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

## Summary
Neurons sent out long-range projections to their newly fused neighbour organoids, formed synapses and generated coordinated activity across regions. “That showed that a surprising amount of the information needed to assemble human neural circuits is embedded in developmental programmes,” says Pașca. “So now we can begin to extract the rules that guide circuit formation.” His first assembloid 8 involved two regions of the forebrain — the cortex and the subpallium — with different proportions of excitatory neurons, which activate other neurons, and inhibitory neurons, which dampen activity. Once the cortex and subpallium organoids were joined, the inhibitory neurons began to point towards and then move into the cortical organoids — exactly like they move in the embryonic brain. “They would literally jump 30 microns at a time,” says Pașca, who is now a Stanford faculty member. “We were mesmerized and would watch the movies for hours in lab meetings.” A cross-section through a human brain organoid, showing neural progenitor cells (green) and neurons (magenta). Article PubMed Google Scholar Download references Reprints and permissions Related Articles Brain organoids are a transformative technology — but they need regulation Brain tissues, assemble! Ethics need to keep up with human brain organoid research Subjects Neuroscience Developmental biology Stem cells Latest on: Neuroscience Developmental biology Stem cells Brain organoids are a transformative technology — but they need regulation Editorial 08 APR 26 Don’t rush use of lymphatic surgery in Alzheimer’s disease Correspondence 07 APR 26 Is social media addictive?

## Article Content
Email
Bluesky
Facebook
LinkedIn
Reddit
Whatsapp
X
Neurons (green) migrate inside a laboratory-grown brain model called an assembloid, made by fusing organoids. Credit: Sergiu Pasca's Lab, Stanford University
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.
Brain organoids are a transformative technology — but they need regulation
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.
Brain tissues, assemble! Inside the push to build better brain models
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 3D
1
.
The first organoids
The next breakthrough was what developmental biologist Madeline Lancaster, now at the University of Cambridge, UK, calls a “semi-accident”. She had joined Knoblich’s lab as a postdoc in 2010, intending to culture mouse rosettes as a research tool. It didn’t go well. Her cells tended to clump together. But examining the clumps under the microscope, she was astonished to see that they comprised tiny spheres that bore a striking resemblance to the embryonic mouse brain.
“It was a life-changing moment,” she says.
Chimeric brain organoids capture human genetic diversity
Urgent lab meetings ensued. Lancaster immediately decided to use human iPS cells to make organoids, letting them follow their own internal genetic instructions. “I t

---

## Expert Analysis

### Merits
- The first organoids The next breakthrough was what developmental biologist Madeline Lancaster, now at the University of Cambridge, UK, calls a “semi-accident”.
- Only primates have these cells in significant numbers — and humans have many more than do non-human primates.
- Muotri, for example, found that swapping a modern human gene that is important for neural maturation with a slightly different version from Neanderthals led to smaller organoids with neurons that proliferated more slowly 4 .

### Areas for Consideration
- 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.

### Implications
- Brain organoids are a transformative technology — but they need regulation First created more than a decade ago, these organoids started off as very simple models.
- 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.
- 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.
- Organoids have helped scientists to identify some species differences that might contribute to the delays.

### Expert Commentary
This article covers brain, organoids, human topics. Notable strengths include discussion of brain. Areas of concern are also raised. Readability: Flesch-Kincaid grade 0.0. Word count: 2297.