DNA Pollution May Be Spawning Killer Microbes
Rogue genetic snippets spread antibiotic resistance all over the
environment.
by Jessica Snyder Sachs
02.14.2008
On a bright winter morning high in the Colorado Rockies, a slight young
woman in oversize hip boots sidles up to a gap of open water in the icy
Cache la Poudre River. Heather Storteboom, a 25-year-old graduate student at
nearby Colorado State University, is prospecting for clues to an invisible
killer.
Image courtesy of Jessica Snyder Sachs
Storteboom snaps on a pair of latex gloves and stretches over the frozen
ledge to fill a sterile plastic jug with water. Then, setting the container
aside, she swings her rubber-clad legs into the stream. "Ahh, no leaks," she
says, standing upright. She pulls out a clean trowel and attempts to collect
some bottom sediment; in the rapid current, it takes a half dozen tries to
fill the small vial she will take back to the DNA laboratory of her adviser,
environmental engineer Amy Pruden. As Storteboom packs to leave, a curious
hiker approaches. "What were you collecting?" he asks. "Antibiotic
resistance genes," she answers.
Storteboom and Pruden are at the leading edge of an international forensic
investigation into a potentially colossal new health threat: DNA pollution.
Specifically, the researchers are seeking out snippets of rogue genetic
material that transforms annoying bacteria into unstoppable supergerms,
immune to many or all modern antibiotics. Over the past 60 years, genes for
antibiotic resistance have gone from rare to commonplace in the microbes
that routinely infect our bodies. The newly resistant strains have been
implicated in some 90,000 potentially fatal infections a year in the United
States, higher than the number of automobile and homicide deaths combined.
Among the most frightening of the emerging pathogens is invasive MRSA, or
methicillin-resistant Staphylococcus aureus. Outbreaks of MRSA in public
schools recently made headlines, but that is just the tip of the iceberg.
Researchers estimate that invasive MRSA kills more than 18,000 Americans a
year, more than AIDS, and the problem is growing rapidly. MRSA caused just 2
percent of staph infections in 1974; in the last few years, that figure has
reached nearly 65 percent. Most reported staph infections stem from MRSA
born and bred in our antibiotic-drenched hospitals and nursing homes. But
about 15 percent now involve strains that arose in the general community.
It is not just MRSA that is causing concern; antibiotic resistance in
general is spreading alarmingly. A 2003 study of the mouths of healthy
kindergartners found that 97 percent harbored bacteria with genes for
resistance to four out of six tested antibiotics. In all, resistant microbes
made up around 15 percent of the children's oral bacteria, even though none
of the children had taken antibiotics in the previous three months. Such
resistance genes are rare to nonexistent in specimens of human tissue and
body fluid taken 60 years ago, before the use of antibiotics became
widespread.
In part, modern medicine is paying the price for its own success.
"Antibiotics may be the most powerful evolutionary force seen on this planet
in billions of years," says Tufts University microbiologist Stuart Levy,
author of The Antibiotic Paradox: How the Misuse of Antibiotics Destroys
Their Curative Powers. By their nature, antibiotics support the rise of any
bug that can shrug off their effects, by conveniently eliminating the
susceptible competition.
But the rapid rise of bacterial genes for drug resistance stems from more
than lucky mutation, Levy adds. The vast majority of these genes show a
complexity that could have been achieved only over millions of years. Rather
than rising anew in each species, the genes spread via the microbial
equivalent of sexual promiscuity. Bacteria swap genes, not only among their
own kind but also between widely divergent species, Levy explains. Bacteria
can even scavenge the naked DNA that spills from their dead compatriots out
into the environment.
The result is a microbial arms-smuggling network with a global reach. Over
the past 50 years, virtually every known kind of disease-causing bacterium
has acquired genes to survive some or all of the drugs that once proved
effective against it. Analysis of a strain of vancomycin-resistant
enterococcus, a potentially lethal bug that has invaded many hospitals,
reveals that more than one-quarter of its genome-including virtually all its
antibiotic-thwarting genes-is made up of foreign DNA. One of the newest
banes of U.S. medical centers, a supervirulent and multidrug-resistant
strain of Acinetobacter baumannii, likewise appears to have picked up most
of its resistance in gene swaps with other species.
