Since the inception of brain organoids by Madeline Lancaster in 2013, these structures have become invaluable in global brain research. But what are they really? Are they simply miniaturized brains? Could implanting them into animals yield a super-intelligent mouse? Where do we draw the ethical line? Michael Le Page explored these questions at Lancaster’s lab at the MRC Institute of Molecular Biology in Cambridge, UK.

Michael Le Page: Can you clarify what a brain organoid is? Is it akin to a mini brain?

Madeline Lancaster: Not at all. There are various types of organoids, and they are not miniature brains. We focus on specific parts of the human brain, and our organoids are small and immature. They don’t function like developed human brains with memories. In scale, they’re comparable to insect brains, lacking the necessary tissue present in those brains. I would categorize them closer to insect neural structures.

What motivated you to create your first brain organoid?

I initiated the process using mouse embryonic brain cells, cultivating them in Petri dishes. Some cells didn’t adhere as expected, leading to a fascinating outcome where they interconnected and formed self-organizing cell clusters indicative of early brain tissue development. The same technique was then applied to human embryonic stem cells.

Why is the development of brain organoids considered a significant breakthrough?

The human brain is vital to our identity and remained enigmatic for a long time. Observing a mouse brain doesn’t capture the intricacies of the human brain. Brain organoids have opened a new perspective into this complex system.

Can you provide an example of this research?

One of our initial ventures involved modeling a condition called micropathy, where the brain is undersized. In mice, similar mutations don’t alter brain size. We tested whether we could replicate size reduction in human brain organoids, and we succeeded, enabling further insights into the disease.

What has been your most significant takeaway from studying brain organoids?

We are gaining a better understanding of what distinguishes the human brain. I’m fascinated by the finding that human stem cells which generate neurons behave differently from those in mice and chimpanzees. One key difference is that human development is notably slower, allowing for more neurons to be produced as our stem cells proliferate.

Are there practical outcomes from this research?

Much of our foundational biology research has crucial implications for disease treatment. My lab primarily addresses evolutionary questions, particularly genetic variances between humans and chimpanzees. Specific genes that arise are often linked to human disorders, implying that mutations essential for brain development could lead to significant damage.

What types of treatments might emerge from this work in the future?

We’re already utilizing brain organoids for drug screening. I’m especially optimistic about their potential in treating mental health conditions and neurodegenerative diseases, where novel therapies are lacking. Currently, treatments for schizophrenia utilize medications that are five decades old. Brain organoid models could unveil new approaches. In the longer term, organoids might even provide therapeutic options themselves. While not for all brain areas, techniques have already been developed to create organoids of dopaminergic neurons from the substantia nigra, which are lost in Parkinson’s, for potential implantation.

Are human brain organoids already being implanted in animal brains?

Yes, but not for treatment purposes; rather, these practices enhance human organoid research. Organoids usually lack vascularity and other cell types from outside the brain, especially microglia, which serve as the brain’s immune cells. Thus, to examine how these other cells interact with human brain matter, various studies have implanted organoids into mice.

Should we have concerns regarding the implantation of human organoids in animals?

Neurons are designed to connect with one another. So, when a human brain organoid is inserted into a mouse brain, the human cells will bond with mouse neurons. However, they aren’t structured coherently. These mice exhibit diminished cognitive performance after implantation, akin to a brain malfunction; hence, they won’t become super-intelligent.

Is cognitive enhancement a possibility?

We’re quite a distance from that. Higher-level concepts relate to how different brain regions interlink, how individual neurons connect, and how collections of neurons communicate. Achieving an organized structure like this could be possible, but challenges like timing persist. While mice have a short lifespan of about two years, human development toward advanced intelligence takes significantly longer. Furthermore, the sheer size of human brains presents challenges; a human-sized brain cannot fit within a mouse. Because of these factors, I don’t foresee such concerns emerging in the near future.

Regarding size, the main limitation is the absence of blood vessels. Organoids start to die off when they exceed a few millimeters. How much headway has been made in addressing this issue?

While we’ve made strides and should acknowledge our accomplishments, generating brain tissue is relatively straightforward as it tends to develop autonomously. Vascularization, however, is complex. Progress is being made with the introduction of vascular cells, but achieving fully functional blood perfusion remains a significant hurdle.

When you reference ‘far away’…

I estimate it could take decades. It may seem simple, given that the body accomplishes this naturally. However, the challenges arise from the body’s integrated functioning. Successfully vascularizing organoids requires interaction with a whole organism; we can’t replicate this on a plate.

If we achieve that, could we potentially create a full-sized brain?

Even if we manage to develop a large, vascularized human brain in a lab, without communication or sensory input, it would lack meaningful function. For instance, if an animal’s eyes are shut during development and opened later, they may appear functional, but the brain can’t interpret visual input, rendering it effectively blind. This principle applies to all senses and interactions with the world. I believe that an organism’s body must have sensory experiences to develop awareness. Certain patients who lose sensory input can end up experiencing lock-in syndrome, an alarming condition. But these are individuals who have previously engaged with the world. A brain that has never engaged lacks context.

As brain organoid technology progresses, how should we define the boundaries of ethical research?

The field closely intersects with our understanding of consciousness, which is complex and difficult to measure. I’m not even certain I have the definitive answer about consciousness for myself. However, we can undoubtedly assess factors relevant to consciousness, like organization, sensory inputs and outputs, maturity, and size. Mice might meet several of these criteria but are generally not recognized to possess human-like consciousness, largely due to their size. Even fully interconnected human organoids won’t achieve human-level consciousness if they remain small. Establishing these kinds of standards offers more practical methods than attempting to directly measure consciousness.

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