Crossing disciplines, Yale scientists unravel Zika’s secrets

Two black chalkboards, covered with squiggles and ovals in blue, arrows in yellow, and words like “mitophagy” and “necrosis” in all caps, occupy half of the wall space in Tamas Horvath’s office. Horvath, D.V.M., Ph.D., the Jean and David W. Wallace Professor of Comparative Medicine and professor of neuroscience and of obstetrics, gynecology, and re-productive sciences, put these walls up 11 years ago; he does his best thinking in chalk. Earlier this spring, after thinking about a patient with cerebellar ataxia, Horvath filled his chalkboard with squiggles, ovals, and arrows that laid out a hypothesis about the Zika virus that would eventually bring together seven departments at Yale and result in three published papers within nine months.

Cerebellar ataxia is a balance disorder—patients walk with a shuffle as if they are about to fall forward. A mutation causes certain brain cells to overproduce TBK1, a protein that defends the cells against viruses and flushes out damaged mitochondria. Too much of this protein, however, can cause the cells to die. As the mysterious mosquito-borne virus called Zika started spreading in Brazil in early 2015, Horvath wondered: What if it was also causing the cells to overproduce TBK1? What if that was the mechanism behind microcephaly—the underdeveloped brains of children born to mothers with Zika? “When I came to this, I got so excited. I’ve been doing research for 26 years; I thought I couldn’t be so excited anymore,” Horvath said.

Unfortunately, federal funding for Zika research is scarce. The World Health Organization deemed Zika a health emergency in February, but Congress has appropriated just half the funding that federal agencies said they’d need.

About the same time that Horvath was drawing diagrams on his chalkboards, colleagues were conducting independent research that would help in the fight against Zika. Brett D. Lindenbach, Ph.D., associate professor of microbial pathogenesis, was stockpiling the virus to study its replication. Akiko Iwasaki, Ph.D., the Waldemar Von Zedtwitz Professor of Immunobiology, was studying vaccines for the sexually transmitted herpes simplex virus. Nenad Sestan, M.D., Ph.D. ’99, professor of neuroscience, was growing human fetal stem cells that unbeknownst to him were the same cells targeted by the virus. Gil E. Mor, M.D., Ph.D., M.Sc., professor of obstetrics, gynecology, and reproductive sciences, was working on the immunology of implantation and how viruses affect pregnancy. Some of these projects were funded through nonspecific research grants. Lindenbach also worked on his own time. “It was like I was back in grad school again,” he said.

By pooling their resources, Yale researchers could launch studies on the Zika virus without federal funding. For months, the researchers, who had previously discussed working together, met in Horvath’s office to figure out where to focus their research. They chose to look at how the virus was affecting babies in utero. “It was the perfect storm,” said Lindenbach. “We had all these researchers with complementary skills.”

Iwasaki asked Laura J. Yockey, an M.D./Ph.D. student in her lab, to address one of their most pertinent questions—would Zika virus in the vaginas of pregnant mice lead to brain infection in their fetuses? Within three months, a draft had reached Cell, and was published in August 2016. Zika virus in the vaginas of pregnant mice, the researchers reported, did in fact lead to brain infection in the fetuses. They also found that the vaginal tract is a welcoming environment for the Zika virus, supporting studies in humans that reported sexual transmission of the virus. “Not everyone understands the dangers of sexual transmission of the Zika virus,” Iwasaki said. “This study emphasizes that.”

The collaborations continue: Two other multi-department studies were published in Cell Reports and the American Journal of Reproductive Immunology. Iwasaki is working with Horvath and Erol Fikrig, M.D., FW ’91, the Waldemar Von Zedtwitz Professor of Medicine (infectious diseases), who is leading the study on Zika’s effects on the testicles. Lindenbach and Yockey are trying to figure out why the Zika virus affects some cells and not others. “There are a lot of institutions where there is a lot of internal competition,” Lindenbach said. “But it’s really rare at Yale, in my experience, and that’s a good thing, because the way we do science nowadays really requires people with different expertise.”