To persuade human nerve cells in a laboratory to thrive, there are three magic words: location, location, location.
Many experiments grow human nerve cells in laboratory dishes. But a new study enlists some real estate that’s a little less conventional: a rat’s brain. Implanted groups of humans Neurons get larger and more complex. than their dish-grown cohorts, the researchers report online Oct. 12 at Nature.
Not only that, but human cells also appear functional, albeit in a very limited way. The implanted human cells can receive signals from rat cells and influence the rats’ behavior, connections that “demonstrate a more substantial integration of the transplanted neurons,” says Arnold Kriegstein, a developmental neuroscientist at the University of California, San Francisco, who wasn’t involved in the study. “This is a significant advance.”
Over the past decade, scientists have been building increasingly complex brain organoids, three-dimensional clusters of cells derived from stem cells that grow and mimic the human brain (Serial number: 02/20/18). These organoids do not recreate all the complexity of human neurons that develop in a real brain. But they may be windows into an otherwise inscrutable process: the development of the human brain and how it can go wrong (Serial number: 9/3/21). “Even if they’re not quite perfect, [these models] they are substitutes for human cells in a way that animal cells are not,” says Kriegstein. “And that’s really exciting.”
To bring these cells closer to their full potential, Sergiu Pasca, a neuroscientist at Stanford School of Medicine, and colleagues surgically implanted human brain organoids into the brains of newborn rat pups. Along with their hosts, the human organoids began to grow. Three months later, the organoids were about nine times their initial volume and ultimately made up about a third of one side of the rat’s cortex, the outer layer of the brain. “It leaves out the rat cells,” says Pasca. “Grow as a unit.”
These human cells flourished because rat brains offer advantages that laboratory dishes cannot, such as blood supply, a precise mix of nutrients, and stimulation of nearby cells. This environmental support coaxed individual human neurons to grow larger — six times larger by one measure — than the same type of cell grown in dishes. The cells that grew in the rats’ brains were also more complex, with more elaborate branching patterns and more cellular connections called synapses.
The cells seemed more mature, but Pasca and his colleagues wanted to know if the neurons would behave that way, too. Tests of electrical properties showed that the implanted neurons behaved more similarly to cells developing in the human brain than cells grown in dishes.
Over months of growth, these human neurons established connections with their rat host cells. The human organoids were implanted in the somatosensory cortex, a part of the rat brain that handles input from whiskers. When the researchers blew air into the whiskers, some of the human cells responded.
In addition, the human cells could influence the behavior of the rat. In subsequent experiments, the researchers genetically tuned the organoids to respond to blue light. Triggered by a flash of light, the neurons fired signals, and the researchers rewarded the rats with water. Soon, the rats learned to move toward the water spout when their human organoid cells sent signals.
In behavioral tests, the human-implanted rats showed no signs of increased intelligence or memory; in fact, the researchers were more concerned about deficits. The human organoids were pushing the brains of their hosts, after all. “Will there be memory deficit? Will there be motor deficits? Will there be seizures? Easter asked. But after extensive testing, including behavioral tests, EEGs and MRIs, “we couldn’t find any differences,” says Pasca.
Other experiments included nerve cells from people with a genetic disorder called Timothy syndrome, a serious developmental disorder that affects brain growth. Growing organoids created from these patients’ cells in rat brains could reveal differences that other techniques might not, the researchers reasoned. Sure enough, neurons in these organoids had less complex message-receiving dendrites than those in organoids derived from people without the syndrome.
Organoids made from patient-specific cells could one day even serve as test subjects for treatments, says Pasca. “Challenging disorders will require bold approaches,” she says. “We will need to build human models that recapitulate more aspects of the human brain to study these unique human conditions.”