s no specific experiment to discuss in this study, just a summary of all the different advances in the field of developing cerebral organoids. Thus, there is far more information than can even be summarized into this article as a summary of the summary review. I will just address the highlights and try to condense the information as much as I can, but I do recommend readers to look at the study themselves for a more in-depth understanding.

The review begins by looking over the research that had already been accomplished by studying rodents and primates and the development of cortical neurons and other structures. The primary focus has been on understanding corticogenesis, the formation of the cortex of the brain. Pluripotent stem cells can be used to form into several thousand cell organoids that form a part of the cerebral cortex, including the mannerisms of its neurons and how they form connections between each other.

Formation and usage

There are still many questions surrounding these organoids and whether they can properly form various characteristics of the brain, which requires further testing. One of the main discoveries is that, while lacking some capabilities, organoids developed from pluripotent stem cells appear to be able to form almost completely without outside stimulation, implying that their multi-cell structure is already coded into the cells themselves and not from outside application of hormones or other signals.

One of the joint applications of PSCs and CRISPR that is looked into is the deciphering of Zika virus and how it affects the brain by growing organoids infected with the virus. This allows researchers to understand how Zika affects the growing brain of an embryo and gives the opportunity to use CRISPR to alter the genes involved in an attempt to mitigate or even negate the effects of the virus on the developing brain. Other neurodevelopmental diseases and disorders may be treated in this manner as well.

Limitations

The limitations of these approaches must also be pointed out, however. The lack of the lamination (layered organization pattern of the neurons in the brain) found in embryonic brains suggests that some of the neuron migration to other parts of the brain doesn’t occur properly in organoids that only represent part of a whole brain.

So, they may only represent very early development of the brain and not some of the later features during gestation. This is likely due to them being grown in petri dishes and not receiving all of the outside inputs needed to form later structures.

Conclusion

The growth of cerebral organoids is still in the early stages of testing and research. There remain many questions that need to be investigated on how they function and how closely they can match the actual functionality of full grown brains. But, at minimum, they allow scientists to replicate how certain parts of the brain develop and open up pathways to investigating specific neural diseases. Combined with CRISPR, there is a high possibility that genetic fixes for a variety of diseases could be obtained, though likely through much trial and error in experimentation.

The progress of science is often slow and methodical, Certain jumps can be made all at once in our ability to progress, such as with CRISPR, but it remains that it is the accumulation of knowledge over time that we truly take steps toward answers. Given time and enough research and I don’t believe there is anything we can’t discover.

Study Link:

Building brains in a dish: Prospects for growing cerebral organoids from stem cells

Photo CCs: Brain v.2 by Amy Leonard

Synapses by RuffRootCreative

Brain Cactus by Teresa Alexander-Arab