From Cells to Mini-Brains: How Organoids Are Advancing Neuroscience

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For years, scientists have been reliant on models with animals and donated human tissue to study the most complex organ in the human body: the brain. Approaches in traditional cell cultures have also led to countless discoveries, but each has limitations. Animal brains do not reproduce human biology perfectly, while conventional cell cultures cannot replicate the three-dimensional architecture of brain tissue. Now scientists have created a new model that may help bridge the gap; brain organoids.

Brain organoids are three-dimensional, lab-grown tissue models that mimic aspects of a human brain structure and development. In controlled conditions, these cells organize themselves into structures that house multiple types of brain cells and reproduce specific characteristics of early brain development within humans. These brain structures are often referred to as “mini brains,” however this nickname can be misleading. Brain organoids are NOT miniature human brains and they do not contain the same full structure or functionality of an actual human brain. Alternatively, they are models that allow scientists to study certain aspects of human neurological development and disease. (Nature Reviews Neurology)

One of the largest challenges in neuroscience is researching the developing human brain. Much of the understanding about brain development that scientists have comes from animal models and examinations of the human tissue after development of the brain has occurred. However, the human brain is very unique in the fact that the developmental process is not always replicated in other species. This creates an issue when researchers are trying to comprehend conditions that are particularly human. Brain organoids offer a possible solution, since they are made from human cells giving researchers the opportunity to observe different properties of human brain development in a laboratory environment. According to a review in Nature Review Neurology, organoids have been used to inquire neurological conditions including Alzheimer's disease, Zika virus infection, microcephaly, and several neurodevelopmental disorders.

Their three-dimensional structure is important to also take notice of. While traditional cell cultures typically grow as a flat layer, organoids can develop more complex tissue architecture. This allows researchers to study interactions between the cell types and examine how the cells organize during development. Scientists investigate biological processes that would be harder to observe using traditional two-dimentional cultures. (Nature Neuroscience)

One of the most interesting employments of brain organoids is their ability to model a neurological disease. Researchers create organoids using induced pluripotent stem cells (iPSCs). These cells are generated from an individual’s cells and then they are modified into a stem-cell like state. Scientists are able to create patient specific models of neurological disorders because they are able to produce organoids containing the person’s genetic information. Scientists are able to create an organoid that contains a mutation that is then compared to an organoid that does not have it, this creates a frame for researchers to approach an investigation of how the mutation affects brain development and cellular function. Furthermore, helping identify disease mechanisms and potentially test treatments in human-derived tissue before moving towards clinical applications. This is important for diseases that are harder to reproduce accurately in animals.

The reality is that a treatment that works on a mouse for instance may not necessarily work in a human because of differences in genetics. While this concept is still developing, organoids cannot currently predict a patient's response to a treatment option and organoids can be used as an important tool for how individual genetic variations contribute to neurological diseases.

The potential to create organoids allows the opportunity for personalized medicine. Visualise two patients getting diagnosed with the same neurological disorder. Even though they may have the same diagnosis, their backgrounds and responses to treatment can vary. Despite their potential, organoids are far from being complete models of the human brain. One of the major limitations is maturation. Many organoids are relatively resembled in the early stages of brain development instead of having a mature adult brain. Scientists are continuing to create methods that make organoids more mature, consistent and complex biologically. Another main limitation is variability. While two organoids can be created using similar procedures they may not curate the same way. Differences in the starting cells and growth conditions can influence the overall result of the organoid. This makes comparing results across laboratories very difficult. These limitations alone mean that organoids should steer away from the common misconception that they can be viewed as replacements for human patients, animal models, or other laboratory systems. Instead, their greatest value may come from the collaboration of existing approaches. Researchers use organoids to study human-specific processes while using other models to investigate questions that organoids cannot particularly answer. (Nature Bioengineering)

As brain organoids continue growing they also raise the question: Could the organoids ever become complex enough to form consciousness or a morally relevant experience?

The increasing complexity of the human brain has allowed scientists, policymakers, and ethicists to consider what ethical standards should apply as the technology develops. Additional questions arise when the human brain organoids are incorporated into animal research or used in transplantation studies.

Brain organoids provide an opportunity to investigate human development and neurological disease in a three-dimensional, human-cell based system. At the same time, their limitations remind us that no single model can capture the extraordinary complexity of the human brain. These brain organoids can reveal biological processes that traditional cell cultures and some animal models cannot fully reproduce. With the help of neuroscience there can be an increased amount of patient data, animal models, conventional cell cultures, and brain organoids to answer different parts of the same question. Brain organoids make a connection with stem-cell biology, medicine, and bioethics. As researchers continue to learn more about models and how to make them more accurate and reproductible, they may help scientists understand why neurological diseases develop, uncover previously inaccessible stages of human brain development, and identify potential treatments.