How brain organoids are revealing what truly makes humans unique

Since Madeline Lancaster created brain organoids for the first time in 2013, they have become widely used for brain research in the world. But what are they exactly? Are they effectively miniature brains in dishes? Could them for animals create super intelligent mice? How much is we close to crossing the ethical lines? Michael The page visited Lancaster in his laboratory at the MRC Molecular Biology Laboratory in Cambridge, in the United Kingdom, to discover it.

Michael Le Page: Can you explain what a brain organoid is? Is it a mini-brain?

Madeline Lancaster: They are not really miniature brains. And there are many different types of organoids. The human brain has many parts, and we make an organoid of a part, or perhaps a couple. They are very small and are also immature. They are not like a fully functional human brain with memories. In terms of size, organoids are similar to a brain of insects. But they do not have the organization that an insect brain a. I would probably place them below insects.

How did you come to cultivate the first brain organs?

I started working with embryonic brain cells, placing them in a petri box to let them grow. Some cells did not stand in the dish as they were supposed to do. They detached themselves and began to fix each other, forming these beautiful cells of self-organization of cells which resemble the early stages of the development of the brain tissue. Later, we were able to do the same with human embryonic stem cells.

Why was the creation of cerebral organoids such a great breakthrough?

The human brain is special, it makes us who are. There was a black box for a very long time. If we look in a mouse, we just can’t capture all the complexity of the human brain. Brain organoids suddenly opened a window on this black box.

Can you give an example?

One of the first things we have done with brain organoids was to model a disease called microcephaly, where the brain is too small. In mice, if you introduce the same mutation, you find yourself without any effect on the size of the brain. We decided to see if we could see a reduction in size of human brain organoids. We could – and we could also learn something about the disease.

What are the most important things we have learned so far from cerebral organoids?

We have started to better understand what makes the human brain unique. I am really enthusiastic about the observation that human stem cells which give birth to neurons behave differently from those of a mouse or even a chimpanzee. What makes us unique, it seems is that we are developing much more slowly. Stem cells have more time to develop and generate more stem cells, so we end up with much more neurons.

Will this kind of work have a practical application?

Much of the fundamental biology that we make has important implications for the treatment of the disease. My laboratory focuses mainly on evolutionary issues, on genetic differences between humans and chimpanzees. But the genes that appear are involved in human disorders, which makes sense because if something is important for the development of the human brain, then if it is transferred, it will probably cause a cerebral disorder.

What kind of treatments will you do?

In the immediate term, we will see brain organoids used for drug detection. I am particularly enthusiastic about mental health disorders or neurodegenerative diseases where we do not have new treatments. I mean, we always deal with schizophrenia with drugs aged 50 years. We hope that brain organized models can give us new breakthroughs. In the longer term, organoids themselves could be therapy. Perhaps not for all regions of the brain, not for the hippocampus or our frontal lobe, the parts of the brain that store our memories and make us who are. But with things like dopaminergic neurons in the substantia nigra, which is lost in Parkinson’s disease, we could make organoids and then transplant them.

I understand that human brain organoids are already implanted in the brain of animals?

Yes, no not as therapy, but to improve human organoids. Organnoids lack vascular and they lack other types of cells that come from outside the brain, including microglia, which are the immune cells of the brain. So, to see how these other cells interact with human brain tissue, other groups have started to transplant organoids in mice.

Should we worry about putting human organoids in an animal?

The function of a neuron is to connect with other neurons. And so, if you put a human brain organoid in a mouse brain, you start to see these cells connect with the mouse. But they are simply not organized. After transplantation, these mice work less well in cognitive measurements. It is as if you had short-circuited their brain. So you don’t make super intelligent mice.

Could we arrive at the point where he improves cognition?

We are far enough. Our superior thought has to do with the way the different parts of the brain are connected, how individual neurons connect to each other, then how the neurons connect with other groups, then how the whole brain regions connect with other brain regions. This is all this structure. So, if it becomes possible to generate something that is organized in this way, perhaps. But you always encounter problems like timing. A mouse only lives about two years, but it takes more than two years for humans to become very intelligent beings. And the other thing is size. The human brain is so incredible because it is so large. There is no way to adapt a human -sized brain in a mouse. So, for many of these types of questions, I think we probably don’t have to worry about it in the near future.

Regarding the size, the great limit is the lack of blood vessels, which means that organoids are starting to die when they have only a few millimeters in diameter. How much progress is made to overcome this limit?

I don’t want to minimize what we have done, but it turns out that the brain fabric is actually quite easy to do. It develops. The vascular system is so much more complex. People have started to make progress by introducing vascular cells. But obtaining a real functional infusion of blood is still far enough.

When you say far …

I would say decades. It looks like it shouldn’t be so hard, right? The body does it very well. But it’s the whole body that works together, so really if you want to vascularize an organoid, it needs a body. We are not going to generate a whole body in a dish of soon.

If we manage to achieve it, could full-size brains be created?

Even if you had a large, fully formed human brain developing in a dish, if it has no starter or exit, it has nothing to think. We know that if an animal’s eyes are closed during development, then open later, the eyes still work well, but the brain cannot interpret the visual intake and the animal is functional. This applies to all the senses and everything we interact in the world. I would say that you need a body at some point in your development to be aware. There are patients who lose sensory contributions and suffer from locked syndrome, and it’s horrible. But these are people who had a body, have developed links with dear beings. If the brain has never experienced anything, it has nothing to think.

As brain organoids become more advanced, how do we say where we should not cross?

The field can be quite suspended in the way you define and measure consciousness. I am not sure that we will get an agreement on this subject because I do not even know if you are aware – all I know is that I am. But what we can do is say, well, there are other things that we can measure that are necessary for consciousness, such as organization, entry and exit, maturity and size. A mouse can meet many of these criteria, but we do not think that it has the same level of consciousness as a human, and a large part of it is the size. So, even if we manufacture totally connected human organoids as long as they are small, they will not have a conscience at the level of man. These types of criteria are a more practical path than trying to measure consciousness.

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