After exploring a cave, your clothes take on a certain smell. It’s earthy, the essence of dirt and dampness. Some cavers like to pick up their coveralls and take a deep sniff to get a caving fix between trips. They covet the smell, protect it.
Hazel Barton doesn’t do this. She’s an avid caver, but she’s also a microbiologist. She knows that the smell comes from compounds made by a microbial phyla called Actinomycete, which decomposes organic materials. Before entering a cave, she washes those bugs away, ties back her auburn hair, and takes care not to spill a single crumb of food—it can feed a million microbes for months. She needs to be as clean and unobtrusive as possible.
Deep in the recesses of the earth, she’s not just caving for the thrill; she’s also collecting microbes whose lack of outside contamination is their greatest asset and that could help us deal with a growing threat: antibiotic resistance.
Most of our antibiotics have come from microbes that live in the soil. These organisms naturally make antibiotics for their own survival, to compete against other bacteria. We’ve mined this resource for ourselves, but now the soil is coming up dry. Antibiotic discovery peaked in the 1950s, in the so-called golden age of antibiotics, and the rate of new antibiotic discovery has been dropping ever since. In 2017, the World Health Organization said that most of the antibiotics currently in the clinical pipeline are “modifications of existing classes of antibiotics and are only short-term solutions.”
Pathogenic resistance to our current antibiotics is associated with 700,000 deaths each year, and recent predictions have estimated that by 2050 these “superbugs” will kill more people annually than cancer currently does. The hunt is on for new antibiotics, and researchers have started to look in strange places: Komodo dragon blood, the bottom of the ocean, or antimicrobials produced by ants.
Finding new antibiotics in these remote environmental sources has proved to be a challenge. But deep in the caves, Barton has found something different—microbes that have already developed antibiotic resistance. “Immediately when you start looking, you find them,” she says. “It’s not that we had to search. They were everywhere.” Antibiotic resistance is everywhere, but that might not be as bad as it sounds.
Gerry Wright, the director of the Michael G. DeGroote Institute for Infectious Disease Research at McMaster University, has been studying antibiotic resistance for 25 years. The pattern has always been the same, he says. We discover an antibiotic, we introduce it into clinical use, and inevitably, resistance emerges in pathogenic bacteria. This happens time and time again, and has led many researchers to believe that resistance is mostly a response to human activity—a modern occurrence directly related to our overuse of antibiotics. But Wright wasn’t so sure.
The average person might not understand the immensity of the threat, he says. The worst-case scenario could plunge us back into the dark ages of medical care. “You couldn’t do surgery without an infection,” he says. “You could never do something as crazy as a heart transplant or a kidney transplant. All of these things that we take for granted in modern medicine, they’re gone. We lose it all.”
For that reason, it’s crucial that we come to understand how antibiotic resistance works, how old it is, and how it evolves. In 2006, Wright’s lab published a paper in Science proposing that microbes from urban, agricultural, and forest locations could carry resistance that they developed on their own. Critics of the study asked how he could be sure the bacteria he tested had never been exposed to human activity. In a 2011 follow-up, Wright’s lab published a paper in Nature that sampled bacteria from various sites, including 30,000-year-old Beringian permafrost sediments. He found that even in these isolated places, bacteria could show resistance. His paper argued that resistance is not a phenomenon that began with our overuse of antibiotics, but that it is as old as bacteria themselves. Pathogens were becoming resistant with outside help: from microbes that already had it.
“We’re living in the Anthropocene, so there’s not a place on the planet, whether it’s the top of the tallest mountains or Antarctica or anything, that you can’t find evidence of human activity,” he admits. Then he saw Barton give a talk on hunting for microbes in secluded caves untouched by human civilization. “That’s when the light bulb went off. I thought: Ah, that’s where we need to look. We need to look under the planet.”
Barton began caving at 14 as part of a youth outdoors program near her home in Bristol, England. Alongside her budding interest in caving was a fascination with microbiology. At age 11, she says her class collected “pond goop” and looked at it under a microscope. “It totally blew my mind,” she remembers.
Caving and microbiology remained separate passions for a long time. In graduate school, she put in long hours at the lab studying infectious disease during the week, and in her spare time on weekends, she would go caving—returning a few days later beaten up from exploring. Her adviser sat down with her, and said that her hobby was a distraction. She would have to choose: caving or microbiology.
“He basically had a come-to-Jesus talk with me and said I needed to decide because I couldn’t do both. It was an easy problem to solve,” she says, laughing. “I just hid it from him after that.”
When she joined the lab of microbiologist Norm Pace at the University of Colorado in 1999, Pace recognized how rare her combination of skills was. Her research with tuberculosis had made her really good at extracting tiny amounts of bacterial DNA from deposits in people’s lungs that have the disease. Those are made of mostly calcium, extremely similar to the rock that makes up cave walls.
