Monkeypox’s Biggest Mystery: It Suddenly Appeared In Labs From 1958 Onwards Without Explanation

Shin

And the source still remains unknown.

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It’s no secret that monkeypox was first discovered in laboratory monkeys in Denmark in 1958. But the big question is, how did the laboratory monkeys get monkeypox in the first place? 

Monkeypox has triggered a global outbreak of over 60,000 cases in more than 100 countries as of September 2022. As with Covid-19, understanding the disease’s origin is key to preventing the next one. But, as with Covid-19, we still don’t know the true origin of monkeypox.  

So, let’s see what we know and don’t know about monkeypox’s origin. 

How monkeypox was discovered in 1958

In a 1959 paper, Magnus et al. at Statens Serum Institut, a research institute in Denmark, admitted that “During the summer and fall of 1958 two outbreaks of a non-fatal pox-like disease in cynomolgus monkeys have been observed in the monkey colony in this institute.” 

Back then, this institute received monkeys from Singapore used for research purposes. The institute had an animal house accommodating 25–50 monkeys in their main building and another larger house housing 100–150 monkeys in another building about 200 yards away. 

The first monkeypox outbreak occurred in the main building in June 1958, involving six out of 32 monkeys. No sign of monkeypox was noted in the monkeys in the other building. But four months later in November, a second outbreak occurred in the other building, affecting 23 out of 120 monkeys, and no monkeys in the main building were affected.

“Both outbreaks occurred rather late after the monkeys had been received, i.e. 51 and 62 days after arrival and only a small percentage of the exposed animals showed signs of illness,” the scientists wrote. 

All the monkeypox cases in the monkeys are mild and recoverable after a few weeks or months. Autopsies were conducted on some of the deceased monkeys (the cause of death was unstated but perhaps sacrificed for other purposes), revealing no organ damage. 

Virus isolation was then attempted on three cases — one from the first and two from the second outbreak — which were all successful. Viruses from both outbreaks were similar and culturable in lab-grown tissues or cells, which showed cell/tissue damage upon infection. 

The scientists even infected other monkeys, rabbits, and mice with the isolated viruses, who then developed monkeypox within a week. But guinea pigs and chickens did not develop any disease after deliberate infection. 

Subsequent antigenic tests confirmed that the isolated virus is a type of poxvirus, like cowpox or smallpox. Electron microscopy further revealed rectangular viruses, which are characteristic of poxviruses (see figure below). But the isolated virus’s antigenic and disease patterns do not fit into the known poxviruses at that time, which means it was a new poxvirus.

And so, monkeypox was discovered and coined.

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The figure shows electron micrographs of the monkeypox virus (at 30,000x magnification).Magnus et al. (1959).

But we don’t know where it came from

The authors justified that “it seems unlikely that the virus was introduced into the monkey colony after the animals had arrived in this country.” 

The reasons are that no cases of human smallpox were detected for over 25 years and cases of animal pox diseases were rare in Denmark, plus the monkeys were quarantined and unlikely in contact with other animals. 

But the authors also admitted that “the long period of time which elapsed between the arrival of the monkeys in the laboratory and the outbreaks of the disease, i.e. 51 and 62 days, respectively, is rather puzzling and can hardly be attributed to an incubation period of this length.”

In their study, monkeypox only had an incubation period (time from infection to disease onset) of 7 days. And the monkeys arrived at the Danish research institute in good health. 

Despite this fact, they conclude that “the most likely explanation of the long latent period is that the virus was present on arrival in some of the animals as a silent infection. This is, however, the only evidence to suggest that long-term latency can occur.”

Their confidence in such a conclusion is that they, intriguingly, managed to culture monkeypox viruses from the kidneys of healthy monkeys sacrificed for other purposes during and shortly before the outbreak. This means that monkeys could harbor asymptomatic monkeypox infection.

As the two buildings were at least 200 yards apart, it’s inconceivable that monkeypox spread from the main to the other building. So, it’s more likely that the original shipment of monkeys from Singapore was already contaminated with silent or asymptomatic monkeypox infection. No further investigations were conducted on monkey supplies from Singapore.

Monkeypox suddenly appeared in other labs

Later, more monkeypox outbreaks occurred in research institutes in other countries, as summarized by Arita and Henderson (1968) in table 1: 

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List of monkeypox outbreaks occurring in research institutions.Arita and Henderson (1968).