So where in Hades did this devilishly clever DNA come from? The ultimate
source may lie in the dirt beneath our feet.
For the past decade, Gerry Wright has been trying to understand the rise of
drug resistance by combing through the world's richest natural source of
resistance-enabling DNA: a clod of dirt. As the head of McMaster
University's antibiotic research center in Hamilton, Ontario, Wright has the
most tricked-out laboratory a drug designer could want, complete with a $15
million high-speed screening facility for simultaneously testing potential
drugs against hundreds of bacterial targets. Yet he says his technology
pales in comparison with the elegant antibiotic-making abilities he finds
encoded in soil bacteria. The vast majority of the antibiotics stocking our
pharmacy shelves-from old standards like tetracycline to antibiotics of last
resort like vancomycin and, most recently, daptomycin-are derived from soil
organisms.
Biologists assume that soil organisms make antibiotics to beat back the
microbial competition and to establish their territory, Wright says,
although the chemicals may also serve other, less-understood functions.
Whatever the case, Wright and his students began combing through the DNA of
soil microbes like streptomyces to better understand their impressive
antibiotic-making powers. In doing so the researchers stumbled upon three
resistance genes embedded in the DNA that Streptomyces toyocaensis uses to
produce the antibiotic teicoplanin. While Wright was not surprised that the
bug would carry such genes as antidotes to its own weaponry, he was startled
to see that the antidote genes were nearly identical to the resistance genes
in vancomycin-resistant enterococcus (VRE), the scourge of American and
European hospitals.
Yet here they were in a soil organism, in the exact same orientation as you
find in the genome of VRE," Wright says. "That sure gave us a head-slap
moment. If only we had done this experiment 15 years ago, when vancomycin
came into widespread use, we might have understood exactly what kind of
resistance mechanisms would follow the drug into our clinics and hospitals."
If nothing else, that foreknowledge might have prepared doctors for the
inevitable resistance they would encounter soon after vancomycin was broadly
prescribed.
Wright wondered what else he might find in a shovelful of dirt. So he handed
out plastic bags to students departing on break, telling them to bring back
soil samples. Over two years his lab amassed a collection that spanned the
continent. It even included a thawed slice of tundra mailed by Wright's
brother, a provincial policeman stationed on the northern Ontario-Manitoba
border.
By 2005 Wright's team had combed through the genes of nearly 500
streptomyces strains and species, many never before identified. Every one
proved resistant to multiple antibiotics, not just their own signature
chemicals. On average, each could neutralize seven or eight drugs, and many
could shrug off 14 or 15. In all, the researchers found resistance to every
one of the 21 antibiotics they tested, including Ketek and Zyvox, two
synthetic new drugs.
"These genes clearly didn't jump directly from streptomyces into
disease-causing bacteria," Wright says. He had noted subtle variations
between the resistance genes he pulled out of soil organisms and their
doppelgängers in disease-causing bacteria. As in a game of telephone, each
time a gene gets passed from one microbe to another, slight differences
develop that reflect the DNA dialect of its new host. The resistance genes
bedeviling doctors had evidently passed through many intermediaries on their
way from soil to critically ill patients.
Wright suspects that the antibiotic-drenched environment of commercial
livestock operations is prime ground for such transfer. "You've got the
genes encoding for resistance in the soil beneath these operations," he
says, "and we know that the majority of the antibiotics animals consume get
excreted intact." In other words, the antibiotics fuel the rise of resistant
bacteria both in the animals' guts and in the dirt beneath their hooves,
with ample opportunity for cross-contamination.
Nobody knows how long free-floating DNA might persist in the water.A 2001
study by University of Illinois microbiologist Roderick Mackie documented
this flow. When he looked for tetracycline resistance genes in groundwater
downstream from pig farms, he also found the genes in local soil organisms
like Microbacterium and Pseudomonas, which normally do not contain them.
Since then, Mackie has found that soil bacteria around conventional pig
farms, which use antibiotics, carry 100 to 1,000 times more resistance genes
than do the same bacteria around organic farms.
