Mini-colon and brain ‘organoids’ shed light on cancer and other diseases. Is there a good animal model for Timothy syndrome?
In the second paper, bioengineers at the Swiss Federal Institute of Technology in Lausanne and their colleagues used mouse stem cells to model the gut tissue that makes up the colon and rectum. The researchers grew the cells on a scaffold to make them look like the tube structures seen in real gut tissue.
Paca says that there are no good animal models for Timothy syndrome because of the underlying abnormality that is not related to the symptoms in rodents. It was clear to us that we would need to find a way of testing.
To do this, they identified short pieces of nucleic acids called oligonucleotides that can stop cells producing the mutated form of the protein by interfering with genetic transcripts. Two weeks after the rats were injected, most of the calcium channels in the organoids had changed to other versions. The organoids had changedshape, from small, less complex forms similar to those found in people with Timothy syndrome to larger, more complex shapes typical of healthy neurons. Paca did not think it would work well.
Human neurons have four different forms of this calcium channel, but only one of them is defective in Timothy syndrome. The researchers say that getting rid of the mutated channel would allow healthy channels to take over.
Testing a model of colon cancer by mixing rat and mouse neuronal cells with blastocysts in an animal model
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 treatment would work for three months, so people need to get injections often. The advantage, Pașca says, is that the biological effects of the treatment would be reversible and any side effects would be short-lived.
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.
When the researchers allowed these blastocysts to develop into mice without forebrains, the animals died shortly after birth. The forebrains that were created when the team injected rat stem cells into blastocysts were made entirely of rat cells. The mice were healthy once they had grown, but it would be difficult to determine if there were any differences between them and normal mice.
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. She says neurosciences are not just Legos.
In a paper published by one of the teams on 25 April in Cell1, Baldwin, molecular biologist Jun Wu at the University of Texas Southwestern Medical Center in Dallas and their colleagues attempted to test this by mixing rat and mouse neuronal cells very early in the mice’s development.
First, they engineered the genes in a group of mice in a way that destroyed some neurons in the animals’ olfactory systems. The mice that the researchers had buried in various places throughout the cages were unable to use their sense of smell due to the disrupted olfactory circuit in their nose.
The second team published a Cell paper on 25 April2 that included a new strategy for getting rat cells into a mouse’s brain. The researchers wiped out the entire Hesx1 gene in a group of mouse blastocysts using a genetic-editing tool called C-CRISPR. This gene controls the development of the forebrain: a large region in the brain that coordinates much of an animal’s behaviour.
Some long-standing concerns about developing chimaeras are addressed by their research, which addresses the issue of transplants from pigs into people. There is concern that the human body will reject a transplant. But because the teams added the rat cells so early in the mice’s development — long before the embryos had formed an immune system — the animals’ bodies never learnt to recognize the cells as foreign and never attacked them.
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.