Human beings have faced new diseases, and more deadly forms of old diseases, all through history. Today fears of an epidemic are on the rise, fueled by reports of exotic infections and antibiotic-resistant “super bugs.” Despite sophisticated modern techniques for tracking killer pathogens, figuring out where the next deadly disease will come from—and how to stop it—is not a simple task.
In June 2006, 46 fifth-graders and a dozen younger students in Franklin, Massachusetts, came down with diarrhea, stomach cramps, and fever. Doctors soon confirmed the kids had been infected with Salmonella, a bacterial pathogen usually transmitted through food. Food wasn’t the culprit this time, though. This outbreak stemmed from a class project in which the kids had handled owl pellets, the wads of hair, bone, and other indigestible stuff owls regurgitate after a meal. And when public health officials compared the DNA fingerprint of Salmonella isolated from the students and pellets with a nationwide database, they found a match.
“It was a strain which is really localized in Washington State,” says Margaret Davis, a veterinary epidemiologist at Washington State University. She studies the type of Salmonella known as Typhimurium and had seen the fingerprint from the Massachusetts case before. “As it turned out, they got the owl pellets from Washington.”
Salmonella is a hardy bug that gets around on food, owl pellets, and unwashed hands, among other things. It has been making people sick for centuries and still erupts distressingly often, despite our sophisticated techniques for tracking it. In 1985, Salmonella-tainted milk sickened up to 200,000 people in the Midwest and killed at least two; in 1994, ice cream carrying the bug sickened more than 3,000 people in 41 states.
Like other zoonotic diseases, which pass from animals to humans, Salmonella poses special challenges with respect to detection and control. With zoonotics we don’t just have to monitor human cases. Since the pathogens are harbored in animal “reservoirs,” we need to be aware of what’s going on in animals as well. It’s a huge issue; infectious disease is the number-one cause of death for humans worldwide, and many of the most frightening new diseases we face are zoonotics. HIV came from apes; SARS started in civet cats and perhaps bats; Ebola probably originated in bats.
While it often seems as if we see a new epidemic disease every few years, Tom Besser, who heads WSU’s zoonotic disease research team, says the perception that outbreaks of scary diseases have become more frequent or more deadly in recent decades is largely due to better detection and reporting.
Still, outbreaks do happen. Besser, Davis, and other WSU researchers are working to figure out how and why. What makes some strains of a bug nastier than others? Why do they emerge when and where they do? Are we more susceptible now than in the past, and if so, why?
Until the 1980s, the numbers of Salmonella Typhimurium cases identified in animals in the Pacific Northwest rose and fell slightly from year to year, but on average stayed pretty much the same. WSU researchers saw about 50 cases a year in cattle in the state. Then came DNA fingerprinting and other strain-typing techniques, and the discovery that not all Typhimurium are the same.
“Instead of being a steady state, we learned that we were having waves of infection due to different strains that are coming and going,” says Besser. He and the WSU zoonotics group track outbreaks of Salmonella and Escherichia coli in the Pacific Northwest by analyzing the DNA fingerprint pattern of each sample they’re sent from doctors, veterinarians, and public health officials. They and their counterparts around the world have found that an individual strain of Typhimurium will become dominant for a few years and then decline, as a different strain becomes more abundant.
The strain called Typhimurium DT104, for instance, was first detected in wild birds in England in the early 1980s. It stayed mostly confined to birds until 1989-90, when many cases appeared in British cattle—and people. Within a few years it was found in cattle and humans worldwide; by 1994 every case of Salmonella Typhimurium tested by the WSU lab was DT104.
“It made the cover of U.S. News & World Report,” says Besser. “That strain got attention because it was the first widespread Typhimurium strain that was resistant to the antibiotic chloramphenicol.” That was frightening, because at the time, chloramphenicol was needed for treating severe cases of Salmonella infection in humans. We appeared to be facing a worldwide epidemic of untreatable Salmonella.