"These animal operations are real hot spots," he says. "They're glowing red
in the concentrations and intensity of these genes." More worrisome,
perhaps, is that Mackie pulled more resistance genes from his deepest test
wells, suggesting that the genes percolated down toward the drinking water
supplies used by surrounding communities.
An even more direct conduit into the environment may be the common practice
of irrigating fields with wastewater from livestock lagoons. About three
years ago, David Graham, a University of Kansas environmental engineer, was
puzzled in the fall by a dramatic spike in resistance genes in a pond on a
Kansas feedlot he was studying. "We didn't know what was going on until I
talked with a large-animal researcher," he recalls. At the end of the
summer, feedlots receive newly weaned calves from outlying ranches. To
prevent the young animals from importing infections, the feedlot operators
were giving them five-day "shock doses" of antibiotics. "Their attitude had
been, cows are big animals, they're pretty tough, so you give them 10 times
what they need," Graham says.
The operators cut back on the drugs when Graham showed them that they were
coating the next season's alfalfa crop with highly drug-resistant bacteria.
"Essentially, they were feeding resistance genes back to their animals,"
Graham says. "Once they realized that, they started being much more
conscious. They still used antibiotics, but more discriminately."
While livestock operations are an obvious source of antibiotic resistance,
humans also take a lot of antibiotics-and their waste is another
contamination stream. Bacteria make up about one-third of the solid matter
in human stool, and Scott Weber, of the State University of New York at
Buffalo, studies what happens to the antibiotic resistance genes our nation
flushes down its toilets.
Conventional sewage treatment skims off solids for landfill disposal, then
feeds the liquid waste to sewage-degrading bacteria. The end result is
around 5 billion pounds of bacteria-rich slurry, or waste sludge, each year.
Around 35 percent of this is incinerated or put in a landfill. Close to 65
percent is recycled as fertilizer, much of it ending up on croplands.
Weber is now investigating how fertilizer derived from human sewage may
contribute to the spread of antibiotic-resistant genes. "We've done a good
job designing our treatment plants to reduce conventional contaminants," he
says. "Unfortunately, no one has been thinking of DNA as a contaminant." In
fact, sewage treatment methods used at the country's 18,000-odd wastewater
plants could actually affect the resistance genes that enter their systems.
Every tested strain in a dirt sample proved resistant to multiple
antibiotics.Most treatment plants, Weber explains, gorge a relatively small
number of sludge bacteria with all the liquid waste they can eat. The
result, he found, is a spike in antibiotic-resistant organisms. "We don't
know exactly why," he says, "but our findings have raised an even more
important question." Is the jump in resistance genes coming from a
population explosion in the resistant enteric, or intestinal, bacteria
coming into the sewage plant? Or is it coming from sewage-digesting sludge
bacteria that are taking up the genes from incoming bacteria? The answer is
important because sludge bacteria are much more likely to thrive and spread
their resistance genes once the sludge is discharged into rivers (in treated
wastewater) and onto crop fields (as slurried fertilizer).
Weber predicts that follow-up studies will show the resistance genes have
indeed made the jump to sludge bacteria. On a hopeful note, he has shown
that an alternative method of sewage processing seems to decrease the
prevalence of bacterial drug resistance. In this process, the sludge remains
inside the treatment plant longer, allowing dramatically higher
concentrations of bacteria to develop. For reasons that are not yet clear,
this method slows the increase of drug-resistant bacteria. It also produces
less sludge for disposal. Unfortunately, the process is expensive.
Drying sewage sludge into pellets-which kills the sludge bacteria-is another
way to contain resistance genes, though it may still leave DNA intact. But
few municipal sewage plants want the extra expense of drying the sludge, and
so it is instead exported "live" in tanker trucks that spray the wet slurry
onto crop fields, along roadsides, and into forests.
Trolling the waters and sediments of the Cache la Poudre, Storteboom and
Pruden are collecting solid evidence to support suspicions that both
livestock operations and human sewage are major players in the dramatic rise
of resistance genes in our environment and our bodies. Specifically, they
have found unnaturally high levels of antibiotic resistance genes in
sediments where the river comes into contact with treated municipal
wastewater effluent and farm irrigation runoff as it flows 126 miles from
Rocky Mountain National Park through Fort Collins and across Colorado's
eastern plain, home to some of the country's most densely packed livestock
operations.
