Πέμπτη, 1 Οκτωβρίου 2015

The Age of Infection

Kim Lewis collects dirt. For the past decade, he and his colleagues—all scientists in Massachusetts—have asked friends and family around the United States to send them 1-gallon Ziploc bags of backyard soil. It might not seem like much, but it turns out that a little grime can hold a trove of groundbreaking scientific discoveries.
In 2011, Lewis’s team began analyzing a bag of soil from a grassy field in Maine, focusing on bacteria naturally growing inside. The scientists mixed some of the dirt with water and nutrients—proteins, for instance, and potato starch—and poured the mixture over specially designed domino-sized plastic blocks punctured with dozens of tiny wells. Each minuscule compartment captured 20 microliters of the slurry, which, thanks to the dilution, contained just a single bacterial cell. Finally, the researchers packed the small plastic slabs in buckets with the remainder of the soil and left them alone for a month.

The procedure’s relative simplicity belied its true sophistication. When Lewis, a microbiology professor at Northeastern University, and the other researchers unearthed the blocks, they found just what they were hoping for: The bacteria had multiplied. The wells were teeming with microbes, many of which were species no scientist had ever studied.
The team analyzed 10,000 individual strains of the bacteria and tested whether they could kill other microbes by pitting them against one another in petri dishes. One species, which the scientists dubbed Eleftheria terrae (“free from the earth”), was an especially successful gladiator. The researchers pinpointed E. terrae’s primary weapon, a molecule they named teixobactin, and discovered that it could wipe out the microbes responsible for anthrax and tuberculosis. Teixobactin also saved mice from infections of MRSA (methicillin-resistant Staphylococcus aureus), one of the most infamous superbugs—bacteria that are immune to several different drugs. What’s more, when the researchers coaxed the microbes to evolve resistance to teixobactin, it didn’t work.
In that bag of dirt, Lewis’s team had found an entirely new kind of antibiotic, one of only a few to emerge in the past 50 years—and a potent one at that. The findings, published this January, garnered widespread enthusiasm: “New Antibiotic May Conquer Superbugs,” declared NBCNews.com. “A New Antibiotic That Resists Resistance,” a blog post on National Geographic’s website proclaimed.
The iChip, short for isolation chip, is a plastic block that captures microbes from soil.
Even more exciting is the innovation used to discover teixobactin: the unassuming plastic blocks. Each one is called an iChip, short for isolation chip, so-named because of how it captures microbes from soil. Until now, scientists hunting for antibiotics haven’t been able to study 99 percent of the world’s microbial species because, when ripped from the outdoors and encouraged to grow under desolate laboratory conditions, the vast majority of bacteria die. The iChip overcomes this problem by keeping things dirty: Burying soil microbes in their natural habitat during the culturing process preserves the organic compounds they need to thrive, enticing previously stubborn microorganisms to multiply under human supervision.
The iChip unveils a universe of unexplored bacterial diversity—and of potential antibiotics. Teixobactin may be only the beginning.
This revelation couldn’t be more welcome, because the world’s arsenal of antibiotics is rapidly shrinking, with dire consequences. An investigation by a U.K. government task force estimates that the global toll of antibiotic resistance is 700,000 deaths per year—and that it could soar to 10 million by 2050. In the United States, at least 2 million people are infected with antibiotic-immune bacteria annually; some 23,000 die. (The director of the Centers for Disease Control and Prevention has called the estimate “a bare minimum.”) All that illness and death exacts substantial economic losses, too: The U.K. task force projects that resistance will sap between 2 and 3.5 percent of the world’s GDP—about $100 trillion—over the next 35 years.
When it released its very first report on the subject in 2014, the World Health Organization (WHO) declared antibiotic resistance a “major threat to public health” that “is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country.” This January, Barack Obama’s administration announced it was asking for $1.2 billion to combat the problem—double the dedicated amount from the previous year’s budget—and two months later, the White House released a national action plan for dealing with resistance; facilitating antibiotic research is a top priority.