And then, DT104 went away. In Washington, within a few years it dropped to about 10 percent of all Typhimurium cases. Subsequent waves of other strains have come and gone since then—and nobody knows why.
According to conventional wisdom, our over-use of antibiotics could drive the process by selecting for antibiotic-resistant pathogens. Sounds reasonable; decades of records show that within a few years of introducing a new antibiotic, strains of bacteria arise that are resistant to it. However, the role of antibiotic resistance in emergence of new Salmonella strains isn’t clear-cut. It certainly is very bad news to come down with an infection that resists all the drugs available to fight it; but whether the bug’s resistance has anything to do with your catching it in the first place isn’t known. Emerging strains of Salmonella don’t always have more antibiotic resistance than the strains they’re replacing. Often they have less. In Belgium, for instance, DT104 had less antibiotic resistance than the strain it replaced. When another strain of Salmonella called DT10 swept across Canada and the U.S. in the 1970s, it was pan-susceptible: all of our standard antibiotics killed it.
“There were actually papers written showing decreased ampicillin resistance in Salmonella,” recalls Besser. “Some attributed it to improved drug-use policies in hospitals, but really it was the displacement of the ampicillin-resistant strains by DT10.” In all likelihood, he says, the rise of DT10 was due to whatever causes the normal cycling of different strains of Salmonella.
“Antibiotic resistance undoubtedly can play a role in the success of a strain,” he concludes. “It’s just that there’s enough examples to the contrary to show that that’s not always the driving force. It may only occasionally be the driving force.”
So what causes the cycling? Evolutionary ecologist Mark Dybdahl has found a similar pattern in a very different system. He studies the ongoing “arms race” between a species of snail and the trematode worms that infect it. Native to New Zealand, the tiny snails—each about the size of a grain of rice—and parasitic worms engage in a seesaw relationship that looks a lot like the predator-prey cycles between lynx and snowshoe hares we learned about in high-school biology class. (See “New Zealand Mud Snails,” WSM, February 2005.)
The snails come in two reproductive varieties, sexual and clonal. Every now and then, for reasons we don’t yet understand, sexually reproducing snails spawn female offspring that will reproduce on their own, with no input from a male. Each of these females becomes the founder of a new strain of snails that are genetically identical to each other—they are clones. A single lake may be home to a few, or many, different clones of snails. The neat thing Dybdahl has found is that each clone of snails is preferred by a different strain of the parasite.
Dybdahl uses genetic fingerprints to pinpoint which clone a given snail belongs to and how often the worms infect each strain of snail. He’s fo und a cyclical pattern: as one clone of snail becomes abundant, parasites that are able to infect that strain thrive. They produce more young, which hit that clone of snails even harder. After a year or two of heavy infestation, that snail population crashes. With fewer target hosts around, the parasite able to infect that clone crashes too. As one snail clone crashes, another snail clone becomes common, prompting a burst in the population of parasites that are genetically adapted to infect it.
“Whenever a genotype becomes common, there’s going to be a much stronger advantage to the parasite that can infect that clone,” says Dybdahl. “We expect the parasites to evolve to infect the most common host genotype. The parasite evolves to the host, and the host evolves in response to the parasite. And it keeps going.”
Molecular epidemiologist Doug Call says that kind of population control could be at work with Salmonella. If microbes in our digestive tracts target specific strains of the bacteria, then as a strain of Salmonella becomes superabundant, the microscopic predators that target it will thrive. Eventually they’ll hammer that strain so hard it nearly disappears, to be replaced by another strain whose own enemies aren’t so numerous yet.
In lab experiments, different gut protozoans do attack different strains of Salmonella, says Call. Proving it happens inside a living animal is not yet within our reach. Most gut microbes can’t be grown in a lab; few have even been identified and named.
“We don’t like to think of bacteria as being part of our systems, but they’re there,” says Besser. “It’s a very complex ecosystem.”
