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Authors: Donald G. McNeil

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BOOK: Zika
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Once in a while, one of the viruses leaps out of obscurity and into the headlines: Ebola. SARS. West Nile. Spanish flu. Swine flu. Bird flu.

But Zika virus is like no other. As Dr. Anne Schuchat, the principal deputy director of the Centers for Disease Control and Prevention (CDC), the world's premier disease-fighting agency, has said, “The more we learn about Zika, the scarier it gets.”

It is the only mosquito-borne virus that routinely crosses the placenta to kill or cripple babies. Scientists do not know why or how it crosses the placenta when other mosquito-borne viruses like dengue, yellow fever, West Nile, and Japanese encephalitis almost never do.

It seems to be able to do so at any time in a pregnancy.

It is the only mosquito-borne virus that is also sexually transmitted.

And the mosquito that transmits it,
Aedes aegypti
, known as the yellow fever mosquito, is in 30 U.S. states, not 12, as was originally thought. A related mosquito that might transmit it,
Aedes albopictus
, known as the Asian tiger mosquito, is found in almost every state—its range in the hottest summers touches parts of Maine and Minnesota.

“Ziika”—the spelling was shortened—means “overgrown” in Luganda, one of the main languages of Uganda. The Zika Forest is no longer remote. It's on the highway between Kampala, the capital, and Entebbe, the country's main airport.

Quite a bit has been chopped down, so it is now less than one-tenth the size of Manhattan's Central Park. But in 1936, the Rockefeller Foundation established its Yellow Fever Research Institute in Entebbe, seven miles south of the forest. The forest was convenient and buggy; it bordered on a papyrus swamp.

Caged “sentinel monkeys” were suspended in six tall towers. The towers reached to treetop level, where the mosquito population was different from that of the forest floor. The monkeys were lowered daily to be checked, and their rectal temperatures taken and graphed.

Under 1940s-era medical ethics, it was perfectly acceptable to chain monkeys in trees to get sick or die. (Nowadays, all work with primates must be approved by ethics boards.)

It was not ethical in 1947 for scientists to use Africans as bait. That was progress. White farmers in some parts of colonial Africa protected their cattle from tsetse fly diseases by paying “fly boys.” Tsetse flies hatch near rivers and are attracted to dark colors—including black skin. Young men—the fly boys—would stand shirtless in riverside brush, slapping dead every fly that landed on them. At day's end, they were paid a bounty per fly. The risk they took was that tsetses carry the parasite for sleeping sickness, a human disease that leads to a horrible death. It resembles rabies; victims may be driven mad, attack their own families with machetes, develop an unquenchable thirst but feel that the touch of water is burning them. Only in the end do they lapse into the coma that gives the disease its name, and die.

On April 19, 1947, in the Zika Forest, a monkey known simply as Rhesus 766 developed a fever of 104 degrees and was taken down from its platform and brought to the lab for a blood draw. It was an Asian monkey, not an African one. That presumably is the reason it got sick and the virus was discovered. Zika no doubt circulated in African monkeys for thousands of years, and they would have evolved resistance to it.

In those days, of course, it was not easy for scientists to figure out what a monkey had. There were no DNA-sequencing machines. The double-helix structure of DNA had not even been described yet. There were also no electron microscopes to let scientists see something as small as a virus. (Viruses are far tinier than bacteria, which are easy to view under a regular microscope.)

The scientists reported that they had found
a “filterable, transmissible agent” in the monkey's blood. That meant they had spun down the blood to separate and remove the red cells, white cells, and platelets, and then had pushed the remaining clear serum through a ceramic filter with pores tiny enough to remove any parasites, like the ones that cause malaria, and all the bacteria. Then the serum would be injected into a healthy monkey. If that monkey fell ill with similar symptoms, then the first monkey's blood had contained a “filterable, transmissible agent”—likely a virus.

But then two far more complicated questions had to be answered: Was whatever made Rhesus 766 sick something new, or just one of dozens of other mosquito-borne viruses that caused similar symptoms? And how did one know that Rhesus 766 fell ill from something in a mosquito bite, and not from something it ate or touched, or from a biting fly or some other source?

