How an off-hand remark sparked a breakneck collaboration to stop the Zika virus

BALTIMORE – Leave it to the youngest person in the lab to think of the Big Idea.

Xuyu Qian, 23, a third-year graduate student at Johns Hopkins, was chatting in late January with Hongjun Song, a neurologist. Song was wondering how to test their three-dimensional model of a brain — well, not a brain, exactly, but an "organoid," essentially a tiny ball of brain cells, grown from stem cells and mimicking early brain development.

"We need a disease," Song said.

Qian tossed out something he'd seen in the headlines: "Why don't we check out this Zika virus?"

Within a few weeks — a nanosecond compared with typical scientific research time — that suggestion led to one of the most significant findings in efforts to answer a central question: How does the Zika virus cause brain damage, including the abnormally small heads in babies born to infected mothers?

The answer could spur discoveries to prevent such devastating neurological problems. And time is of the essence. One year after the virus was first confirmed in Latin America, with the raging crisis likely to reach the United States this summer, no treatment or vaccine exists.

"We can't wait," said Song, at the university's Institute for Cell Engineering, where he and his wife and research partner, Dr. Guo-Li Ming, provided a pipette-and-petri-dish-level tour. "To translate our work for the clinic, to the public, normally it takes years. This is a case where we can make a difference right away."

The laboratory's initial breakthrough, published in March with researchers at two other universities, showed that the Zika virus attacked and killed so-called neural progenitor cells, which form early in fetal development and generate neurons in the brain.

In April, the team and other collaborators published a study in the journal Cell showing that this assault by Zika resulted in undersized brain organoids: Damaged progenitor cells created fewer neurons, leading to less brain volume. That may explain the smaller brains, a condition called microcephaly, of some babies exposed to Zika during pregnancy.

"I think they've nailed it," said Dr. Eric Rubin, a professor of immunology and infectious diseases at Harvard. "That is totally consistent with the pathology that has been seen."

The experiments suggest other worrisome aspects of Zika infection: that even low doses of the virus for short periods can cause damage and that it is most dangerous in the first trimester of pregnancy but can also be harmful in the second. "The really sad news is not only can the virus infect neural progenitor cells, but it turns them into a factory," Song said.

"The cells produce more virus and they actually can spread it," Ming said.

And the organoid results contain a frightening hint of why Zika is also associated with adult neurological disorders, including Guillain-Barré syndrome, a temporary paralysis. Song said they found that Zika infection is "even worse" in glial cells, which support and insulate neurons and are present throughout life, not just in fetal development.

But there is much more to learn, and the collaboration catalyzed by a remark from a junior scientist now includes nine labs at six sites across the country.

Among them is a specialized lab at the National Center for Advancing Translational Sciences, which is testing drugs on neural progenitor cells, hoping to find compounds that can stop the virus. Rapidly testing thousands of compounds in varying doses, the lab has already zeroed in on a promising candidate. If the drug succeeds in further testing, it could allow scientists to skip much of the safety evaluation necessary for creating new drugs or vaccines.

Other researchers are rushing to understand how Zika wreaks its damage. Teams in Brazil and at the University of California, San Diego, have also found that the virus attacked neural progenitor cells and shrank brain organoids. The San Diego team reported that Zika overactivated a molecule that normally protects against viruses, and the excess activity seems to switch on genes that galvanize progenitor cell destruction.

In Rio de Janeiro, Stevens Rehen, a neuroscientist at D'Or Institute for Research and Education, said that they can test only those approved in Brazil. "The idea is to be fast," Rehen said.

At the University of Pittsburgh, Carolyn Coyne, a microbiologist, and Dr. Yoel Sadovsky, an obstetrician and microbiologist, are investigating how the virus enters the placenta. Scientists at other institutions, including Vanderbilt; the University of California, San Francisco; and Washington University in St. Louis, are examining questions like how the immune system recognizes the virus.

Experiments from all these labs will provide clues, Rubin said. But they will not tell the whole story. "In a person, it's way more complicated," he said.