At stake, quite simply, is the future. Numerous health experts have warned that, without new antibiotics, the world risks a return to the medical dark ages, when the slightest knick or scratch could spawn a lethal infection that doctors had no way to treat. Common surgeries—appendectomies, joint replacements, cesarean sections—could become life-threatening. The U.K. National Risk Register of Civil Emergencies warned this year that a widespread outbreak of drug-resistant blood infections could kill up to 80,000 people in that country. “A post-antibiotic era means, in effect, an end to modern medicine as we know it,” Margaret Chan, the WHO’s director-general, said at a 2012 conference in Denmark.
Lewis believes the iChip is the key to avoiding this awful jump back in time. In fact, he thinks it offers a chance to start a new clock altogether. “Using iChip to find and introduce compounds like teixobactin will solve the problem of resistance,” he says, “not temporarily, but period.”
Even if the iChip launches a new era of antibiotic discovery, however, scientific consensus holds that resistance is a whirlpool humankind can tread but never escape. On top of that, many economic, bureaucratic, and other human-created barriers have long limited antibiotic research and development, and they won’t be easy to scuttle. The iChip could prove an essential tool for warding off bacteria’s looming assault on humans, but it’s not a cure-all. “Bacteria … have been fighting this battle much longer than we have,” says Gerry Wright, director of the Michael G. DeGroote Institute for Infectious Disease Research at McMaster University in Canada. “Whether you try a drug or a vaccine or whatever you can dream of, there’s going to be a way to get around it.”

Microorganisms were the first cellular life forms to evolve on Earth, around 3.2 billion years ago. They have been competing for the planet’s resources ever since, inventing new ways to injure and kill each other. In the 1930s and ’40s, scientists started to grow microbes in giant fermentation tanks, extract the molecules that the microbes use to fight each other, and commandeer them to battle bacteria that make people sick. The most well-known outcome of this process, of course, is penicillin: Derived from mold, the drug was first used to cure an infection in 1930. By 1945, U.S. companies were churning out 650 billion units each month.
MICROORGANISMS WERE THE FIRST CELLULAR LIFE FORMS TO EVOLVE ON EARTH, AROUND 3.2 BILLION YEARS AGO. THEY HAVE BEEN COMPETING FOR THE PLANET’S RESOURCES EVER SINCE, INVENTING NEW WAYS TO INJURE AND KILL EACH OTHER.
Initially, the drug easily warded off Staphylococcus aureus, or staph, which typically infects skin and the respiratory tract. But mass-producing penicillin put intense evolutionary pressure on bacteria to mount stronger defenses. In certain patients treated with the antibiotic, a few microbes survived—those with at least some innate ability to resist the drug—and they then multiplied into hardy colonies; trying to eradicate these clusters with more penicillin started the process all over again. It was natural selection at its finest. (Bacteria can acquire resistance in other ways, too: through chance genetic mutations that alter their cellular structures and through horizontal gene transfer, in which bacteria swap small sections of DNA, including material that supports resistance.)
By the 1960s, 80 percent of staph bacteria were resistant to penicillin. A new drug, methicillin, was introduced in 1959, but immunity developed within two years—spawning the new superbug, MRSA. By 2002, nearly 60 percent of staph bacteria were resistant to methicillin. Today, these microbes are impervious to even more drugs.
Over the past 75 years, this story has repeated itself as medicine has exposed bacteria to millions of metric tons of antibiotics. By 2004, for example, resistance had emerged to all classes of antimalarial drugs, except for one: artemisinins, derived from an herb called sweet wormwood. Ten years later, artemisinin resistance was firmly established in Southeast Asia. Cephalosporins, the class of drugs that is the last resort for gonorrhea, have already failed in several countries.
Human hubris and carelessness have contributed to this crisis. Doctors have prescribed antibiotics when they were not necessary; patients have taken drugs in the wrong dosages for too much or too little time; and farmers have pumped cattle and chickens full of antibiotics because they plump up the animals (possibly because the antibiotics kill benign gut bacteria that usually take some of the creatures’ daily calories for themselves). Together, these practices have given bacteria surplus opportunities to meet their adversaries and evolve to defeat them.
