Madison, Wisconsin – Technology developed at the University of Wisconsin–Madison to grow “rosettes” of brain and spinal tissue gives scientists new ways to study the growing human brain, including a recent study of how genetic mutations linked to autism affect early stages of human brain development.
It’s the latest discovery using RosetteArray technology, a screening tool that uses stem cells to generate embryonic forebrain or spinal cord tissue structures called neural rosettes. Neural rosettes are the starting material for generating human stem cell-derived neural organoids — clusters of cells that resemble larger, more complex organs — and can be used to assess whether different genetic makeups or exposure to chemicals increase the risk of neurodevelopmental disruptions.
“This technology gives us access to an embryonic model of human central nervous system development that we would otherwise not have access to,” says Randolph Ashton, a UW–Madison professor of biomedical engineering and associate director of the Stem Cell and Regenerative Medicine Center. “This is useful, because not only can we now understand more about human development, but we can get an understanding of when it goes wrong.”
Ashton and Gavin Knight, a scientist at the Wisconsin Institute for Discovery who earned his doctorate in Asthon’s lab, developed the technology behind RosetteArrays, which are marketed by Neurosetta, a company they co-founded with support from UW–Madison Discovery to Product and the Wisconsin Alumni Research Foundation’s (WARF) Accelerator Program.
RosetteArray technology played an important role in a study published recently in Nature Neuroscience. The study, led by University of Southern California stem cell biologist Giorgia Quadrato, with Ashton and Knight as co-authors, investigated mutations of a gene called SYNGAP1.
SYNGAP1 mutations have long been associated with risk factors for autism spectrum disorder, epilepsy, neurodevelopmental disability and more, but until now the gene has mainly been studied in animal models and focued on the impact of SYNGAP1 on synapses, the structure at the tips of long brain cells called neurons that allow them to pass signals to neighboring cells.
In their new SYNGAP1 autism study, Quadrato and her lab used RosetteArray technology to grow neural rosettes from healthy human cells as well as from the cells of a patient with a disease-causing variant in SYNGAP1. By analyzing these young, developing neural organoids, Quadrato determined that human radial glia cells — the cells responsible for producing all the neurons in the outer layer of the brain called the cerebral cortex — can express SYNGAP1. When SYNGAP1 is mutated, it leads to disrupted organization of the cortical plate, an early brain structure that gives rise to the cerebral cortex. This shows that SYNGAP1-related brain disorders can arise through non-synaptic mechanisms.
Quadrato Lab and Neurosetta plan to partner on further studies to explore the extent of autism spectrum disorder genetic backgrounds that can be modeled using RosetteArray technology, which Ashton hopes will eventually lead to new precision medicine approaches.
“Simply being able to model early human development, in this case brain and spinal cord formation, gives you a very powerful platform to try to improve human health,” says Ashton. “We’ve been surprised to see the effects of neurological disease-causing mutations in the earliest stages of these tissues’ formation. RosetteArrays model approximately four to six weeks post conception, and we’re learning that you can start to see markers for autism then, which is a disease that people typically aren’t diagnosed with until post 2 years of age. So, the fact that we can see this very early in our model of human development is amazing.”
Ashton says researchers using technologies like the RosetteArray are finding that the risk factors for autism spectrum disorder are boiling down to a couple of core pathways, that seem to have roles very early in human brain development, which is helpful information as researchers work on treatments.
While this paper focused on studying brain tissue, Ashton has used the RosetteArray platform in his own lab to study defects in neural tube formation.
“(The neural tube) is a structure that goes from the head of the embryo all the way down through the back of the spinal cord. All brain, spinal cord and eye tissue comes from this neural tube,” says Ashton. “It so happens that a lot of things can disrupt that process, and if that formation is disrupted early enough, then it causes lots of issues. It can cause congenital birth defects known as neural tube defects, for example spinal bifida, which is when the lower spine doesn’t fully close. Or, if you have a failure of closure higher in the neural tube that leads to a failed pregnancy, so understanding this process is crucial.”
Ashton and his lab members have been using RosetteArrays to investigate what may be causing spina bifida defects and how they can be mitigated.
“There are examples of known chemicals we use in our food supply, pesticides, and anti-cancer drugs that have historically been correlated with causing neural tube defects. So, it’s important that we have a way to test new chemistries and chemical processes to make sure they don’t have these effects on human development,” says Ashton. “We’ve used rodent models but there’s a difference between animals and humans. The RosetteArray provides a way to test these chemicals on early human brain and spinal cord development.”
The RosetteArray platform may also be used for individualized medicine, as it can be used to screen individual patients’ cell lines to better understand how mutations in a person’s genomic background can lead to a disorder — as well as how the interaction between a person’s genomic background and the chemicals that they’re exposed to may lead to a health risk.
“We think this platform will be highly useful for both commercial applications for screening for chemicals that can cause neurodevelopmental risk, as well as for clinical application,” Ashton says. “And I think the real power of the tool is for precision medicine and drug discovery.”