Although we don’t know whether our natural microbial flora are responsible for Salmonella cycling, we have good evidence that they do protect us from infection—if we haven’t decimated them by long-term or frequent personal use of antibiotics. Helpful bacteria are just as vulnerable to antibiotics as nasty ones, and with the good guys gone, the way is clear for bad guys to move in. Besser says the dose of Salmonella it takes to make a healthy adult human sick “is in the Carl Sagan range. You know, billions and billions. By taking an antibiotic, an oral pill especially, that you would absorb [through the gut], you can get down as low as 10 cells that could make you sick. So it’s a huge factor.”
What determines how damaging a given strain of pathogen will be is still something of a mystery. Some of the nastiest infectious agents in humans aren’t even full-time pathogens. They cause few problems in their animal host—like E. coli in cattle or Salmonella in reptiles—or they are free living, with no host at all—like Listeria, a food-borne pathogen in humans.
Doug Call uses molecular techniques to try to figure out what makes some strains of Salmonella and Listeria infective. He suspects it takes more than a single gene to turn a bug into a killer; it’s more likely that a strain needs a suite of dozens of genes in order to be virulent. Call says that when his recent graduate student, Min-Su Kang, began his research, he was certain there had to be a unique gene or small group of genes that allows one strain of Salmonella to be nastier than others. After much fruitless searching, the student concluded there was no such “virulence gene.”
“He did a very good job,” says Call. “If anyone was going to find it, he was.”
Ecologist Andrew Storfer is exploring the possibility that pathogens can become more deadly when something in the environment lowers our natural defenses.
He’s working to understand why amphibian populations worldwide have gone into freefall in the last few decades. Nearly half of the 6,000-plus species of amphibians on earth are declining. Ten percent have gone extinct or nearly extinct in recent decades.
“This is unparalleled, unprecedented, by other vertebrates,” says Storfer.
Along with loss of habitat and competition from invasive species, amphibians have been getting hammered by diseases they once fought off with some success, such as an iridovirus and a fungal skin infection. Storfer began to wonder if their immune systems might have been compromised by something in their environment. Because they breathe through their skin and are exposed to contaminants both in the water and on land, amphibians might be peculiarly vulnerable to pollution. Could toxins in the water be affecting their ability to fight infection?
Storfer and his research team exposed tiger salamander larvae to atrazine, a widely used herbicide, and iridovirus, starting when they were 12 weeks old. At that age, the salamanders are entirely aquatic, and their immune systems are fully functional. The atrazine was applied at levels found in ponds across the U.S. in springtime, the result of run-off from farm fields. The larvae were monitored for three months, until they were ready to metamorphose and become adults.
The results were striking. Atrazine decreased white-blood-cell counts in the salamanders and doubled their infection rate. And since the salamanders were housed individually, the experiment probably low-balled the incidence of disease; in a crowded natural pond, the virus would likely spread even more.
“The dynamics of this disease are what is called density dependent,” says Storfer. “The more animals [that are] infected, the more get infected.” If atrazine causes the same effects in nature that it did in his experiment, he says, the difference in infection level could mean the difference between a population surviving or going extinct.
Those results offer a clear warning, says Storfer. Amphibians have many of the same disease-fighting tools we have. Their immune systems are more primitive than ours, but have the same basic components.
“If these guys are the first to go and they’re sort of a litmus test of environmental quality, then that means as it gets worse, it’s going to start affecting other vertebrates—like us,” says Storfer. “If their immunity is being compromised at certain levels of pesticides or other things in the environment, we have to worry about what’s going to happen to us.”
What is going to happen to us? Even in the short term, with diseases we know a lot about, that’s a tough question to answer. Besser, Davis, and Call run a surveillance project aimed at detecting rising strains of Salmonella and perhaps heading off the next outbreak. The microbe’s biology makes that difficult; human actions make it even harder. Salmonella is a “reportable” disease in humans, which means that doctors are legally required to report it to public health authorities when they diagnose it; but if the patients don’t come in, the doctors have nothing to report.
“If you get diarrhea and the cramping and all that, how many people go to the doctor?” asks Call. Most likely, he says, “You wait it out, and you’re fine again [after a few days], and you never know what it was.”
