The human brain is a remarkably complex system, yet the vast majority of it forms from a single type of cell, one that also gives rise to the skin. The specification of nerve cells and the gradual generation of many specialized types of nerves take place through an elaborate set of signals, growth, and changes in shape and organization.

It's possible to study many of these processes in other organisms, but the human brain forms specific structures that simply don't exist in lab animals like mice and fish. To make it more difficult, some of these structures form fairly early in development. But now researchers have figured out a way to get human stem cells to form a structure that looks a lot like the cerebral cortex, complete with much of the normal developmental programming. By making stem cells from a patient with microcephaly, they were able to identify the defect involved in the patient's disorder.

The mature cerebral cortex is a brain structure with multiple specialized layers. But during development, it starts off as a layer of undifferentiated and proliferating cells. Over time, these undifferentiated cells give rise to bursts of neurons, which then migrate upward, passing through any existing layers of cells. Once they reach the top of this structure, they form a new layer and begin to establish connections with other nerve cells. This process continues until six distinct layers are formed. Mice do form a cerebral cortex, but the process differs in significant ways from what happens in humans, making them a limited model for studying it.

It's possible to induce stem cells to differentiate into cortical neurons, but that also has its limits. A variety of factors are needed to push cells down the developmental path, and they tend to produce a mixture of cells from different layers that lack the organizational structure of the cortex.

The new work takes two distinct approaches to getting stem cells to form a more organized cortex. The first involves the culture conditions. Rather than growing them in a dish or a gel, the researchers put the stem cells in small (4mm) beads of a material (called matrigel) that mimics the mesh of proteins that they'd normally develop in. Once the beads are seeded with stem cells, the beads are placed in a mixture of growth factors and nutrients that's constantly mixed and regularly replaced. Under these conditions, the cells in the interior of the culture died off (presumably due to their inability to access the nutrients), but the outer layers of cells could survive for up to 10 months.

The second key aspect of the work is that the researchers didn't try to force the stem cells to adopt a cortical fate. Rather, they simply induced the stem cells to form the progenitors of the brain (neuroectoderm cells) and then let them organize themselves. This resulted in a variety of structures, including the precursor of the eye (optic cups) and the structure that creates cerebro-spinal fluid (the choroid plexus). But in many cases, the cells spontaneously formed something that looked like the early cerebral cortex with the appropriate layers of dividing cells and signs of neurons migrating within the beads. Various tests indicated that the cells were adopting the right fates, and tests with embryonic stem cells from mice showed they did not form this human-like pattern of layers.

They call the results "organoids" and suggest that the general approach could be used to study a variety of other processes involved in brain development.

Although a fantastic technical achievement, the researchers also wanted to demonstrate that the system they developed is useful. So, they focused on a patient that suffers from microcephaly (literally, small head), a developmental disorder that results in a reduced brain size. They took cells from the patient and converted them into induced stem cells and then put the stem cells through their culturing system. What they found was that rather than forming organized layers on top of a set of proliferating cells, most of the proliferating cells rapidly developed into neurons and stopped dividing. This strongly suggests that the microcephaly results from forming too many nerve cells too soon and don't reserve enough growing cells to replenish them.

Most people have ended up viewing stem cells as a promising way of repairing damaged tissues. But for many scientists, they're now providing a way of studying mutations and processes that are too difficult to examine any other way. Techniques like organoid formation provide additional tools to make these studies as relevant to human biology as they possibly can be.

Nature, 2013. DOI: 10.1038/nature12517 (About DOIs).