No Two Brains Are the Same: How Neuroscience Is Advancing to Account for This

A human-derived brain organoid. Image courtesy of Alysson Muotri’s lab at the University of California, San Diego

Your brain is not like mine. In fact, your brain is not like anyone else’s. I don’t mean that in some philosophical or abstract way; I mean it literally. The precise wiring of your brain is unique to you. During development, your genes specified a blueprint that resulted in your brain having roughly the same organization as mine. But that genetic blueprint wasn’t designed to specify the precise connection patterns between all the neurons in your brain.

The exact wiring diagram of the networks of cells in your brain is the result of random processes influenced by external and environmental factors and stressors — in other words, the ways in which you interact with the world and the world interacts with you. As a result, how your brain takes in and processes information is also specific to you. You truly are a neurobiologically unique individual. We all are.

But this presents a problem for neuroscience because neuroscientists study “the brain,” and yet we’ve just established that no two brains are the same. So how do we take that into account? We do things like average a lot of data across different individuals, by design smearing out potentially subtle but important differences about how your brain responds compared to how someone else’s brain responds.

For instance: Why do you prefer tomatoes to olives? Or more importantly, why does that migraine medication make you drowsy, but it doesn’t affect a close family member? How is the brain of a child who is on the autism spectrum different from that of their sibling? How and why do those differences limit or enhance what each sibling is able to do? There is a popular saying in the autism community that if you’ve met one person with autism, you’ve met one person with autism.

You don’t actually need stem cells or any kind of brain cell from a person to make organoids. It’s this unique fact that makes them such a potentially important model of the brain.

We neuroscientists can study you as a whole person and look at your cognitive and behavioral functions. We can also study your specific brain at a high, rather coarse-grain level using tools such as functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). But we can’t study the actual network of connected cells specified by your unique genetic program. We just haven’t had the methods to do so. Nor can we study the resultant wiring diagram and the way your neurons and other cells interact. As a result, it isn’t possible to interpret how the wiring of your brain affects the way you learn and what you’re able to do. In other words, we can’t understand the fundamental neurobiology responsible for you being you. Because of this, it isn’t possible to make the connection between how your neurobiological details determine your cognitive uniqueness or how you might respond to clinical treatment.

All of that may be about to change thanks to an experimental technology (and model of your brain) called brain organoids and the study of organoids using advanced mathematical and computational models. I’m a professor of bioengineering and neurosciences at the University of California, San Diego (UCSD) who has been studying how the brain computes and processes information my entire career. I recently wrote a commentary explaining organoids with colleagues Alysson Muotri at UCSD and Christopher White at Microsoft Research.

Your brain in a dish: Human-derived brain organoids

Brain organoids were first developed by Yoshiki Sasai and colleagues in 2013, who showed that neural structures can be derived from human stem cells. However, you don’t actually need stem cells or any kind of brain cell from a person to make organoids. It’s this unique fact that makes them such a potentially important model of the brain.

Brain organoids are pin-sized, three dimensional, self-organizing structures composed of roughly 2.5 million neural cells. That may sound like a lot, but it’s just a tiny fraction of the roughly 86 billion cells that make up the adult human brain. While these neural cells can be generated from different types of human stem cells, they can also be made from genetically reprogrammed cells in a dish, such as skin fibroblasts or cheek cells taken from a swab of your mouth. The process causes a de-differentiation of the initial cells back to an embryonic-like stem cell state. In turn, the stem cells are then led to differentiate into different types of neurons and other neural cells. This re-differentiation process in a dish is guided by the cell’s own genetic program. But because the cells are your cells, the material on display exhibits your unique developmental genetic program — or at least certain aspects of it.

This process produces three-dimensional structures that spontaneously self-organize at a cellular scale into anatomical structures that resemble aspects of your brain development. The molecular composition of the constituent cells is similar to mature neurons and other brain cells, although immature cells are also present. The organoid is a tiny model of your unique brain made from your own cells in a dish. And thousands of such organoids can be made from a single sample of your skin cells.

The similarities of organoids to a real brain don’t just stop at the structural and anatomical level. Muotri and his collaborators were recently able to show that if the chemical conditions in which they grew brain organoids were optimized to support cellular development, they’d mature enough to display electrical patterns of activity that are similar to the electrical activity of a developing brain in a preterm infant. In fact, the similarity of the activity patterns were such that when they trained a machine-learning algorithm to recognize those patterns, the algorithms were able to match the relative age of the organoids to the corresponding developmental age of a brain in a preterm infant.

Human-derived brain organoids reflect a personalized model of the brain unique to each individual.

Yet, despite these results, brain organoids are not fully mature or developed brains. They are not “mini-brains.” While they display some of the early developmental anatomy of the brain and complex organized electrical activity to some degree, they continue to have immature cells and are not vascularized, for example. It is more proper to think of them as a model of your real brain in the sense that they express certain key properties that are scientifically useful, but like any model, they are limited and reduced versions of the real thing.

Organoids are not autonomous conscious entities. Nonetheless, scientists and bioethicists are taking these important questions very seriously, and there is significant ongoing work investigating the ethical implications, especially as the technology continues to improve. And since they can be made from simple skins and do not require human embryonic stem cells, there are no ethical considerations with how they are made.

Bridging neuroscience to clinical and cognitive research

Human-derived brain organoids reflect a personalized model of the brain unique to each individual. Because of this, they could provide an opportunity to bridge biological experiments and computational models about how the brain works with behavioral, cognitive, and clinical studies specific to that person. This is something no other experimental model is yet able to achieve. Organoids derived from neurotypical individuals or patients can be experimentally studied in parallel with cognitive experiments or clinical trials being carried out in the same individuals. This approach could effectively place the unique neurobiology distinct to each participant in context with personalized cognitive and clinical results.

We are currently pursuing this approach in a study at UCSD focused on the effects of cannabidiol (CBD) on autism. A key objective of our study is to test a hypothesis in patient-specific brain organoids that there is a breakdown in how networks of neurons communicate with each other in autistic individuals. We are investigating this by attempting to reconstruct organoid neural networks from patient experimental data and then use these reconstructions to measure deviations in a calculation we call the refraction ratio. This ratio reflects a balance between how fast information is propagating in a neuron or network of neurons, relative to how much time the cells need to process and react to that information. We have shown that real neurons seem to optimize their shape (morphology) to this ratio and that a mismatch in the refraction ratio can cause a complete breakdown in network signaling.

It is conceivable that in future clinical studies, parallel experiments with brain organoids in a dish will be used to optimize testing or dosing conditions and put aspects of an individual’s personalized neurobiology in context with clinical outcomes. For example, it might be possible at some point to predict how you would clinically respond to one specific drug versus another by doing personalized experiments and analysis of your organoids before any drug is prescribed.

It is intriguing and encouraging to consider that the future of neuroscience holds the opportunity to understand how the brain works not just as an engineered system but also in a personalized way.

Professor of Bioengineering and Neurosciences, University of California San Diego

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