By Paige Winokur
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.
...imagine a mini brain growing in a dish.
In order to study a neurodegenerative disorder like MS, researchers must find ways to induce and mimic the human disease in non-human animals. This is particularly difficult when the causes of the disease in the first place are unknown. As a result, disease models may or may not accurately represent human pathology. We simply don’t know. This is a major roadblock to treating all kinds of different diseases, neurological disorders included.
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.
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.
This process demanded several rounds of trial and error to achieve the most ‘brain-like’ organoid.
Eventually, the researchers found that the order in which the different cell types were introduced to the artificial brain was crucial. Their initial attempt to simultaneously combine all six cell types worked to some extent, with the exception of numerous gaps in the outer coating of the organoid. They continued to adjust their preparation techniques until they were satisfied that the organoid recapitulated all of the structural hallmarks of the actual human brain, much like trying to come up with a recipe for a favorite meal you had at a restaurant. Their method of strategically adding designated groups of cells at distinct time points is referred to as staged assembly.
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.
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.
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.
This ambitious yet realistic goal involves custom-designed treatments administered to individual patients according to their own symptoms and genetic makeup, in contrast to therapies targeted to the ‘average’ participant in clinical trials.
Down the line, innovations like 3D brain organoids that incorporate human stem cells might enable precision or personalized medicine. This ambitious yet realistic goal involves custom-designed treatments administered to individual patients according to their own symptoms and genetic makeup, in contrast to therapies targeted to the ‘average’ participant in clinical trials. If you’ve ever had a bacterial infection, your doctor has probably swabbed or biopsied the affected area to determine which antibiotics have the capacity to kill the bacteria. You wouldn’t want to be treating a nasty infection with a drug to which the bacteria have grown resistant. The same principle applies to personalized medicine.
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.
This article was originally published on Massive Science