Investigators at the Uganda Virus Research Institute first isolated the Zika virus from this forest.

Investigators at the Uganda Virus Research Institute first isolated the Zika virus from this forest.

Andrew Haddow

Zika’s long, strange trip into the limelight

On 18 April 1947, a rhesus monkey that researchers identified as 766 ran a fever of 39.7°C, about 2°C higher than normal. The monkey was part of a study hunting for yellow fever virus and was living in a cage on a platform built into the tree canopy in the 1.5-kilometer-long Zika Forest, which runs adjacent to an arm of Lake Victoria in Uganda. Three days later, the investigators took a blood sample from Rhesus 766 and injected it into the brains of Swiss albino mice. The mice “showed signs of sickness” after 10 days, and the researchers harvested their brains, from which they isolated a “filterable transmissible agent.”

Come January of the following year, the same researchers trapped mosquitoes from these canopy platforms and took their bounty back to the lab, hoping to isolate yellow fever virus. Others had shown that one of these species they caught, Aedes africanus, shuttled the yellow fever virus, so the investigators put 86 of the insects in a refrigerator to “render them inactive” and then ground them up in a blood-saline solution, which they again injected into the brains of mice. The animals “appeared inactive” after 7 days, and tests showed they harbored the same transmissible agent that had sickened Rhesus 766.

The researchers called their “hitherto unrecorded virus” Zika.

For nearly 7 decades, the Zika virus would remain a virological curiosity, receiving little more attention than other obscure members of the Flaviviridae family that are transmitted by mosquitoes, such as Spondweni, Wesselsbron, and Ntaya. But now that it appears as though Zika might be causing serious harm to babies in Brazil, the World Health Organization has deemed it a “public health emergency of international concern.” It’s fast earning the reputation of the scariest virus on the planet. And the recent explosive spread of Zika around Latin America and the Caribbean serves notice, yet again, that remote places are no longer as remote as they used to be—so expect ever more exotic pathogens lurking in nature to become commonplace.

The Uganda Virus Research Institute in Entebbe, located 11 kilometers northeast of the Zika Forest, just after the end of World War II carried out the meticulous work that isolated the pathogen du jour. The researchers included a Scottish virologist, George Dick of the National Institute for Medical Research in London, and two former members of the Rockefeller Foundation in New York City, Stuart Kitchen and Alexander Haddow. They waited until September 1952 to publish their findings, which appeared in back-to-back papers in the Transactions of the Royal Society of Tropical Medicine and Hygiene. In addition to experiments with more rhesus monkeys and mice, their exhaustive studies put the Zika virus into grivet and red tail monkeys, cotton rats, guinea pigs, and rabbits. The virus caused damage to neurons only in mice. Six of 99 humans they tested in four different Ugandan locales had antibodies to their new bug, but none showed evidence of disease.

As one of the two papers drily concluded: “The absence of the recognition of a disease in humans caused by Zika virus does not necessarily mean that the disease is either rare or unimportant.”

Zika virus co-discover Alexander Haddow at the Uganda Virus Institute circa 1960 when he was lab director.

Andrew Haddow

The same journal would publish 10 of the 24 total Zika studies that appeared in the scientific literature over the next 30 years, including a 1954 paper that attempted to link the virus to an epidemic of jaundice in Nigeria. The data in this study by esteemed virologist Francis Macnamara were sketchy and the correlations weak, save for the detail that 50 of 84 people tested had antibodies against the strange agent—the first clue that it was widespread. Mice also became ill when injected with Zika-antibody-positive serum taken from one 10-year-old girl who had a temperature of 38.2°C and a headache. But she did not have jaundice.

Confused by the results, medical researcher William Bearcroft decided to take matters into his own hands—literally. As he reported in September 1956, a 34-year-old European male who had been living in Nigeria for 4.5 months—that would be Bearcroft himself—injected into his arm a suspension of Zika-infected mouse brain used in the 1954 study. Eighty-two hours later, Bearcroft had a headache and a slight temperature.

Curious about the route of viral transmission, on the 5th day after the injection—by which time his symptoms had disappeared—Bearcroft put a batch of female A. aegypti mosquitoes on his left forearm, and 95 of them became engorged with his blood. He did this two more times over the next few days and then put some of the mosquitoes on baby mice and ground up others, injecting them into the rodents. Nothing happened.

Bearcroft suggested that his symptoms resembled those seen in the 10-year-old girl. “Whilst no conclusions can be drawn from an experience limited to two cases, it should be noted that in those which represent the only proved examples of the human disease no evidence of jaundice appeared,” he wrote.

William Bearcroft injected himself with Zika virus, offering the first solid evidence that it caused disease in humans.

