Building a better mini brain: How these tiny organoids can boost fight against Alzheimer’s, Parkinson’s

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A mini midbrain organoid in a petri dish. Image credit: The Agency for Science, Technology, and Research

Among the most urgent needs in laboratories focused on treating and preventing disease are more realistic models with which to study the diseases themselves. Despite progress made in terms of improving the quality of life of those suffering from neurodegenerative diseases like Alzheimer’s (AD), Parkinson’s (PD), and multiple sclerosis (MS), we still have much to learn.

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Scientists have recently developed tiny 3D human brains called organoids with the potential to overcome current barriers to disease research. To conceptualize the scifi-esque human organoid, imagine a mini brain growing in a dish. Still can’t see it? Think tiny chia pet; but instead of chia seeds, you plant specific human brain cells, feed and nurture them, and watch as they morph not into chia sprouts resembling animal fur, but spherical tissue masses with the organization of the human brain. A critical feature of this structure is a barrier comprised of blood vessels that encapsulates and protects the interior of the organoid from any surrounding toxins or other unwanted substances.

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It’s hard to believe but Chia pets were all the rage like 20 years ago. Image credit: Jeremy Noble via FLICKR

In the actual human brain, this structure is referred to as the blood-brain barrier (BBB), and it serves as a vital gatekeeper for the brain. The barrier itself is composed of specialized cell types responsible for lining the interior surfaces of blood vessels and interacting with external processes, like in nutrient acquisition. These barrier cells work in tandem to prevent foreign and toxic substances from entering the brain.

Various cell types are involved in maintaining BBB integrity, including immune cells, neurons, and cells that help send signals along neurons. With this in mind, researchers from Wake Forest University, led by neurobiologist Goodwell Nzou, ambitiously tasked themselves with constructing a 3D brain comprised of brain cells extracted directly from human tissue, corresponding to the six cell types we now know play fundamental roles in BBB health. This process demanded several rounds of trial and error to achieve the most ‘brain-like’ organoid.

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Hang on the brains are almost ready. Image credit: National Archief via Wikimedia

You might be curious as to how scientists can measure the ‘brain-likeness’ of a small orb generated by throwing a bunch of cells together. Prior to staged assembly, the unique cell types were labeled with different dyes to allow the researchers to track their migration patterns and final positions in the fully formed organoid. Visualization with a fluorescent microscope revealed that the cellular organization of the organoid mirrored that of the real human brain. In addition, the cells in the organoid exhibited behaviors mimicking those seen in the adult BBB.

Nzou’s group found that several toxins that are not typically permitted to traverse the BBB could not access the internal space of the organoid either. Perhaps the most spectacular aspect of this spontaneous assembly is just that…its spontaneity! These cells are intrinsically programmed to interact with each other and behave in specific ways that have evolved to optimize brain function. More comprehensive studies are warranted to further validate the human brain organoids as a legitimate BBB model, but the data accumulated thus far provide a highly encouraging starting point.

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Other than the fact that growing a mini version of your own brain in a dish is downright extraordinary, you’re probably wondering why scientists are going to such great lengths to deconstruct and reconstruct the human brain on a small scale. The short answer is physiological applicability. One of the most daunting obstacles in biomedical research is the need for animal and cellular models that match the human condition as closely as possible in terms of clinical symptoms and at the molecular level.

Pictured: the source of the human condition. Image credit: Wellcome Collection

Although various organisms commonly used in the lab like rodents and even yeast share the vast majority of their DNA with humans, the only way to ensure relevance is to work with specimens originating from your source of interest. In other words, human-derived brain cells are more likely than any others to clarify and broaden our understanding of how the human brain operates.

Nzou and his colleagues’ novel research will ideally lead to more accurate models of neurodegenerative disorders, identification of what exactly goes astray in these diseases, novel drug discovery, and more reliable clinical trials that serve as better predictors of short- and long-term drug efficacy based on ability to penetrate the BBB.

In this case, scientists could test a plethora of pharmacological agents and/or other therapeutic modalities on cells derived from an individual human being, thus minimizing wasted time with unproductive treatments and maximizing the odds that the chosen treatments will produce the desired results. The human brain organoid may thus prove to be a major breakthrough in the treatment of neurodegenerative diseases that have evaded scientists and medical professionals, and needlessly plagued patients for so long.

Paige Winokur is a graduate student at Rockefeller University studying multiple sclerosis. She is exploring disease pathogenesis and repair from a neuroendocrinological perspective, specifically looking at the role of neurosteroid hormones like progesterone.

A version of this article was originally published on Massive’s website asScientists have got the recipe for growing miniature human brains just rightand has been republished here with permission.

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