The Obama administration’s neuroscience initiative highlights new technologies to better understand the workings of brain circuits on both a small and large scale. Various creatures, from roundworms to mice, will be centerpieces of that program because the human brain is too complex—and the ethical issues too intricate—to start analyzing the actual human organ in any meaningful way.
But what if there were already a means to figure out how the brain wires itself up and, in turn, to use this knowledge to study what happens in various neurological disorders of early life? Reports in scientific journals have started to trickle in on the way stem cells can spontaneously organize themselves into complex brain tissue—what some researchers have dubbed mini-brains. Christopher A. Walsh, Bullard Professor of pediatrics and neurology at Harvard Medical School, talked to Scientific American about the importance of just such work for understanding brain development and neurological disease. (Also, check out the Perspective Walsh did for Science on this topic, along with Byoung-il Bae.)
Can you tell me what tools are lacking to be able to gain better understanding of how the brain develops?
In order to be able to understand the way the brain solves this tremendously complex problem of wiring itself up, we need to be able to study it rigorously in the laboratory. We need some sort of model. We can’t just take humans and put them under the microscope, so we have to find some way of modeling the brain.
The mouse has been tremendously useful for understanding brain wiring and how cells in the brain form. And the mouse will continue to be very useful. The mouse is particularly useful in studying cellular effects of particular genes, but, as we get smarter and smarter about what the problems are, we’re increasingly able to think, not about things that we share with mice, but the differences that distinguish us from mice.
It is these human-specific features that we’re increasingly impatient to try to understand and that is where stem cell models are starting to have an increasingly large impact because they’re really human cells and we’re able to manipulate them in ways that we had previously not been able to dream of, allowing them to make in a dish the precursors of a brain that has some really primitive human features.
Can you talk more specifically about these developments?
For several years, we have been able to grow human embryonic stem cells in cultures. Stem cells are very powerful cells because they can form a whole variety of cell types and allow us to study complex cell types in culture. What has happened in the last few years however, is that groups in Japan as well as in Austria have developed methods of getting stem cells to form complex shapes in culture that are starting to look like pieces of the body. [Yoshiki] Sasai’s group in Japan has been able to make embryonic stem cells in culture and turn them into what looks like an eye. And most recently Juergen Knoblich’s lab in Austria has gotten stem cells to organize themselves into something that looks very much like a very small, very early human cerebral cortex, which some people call an organoid or a mini-brain.
We know that a lot of the keys to development lie in processes that take place in the context of structural shapes and the complex environments in which stem cells develop. And so now we’re seeing that these stem cells can recapitulate, not just a cell type, but actually a structure and an environment where cells interact with one another in complex ways and where the signals that are passed from one cell to another can influence development. Studying these complex structures in the lab allows us to have a much better model of what’s going on in a human brain during early development.
What are some of the questions you might be able to tackle as the technology improves?
One important question that we can address with these new tools is the mechanism of human diseases. Some of these are very well modeled in the mouse, so we can create a mutation in a mouse and learn about a mechanism of how a disease functions in the human brain. But other genes look like they do very different things between humans and mice and so we only get a primitive understanding of what they’re doing in humans by studying them in mice. So human stem cells allow additional insight that can be put together with mouse work as well as direct study of human cells.
How can these systems be made better?
It’s been a tremendous stunner that stem cells can form embryonic shapes like retinas and brains. It’s kind of like a dog dancing on its hind legs, you’re amazed that it can do it all. But for these mini-brains to be a really rigorously useful scientific tool; we’ll have to figure ways to grow these structures reproducibly and reliably time and after time so we can study what happens when the process is disrupted.
As of now, we’re only able to get this to happen sometimes. And that’s always the way it is as a first step in science. But the technical refinements I’m sure are just around the corner.
Are there other technologies under development as well?
People are interested in seeing if we can understand more about the brain by putting human cells into the mouse brain and letting them develop there. That allows a small proportion of human cells to develop in a large mouse brain in a relatively normal environment where we can see how they wire up into structures.
Another approach though is actually letting human stem-cell organoids develop to the point that they actually have firm connections that we can study with technology that allows us to observe the electrical activity of these neurons. That’s something we haven’t done yet, but we can think about doing now, building complex structures in the test tube.
The organoid paper shows recordings of electrical activity in there, but they didn’t do precisely directed studies of detailed electrical activity. From what’s been shown so far, you can see that’s likely to be possible.
Is that exciting?
That's really tremendous. Disorders like intellectual disability and autism are disorders of electrical activity between neurons. But we think that the way our brains are connected up is pretty different from that of a mouse brain. So it would be nice to see what autism genes do in real human cells. Cognitive disorders such as autism and intellectual disability and schizophrenia are big areas because cognition in humans is so different than cognition in mice.
Is there other research where these models could help?
These techniques would be useful in understanding the function of the genes that regulate development of the human brain, but which because they have been under evolutionary pressure, act differently than in mice. One example from Knoblich’s mini-brain paper is CDK5RAP2, which regulates cell division in the brain, so it regulates the size of brain. It causes micorcephaly when mutated in humans and regulates behavior of human neural stem cells.
Image Source: Madeline A. Lancaster