At that point, Barton says no one really knew what microbes lived in deep caves. Traditional microbiology methods entail collecting bacteria from the environment and growing them in a petri dish in the lab. But most environmental microbes cannot be cultured this way, and especially not cave microorganisms. They have adapted to low levels of energy and nutrients. When put on a petri plate and encouraged to grow, they gorge themselves to death on the abundance of food.
So Barton’s first microbiology-cave mission was to identify microbes without trying to grow them outside the cave. After extracting DNA from rock, she used PCR, or a polymerase chain reaction, to make copies of it. By looking for similarities or differences in a specific gene that all bacteria share, she could determine where a microbe fell on the bacterial family tree, and identify it. “We were the first people that looked a regular cave environment this way,” she says. She published that work in 2001, and her two passions have been wedded since then.
When talking about herself, Barton tries to be modest—but the truth is that deep caving is not for the faint of heart. Someone who can do it, while also noticing subtle signs of microbial life in the light of a headlamp, is a rare breed.
“When you’re in the cave, you kind of get a feeling for what it felt like to stand on the moon for the first time,” she says. “You’re the first person ever to see it. There are very few things that give you that sense of exploration anymore, where you can go and find unknown land that people didn’t know exist.”
In Wind Cave, in South Dakota, it takes hours to get to the cave itself. You’re either crawling on your belly, climbing straight up, or squeezing straight down for four hours. The cave narrows to 20 centimeters before Barton can get to her sampling site. She has to fit through it, and so does all of her gear. Other trips require less gymnastics, but more stamina. She recently came back from a cave where she camped for eight days. Her backpack was 41 pounds, and she had to climb up 13 ropes to get out.
She says she used to be afraid of heights, but isn’t anymore. Still, when you’re strapped with so much weight and hanging by a rope, certain thoughts are unavoidable. “What tends to go through your mind is, if I mess this up, all the ways I will get hurt on the way down,” she says. “Like, if you drop off the edge of a very big pit. One pit we do quite often is 165 feet, and if you don’t hook yourself in, that’s a non-survivable fall.”
“It’s terrifying,” Wright says. “Doing that scares the pants off of me. Hazel’s like the Lara Croft of microbiology.”
After seeing Barton speak, Wright teamed up with her to see what they could find in Lechuguilla Cave in Carlsbad Caverns National Park. Between 2008 and 2011, Barton went into areas of the cave that had been almost completely isolated for millions of years. In a region known as “Deep Secrets,” more than 1,300 feet from the surface, Barton found microbes that were resistant to multiple antibiotics we use in medical care. The cave has been closed to humans without a permit since it was discovered in 1986. Barton sampled from areas away from the path that have had, at most, four to six people in its vicinity in millions of years’ time.
“Some of the antibiotic-resistant microbes we are looking at are at least 4 million years old,” Barton says. “The continued notion that resistance just emerged in the last 60 to 80 years is a bit silly. Antibiotic resistance probably evolved with the evolution of antibiotics themselves. Which means whatever antibiotics we might find, there’s going to be resistance to it out in the environment.”
She collected 93 strains of bacteria from Deep Secrets, and screened them against 26 antimicrobial products. They found that even here, bacteria showed resistance across most of the major drug families. Seventy percent of the bacteria were resistant to three to four different antibiotics, and three strains were resistant to 14 antibiotics. Those three bacteria were also highly resistant to our newest antibiotic, daptomycin.
In a follow-up study last year, Wright and Barton focused on one bacterium they found, Paenibacillus sp. LC231, which was resistant to 26 out of 40 antibiotics they exposed it to. By studying its genome, they could see how. They found five new ways the bacterium was resisting antibiotics, and 12 genes that were similar to strategies we already knew about.
Barton and Wright do this work because they think that if we know all the ways bacteria can become resistant, we’ll be better equipped to interfere. Barton calls it “inhibiting the inhibitor.” Some microbes evolve the ability to produce specific molecules to block antibiotics. According to Barton, if we can figure out what those are, we can, in turn, block them, allowing the antibiotic to be effective again.
This doesn't mean that humans are off the hook for being a major contributing factor to resistance. If natural selection is a slow-burning fire, we dumped lighter fluid on it with our overuse of antibiotics in healthcare and agriculture. But knowing that resistance is an ancient trait can help human beings better understand our role and what we can realistically do to fight it. Pulling back on antibiotic use is one thing, and focusing on interrupting resistance and putting more efforts into vaccines and bacteriophages are other strategies. But if resistance is millions of years old, a complete victory is not an outcome to fight for. “If resistance is a result of evolution, you cannot stop evolution,” Wright says. “What we need to do is change our mind-set. The idea of conquering this is not possible.”
Though it sounds like a doomsday scenario, Barton thinks that natural antibiotic resistance should be viewed with optimism. “We would be scared if all the microbes on Earth would have been wiped out,” she says. “If it was this all-powerful thing that couldn’t be overcome, there wouldn’t be any microbial life on Earth.”
Instead, there are answers to our questions, and potential solutions—they just lie in extreme parts of the world, or miles underneath our feet.
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