Mini models of the human brain are revealing how this complex organ takes shape

SYNTHESIS

Lab-grown organoids are turbo-charging the study of human brain development and disease.

The development of the human brain, with its extraordinary range of cognitive abilities, is an awe-inspiring feat of evolution. Each of its tens of billions of cells must be born at precisely the right time, migrate to the correct locations, differentiate into as many as 3,000 distinct cell types, and form exquisitely specific synaptic connections with one another. Most of this happens before birth, but development continues for nearly three more decades. None of this is easy to study. Conventionally, scientists have relied on animal models and scarce human brain tissue. But the advent of tiny laboratory-grown models of human brains called organoids has transformed their options.

First created more than a decade ago, these organoids started off as very simple models. But in the past few years, scientists have refined the technology to grow more-intricate systems that represent more brain regions. Research has snowballed as scientists have used organoids to probe brain development, model neurodevelopmental conditions such as autism and schizophrenia and test new treatments for brain diseases. These tiny spheres are helping researchers to get at difficult-to-answer questions such as why the human brain develops so much more slowly than other mammalian brains do.

And this year, researchers are hoping to run the first clinical trial of a brain-disorder treatment developed entirely in organoids.

"“The field is at an inflection point,” says developmental biologist Jürgen Knoblich at the Institute for Molecular Biotechnology in Vienna."

But organoids are not without their limitations. It’s hard to sustain them in the lab for more than a few months, for instance. And they lack complexity. Looking ahead, there are also questions about whether properties such as sentience or even consciousness could emerge as technologies improve. “This is not remotely feasible at the moment,” says molecular neuroscientist Giuseppe Testa at the University of Milan in Italy, “but at some point, we may need to start scrutinizing for the emergence of more complex behaviour in a dish.”

The neuron’s journey

The first structure that will become the human brain starts to develop just three weeks after conception. It’s a hollow tube made up of the earliest neural progenitor cells. This starter population will eventually give rise to all of the brain’s diverse neurons and support cells, as the tube expands into sections and the production of neurons ramps up — at its peak, to around 250,000 per minute. Some of these neurons provide a scaffold to help others climb to their correct positions. Axons and dendrites extend from the neurons, connecting distant brain regions. Next begins the production of glial cells, which support and insulate neurons, and after that, at around seven months of gestation, the brain begins to generate coordinated electrical activity.

Ana González - Timothy Archibald - Some brain organoids can live for months or even years in the lab..

Brain organoids can’t duplicate the fiendish tangle of the real human brain. But they do develop in a surprisingly similar way. They are made with induced pluripotent stem (iPS) cells — adult cells reprogrammed back into an early developmental state. Given the right signalling molecules, iPS cells differentiate much like natural neural progenitors, according to a species-specific blueprint and timetable; human cells differentiate at the stately pace of a human pregnancy, mouse cells as speedily as a mouse pregnancy. Researchers began by culturing the cells to form 2D rosette shapes that approximate the neural tube. “We learnt a lot from these cultured cells and continue to do so,” says Pierre Vanderhaeghen, a developmental neuroscientist at the Catholic University of Leuven (KU Leuven) in Belgium. But what neuroscientists really wanted was something that better mimicked the complex spatial aspects of fetal development. By 2008, neuroscientists had worked out how to coax neural progenitors into 3D1.

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