The Case that Clinched the Zika-Brain Connection

Normal male fetus EKP
Normal fetus

Rita Levi-Montalcini, the first Nobel laureate to reach 100, graduated from the Turin medical school in 1936, and soon started working on the developing nervous system. Two years later, when Mussolini barred Jews from faculties, she set up a lab in her bedroom—such was her passion for understanding brain growth, for discoveries that might someday help prevent brain defects.

I thought of her on April 13th, when the CDC released its statement confirming that Zika causes microcephaly. It seems they were awaiting a then-just-published study that reviewed all the evidence and matched it against stringent criteria. “This study marks a turning point,” said CDC director Tom Frieden.

Well, it wasn’t exactly a study, it was a review paper in the New England Journal of Medicine, and it said among other things that there was “no ‘smoking gun’ (a single definitive piece of evidence that confirms Zika virus as a cause of congenital defects).” Hence the wait for a comprehensive review.

By then I was growing a impatient. On March 10th the same journal published a case study that seemed a smoking gun to me, and that was how I presented it to the 170 students in my “Disease and Human Behavior” class.

We’d been tracking Zika since January—pretty much when the story broke, the week the course started. Evidence had been mounting, partly thanks to the CDC. There’d been a diversion caused by the claim that an insecticide was damaging fetal brains, but that didn’t last.

Okay, this was a case study, not a make-or-break event for a medical scientist. But I tore it out of the journal—sorry, I still get paper—ran to class with it, and stuck it under the document camera.

Just a case study, I told the students. But it’s a long way from the university hospital in Ljubljana to the New England Journal, and they were there. Jernej Mlakar and 13 other Slovenian scientists reported the sad case with amazing elegance.

An expectant mom returned from Brazil, where she’d had a fever and a rash in her thirteenth week of pregnancy. There was a Zika epidemic in the town where she’d volunteered; she had all the signs and symptoms. Weeks later, back in Europe, she noticed that the fetus was moving less; ultrasound showed microcephaly.

She chose to end the pregnancy. At autopsy the brain was tragically stunted—tiny for its age and without the folds that make our brains unique. But the evidence was circumstantial.

That’s when they ran a brain sample and found the complete Zika RNA sequence. It was the Bahia, Brazil strain, with an ancestor in French Polynesia, exactly in line with the virus’s known history.

That wasn’t all. Under the microscope the neurons—the brain’s key cells—showed signs of mobilizing against viruses. And most importantly, the electron microscope—the high-resolution tool needed to see these tiny enemies—photographed viruses closely resembling Zika, lurking and reproducing in neurons, and inside their protein-making machinery at that. These subcellular factories were badly disrupted, which is why the brain could no longer grow.

This is the point at which, if I had been on the team, I would have blown the smoke off the barrel of my gun with a certain amount of arrogance.

I get that the CDC can’t make premature pronouncements that trigger big costs and risks. But it’s also true that both they and the World Health Organization took way too long to respond to Ebola . Mathematical models showed that if the world had mobilized even a month earlier, thousands of lives would have been saved.

So I guess I wonder whether the relevant authorities had to wait another month after that case study to make an announcement. If Dr. Levi-Montalcini could have seen it, she would no doubt have found the story sad and the virus frightening. But she so would have loved the science.


  1. Jill Kosanke says:

    Your description of the way this virus operates leads me to wonder about the longitudinal effects. I confess not to know much about virology, but once one is infected with this virus (and, being a virus it lives on in its host), are subsequent pregnancies/fetuses at risk for microcephaly? Does anencephaly also occur? What are the realistic risks of a greater spread of the disease from crowds of international tourists coming to the Brazil Olympic games and then returning home, especially now that we know that the virus can be spread via sexual contact?

    • Mel says:

      Dear Jill, thank you for these questions. I’m not an expert either, but I have checked the latest sources in order to answer you. Official wisdom says that a woman should wait eight weeks after a Zika fever to get pregnant, but it also says that a man should wait six months before attempting conception, because the virus lives that long in semen. It is also found in breast milk. It seems to be cleared from blood and urine within a few weeks, but I don’t think we know how long it can live in other bodily fluids and tissues. I don’t like to be alarmist but I don’t like premature or false reassurances either. As far as I can tell anencephaly has not been found to be caused by Zika, although it was investigated in a cluster of cases in Seattle. Anencephaly is usually a type of neural tube defect (like spina bifida), and many or most cases can be prevented with folic acid supplements. Microcephaly denotes a range of brain sizes, it has a number of causes, and it involves stunting brain growth, not the absence of a brain. Anencephaly (blessedly in my opinion) is usually fatal within hours or days, while microcephalic infants can live and grow a long time, just not normally. I don’t think subsequent pregnancies can be affected, but again, these are early days for the science of Zika. As far as the Olympic games go, there may be safety in the crowds as there are only so many mosquitoes in those venues. CDC points out that daily travel to Brazil far swamps the numbers that will be added by the games. To all this I would only add: Mosquitoes and viruses are evolving, the latter every day. The science of any virus, or any pathogen for that matter, is therefore a moving target. I would strongly advise my three daughters, my son, and their partners to stay away from Brazil for the immediate future. Mel

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