But scientific failure has been a problem too. During the so-called golden age of antibiotic discovery, from roughly 1940 to the 1960s, scientists and pharmaceutical companies introduced more than a dozen new classes of drugs. Then the rate of discovery practically ground to a halt. Researchers were trying to derive antibiotics from the very few soil microbes that readily grew under standard lab protocols: Bacteria were mined from dirt, smeared onto petri dishes filled with a gelatin, and kept warm. Yet that gelatin, known as a growth medium, was simply too barren to sustain most microbes. Only 1 percent of species survived, and by the 1960s researchers had exhausted this sliver of a resource.
Eventually, drug companies’ priorities shifted from discovering new antibiotics to creating slight variations of existing ones—a quicker, less expensive, and seemingly less discouraging process. But such “analogues,” as they’re known, proved more finite than expected and were generally more susceptible to resistance because of their similarity to existing drugs that microbes had already encountered. By 1990, half of the biggest drug companies in the United States had slowed or stopped their antibiotic research programs. Discoveries have been slim ever since. What few new antibiotics have made it to market typically have encountered resistance within two years.
The situation prompted a trio of microbiologists to state bluntly in a 2011 article in the British Journal of Pharmacology, “The world is running out of antibiotics”—a sentiment echoed by many scientists. But then, just when it seemed like the supply line for weapons needed to battle bacteria had fallen into permanent decline, a breakthrough happened.

HOW THE iCHIP WORKS

Researchers dilute soil in a mixture of molten agar and nutrients so that there is only one bacterial cell in every 20 microliters.
As with many great inventions, the concept behind the iChip might seem blindingly obvious: If bacteria won’t grow outside their homes, bring their homes into the lab. “Honestly, I have no idea why no one did this before,” Lewis says. “I always thought it was a fantastic intellectual challenge.”
Lewis started working on this puzzle in 2000. Rather than trying to determine what biological compounds soil bacteria need to flourish—science still doesn’t have a precise answer—he focused on the simple fact that many microbes are happy in dirt. By 2002, Lewis and fellow Northeastern University microbiologist Slava Epstein had built a diffusion chamber that would allow bacteria to grow in a lab while still being immersed in their natural environment: a metal washer sandwiched between two porous membranes. The scientists extracted bacteria from beach sand and mixed them with water and agar, a gelatinous substance that can both nurture microbes and hold them in place. They put the concoction in the middle of the washer and stuck the whole chamber in an aquarium filled with the same sand; the membranes allowed chemicals and nutrients from the sand to flow to the bacteria inside. After a week, microbes that had once refused to grow were multiplying like crazy.
Based on the promise of this technology, Lewis and Epstein co-founded NovoBiotic Pharmaceuticals, a drug-discovery company. The iChip is their latest technology, a sleeker and all-around more sophisticated version of the original diffusion chamber. Think of it as a portable nursery for microorganisms: After populating an iChip with bacteria drawn from dirt, scientists place semipermeable plastic coverings on the small blocks. These allow the microbes, held by agar, to soak up everything they need from the soil in which they are buried. The point of ensuring that each well contains just one microbe by diluting some of the dirt into a slurry—a big improvement over Lewis’s and Epstein’s first design—is to save scientists time they otherwise would have to spend differentiating the mess of cells that proliferate while an iChip is interred.
THE GOAL ISN'T JUST TO INCREASE THE NUMBER OF ANTIBIOTICS; IT'S ALSO TO FIND ONES THAT WORK BETTER.
With this culturing method, about 50 to 60 percent of bacterial species found in a soil sample are able to survive in a lab. The iChip is the difference between a telescope that glimpses only the solar system and one that takes in the full breadth of the Milky Way. Amy Spoering, director of biological research at NovoBiotic, says the iChip has already yielded more than two dozen potential antibiotics that are structurally different from existing drugs and are under further investigation. And she believes much more is to come: “We have hundreds and hundreds of iChips that we use on soil all the time.”
