Before last year, scientists knew very little about the Zika virus. As late as 2007, there had only been 14 documented Zika cases in the world. Research on the virus was so limited, in fact, that printouts of all the world's published literature could basically fit into a shoebox.
Suffice to say, researchers now have a lot of questions about Zika. After the mosquito-borne virus exploded around Brazil last year, moving on to most of Latin America and the Caribbean, an effort to better understand Zika was on. Here are the most pressing questions scientists are currently trying to tease out:
1) Does Zika cause microcephaly?
If Zika hadn't been linked to an awful birth defect, it probably wouldn't have garnered many headlines or much research funding. It would have just been a strange, mostly benign virus that only affects about 20 percent of infected people with flu-like symptoms.
But the outbreak grabbed everyone's attention once new evidence suggested that women infected with Zika during pregnancy could give birth to babies with microcephaly, a condition that's characterized by a shrunken head and incomplete brain development. That drove headlines. And the search to figure out more about this birth complication began.
Proving that Zika causes microcephaly — or not — is currently the key question about this virus.
So far, researchers mostly have circumstantial evidence of a link. The virus has been found in the amniotic fluid of pregnant women carrying babies with microcephaly. It's been found in the brains of babies with the birth defect who died within 24 hours of being born and in an aborted fetus with microcephaly. Brain scans have also revealed the extent of the damage Zika causes: calcifications in some areas of the brain and complete underdevelopment in others.
"The geographic and temporal associations of infection of mothers with Zika and congenital abnormalities with children with microcephaly is mounting," says Dr. Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases.
There are other tantalizing hints too. Similar clusters of microcephaly have been found in other Zika outbreaks. A look back at the data from a Zika outbreak in the French Polynesian islands in 2013 to 2014 revealed a rise in birth defects following the arrival of Zika.
Still, scientists don't yet consider this evidence conclusive. "We still don't have the definitive proof of the direct causal relationship," says Fauci. And that's exactly what researchers are trying to gather now.
Proving that Zika is causing these birth defects and not something else requires what's called a "case-control study." Researchers are comparing the rates of microcephaly in groups of pregnant women who are infected with Zika to those who are not. If moms who had Zika during pregnancy have a statistically significantly higher rate of microcephaly than the moms who didn't have Zika, the researchers can be confident that the virus is what's making the difference.
The moms who test positive for Zika and have babies with microcephaly would also need to be screened for other known causes of the birth defect, including other viruses like toxoplasmosis, syphilis, or rubella, and even malnutrition.
2) How often does Zika lead to birth defects, and how does it affect babies' brains?
If Zika is indeed the culprit of this devastating birth defect, there will be many more questions to answer. The main one: How often does Zika cause microcephaly?
Are all mothers infected with Zika in pregnancy at risk for birth complications? Or only some? Are there certain factors that can increase the risk of birth complications — say, infection at a certain point in pregnancy, leftover antibodies from another virus, malnutrition? Is microcephaly more likely in women who acquire Zika through sex compared with those who are infected by mosquito bites? Researchers don't know.
Figuring this out will require better data on how prevalent microcephaly is. The initial media reports in Brazil suggested a massive uptick in the condition after the arrival of Zika. It turns out this wasn't quite accurate.
There are some good reasons to think the increase of microcephaly in Brazil since 2014 may be exaggerated. The first is an "awareness bias." When doctors began to sound the alarm over Zika, health officials massively ramped up the effort to find babies who may have been harmed by the virus.
People were freaked out, and so were doctors. In that context, doctors were looking for microcephaly and may have been more likely to report the birth complication than in the past — perhaps including borderline cases that would have never been reported in the past and cases that aren't actually microcephaly at all.
Conversely, there's now some suspicion that Brazilian doctors actually underreported microcephaly prior to Zika's arrival. That means their pre-Zika baseline of a couple hundred cases per year was too low.
Experts don't think these problems with measuring microcephaly cases entirely account for Brazil's uptick, but they may give a skewed picture of the extent of the problem. Getting the numbers right will require painstaking checks — and that takes time.