Answering those questions took five years. The three scientists who did the work—Alexander J. Haddow and Stuart F. Kitchen of the Rockefeller Foundation and George W. A. Dick of the National Institute for Medical Research in London—did not publish their findings until 1952.

The search also consumed thousands of albino mice—“Swiss mice from Carworth Farms, New York,” according to the original paper, published in the journal
Transactions of the Royal Society of Tropical Medicine and Hygiene
. The mice were all experimented upon when they were between 35 and 42 days old. Just breeding and feeding them, and keeping track of their ages, was a time-consuming job.

The first roadblock was that Zika virus didn't naturally make mice sick. When serum from a sick monkey was injected into their abdomens, nothing happened.

But if a tiny amount was injected directly into their brains, some became somewhat sick. The virus was “neurotropic,” meaning it homed in on nerve cells, including brain cells.

So the scientists had to start “passaging” the virus through a series of mice. They took the brain of the first mouse to fall sick, made a slurry of it, diluted it with saline, centrifuged and filtered it, and injected some of that into another mouse brain, and then waited however long it took for that mouse to get sick. By repeating that process 17 times, they forced the virus to “adapt” to growing in mice. At the end, they had something they could reliably inject into mice with the knowledge that they would fall ill and probably die. It was no longer the pure “wild-type” Zika virus that in the forest was moved from monkey to monkey by mosquitoes. But it was close—and it worked in an animal model.

To make sure Rhesus 766 had caught a mosquito virus, they had to do a separate, parallel series of experiments. Other traps in the same platforms caught hundreds of mosquitoes. They had to be hand-separated by species for testing. Then batches of
Aedes africanus
mosquitoes were chilled to kill them, ground up, diluted, centrifuged, and filtered to produce a “supernate,” an extract that the scientists hoped would contain enough virus from the guts and tiny salivary glands of some of the mosquitoes in the batch to make a monkey and/or a mouse sick.

One batch of 86 mosquitoes trapped on January 12, 1948—afterwards known as lot E/1/48—did the trick. It made mice somewhat ill.

After that, a long series of experiments ran in parallel to show that the filterable agent taken from the blood of Rhesus 766 and the filterable agent from lot E/1/48 were the same, and that they weren't any previously known virus.

That was done by testing the mystery virus against “convalescent serum,” that is, against whatever magic component was in the blood of monkeys that the scientists had deliberately made sick by injecting them with the virus—and then had recovered.

Rhesus 766 hadn't died of Zika. It had gotten better, so the scientists knew that blood taken from it one month later had to contain whatever mysterious agent had “neutralized” the virus.

We now know that agent to be antibodies—tiny Y-shaped proteins that glom onto viruses, attaching all over their shells.

Viruses' outer shells—actually called envelopes—have spikes that fit, like keys into locks, onto receptors on the outsides of cells. Cold and flu viruses, for example, have spikes that perfectly fit the surface receptors on the cells lining human noses.

Viruses come in many shapes. The long, wiry Ebola virus is a filovirus, from
filum
, Latin for “thread.” SARS, which is covered with spikes, is a coronavirus, from the Latin for “crown” or “halo.” Zika is a flavivirus, and that family is instead named for its most famous member, yellow fever, which turns its victims yellow from jaundice.
Flavus
is Latin for “yellow.”

There are more than 70 flaviviruses, including dengue, West Nile, and Japanese encephalitis; most are spread by mosquitoes or ticks. Under an electron microscope, they all look like little balls or spheres, but up close they turn out to be 20-sided polygons called icosahedrons. They resemble sinister Christmas ornaments. Inside each hollow ornament is the payload—a strand of RNA about 10,000 nucleotides long that it injects into the cell it invades. 

The RNA turns itself into DNA and hijacks the internal machinery every cell uses to copy its own DNA and make new cells. Like commandos invading a town and converting its car factory into a bomb factory, the virus makes thousands of copies of itself. Eventually, the cell explodes, and the viruses are released to attack other cells, spreading the illness.