The goal isn’t just to increase the number of antibiotics; it’s also to find ones that work better. Not all antibiotics are equally vulnerable to microbial resistance. Some retain their effectiveness longer than others. Because they are screening so much soil and growing so many microbes that have never been grown before, the NovoBiotic scientists think they are bound to hit upon particularly resilient compounds.
Teixobactin is the toughest, most promising find to date because of the novel way it works. Most antibiotics target bacterial proteins encoded by specific genes, meaning that a single DNA tweak can help microbes elude drugs. Teixobactin, by contrast, gloms onto molecules that aren’t encoded by genes, but rather are chemically synthesized through an elaborate process involving many cooperating enzymes. That means bacteria cannot evolve resistance to teixobactin by fine-tuning a gene or two; instead, they must undergo a series of mutations that fundamentally alters the enzymes’ activities—a much more convoluted feat of adaptation.
NovoBiotic’s website proclaims that teixobactin is “essentially free of resistance,” and Lewis is confident that it will take many decades for immunity to emerge. (Vancomycin, a similarly behaving antibiotic approved for use in 1958, remained resistance-free for nearly 30 years.) The iChip will allow researchers to discover other similarly invulnerable antibiotics, Lewis says, buying time until the scientific community has developed a rapid, expedient method of concocting antibiotics synthetically, rather than borrowing properties from microbes. In Lewis’s grand vision, when one drug becomes ineffective, researchers will just whip up another—and be sure to have lots on hand for future failures—thus “solving” the crisis of antibiotic resistance.
If only it were that simple.

Some of Lewis’s peers don’t agree that a stock of teixobactin-like drugs followed by an era of endless synthetic drugs will provide a final solution. As the first and most fundamental stumbling block, they point to biological realities. Microbes typically need around one hour to produce a new generation; the fastest can double their populations in under 10 minutes. And every act of reproduction provides countless opportunities for the sort of genetic adaptation that leads to resistance. “At the end of the day, whatever technology you use, it’s still this cycle of innovation, exploitation, desperation,” says Wright of McMaster University. “To get rid of resistance, you would have to refute natural selection, and to me that is not possible.” Margaret Riley, a professor of microbial evolution at the University of Massachusetts, Amherst, has high praise for the iChip—“I love it”—but echoes Wright on the device’s limitations: “No matter what we throw at them, bacteria will evolve resistance,” she says. “We can’t ever escape that.”
Some scientists are developing strategies for the germ wars that, unlike most antibiotics, focus specifically on slowing resistance’s development. Riley, for example, points out that the majority of drugs are broad-spectrum, destroying all vulnerable bacteria they meet, including the benign and beneficial, and leaving behind lots of real estate for dangerous, drug-immune colonies to develop. So she has partnered with Sichuan University scientist Xiao-Qing Qiu to hone the power of bacteriocins, toxic proteins that bacteria produce to kill other species. A particular bacteriocin, called colicin Ia, punches a lethal hole in bacterial cells’ membranes. By linking colicin Ia to molecules that only bind to certain microbes, Qiu has created highly specific bacteria-killing missiles. He calls them pheromonicins; the Chinese government has committed $400 million a year to support his work. “We can now create in weeks to months a cocktail of pheromonicins that target exactly the bacteria we are going after,” Riley says.
WHO PAYS IS ONE OF THE BIGGEST HURDLES TO DEFERRING THE POST-ANTIBIOTIC ERA. FROM A COLD-EYED BUSINESS PERSPECTIVE, ANTIBIOTICS DON'T TURN BIG PROFITS FOR DRUG COMPANIES.
