We've seen beating heart tissue, windpipes and bladders all grown from stem cells. Now researchers have taken another important step forward by growing mini brains from these programmable cells.
They're not actually functioning brains -- in the same way that a car with the engine on its roof or wheels on its hood isn't a drivable vehicle -- but the parts are there, and that's an important scientific advancement, according to Juergen Knoblich, senior author of a new study on using stem cells to grow brain tissue.
Scientists have created what they are calling "cerebral organoids" using stem cells. These pea-sized structures are made of human brain tissue, and they can help researchers explore important questions about brain development and disorders that occur during these first stages of life.
The organoids, as described in the journal Nature, have components resembling those of a brain of a 9- or 10-week-old embryo, said lead study author Madeline Lancaster, a researcher at the Institute of Molecular Biotechnology at the Austrian Academy of Science in Vienna, at a press briefing Tuesday.
She and colleagues have created hundreds of these organoids.
At this early stage of human development, several key regions of the brain are already distinctive features, including the dorsal cortex, the ventral forebrain, the choroid plexus -- which generates cerebrospinal fluid -- and regions that resemble the midbrain and hindbrain. Lancaster and colleagues say they've identified some of those same regions in these new mini brains.
However, these regions did not naturally fall into place in the stem cell models the same way they would have in a normal brain.
"These different regions are not organized in the same kind of fashion that you would see in the developing embryo," Lancaster said.
The organoids also lack certain features that human embryonic brains at 9 weeks do have: most importantly, the cerebellum, which is involved in motor movement. Also, the hippocampus, a seahorse-shaped structure crucial for memory, was rarely detected in these brain-like structures.
Researchers used human embryonic stem cells and induced pluripotent stem cells (IPS cells) for this research. Both embryonic stem cells and IPS cells have the ability to turn into any part of the body. But embryonic stem cells are very controversial because in the process of retrieving them for research, the 4- or 5-day-old embryo they are taken from is destroyed. IPS cells don't come with the same controversy because scientists take a cell -- typically a skin cell -- then coax it using a chemical bath to revert to a state that resembles a developing embryo.
There did not appear to be an obvious difference between organoids derived from embryonic stem cells and those produced from IPS cells, said Knoblich, also of the Austrian Academy of Science.
Study authors found variability in the organoids they generated; occasionally some of the brain regions they were studying failed to appear.
Lancaster attempted to direct the development of these regions in some of the organoids by applying growth factors, substances that promote the proliferation of cells. Surprisingly, when she tried to grow the mini brains with more dorsal cortex tissue, the resulting structures had less of this tissue than the organoids that had developed on their own.
"We actually think that the cross-talk between these different regions -- the communication between these different brain regions within the organoids -- is really important for each individual region's development," she said.
The researchers used this model to look at a neurodevelopmental disease called microcephaly, a disorder in which the size of the brain is reduced. The brain region they were most interested in exploring, the dorsal cortex, is the region most highly impacted by this disease.
Researchers grew some of these organoids using cells from a patient who had a genetic form of microcephaly, and compared them with the mini brains derived from healthy participants' cells.
In the organoids made from the microcephaly patient's cells, it appeared that more stem cells had been turned into neurons -- a process called differentiation -- than in the mini brains derived from healthy patients' cells. This suggests that in people with this condition, neurons prematurely differentiate, which could be the mechanism behind this form of the disease, said Oliver Brustle at the Life & Brain Centre at University of Bonn, in an accompanying article in Nature.
This research builds on other studies that have attempted to model brain tissue from stem cells. A 2008 study showed that mouse embryonic stem cells could be coaxed into producing "waves" of neurons. A different research group showed in 2012 that primitive eye structures and stratified retinas could form from embryonic stem cells taken from both mice and humans. Study authors said they have no intention of growing a full-sized human brain.
"It is very clear that our system is not optimized
for generating an entire brain, and that is also in no way our goal," Knoblich said.
As for growing a brain structure from stem cells that's capable of conscious thought, Knoblich said this would likely not be possible, or desirable.
Although the organoids are an important step forward, the researchers are nowhere near being able to model circuits found in the functional central nervous system. Moreover, Knoblich said, sensory input is required for such functional circuits to form. A classical experiment showed that the optic cortex will not organize properly if it does not have input from an eye, he said.
Knoblich is also pessimistic about the idea of growing brain structures from stem cells with the intention of replacing faulty ones in human patients. The brain is so complex, and its regions so intimately integrated, that it would be difficult to repair any specific part through substitution.
A more promising possibility, he said, would be to put the stem cells directly into the patient and let them organize themselves. But the future of this line of research is still unknown.
Brustle, who was not involved in this research, called the study "remarkable" and noted that it "clearly puts neural aggregation cultures on the map of research tools for both developmental biology and biomedicine."
That's a lot from a little tissue.