The suspected link between Zika and microcephaly is looking stronger and stronger.
At first, you may recall, the link was pure correlation: Brazil saw a huge uptick this fall in cases of microcephaly, a condition where babies are born with brains that are too small, at the same time Zika spread through the country. In the past few months, scientists have found the virus in the placenta, amniotic fluid, and—most tellingly—brain tissue of microcephalic fetuses.
Now two new papers show that Zika kills developing brain tissue culture in a dish. Those results don’t completely solidify the link between the virus and birth defects, but public health officials aren’t taking any chances. “The association is strong enough that we need to assume that it is true until we show that it’s not,” says Amelia Pinto, an immunologist at St. Louis University, who was not involved in either study.
In one paper, a team based at the Federal University of Rio Janeiro grew neural stem cells into tiny little balls of brain tissue called cerebral organoids. These aren’t as complex as full brains, but they give scientists a window into brain development, namely how an undifferentiated mass of stem cells turns into the different tissues of the brain. And with Zika, it didn’t look good. In the eleven days after the organoids were infected with Zika, they grew 40 percent less than the healthy ones. The paper was uploaded to the preprint archive PeerJ, though it has not been peer reviewed or published in a journal yet.
In a second paper published today in the journal Cell Stem Cell, a Johns Hopkins University group didn’t grow brain balls. Instead, they took stem cells and turned them into a specific type of human neural progenitor cells, which are the precursor to cortical neurons. They found that these neural progenitor cells were especially vulnerable to Zika. The virus had marginal effects on the cells they grew from (stem cells) or the cells they grew into (cortical neurons), but it killed nearly a third of the human neural progenitor cells.
What’s going on with the neural progenitor cells? Zika infection seemed to scramble normal gene expression in those cells, tamping down genes that help them grow into neurons and turning on genes for cell death. The group is now continuing this work in cerebral organoids says Guo-Li Ming, a neuroscientist at Johns Hopkins who led this study.
As with any cell culture experiment, these papers have limitations. One caveat is the type of stem cells both groups used. They started with fully fledged adult cells that were “backwards aged” into stem cells and then chemically coaxed into neural stem cells. That’s not how brains develop in fetuses. But using actual human fetal brain tissue is very difficult. (See the whole controversy over Planned Parenthood’s role in providing fetal tissue last year.)
More obviously, though, cells in a dish are not developing fetuses. Scientists hope to use animal models to piece together the complete story. Pinto is one of multiple researchers now using immunocompromised mice as a model for Zika infection. She’s especially interested in how the immune system’s inflammatory response to the virus may also might play a role in the brain defects. The story might get more complicated before it gets untangled.