Meanwhile, Brad Spellberg, chief medical officer of the Los Angeles County-University of Southern California Medical Center, thinks the ideal defense is one that doesn’t directly destroy microbes at all. “If you are not attempting to kill bacteria,” Spellberg explains, “there is minimal selection pressure to evolve resistance.” This is because the microbes don’t have as clear a target to resist. Spellberg is interested in components of bacterial cell membranes, called lipopolysaccharides (LPS), that trigger strong immune responses—inflammation, fever, organ failure—when microbes infect people. In recent studies, Spellberg and his colleagues have used a drug known as an LpxC inhibitor to render Acinetobacter baumannii, a notorious antibiotic-resistant species, incapable of producing LPS. When they’ve exposed lab mice to both A. baumannii and the drug, the animals have remained healthy and have gradually expunged the microbes from their bodies. An LpxC inhibitor, in other words, might help people survive infections by taking an oblique approach to their removal, rather than bludgeoning microbes head-on.
Successfully delivering any innovative treatments to patients, however, requires money—lots of it. And broadly speaking, who pays is one of the biggest hurdles to deferring the post-antibiotic era. From a cold-eyed business perspective, antibiotics don’t turn big profits for drug companies.
It costs about $2.6 billion to develop a single drug and win marketing approval, according to the latest data from the Tufts Center for the Study of Drug Development. In the case of an antibiotic, it takes a pharmaceutical company an exceptionally long time to earn back its investment because the drug is usually taken for just a few weeks or months and is much cheaper than medicines used to treat diabetes, heart conditions, and other chronic ailments. In 2003, for example, Pfizer made $2.01 billion from its best-selling antibiotic, Zithromax, but more than four times as much—$9.23 billion—from cholesterol-lowering Lipitor. Further complicating things, the more of a particular antibiotic that a pharma outfit sells, the greater the risk that bacteria, mutating each time they encounter the drug, will evolve resistance—and diminished effectiveness against infection means the drug won’t sell as well.
As a result, companies have continued to abandon antibiotic R&D in droves. About 15 years ago, Eli Lilly and Bristol-Myers Squibb shuttered their antibiotic research divisions. In 2011, Johnson & Johnson stopped investing in novel antibiotics and Pfizer closed its primary antibiotic research center in the United States, announcing that it planned to open a new one in China; the fate of that facility remains unclear. There are still about 31 companies with antibiotics in clinical development today, according to the Pew Charitable Trusts, but only five are big names that rank among the top 50 by sales; most are start-ups and small biotech outfits with limited resources.
Eleftheria terrae, the bacterium that produces teixobactin.
Several proposals have been put forward to revitalize antibiotic R&D. Jim O’Neill, the economist who chairs the U.K. task force on antimicrobial resistance, suggests delinking drugs’ profitability from sales. According to his commission’s May 2015 report, O’Neill envisions a global organization that pays drug companies lump-sum payments of between $1 billion and $3 billion to either defray or cover the costs of antibiotic development and a global innovation fund to support “blue-sky research into drugs and diagnostics.” Overall, his plan would cost $16 billion to $37 billion over the next 10 years, depending on how exactly its component parts were set up.
Although some experts agree that delinkage would be beneficial, they say it’s unclear how implementation would work. David Shlaes, author of Antibiotics: The Perfect Storm and a former vice president of Wyeth Pharmaceuticals, has called O’Neill’s plan “Antibiotics in Neverland.” Shlaes suggests an alternative: higher prices for antibiotics. Insurance providers and patients are willing to pay hundreds of thousands of dollars for cancer treatments that may grant only two or three extra months of life, yet they are accustomed to paying only a couple of hundred dollars, at most, for antibiotics that are usually guaranteed to work. That expectation must change, Shlaes says, in order for drug development to be viable from the pharma industry’s perspective.
But consider how people reacted to the price of Sovaldi, a cure for hepatitis C that received U.S. Food and Drug Administration (FDA) approval in 2013 and costs about $1,000 per pill. This price incited what the San Francisco Chronicle called “an all-out revolt” among lawmakers, insurers, pharmacy-benefit managers, and patient advocates, who considered the cost exploitative. A similar outcry likely would emerge if antibiotics, long affordable, suddenly were not.