Specifically, at least eight more episodes of monkeypox outbreaks occurred in labs in the Netherlands and U.S. after 1958: 

  • Episode 1: Denmark, 1958; virologically confirmed. 
  • Episode 2: Utrecht, Netherlands, 1964–1965; virologically confirmed.
  • Episode 3: Rotterdam, Netherlands, 1964; virologically confirmed.
  • Episode 4: New York, the U.S., year unclear. 
  • Episode 5: New Jersey, the U.S., 1959; virologically confirmed.
  • Episode 6: Indiana, the U.S., 1965.
  • Episode 7: Washington, the U.S., 1962; virologically confirmed.
  • Episode 8: Pennsylvania, the U.S., year unclear. 
  • Episode 9: California, the U.S., year unclear. 

Note: Virologicaly confirmed means that virus isolation and culture were performed (with electron microscopy optional), verifying the infectious disease in question as monkeypox. 

In all of the episodes, no cases of monkeypox jumped to humans were reported, and the source of the monkeypox is unknown, with some hints pointing to supplies from Singapore, India, the Philippines, and Malaysia. These were non-developed countries back then, so they probably lacked the necessary technology to diagnose and catch monkeypox, leading to unnoticed monkeypox being exported elsewhere. 

In fact, no outbreaks of any pox diseases in monkeys have been reported in nature since 1936, Arita and Henderson noted. The sudden appearance of monkeypox in labs of several countries is indeed very peculiar. 

One speculation from my end is that research institutions house monkeys in unnatural environments, which probably created stress responses that weakened their immunity. As a result, the monkeys developed diseases, which can easily trigger an outbreak under crowding conditions. 

Then monkeypox suddenly jumped to humans

In 1970, the first human monkeypox case was reported in a 9-month-old boy in Basankusu Territory, Democratic Republic of Congo (DRC). 

Initially, the boy was thought to have smallpox but instead, the monkeypox virus was isolated from the boy. No other people in the territory had pox-like diseases, indicating that it wasn’t human transmission.

The territory had a huge monkey and ape population. So, investigators examined and collected samples from some of those animals but found no evidence of monkeypox infection or disease. 

In the end, how the boy got monkeypox wasn’t resolved. 

From 1970–1975, 19 more monkeypox cases were detected in West and Central African countries, totaling 20 cases from 15 villages. Such a diverse yet sparse spread likely came from several spillover events. But again, investigations into the source of monkeypox in all the cases were futile. 

“Epidemiological investigations of monkeypox cases in man have failed to trace the source,” Arita and Henderson write in their 1976 paper. “Although the animal reservoir of monkeypox virus is still unknown, it is assumed that such a reservoir does exist in West and Central Africa.” 

That said, some hints on monkeypox’s origin were reported later on. 

In 1977, among 204 serum samples collected from monkeys, three samples (from Côte d’Ivoire, a West African country) tested positive for monkeypox-specific antibodies. Similarly, in 1979, among 1,372 serum samples from 98 species of animals (e.g., monkeys, squirrels, pangolins, and rodents) in DRC, seven samples from monkeys had monkeypox-specific antibodies.

However, live monkeypox virus has only ever been isolated from wild animals two times thus far— from a squirrel that had skin eruptions in DRC in 1986 (out of 383 sampled animals) and a monkey that was found dead with skin lesions in Côte d’Ivoire in as late as 2012.

But neither set of evidence proves the source or origin of monkeypox. Monkeypox-specific antibodies only mean that the monkeys had been exposed to monkeypox. And live monkeypox viruses only mean that the virus infected and replicated in the squirrel and monkey.

In later years, studies pinpointed that small forest animals (not monkeys) are carriers of monkeypox, which have likely jumped to humans several times. For example, the 2003 monkeypox outbreak in the U.S. was caused by purchasing a prairie dog from Ghana, West Africa, which bit and infected a 3-year-old girl and later spread to 70 more people. The prairie dog got monkeypox from African rats when housed together. 

And so, since 1970, monkeypox kept circulating in humans (Figure 3), most likely from repeated spillover events from wild animals, given the sparse yet diverse spread pattern, at the initial stages. Later, human-to-human transmission became more obvious, which we neglected until May this year when a global outbreak happened, much to our dismay.

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Science (2022).

But we still don’t know how the wild animals caught monkeypox in the first place — it could be from a laboratory monkey, captured monkey, another wild or laboratory animal, or even a human. And that’s not a good thing as it also means we don’t know how to prevent the next pox disease from emerging.

“Understanding the exact animal origin of any viral outbreak is not easy,” However, it is very urgent and necessary to pinpoint the animal origin with the intermediate hosts of these two viruses (SARS-CoV-2 and monkeypox virus),” Chiranjib Chakraborty, Ph.D., professor of biotechnology, and colleagues stated in a 2022 paper. “With the shortage of data on the precise animal origin of any viral outbreak, future preventive measures to control the disease epidemics and pandemics cannot be done very effectively.”

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