Courtesy of Thomas Monath

Nothing more appeared in the literature about Zika virus infections of humans until 1964 when David Simpson, a student of Zika co-discoverer George Dick, reported that those first two cases likely were not Zika but its close relative, Spondweni. What’s more, Simpson, who was working in the same Entebbe lab that discovered the virus, claimed that he had evidence of the first actual human case: a 28-year-old European male—yes, David Simpson—who had been in Uganda for 2.5 months when he became ill while working with Zika strains isolated from mosquitoes.

Simpson’s symptoms were distinct from the others in one key way: he had a “diffuse pink maculopapular rash which covered the face, neck, trunk and upper arms” and that eventually spread to all four limbs, the palms of the hands, and the soles of the feet. It did not itch, he reported, but the rash lasted for 5 days. He described the disease as “mild,” and noted that there was no “crippling bone pain” as occurred with three other mosquito-borne viruses: dengue, chikungunya, and o'nyong-nyong.

When Simpson inoculated mice with his blood, they became sick and some died. He passaged blood from these mice into the brains of other mice, harvested that “material” and tested antibodies against Zika and 11 related viruses—including Spondweni—to see which stuck. He had Zika, no question. “If this was a typical infection with Zika virus it is not surprising that under normal circumstances the virus is not isolated frequently from man,” he wrote.

Nearly a decade would pass before another report of a human Zika infection appeared and, once again, it was a lab worker, this time in Mozambique with Portugal’s Institute of Hygiene and Tropical Medicine. In the 1973 paper, published in the German journal Archiv für die gesamte Virusforschung (Archive for the Entire Virus Research), C.M.V. Martins described his symptoms as fever with some pain in joints, but no rash. He recovered completely after 1 week.

According to Martins and co-authors, scientists had by then isolated 312 “arboviruses”—meaning spread by arthropods like mosquitoes and ticks—82 of which caused human infections, yet all but 39 were rarely observed diseases. “Thus, the knowledge of the pathogenic potential of about half of the arboviruses capable of causing symptomatic disease in humans has been acquired mainly from the study of laboratory infection,” they concluded. In other words, you needed lab accidents to understand disease.

Loads of countries began reporting evidence of Zika antibodies in humans and wild monkeys in the 1970s and 80s, but documented cases of people with disease remained scarce, with scattered reports of human Zika virus infections trickling in from Nigeria and Indonesia. Then nothing until 2007, when physicians on Yap Island in the Federated Republic of Micronesia noticed an outbreak of a disease that resembled mild cases of dengue but was distinct, in part because people had a rash. A report of this outbreak in 2009 for the first time earned Zika a slot in a high-profile publication, The New England Journal of Medicine. As the authors noted, “No outbreaks and only 14 cases of human Zika virus disease have been previously documented.”

The paper documented 49 confirmed and 59 probable Zika cases.

But household surveys of 557 people found Zika antibodies in 74% of the islanders. The researchers estimated that some 5000 people had been infected, and that 900 of them had illness “attributable to Zika.” No one was hospitalized, and no one died. No mosquitoes, surprisingly, were found with the virus.

Odd case reports soon followed. Two U.S. scientists diagnosed in Colorado were apparently infected in Senegal, and one of them infected his wife, presumably through sex, when he returned home; they only thought to test for Zika because of a chance meeting with a grandson of Alexander Haddow, one of the researchers who discovered the virus. A U.S. Navy research station in Cambodia detected a case in a 3-year-old boy. A 52-year-old woman in Australia was diagnosed after returning home from a holiday in Indonesia. Then in 2013, an outbreak walloped French Polynesia, with 333 confirmed cases and an estimated 19,000 suspected others. For the first time, the disease was associated with serious symptoms: mainly neurological disorders, including Guillain-Barré syndrome, which sometimes causes a temporary paralysis, and, in rare instances, is deadly. Two babies also were infected in utero or during delivery, but neither had lasting health problems.

Andrew Haddow climbs one of the towers in the Zika Forest that his grandfather Alexander used to help discover the virus.

Andrew Haddow

Cases of traveler-associated Zika began to mount: A Norwegian who vacationed in Tahiti, a Canadian who went to Thailand, Japanese tourists who visited Bora Bora, an Australian who explored the Cook Islands, a German who returned from Malaysian Borneo.

The first published report of “autochthonous” cases in Brazil—meaning they were not imported—appeared in June 2015. Eight patients, who all were infected a few months before and were deemed to have a “dengue-like illness,” had confirmed cases. “Although most of the patients had mild illness, clinicians and public health officials should be aware of the risk of expansion of this new emerging virus, especially given the naïve immunological status of the Brazilian population,” the authors cautioned, noting the neurological complications seen in French Polynesia.

A few months later, Brazilian clinicians started reporting an unusually high number of babies born with small heads, a telltale sign of microcephaly.

The rest is history.

See more of Science's coverage of the Zika virus here.

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