Brain organoids: a way to recreate the genetic cause of neurodegeneration and Alzheimer’s disease, and how to replace it with healthy channels
Chen said people spent a lot of time developing and getting familiar with how to make organoids in the last ten years. This is the ideal time to think about how to use the models.
There is no good animal model for Timothy Syndrome because the underlying genes don’t always cause the same symptoms in rodents. He says that it was clear to them that they would need to find a way of testing.
The researchers turned to brain organoids to recreate the disorder. The stem cells were taken from the 3 people with the genetic cause of Timothy syndrome and cultured for about a hundred days, in which time they became brain organoids containing every type of neuron found in the cerebral cortex. To create a more lifelike environment for the organoids, the team then injected these structures into the brains of rats, where the cells formed connections with the rodents’ own neurons. Researchers could test potential treatments for the disorder in a system made by this.
Human neurons have four different forms of this calcium channel, but only one of them is defective in Timothy syndrome. The healthy channels would be allowed to take over if the mutated channel is removed, the researchers suggest.
Injecting cancerous cells into mice and a model of colon cancer using laser-activated neuronal tunneling to induce tumour growth in different species
He adds that his group hope to test the therapy on people in clinical trials eventually, although they will first need to prove that the oligonucleotides are safe by testing them in non-human primates. The researchers think that the treatment would be effective for about three months, so people would need to receive frequent injections. Paca says the advantage is that the biological effects of the treatment would be in place for a long time.
To make a model of colon cancer, they engineered the cells to contain light-sensitive proteins attached to cancer-causing genes. This allowed them to use a blue laser to switch on the genes and trigger the growth of tumours at specific sites in the organoid, then watch how the tumours changed over the course of weeks.
When the researchers injected the cancerous cells into mice, the tumours looked similar to those seen in human colorectal cancer. The organoids accumulated fewer tumours when the researchers restricted calories in their medium, which also happens in people with colorectal cancer.
Two research teams have demonstrated that adding rat neurons to mouse brains that were missing crucial cells could help the organs to recover function1,2. The experiments could help scientists to better understand how different species’ brains develop, and even aid efforts to grow ‘chimeric’ pigs with human organs that could be used for transplantation in people.
How neurons connect with one another, and fire, makes integrating cells from two species complicated, says Kristin Baldwin, a neuroscientist at Columbia University in New York City. “Neurons are not just Legos,” she says.
Baldwin, JunWu and their colleagues tried to combine rat and mouse cell types early in the mice’s development in a paper published on 25 April in Cell1, which was published by one of the teams.
First, they engineered the genes in a group of mice in a way that destroyed some neurons in the animals’ olfactory systems. The research mice could not smell the mini-cookies they were about to be buried in because their sense of smell had been disrupted.
In a Cell paper published by the second team, also on 25 April2, Wu and his colleagues developed a more aggressive strategy for getting rat cells into a mouse’s brain. Researchers wiped out all the traces of a gene called Hesx1 in a group of mouse blastocysts by using a genetic-editing tool called C-CRISPR. The forebrain is a large region in the brain that organizes much of an animal’s behavior.
Wu and Baldwin say that their research addresses some long-standing concerns about developing chimaeras, particularly for the purpose of transplanting tissue or organs from animals such as pigs into people. The human body can reject a chimeric organ due to ethical considerations. The teams added rat cells so early that the animals didn’t know to attack them, because they had formed an immune system.
Another concern is a mismatch in the developmental rates of species. However, the teams found that the mouse brains developed at the same rate as they would normally, rather than at the slower pace at which a rat usually develops.