As of February 17, of the 3,935 suspected cases of microcephaly, the Brazilian Ministry of Health has confirmed 508 and thrown out 837. The rest are being checked, and of the confirmed cases of microcephaly, only a few have been linked with Zika.
If it turns out Zika is definitively the cause of the birth complication, then the next question is: How? What's the mechanism of infection?
Fauci says researchers don't have a clear idea now, although they do have some areas they'd like to explore. "Is it a direct infectious destruction of the neural tissue in the baby? Or is Zika synergizing with something else, some other factor that requires infection of the mother, but cannot itself cause microcephaly?" One possibility is that it may be two diseases working together: A mother with a previous infection like dengue fever might have antibodies that could somehow enhance the likelihood of Zika-related birth complications.
"You've got to keep an open mind about everything," Fauci adds. But the first step, he says, are those case-control studies to see whether Zika is causing the birth defects.
3) Has the Zika virus mutated in some important way?
Zika used to just cause small and sporadic outbreaks in Africa and Asia. Now it's infecting millions of people in an explosive outbreak in Latin America. So there are questions about whether the virus has mutated in some important way.
To be clear, all RNA viruses like Zika mutate as they jump from host to host, but they don't typically mutate so radically as to change functions. (That is, Zika is unlikely to mutate from a virus transmitted by mosquitoes into an airborne virus.) Still, there are questions about whether Zika has mutated in some smaller way that has boosted transmissibility.
"We are doing Zika sequencing, and, with the help of reverse genetics, looking to pinpoint whether or not a mutation of the virus may have been responsible for this change," explains Nikos Vasilakis, a professor and researcher at the University of Texas Medical Branch. But there's a problem with finding out how Zika has changed: Researchers need many sequences of the virus to detect patterns or changes. And since research on Zika is so new, they don't have enough.
Fauci also wonders whether similarly explosive epidemics of Zika have happened elsewhere but have just gone undetected: "The virus has been around in Africa for a while, so one can ask why haven't we had massive explosions of Zika? We may have and they have just gone unnoticed." This is a particular possibility since the health systems of Africa aren't as well developed as those of Brazil.
4) How exactly does Zika spread?
For now, scientists believe that Zika is mainly carried by a specific type of mosquito called Aedes aegypti, which spreads the disease through bites.
Aedes mosquitoes bite during the day and are incredibly well adapted to thrive alongside humans. They can breed and rest in small pools of water and moist environments around people's homes and apartments. (You can see examples of the mosquito's main aquatic habitats here, ranging from rain-filled cavities in trees to outdoor pots and animal drinking pans.)
But there have also been several documented cases of sexual transmission of Zika, which has led to more questions about how Zika can spread. "We don't know the extent of [sexual transmission]," says Fauci. Is this only a very rare pathway for the virus? Or a more common one than was previously believed?
Researchers also don't know the duration and persistence of the virus in semen. Can the virus spread only during acute infection, in the first few days of getting sick? Or is it transmissible as long as it's in the semen? In the UK, researchers found virus in a man's semen 62 days after he got sick.
Finally, there is new — but very limited research — out of Brazil that found the virus in saliva and urine samples of two people infected with Zika. The researchers tested these bodily fluids in people with Zika and found active virus. (This isn't the first time Zika has been found in urine or in saliva.)
There's very little that's known about how infectious these bodily fluids are and whether or how they could infect others. One of the researchers behind the discovery cautioned, "[This] does not mean there is a capacity for transmission through saliva and urine."
5) What other problems can Zika cause?
In the Brazil, Colombia, and French Polynesia outbreaks, researchers noted that some people infected with the virus were later diagnosed with Guillain-Barré, a rare and sometimes deadly neurological condition in which people's immune systems damage their nerve cells, leading to muscle weakness and even paralysis. The symptoms can last weeks, months, or even years. This link hasn't been proven, but Dr. Eric Rubin, a professor of immunology and infectious diseases at Harvard, said it wouldn't be unusual. "Guillain-Barré is often associated with viral infections," he explained.
Zika also seems to cause eye problems in children born with the virus, and there are questions about whether it'll increase the risk of mental illness later in life, even in babies who were not born with microcephaly.
In other words, we're just beginning to understand the full range of Zika's effects.