INSURANCE PROVIDERS AND PATIENTS ARE WILLING TO PAY HUNDREDS OF THOUSANDS OF DOLLARS FOR CANCER TREATMENTS, YET THEY ARE ACCUSTOMED TO PAYING ONLY A COUPLE OF HUNDRED DOLLARS, AT MOST, FOR ANTIBIOTICS.
Recognizing the hurdles stymieing antibiotic R&D, the U.S. government has taken steps to help lower them. Much of its focus has been on the regulatory front. In 2012, Obama signed the FDA Safety and Innovation Act, whose Generating Antibiotic Incentives Now provision grants antibiotics “intended to treat serious or life-threatening infections” an extra five years of market exclusivity during which they do not have to compete with generics; that gives a manufacturer more time to recoup development costs. In September 2014, the President’s Council of Advisors on Science and Technology released a report urging the FDA to establish a high-speed lane for new antibiotics. This would involve approving them for limited use by patients who need them most after reviewing data from small clinical trials, rather than waiting for larger and more diverse, but also costlier and more time-consuming, tests. Most recently, in July 2015, the House passed a bill called the 21st Century Cures Act, designed in part to accelerate drug approval.
Some people, however, caution that this legislation could go too far. The New York Times editorial board, for instance, denounced the Cures Act in July: “It would allow a drug to be tested on humans based on only limited evidence that it is safe and effective,” the board wrote. What’s more, it could contribute to the very crisis of antibiotic resistance that altered regulations are supposed to combat: In providing financial incentives to hospitals to use new, fast-tracked antibiotics, the law could end up “encouraging overuse, potentially breeding resistant superbugs.”
In other words, replacing a draconian attitude with a reckless one would solve nothing.

As they continue to sift through the muddy cache of potential new drugs at their fingertips, the scientists at NovoBiotic are pushing to get market approval for teixobactin. Lewis thinks they can do it in five years, but given other drugs’ track records—10 to 15 years is the average time from lab to patient use—that’s a sanguine estimate.
Even if Lewis’s dream comes true, there is still the looming yet little-discussed matter of what would happen next. Maybe researchers have the technical prowess to glean antibiotics from innovations like the iChip; maybe regulations are loosening enough to get drugs to market more quickly. But do people really have the wisdom and the willpower to use antibiotics responsibly?
Recent data don’t look promising. The WHO reported in April that, based on a survey of 133 countries, public awareness of resistance is “low in all regions, with many people still believing that antibiotics are effective against viral infections,” fostering a misuse of drugs. A few months later, a poll by Consumer Reports found that 27 percent of U.S. respondents thought antibiotics could treat colds and the flu, and 41 percent had never even heard of drug-resistant bacteria. Ignorance, clearly, is fueling a global health crisis.
All may not be lost, however. Trickles of evidence suggest that the right kind of psychological nudge can make a difference. In a recent study, University of Southern California’s Daniella Meeker and her colleagues asked Los Angeles-area clinicians to sign pledges to avoid prescribing antibiotics inappropriately, and then to display poster-sized 18-by-24-inch copies of those pledges in their exam rooms. The reproductions also offered general information about antibiotic resistance and how to prevent it. After 12 weeks, Meeker and her team found that the posters had decreased needless prescriptions by about 20 percent. “When extrapolated to the entire United States,” their final report states, “the posted-commitment-letter intervention could eliminate 2.6 million unnecessary antibiotic prescriptions.”
Dismissing simple behavioral interventions as negligible in the face of antibiotic resistance is easy to do—but that would be an egregious error. Psychology is at the heart of the matter. It is instinctual to focus on bacteria as the enemy, and to some extent they are. However, the brunt of resistance begins in, and circles back to, human hands. To keep treading that resistance maelstrom, the world will need to directly address dangerous microbes with innovations like the iChip and others that neutralize bacteria more intelligently than in the past. But an enduring solution will require people to take a hard look within, too. 
BY FERRIS JABR
PHOTOGRAPHS BY CHRISTOPHER LEAMAN

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