Manufacturing mature brain cells

Simulating the conditions of the brain to help fight neurodegenerative disease...
20 January 2023

Interview with 

Evangelos Kiskinis & Sam Stupp, Northwestern University




A way to make new brain cells, either for the purpose of repairing the nervous system or studying the mechanisms behind degenerative diseases like Parkinson’s and testing new treatments, has been developed by scientists in the US. Although it’s nearly two decades since researchers discovered how to reprogramme adult cells to make them behave like stem cells again so that they could be turned into other cell types like heart or liver cells, it’s nevertheless been a struggle to make mature nerve cells. Now a team at Northwestern University think they know why: they’ve built molecules that better mimic the environment of the developing brain, stimulating the stem cells in the right way to trigger them to turn into fully fledged neurones. It’s early days, but Sam Stupp, and - starting us off - Evangelos Kiskinis think they are on the right track…

Evangelos - A few years ago, some very smart scientists were able to create stem cells from any given individual. Now we have the capacity to turn these stem cells into the building blocks of the brain, the nerve cells. However, one of the longstanding problems with this technique is that the nerve cells were able to generate resemble nerve cells of a newborn baby. So we're really trying to look for ways that will help us turn the stem cell nerve cells into cells of an adult-like nature.

Chris - Do you know, Evangelos, why you were having that problem beforehand? Why these cells produced this halfway house to being a fully developed adult nerve cell and why they stopped there?

Evangelos - Well, I think although nerve cells are fully created when a baby's born, these nerve cells continue to mature and develop functional capacities as the baby becomes an adult. And when we are doing this process in a dish in the lab, we have had no way of essentially shrinking this timeline.

Chris - And Sam, you're going to argue that part of this is because of the environment that those cells are in.

Sam - Absolutely. When cells in our bodies are making that transition from being babies to being fully mature adults, that process relies on the environment that cells are in. Imagine a mesh of filaments surrounding the cells and the mesh has signals that the cells can understand and translate into action. So it is very important to be able to create a synthetic form of that mesh. And this has been the breakthrough here, our ability to create chemically that mesh that's around the cells; to provide them with the right signals so that they can mature from being babies to age in the dish as they become more mature.

Chris - So, Evangelos, what you have effectively done is to create something more akin to the developing brain for these cells to develop in, so they're fooled into thinking they're in the mature nervous system and they follow suit and turn into the right sort of cell for the right sort of environment.

Evangelos - Yes, that is absolutely correct. So one of the problems of studying human processes in a culture dish is you need all the multitude of different components that exist within the human body. Now scientists have made a lot of progress at creating these different components but, for good reason, the focus has been on the primary components which, for example, in the brain, are the nerve cells. Now what we have been doing is we're thinking about all the additional environmental components that feed onto these nerve cells and allow them to function in a way that allows them to communicate with each other and so on and so forth.

Chris - Sam, how did you work out this was the right cocktail, this is the right environment that we need to make these cells turn into mature nerve cells?

Sam - We asked, how do we create those tiny filaments that normally surround the cell? How do we come up with a molecule that self organises into tiny filaments that look like the filaments that naturally surround cells? So we had to design this compound to do exactly that. But actually we went further. We created molecules that, once they formed the filaments, they could actually move in a certain way. And the reason this is important is because those receptors or parts of the cell that understand those signals are also moving. And so it's very important to make the signals move. Just imagine a filament that has 100,000 molecules, so it's a very long filament, imagine all those molecules jumping around. Those movements turned out to be critical in helping cells achieve their maturity. People usually refer to our work as the dancing molecules because they move.

Chris - How do you know, Evangelos, that you have produced neurons that are, to all intents and purposes, mature? They're not these immature forms that we were getting before?

Evangelos - Well, we know that because we look at their morphology. Baby neurons are rather small, whereas adult neurons have an elaborate morphology with really big sizes and a number of processes that they extend quite far away in order to form a functional connection with another. Another assay allows us to measure the electrical properties of these neurons. And when they're cultured in the dish, in the presence of these new environmental factors, we see that they now resemble those of adult, real neurons that we find in the human body.

Chris - Could you also take the cells and put them back into the brain because you are potentially able to make nerve cells that would be a direct match for a patient? Could you put them into that person's brain and potentially remedy a degenerative state?

Evangelos - Yes, eventually that will be the goal. So cell transplantation therapies are a very promising approach to battle adult onset destructive neurodegenerative diseases. I think one of the problems has been the ability to generate nerve cells that can replace the ones that are being destroyed as a result of these disease processes. And certainly this discovery will facilitate the eventual cell transplantation approaches that are out there.


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