One part of the body's immune response is a set of white blood cells that engulf and “inspect” each new virus that enters the body. The cells measure the shape of its spikes and generate millions of new antibodies perfectly fitting that shape. When there are enough antibodies in the blood, and each virus's spikes are covered with matching antibodies, the viruses can't attach to new cell victims. The infection dies out. The host recovers. The antibodies stay in the blood for weeks, still passively on patrol.

Now the scientists had something from Rhesus 766 they could kill a mouse with, as well as something else that matched it, neutralized it, and would save the mouse.

They began asking fellow scientists to send them samples of other viruses and the antibodies that neutralized them.

Several Rockefeller Foundation laboratories obliged. So did Albert Sabin, a virus researcher in Cincinnati, later famous for his polio vaccine. Others samples came from the Wellcome Veterinary Research Station in Frant, England, and from the Virus Reference Laboratory in London.

They started testing them in mice.

If, for example, they infected a mouse with yellow fever, and the mystery antibody didn't save it from death, then the antibody wasn't to yellow fever. To cross-check that, they would infect another mouse with the mystery virus, and if the yellow fever antibody didn't save it, the mystery virus wasn't yellow fever.

It had to be done in many mice at several different strengths, because they weren't sure how much antibody was needed to neutralize how much virus.

And because mice sometimes just spontaneously died, it had to be done in batches of six mice, and the number of dead mice counted, to remove the element of chance. In theory, if they infected six mice with yellow fever, and gave them yellow fever antibody, all six would remain alive. If they obtained a mismatched antibody, all six would die. But another confirmation was seeing a relationship of dose and response. If a very diluted solution killed only one of six, but a strong solution killed all six, they must be on the right path.

When it was all over, they were able to say that their mystery virus wasn't yellow fever, dengue, West Nile, Eastern or Western or Japanese or St. Louis encephalitis, louping ill, Canfield B, Ilheus, lymphocytic choriomeningitis, Bunyamwera, Semliki Forest, Ntaya, or Bwamba fever.

It was “hitherto unrecorded,” they said, and therefore a new discovery. They named it Zika.

But for the next 60 years, until 2007, it was barely heard of. In all that time, only 14 active human infections were described.

The first was described in 1952, by British health authorities investigating an outbreak of jaundice in the Afikpo Division of eastern Nigeria, which was then a British colony.

It was in
“an African female aged 10 years.” She was brought to a clinic because she had fever and headache. She was not jaundiced, but she had a fever of 100.8 degrees.

The two other patients in the study were men, aged 24 and 30. Both had antibodies to Zika but not the virus; only the girl had something in her blood that made mice sick.

By an abbreviated version of the mouse tests done in the first paper, it was shown that she did not have yellow fever, West Nile, Bunyamwera, Bwamba, Ntaya, Mengo, and so on—and that she did have Zika.

The author of the paper describing the first human Zika infection was Francis N. Macnamara, acting director of the Virus Research Institute of Yaba, Nigeria. A lot of top-notch research in tropical medicine during the colonial period was done by British, French, and Belgian scientists, much of it to keep African workforces alive and the troops of the colonizing power healthy. Dr. Macnamara's institute was the foundation for the Nigerian Institute of Medical Research, which is in the Yaba district of Lagos, the country's financial capital. Macnamara noted that the young girl's blood “contained numerous malaria parasites” but reassured readers that “in tropical Africa, infection with more than one pathogen is the rule rather than the exception” and that his tests were not confounded by the presence of malaria.

The 10-year-old female was reported to be “completely recovered six weeks later.” So neither the Zika nor the malaria was fatal. That is not surprising; even today, kids in malarial regions of rural Africa who live past their fifth birthday have usually had malaria so many times that they are largely immune. It normally gives them just a debilitating fever.

Dr. Macnamara's paper was partially off base. He was investigating a big outbreak of jaundice, so its chief concern was whether or not Zika causes jaundice. (It generally doesn't—the poor girl was caught up by accident in an investigation of what was probably a completely different disease.)

But the paper contained a couple of very interesting asides.

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