"Over the course of the river, we saw the concentration of resistance genes
increase by several orders of magnitude," Pruden says, "far more than could
ever be accounted for by chance alone." Pruden's team likewise found
dangerous genes in the water headed from local treatment plants toward
household taps.
Presumably, most of these genes reside inside live bacteria, but a microbe
doesn't have to be alive to share its dangerous DNA. As microbiologists
have pointed out, bacteria are known to scavenge genes from the spilled DNA
of their dead.
"There's a lot of interest in whether there's naked DNA in there," Pruden
says of the Poudre's waters. "Current treatment of drinking water is aimed
at killing bacteria, not eliminating their DNA." Nobody even knows exactly
how long such free-floating DNA might persist.
All this makes resistance genes a uniquely troubling sort of pollution. "At
least when you pollute a site with something like atrazine," a pesticide,
"you can be assured that it will eventually decay," says Graham, the Kansas
environmental engineer, who began his research career tracking chemical
pollutants like toxic herbicides. "When you contaminate a site with
resistance genes, those genes can be transferred into environmental
organisms and actually increase the concentration of contamination."
Taken together, these findings drive home the urgency of efforts to reduce
flagrant antibiotic overuse that fuels the spread of resistance, whether on
the farm, in the home, or in the hospital.
For years the livestock pharmaceutical industry has played down its role in
the rise of antibiotic resistance. "We approached this problem many years
ago and have seen all kinds of studies, and there isn't anything definitive
to say that antibiotics in livestock cause harm to people," says Richard
Carnevale, vice president of regulatory and scientific affairs at the Animal
Health Institute, which represents the manufacturers of animal drugs,
including those for livestock. "Antimicrobial resistance has all kinds of
sources, people to animals as well as animals to people."
The institute's own data testify to the magnitude of antibiotic use in
livestock operations, however. Its members sell an estimated 20 million to
25 million pounds of antibiotics for use in animals each year, much of it to
promote growth. (For little-understood reasons, antibiotics speed the growth
of young animals, making it cheaper to bring them to slaughter.) The Union
of Concerned Scientists and other groups have long urged the United States
to follow the European Union, which in 2006 completed its ban on the use of
antibiotics for promoting livestock growth. Such a ban remains far more
contentious in North America, where the profitability of factory-farm
operations depends on getting animals to market in the shortest possible
time.
On the other hand, the success of the E.U.'s ban is less than clear-cut.
"The studies show that the E.U.'s curtailing of these compounds in feed has
resulted in more sick animals needing higher therapeutic doses," Carnevale
says.
"There are cases of that," admits Scott McEwen, a University of Guelph
veterinary epidemiologist who advises the Canadian government on the
public-health implications of livestock antibiotics. At certain stressful
times in a young animal's life, as when it is weaned from its mother, it
becomes particularly susceptible to disease. "The lesson," he says, "may be
that we would do well by being more selective than a complete ban."
McEwen and many of his colleagues see no harm in using growth-promoting
livestock antibiotics known as ionophores. "They have no known use in
people, and we see no evidence that they select for resistance to important
medical antibiotics," he says. "So why not use them? But if anyone tries to
say that we should use such critically important drugs as cephalosporins or
fluoroquinolones as growth promoters, that's a no-brainer. Resistance
develops quickly, and we've seen the deleterious effects in human health."
A thornier issue is the use of antibiotics to treat sick livestock and
prevent the spread of infections through crowded herds and flocks. "Few
people would say we should deny antibiotics to sick animals," McEwen says,
"and often the only practical way to administer an antibiotic is to give it
to the whole group." Some critics have called for restricting certain
classes of critically important antibiotics from livestock use, even for
treating sick animals. For instance, the FDA is considering approval of
cefquinome for respiratory infections in cattle. Cefquinome belongs to a
powerful class of antibiotic known as fourth-generation cephalosporins,
introduced in the 1990s to combat hospital infections that had grown
resistant to older drugs. In the fall of 2006, the FDA's veterinary advisory
committee voted against approving cefquinome, citing concerns that
resistance to this vital class of drug could spread from bacteria in beef to
hospital superbugs that respond to little else. But the agency's recently
adopted guidelines make it difficult to deny approval to a new veterinary
drug unless it clearly threatens the treatment of a specific foodborne
infection in humans. As of press time, the FDA had yet to reach a decision.