“It’s way underdiagnosed and underreported,” agrees Davis. She says the rule of thumb is that Americans experience 38 times more cases of Salmonella infection than are ever reported.
Monitoring of livestock infections is even more haphazard. Salmonella infections in animals are not reportable, so the WSU team relies on voluntary collections by vets and livestock owners for those samples.
“It’s called ‘passive surveillance,” Besser says. “Farmer A might be really attuned and send in [samples from] the first animal that looks cross-eyed at all, and Farmer B might lose 10 animals before he thinks it’s important enough to call a vet. A lot of farmers don’t even have an established relationship with a vet. So we know we’re probably missing an awful lot.”
The team also monitors healthy cattle herds and water and waste-management systems. What they’ve found there complicates the picture even more.
On-farm waste lagoons often contain Salmonella, which makes sense, since they receive feces from hundreds or thousands of cattle and other farm animals. But Salmonella isn’t just a denizen of cattle farms.
“When we go down to the Pullman sewage treatment plant and get untreated water coming in, more often than not it’s positive for Salmonella,” says Besser. So does the water coming out of Pullman homes has as much Salmonella in it as the water in farm waste ponds? “At least as much, if not more. A little bit different composition of strains,” he says. “It’s there. It’s passing through us all. We find E. coli O157:H7 too, in Pullman’s untreated sewage. It’s not as common as Salmonella, but it’s also going through us on a regular basis.”
E. coli O157:H7. That’s the bug that tainted burgers at Jack in the Box in 1993, and that imperiled our spinach salads in 2006. In humans it causes symptoms ranging from cramping and diarrhea to a potentially lethal form of kidney failure. O157:H7 is especially dangerous for kids. It appears to infect us more easily than Salmonella; with E. coli the infectious dose appears to be just a few hundred cells.
Besser says measures taken since the Jack in the Box incident have greatly reduced our chances of getting meat tainted with E. coli (or Salmonella or other pathogens as well). A major source of contamination was found to be dust on the animals’ hides; when cattle were skinned at the slaughterhouse, dust (and harmful bacteria) settled on the meat. Now, carcasses receive a pasteurizing wash after skinning.
That may be our best line of defense, because Besser’s work shows that it’s unlikely we can ward off E. coli outbreaks by identifying the bug in cows before slaughter. Nearly every herd his team has examined carries it.
“Most of the work I’ve been doing has been going out, working with farmers to find things they can do to reduce the chances that their cattle are carrying O157:H7,” he says. “We haven’t found any magic bullets after 15 years of work.”
He says the often-heard claim that hay- or grass-fed cattle are less likely to carry O157:H7 than cattle that are fed grain is “just not true, in our experience. Grass-fed cattle are as likely to be positive as grain-fed herds.” He says numbers of E. coli vary with the season (more in summer than winter) and age of the cow (more in calves than in adults), but that’s about it for trends.
So O157:H7 simmers harmlessly along in the cow population, every now and then bursting out in humans. In the summer of 2006, a couple of hundred people across the nation were sickened by E. coli from fresh spinach, in an episode that may say more about our ability to spot trouble in a hurry than it does about dangers in our food supply.
“There were 200 cases scattered in 50 states, and it was picked up after the first 20 or 30 cases,” marvels Besser. “We would never have detected it in the past. Never. To put that in perspective, in the average year the CDC [Centers for Disease Control] thinks that there’s somewhere over 50,000 cases of E. coli O157:H7 disease in the United States. The vast majority of them don’t get reported.”
He says the CDC’s report on the incident found that the E. coli originated on a cattle farm half a mile from the spinach field; the bugs were probably carried to the spinach by feral pigs walking through on their way to a water hole.
Now that we know where it came from, what does that tell us about how to stop another outbreak? Not much, says Besser.
“There’s not a single thing we can tell that farmer to do to reduce the likelihood that his cattle will carry E. coli O157:H7. It seems to me that identifying him as a culprit in the outbreak is really not fair.”
