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Hopkins scientists help find possible link between Zika and birth defect

Hopkins scientists take big step toward linking Zika virus with microcephaly.

When scientists in Brazil suspected a link between a troubling upswing in the birth defect microcephaly and the mosquito-borne Zika virus last fall, the hunt began for proof. Johns Hopkins neuroscientists and their partners in Florida and Atlanta now say they've discovered a big clue.

In lab dishes full of stem cells, they may have seen how the virus becomes the disease. Zika damaged and destroyed cells that are the building blocks of the brain.

"It was in a dish, not in a fetus," said Hongjun Song, director of the Hopkins Stem Cell Biology Program and one of the researchers. "But it fits."

Proving the link between Zika and microcephaly is important because it would rule out other potential causes for the surge in babies being born with the often-deadly birth defect — in which babies are born with abnormally small heads and underformed brains — and justify the massive public health response and spending on developing a Zika vaccine.

The Hopkins stem cell study, published Friday in the journal Cell Stem Cell, was accelerated after the World Health Organization declared a public health emergency Feb. 1. Zika infections continue to spread rapidly throughout Latin America and the Caribbean, and more microcephalic babies are being born in those areas.

There have been four Zika cases reported in Maryland — up from three last week — and more than 100 cases in the United States among travelers who have been to the affected countries.

Among those cases were nine pregnant women, four of whom either reported miscarriages and abortions after images showed abnormalities, and one who delivered a baby with microcephaly, according to public health officials.

Officials believe mosquitoes will transmit the virus directly to Americans when warmer weather arrives, particularly along the southern border, where Aedes mosquitoes, which carry the virus, are more prevalent.

For the study, two labs at Hopkins produced specialized stem cells that could grow into brain tissue. The cells were sent to a lab at Florida State University, where they were infected with Zika. The cells were then sent on to a lab at Emory University for analysis.

The team now plans to replicate the effort in a so-called 3-D cell system that will more closely mimic brain development. This could identify Zika more definitively as the culprit — or one of the culprits — behind microcephaly. Other viruses are known to cause the abnormality, and genetic and environmental factors haven't been ruled out.

But Zika remains the prime suspect, said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Disease, which helped fund the study. He said other investigations are underway, including a study involving pregnant women.

"It does not provide definitive smoking-gun proof that Zika is the cause of microcephaly," Fauci said of the study. "But it's another bit of information among the rapidly accumulating evidence."

Fauci and leading microcephaly researchers who have seen brain tissue or images of fetuses from Brazil say the cell study results mirror what they've witnessed.

The brain tissue of stillborn babies with microcephaly showed nerve cell death and damage, which is what the study showed, adding to the "pool of evidence," said Dr. Ernesto Marques, a University of Pittsburgh microbiologist who is collaborating with Brazilian researchers.

Another study published Friday in the New England Journal of Medicine found evidence that Zika can cause a range of abnormalities in pregnant women, including some not connected previously to the virus.

Researchers from the University of California, Los Angeles and the Fiocruz Institute in Brazil followed 42 pregnant women who tested positive for Zika and found through ultrasounds and exams that 12 of the fetuses were subject to "grave outcomes," including fetal death, low to no amniotic fluid, fetal growth restriction and central nervous system damage, including blindness. The effects were seen at various stages of pregnancy, and some affected the fetus and others the placenta, which is the fetal life-support system.

The Hopkins team, lead by Song and Dr. Guo-li Ming, his wife and a fellow neuroscientist in the Institute for Cell Engineering, were using cells from human skin to decode other brain disorders such as epilepsy and Huntington's disease when their students suggested they investigate Zika.

They were about to call Hengli Tang, a virologist friend from graduate school who had a lab at Florida State, to ask if he had a sample of the Zika virus, but he rang first. They immediately prepared different cells, including so-called pluripotent stem cells that are made by reprogramming mature cells so they can become any type of cell in the body. One type of those cells, cortical neural progenitor cells, then develop into the nerve cells that make up the cortex, or outer layer of the brain.

They sent the cells and a pair of experienced graduate students to Florida and then to Emory to assist in the research. The team found a link in the neural progenitor cells. Three days after exposure to Zika, 90 percent of those cells were infected and churning out new copies of the virus.

The cells died or failed to divide normally, which in a fetus would stall brain development — the hallmark of microcephaly. The most severe cases, now seen thousands of times in Brazil, showed extremely small brains and heads, leading to death or serious disability.

"It's very telling that the cells that form the cortex are potentially susceptible to the virus, and their growth could be disrupted by the virus," said Ming.

One doctor involved in analyzing the fetuses with microcephaly said the study's findings "are almost predictable."

Dr. William B. Dobyns, a pediatric neurologist at Seattle Children's Research Institute, said he saw 15 brain scans of Brazilian fetuses with the same devastating version of microcephaly in recent months. He'd only seen the same pattern two or three times before out of about 6,000 cases of microcephaly he'd reviewed over 25 to 30 years.

The cases linked to Zika had four things in common: They were all severe; all had excess space in the skull, as if the brain had shrunk; all exhibited malformation of the developing cortex; and each case had scarring in the brain. All of those elements can be explained by the cell study showing cell death and damage, he said.

"It fits like a glove with what I'm seeing on children's brain scans," Dobyns said. "The connection between the Zika epidemic and microcephaly is beginning to look very, very real."

If further study backs up these findings, he said, it still may be tough to develop an agent to block the chain reaction into microcephaly. Zika in adults lasts less than a week, and damage likely would be done to a fetus before a women even knew she was infected. It might be more effective to develop a vaccine, he said.

NIH's Fauci said several vaccines are in development, and some initial testing on humans might be done this year or next, but larger-scale trials will take longer and could be stymied if the latest outbreak abates and limits test subjects.

Dobyns said Zika has been around for decades, but the link to microcephaly was never made. Either the outbreaks weren't big enough or the public health infrastructure in the affected countries wasn't sufficient to recognize and report it. Also, in past outbreaks in Africa, he said people may have had Zika infections earlier in their lives and developed protective antibodies.

Researchers will continue to investigate the effects of Zika, which also increasingly appears to include another severe neurological disorder called Guillain-Barre syndrome that can lead to paralysis.

In the meantime, officials recommend that women who are pregnant or plan to become pregnant follow the advice of the U.S. Centers for Disease Control and Prevention. That includes a warning to avoid travel to the more than three dozen countries with active transmission of the virus, as well as to the 2016 Summer Olympics in Rio de Janeiro.

Pregnant women and their partners should "take any recommendation from the CDC very seriously," Dobyns said.

Microcephaly

The Zika virus is the prime suspect in thousands of new cases of microcephaly, a brain disorder that causes fetus' heads to be much smaller than usual. It can't be cured and in severe cases, such as those seen recently in Brazil, the infant dies or suffers extreme disability.

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