Spillover: Animal Infections and the Next Human Pandemic

To examine his next disease, malaria, Quammen turns from the relatively recent present to the past—specifically, to a British doctor named Ronald Ross who would later pioneer the study of malaria and develop an interest in infectious disease more generally. Ross grew up in India and returned to his native England to become a doctor. Though he had artistic and mathematical ambitions, he went on to successfully practice medicine. He was posted to Madras, India, where he first began to ponder the causes of malaria and took several blood samples from malaria patients.

Ross’s progress with understanding malaria was somewhat hampered by his remote location. Eventually he learned about a French doctor who “had discovered tiny parasitic creatures (now known as protists) in the blood of malaria patients. Those parasites […] caused the disease” (128). Ross’s later experiments convinced him this conclusion was correct. Ross’s own research is notable, Quammen argues, because he studied malaria in birds to understand its operation and “life cycle.” His other major intervention was to apply his mathematics background to analyzing malaria.

Though viruses might seem far more biological than mathematical, mathematical principles illustrate how diseases successfully persist in populations. One particularly important concept is known as “critical community size” (129): When the population of possible hosts is too low, the disease can’t persist and will “die out.” Measles, in this example, eventually dies out when most of the population is now immune, as more than one infection is impossible. Thus, a disease recurrence requires another population increase and more “vulnerable newborns.” In 1760, the Swiss mathematician Daniel Bernoulli used calculations to demonstrate that smallpox vaccination would offer babies up to “three years and two months of increased lifespan” (131).

The development of “germ theory” to explain disease produced further mathematical models of outbreaks and their duration. Another English doctor, W.H. Hamer, sought to explain why measles outbreaks occurred in cycles. In 1906, he concluded that outbreaks were not a matter of population size alone, but “depended on the likelihood of encounters between people who were infectious and people who could be infected. This idea became known as the ‘mass action principle’” (132).

A Scottish physician named Brownlee presented an alternative hypothesis. He focused instead on the capacity of a pathogen to cause disease. Each epidemic had arisen, he argued, with “‘a high grade of infectivity,’ a sudden increase of the pathogen’s catchiness or potency, which thereafter decreased again at a high rate. The epidemic’s decline, which was generally not quite as abrupt as its start, resulted from this “loss of infectivity” by the disease-causing organism” (133). He was unclear about what exactly this meant—whether infectivity related to the number of people sickened, or “virulence,” or “a combination of both” (133).

Returning to Ronald Ross and malaria, Quammen notes that Ross rejected the concept of “infectivity” and argued that epidemics depend on the “density of susceptible individuals” (134). When this number drops too low, an outbreak ends. Ross also argued that malaria would be difficult to eliminate and could likely only be reduced. Quammen argues that this is because of malaria’s link to “human social and economic considerations” (135).

Next, Quammen considers his own history working on zoonotic disease. Initially, he was told that malaria was not zoonotic—its “vector,” the mosquito, seeks transmission deliberately where the host of a zoonotic disease does not (135). Additionally, it was once thought that the various types of animal malaria did not and could not infect humans. The four existing types of malaria protist, the Plasmodium, all live out a complex life cycle inside mosquitos. “Malignant malaria” kills the most people annually, many of them children. It seems likely, as humans are a new species, that malaria did once “leap” to us—at least four times, given the four different types that routinely infect populations. These “leaps” are distinct from zoonosis because zoonosis is “routine and repeated” (136).

Quammen explains this further via examining malaria’s evolutionary history. While it was once thought that malignant malaria (P. Falsiparum), entered humans from birds, more recent data suggests that a spillover produced a mutation: Chimp malaria became what we now know as P. Falsiparum. This malaria’s current status poses another problem for eradication: it originally seemed to be present in bonobos, meaning that mosquitos could always transmit it back and forth between the chimps and humans. Later research proved that it is also present in gorillas and has a longer history in that species. It likely infected humans in only one spillover.

That’s one mosquito biting one infected gorilla, becoming a carrier, and then biting one human. By delivering the parasite into a new host, that second bite was enough to account for a zoonosis that still kills more than a half million people each year (141).

Before returning to the study of malaria, Quammen introduces two more mathematical heroes who influenced our conception of disease outbreaks. Kermack and McKendrick worked in the Laboratory of the Royal College of Physicians and invented a series of equations to explain outbreaks known as the “SIR model,” which stands for “three classes of living individuals: the susceptible, the infected, and the recovered” (143). The mathematics here requires differential calculus, since people move between groups over time. To fully explain an epidemic, a fourth factor is needed. Quammen describes this as a “‘threshold density’ of the population of susceptible individuals. This threshold is the number of concentrated individuals such that, given certain rates of infectivity, recovery, and death, an epidemic can happen” (144).