Consumers may contribute to the problem of DNA pollution whenever they use
antibacterial soaps and cleaning products. These products contain the
antibiotic-like chemicals triclosan and triclocarban and send some 2 million
to 20 million pounds of the compounds into the sewage stream each year.
Triclosan and triclocarban have been shown in the lab to promote resistance
to medically important antibiotics. Worse, the compounds do not break down
as readily as do traditional antibiotics. Rolf Halden, cofounder of the
Center for Water and Health at Johns Hopkins University, has shown that
triclosan and triclocarban show up in many waterways that receive treated
wastewater-more than half of the nation's rivers and streams. He has found
even greater levels of these two chemicals in sewage sludge destined for
reuse as crop fertilizer. According to his figures, a typical sewage
treatment plant sends more than a ton of triclocarban and a slightly lesser
amount of triclosan back into the environment each year.
For consumer antibacterial soaps the solution is simple, Halden says:
"Eliminate them. There's no reason to have these chemicals in consumer
products." Studies show that household products containing such
antibacterials don't prevent the spread of sickness any better than
ordinary soap and water. "If there's no benefit, then all we're left with is
the risk," Halden says. He notes that many European retailers have already
pulled these products from their shelves. "I think it's only a matter of
time before they are removed from U.S. shelves as well."
Consumers may contribute to the problem of DNA pollution whenever they use
soaps and cleaning products containing antibiotic-like compounds.Finally,
there is the complicated matter of the vast quantity of antibiotics that
U.S. doctors prescribe each year: some 3 million pounds, according to the
Union of Concerned Scientists. No doctor wants to ignore an opportunity to
save a patient from infectious disease, yet much of what is prescribed is
probably unnecessary-and all of it feeds the spread of resistance genes in
hospitals and apparently throughout the environment.
"Patients come in asking for a particular antibiotic because it made them
feel better in the past or they saw it promoted on TV," says Jim King,
president of the American Academy of Family Physicians. The right thing to
do is to educate the patient, he says, "but that takes time, and sometimes
it's easier, though not appropriate, to write the prescription the patient
wants."
Curtis Donskey, chief of infection control at Louis Stokes Cleveland VA
Medical Center, adds that "a lot of antibiotic overuse comes from the
mistaken idea that more is better. Infections are often treated longer than
necessary, and multiple antibiotics are given when one would work as well."
In truth, his studies show, the longer hospital patients remain on
antibiotics, the more likely they are to pick up a multidrug-resistant
superbug. The problem appears to lie in the drugs' disruption of a person's
protective microflora-the resident bacteria that normally help keep invader
microbes at bay. "I think the message is slowly getting through," Donskey
says. "I'm seeing the change in attitude."
Meanwhile, Pruden's students at Colorado State keep amassing evidence that
will make it difficult for any player-medical, consumer, or agricultural-to
shirk accountability for DNA pollution.
Late in the afternoon, Storteboom drives past dairy farms and feedlots,
meatpacking plants, and fallow fields, 50 miles downstream from her first
DNA sampling site of the day. Leaving her Jeep at the side of the road, she
strides past cow patties and fast-food wrappers and scrambles down an eroded
embankment of the Cache la Poudre River. She cringes at the sight of two
small animal carcasses on the opposite bank, then wades in, steering clear
of an eddy of gray scum. "Just gross," she mutters, grateful for her
watertight hip boots.
Of course, the invisible genetic pollution is of greater concern. It lends
an ironic twist to the river's name. According to local legend, the
appellation comes from the hidden stashes (cache) of gunpowder (poudre) that
French fur trappers once buried along the banks. Nearly two centuries later,
the river's hidden DNA may pose the real threat.
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