Although the strain that caused the outbreak was especially nasty, with a lot of sufferers requiring hospitalization, Besser thinks the panic that ensued was a bit overblown. He, for one, didn’t stop eating spinach.
“I think people shouldn’t bear unnecessary risks, but there are some risks we accept every day, like crossing busy streets or driving a car,” he says. “To some extent, we can afford to worry about 200 cases of ill people out of 250 million, because we’ve got lots of resources and not very many other scary things to worry about. Throughout history, I presume that that level of risk would have been just ignored most of the time. And in most parts of the world now, it would be ignored.”
In most parts of the world, the number of people who die from infectious diseases is beyond comprehension. Malaria alone kills about a million people every year, most of them young children.
“It just dwarfs what we’re talking about,” says Besser. Then he adds, “But you know, this bug [E. coli O157:H7] sometimes kills our kids. That’s a terrible thing, even if it only happens once.”
Scientists at WSU and elsewhere have put in a lot of good work tracking pathogens and learning their ways. But even with all the progress of recent decades, we have just a fragmentary understanding of what we’re dealing with and where the next outbreak might come from. It’s a sure bet that other pathogens are out there, chugging along in their animal hosts and fully able to move into humans if they get the chance.
“Diseases often emerge in strange ways, often as a result of human activities that bring species together that don’t normally come together,” says ecologist Storfer. He describes the combination of events that led to an outbreak of Nipah (NEE-puh) disease in Malaysia in 1998-99. Over the course of a few months, the newly recognized disease afflicted 265 people with fever, headache, convulsions, and coma. It killed 105 and left many others with persistent neurological problems.
Storfer says the virus that causes the disease is carried by fruit bats, which themselves aren’t much affected by it. As forests were cleared to make room for the expanding human population, the bats began to forage into orchards and other human establishments, such as pig farms. The fatal chain of events sounds like a biological Rube Goldberg machine: a bat grabs a piece of fruit from the orchard; after taking a few bites, it drops the fruit within reach of the pigs; a pig eats it, picking up the virus from the bat’s saliva on the fruit; the virus gives the pig a flu-like respiratory disease; when the pig coughs or sneezes, its human handler catches it.
“Humans cannot get it from the bat,” says Storfer. “It has to go through the pig, mutate inside the pig, and then it’s infectious to the pig workers. You have to bring bats, pigs, and humans all together in the same place in order for this thing to go from bats to humans. Because you could lick the bat saliva and not get it. It’s got to go through the pig.”
Tom Besser suspects the Nipah virus has spread to humans and domestic animals before, but not in such large numbers. Encroachments into forested lands, coupled with skyrocketing density of people and livestock, have created conditions that could allow the virus to attain epidemic proportions. The Malaysian government squashed its budding epidemic by killing nearly a million domestic pigs in the affected areas. No cases of Nipah disease have been reported there since, but a few appeared in Bangladesh and India in 2001. That suggests the Malaysian outbreak might have been just a warm-up for a main event yet to come. Fruit bats range throughout south and southeast Asia, and everywhere they’ve been tested, they are positive for the virus; and human and pig populations in the region continue to expand.
The issue of diseases passing from wildlife and domestic animals to people is “one of the most important challenges we’re going to face, I think, over the next century,” says Storfer. Surveillance of humans and livestock is spotty; monitoring of wild species is nearly nonexistent. Nobody is really watching the wildl ife from which new diseases might emerge. Even a disease that causes severe problems in wild animals can go unnoticed for years. How bad does an outbreak in wildlife have to be for someone to send up a flare and say, hey, we’ve got a problem here?
“That’s the $100 million question,” says Storfer. “One of the concerns is this idea that there’s a surveillance bias, that we’re only seeing really nasty things, because then you see a big die-off of something. But we’re not seeing a lot of the pathogens that jump hosts, that might get worse someday.
“How do you prepare yourself? I don’t really know. You try to pick the one that’s going to be the worst one, and do something about it.”