Quammen’s next key to mathematical concepts of disease comes from Scottish researcher George MacDonald, who first noticed malaria in a 1934-1935 outbreak in Ceylon (now Sri Lanka). Nearly 20 years later, the WHO was hopeful that the new pesticide DDT would lead to malaria’s eradication. MacDonald began to research the earlier outbreak to assist in this goal. He concluded that a population explosion of mosquitoes had been sufficient to cause an outbreak on a much larger scale.

He also created a new concept to explain why diseases remain present in populations. The key was the effect of the first infected individual to enter an entirely susceptible population. If this individual infected enough other people, the disease would spread. The concept to explain this is called the “basic reproduction rate,” and it had to be “higher than 1.0” for a disease to spread. Quammen provides another example from MacDonald’s calculations: “on the upper side, […] a single infected person, left untreated and remaining infectious for eighty days, exposed to ten mosquitoes each day […], could infect 540 other people” (147). Though MacDonald’s research had important implications, the WHO campaign he was involved with largely failed. The mosquito population became DDT-resistant, and it proved impossible to treat every infected malaria patient so that mosquitos could not reacquire the disease.

Quammen next introduces another type of malaria: P. vivax, which likely entered humans from Southeast Asian primates called macaques. Macaque malaria, or P. knowlesi, is significant not only in medical history but also to Quammen’s study of zoonosis. In India in the 1930s, a researcher named Robert Knowles discovered a new plasmodium “from an imported monkey” (149). He and colleagues injected it into other monkeys and some unwilling human subjects and discovered that the disease had a different duration than known malaria and was “devastating to rhesus macaques” (149). 

At the time, malaria was used in the treatment of syphilis, since high fevers could kill the bacterium. A Romanian researcher applying this technique in the 1950s accidentally made the disease more virulent by repeatedly injecting it into multiple patients. He used samples from those he had previously treated, which allowed the virus to evolve. In 1965, the disease had its first known zoonosis, when a surveyor in Malaysia who may have been engaged in espionage was originally diagnosed with P. malarii but turned out to have P. knowlesi. This was generally attributed to the unusual circumstance of someone becoming infected who could quickly have their blood analyzed, until a team of researchers named Janet Cox-Singh and Balbir Singh investigated a cluster of strange infections in Malaysian Borneo.

Quammen returns to the more recent past to introduce Singh and Cox-Singh and the further adventures of P. knowlesi. The husband and wife team set up their lab in Malaysian Borneo at the University of Malaysia Sarawak. They noticed some strange cases of malaria in a community called Kapit—victims became much sicker than expected for P. malariae, which was their initial diagnosis. Balbir Singh traveled there and carried samples back on filter paper. He ran a DNA test called PCR, which “allows a researcher to see below the level of cellular structure to the letter-by-letter genetic code” (155). This test revealed something surprising: All of these individuals had carried P. knowlesi. Additionally, they had not infected each other by sharing living space. Instead, “each patient seemed to have caught it from a mosquito that had bitten a macaque” (156).

Quammen describes his visit to Balbir Singh’s laboratory in Malaysian Borneo in 2009. Singh demonstrated the close contact between macaques and the people of Kapit, especially at night, when the primates attempt to invade rice paddies and are met by human guards. Naturally, sitting in rice paddies at night leads to mosquito exposure and hence possible disease exposure. 

The team continued collecting blood samples in the field and then applying PCR to determine the virus. They found 120 cases of P. knowlesi, establishing via a paper in the medical journal The Lancet that “P. knowlesi malaria is a zoonotic disease” (159). Further study revealed many more cases, including four human deaths in cases that had been misdiagnosed as P. malariae. This finding caused some controversy, since it demonstrated “something more than that P. knowlesi is a zoonotic disease; they suggested that people were dying because doctors and microscopists were unaware of that fact” (160).

After this controversial paper, Cox-Singh and Singh published another more substantive piece about P. knowlesi’s public health implications. They highlighted that human entry into Borneo’s forests for logging and farming had created new opportunities for mosquitos to bite humans and disrupted their access to macaques, their typical source of blood. They were particularly concerned that this could lead to a “host switch from macaques to humans” (161).

Quammen reflects on P. knowlesi’s unusual nature. It a “generalist,” as it infects multiple kinds of monkeys as well as humans. He notes, “Generalists tend to do well in changing ecological circumstances” (162). P. knowlesi, then, is well equipped to adapt to a world of more humans and fewer monkeys—perhaps to humanity’s detriment, given that the region its hosts inhabit is home to 818 million people. This remains uncertain, though, as Quammen suggests: “It depends on whether the parasite becomes so well established within human populations that monkey hosts are no longer necessary. […] In other words, it depends on chance and ecology and evolution” (163).

It is not yet clear whether P. knowlesi is truly spreading among human populations, though more cases have been discovered now that doctors know what to look for. What the story of P. knowlesi demonstrates, however, is that geographic reach and success in humans matters just as much as host identification.