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October 31, 2014

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More than human: Microbes are an essential part of our world—and us

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When people think of microscopic life, they often think of infection, which this Staphylococcus aureus is known to cause. In fact, it is the root of the dreaded and drug-resistant MRSA. But that is one side of the microbiome, a dynamic ecosystem that includes organisms that are beneficial to humans, from helping us digest food to making vitamins that enable our blood to clot. A National Institutes of Health initiative called the Human Microbiome Project is currently mapping the microbes that live in and on humans, to complete the picture of our genome.

“We really are more than human. They’re on us; they’re in us; they’re everywhere.”

My body, Brian Hedlund casually tells me, has 10 times more microbial cells than human, around 100 trillion. So much for hand sanitizer.

We’re at a coffee shop on Maryland Parkway, talking about alien movies, poker chips and the origin of life. (Microbe-laden asteroid? Spontaneous generation? God?) Hedlund is an associate professor at UNLV, a microbial ecologist who stalks hot springs across the Great Basin in search of “biological dark matter.” I am a germophobe. Not anywhere near the league of Howard Hughes and his Mason jars, but you couldn’t pay me to eat nachos after bowling a few frames. Given the glut of scare-tactic commercials for kitchen wipes and headlines about salmonella in bagged salad and flesh-eating bacteria in a Georgia river, it’s hard not to overreact. Even the content for grade-schoolers on Kidshealth.org characterizes microbes primarily as “tiny invaders.”

Hedlund agrees there are real threats (and that hand washing is wise), but he politely points out that I’m missing the big picture—the huge picture—starting with the fact that the bagel in my hand would be a lot harder to digest without the bacteria in my gut. Our invisible tenants make up the microbiome, a dynamic ecosystem still in the process of being mapped by a National Institutes of Health initiative called the Human Microbiome Project. It sounds familiar because it’s an extension of the Human Genome Project, a 13-year undertaking that sequenced the three billion chemical base pairs that constitute human DNA and identified more than 20,000 genes within it.

“There was this movement as the Human Genome Project was closing that we really didn’t have the whole human genome, in a sense, because we’re always there with our friends,” Hedlund says, explaining that microbes and humans evolved together. “Generally, it’s not to their advantage to kill you. … The term I like is uneasy truce.”

Inside the Microbiome

Tom Schoenfeld, vice president of Wisconsin-based biotech company Lucigen, is also something of a bio-prospector. In collaboration with UNLV associate professor and microbial ecologist Brian Hedlund, Schoenfeld hunts hot springs for Launch slideshow »

The term Hedlund doesn’t like is “germ.” The connotation has contributed to large-scale industrial, medical and personal practices that are encouraging resistance in organisms we should legitimately fear. We overuse antibiotics on our food and misuse them on ourselves. We zealously (and fruitlessly) try to sterilize our skin and everything it touches. In our blanket defense against the tiny invaders, we force them to adapt and potentially become more lethal. And the ironic reality is that no matter what soap I use, living in this crazy, dirty world comes with some risk.

Las Vegas is a perfect microcosm. All day, every day, people come and go from every corner of the world. They shake hands, share drinks, push chips on the felt and buttons on the slots, maybe even make out with a stranger in the back of a cab. This city encourages contact, not to mention activities that weaken the immune system. So just like the armpit it has been likened to, Vegas offers an ideal climate for the greatest diversity of microbes to get busy. Weekly editor Sarah Feldberg ran this theory by Dennis Pirages, a UNLV political science professor and authority on globalization and pandemics, when outbreak blockbuster Contagion hit theaters last fall. “It only takes 24 hours for a disease to spread from Southern Europe to Las Vegas,” Pirages said. “I hate to think of a poker chip as a wonderful way to pass a virus, but …”

Thanks to Hedlund and Bluff magazine, we have an idea of what’s hitching a ride on the Strip’s chips. The magazine approached Hedlund in 2007 about doing a lighthearted sting on local casinos, and he and his students were game. In a single day, the research team fanned out to five properties, buying $5 stacks of $1 chips and “doggy-bagging” with sterile gloves and Ziplocs. Hedlund laughs at the memory, mostly because none of the casino employees batted an eye.

“I didn’t expect any pattern,” he says. “I thought it would just be random, but I was really surprised to see that this one company had significantly less microbes on their chips.”

That company was the only one named in Bluff’s article—the Wynn. On the other end of the spectrum, “Casino No. 3” had one chip carrying more than 5,600 microbes and averaged nearly 3,000 per chip, mostly Staphylococcus and Bacillus. Staph is commonly found on skin, but some forms cause serious infections and one is related to drug-resistant MRSA, though Hedlund’s team didn’t detect it. The Bacillus cereus they did find is known to cause food poisoning. Sounds gross, until he reminds you that one of your hands is home to about 100 billion bacteria (with some fungi thrown in for color). Most of them are either helpful or harmless to healthy hosts.

But these are not the elusive biological dark matter. The life forms Hedlund hunts are rare, require accommodations hot enough to hard-boil a human and are nearly impossible to grow in the lab—three reasons most have never been scientifically described (though it’s worth noting that 75 percent of all major microbial lineages have yet to be studied, even though they comprise the bulk of our planet’s biodiversity). That represents an enormous genetic reservoir, and with major funding from the National Science Foundation, NASA and the U.S. Department of Energy, Hedlund is determined to tap it.

That means regular treks to Nevada’s Great Boiling Spring in the Black Rock Desert and Little Hot Creek in California’s Long Valley, with occasional research trips to Yellowstone and China. You might catch him dunking a “tea bag” of predigested corn material to snare hungry archaea, or helping out a grad student by scooping cyanobacteria (that make their own sunblock!) into tins normally reserved for roasting turkey. While barbed wire signs warn tourists away from the Great Boiling Spring’s 175-degree water, Hedlund combs the shallows for novel groups of these “thermophiles.” The more he learns about how they’re able to munch on and metabolize solid cellulose (a typical waste product of agriculture and landscape maintenance) and how temperature affects their role in the ecosystem (Hedlund says his organisms are like single-celled “plants”), the better he’ll understand how they thrive and use their energy to build community in scalding conditions.

“My angle is to look into finding better microbes that have better enzymes to degrade this stuff. The weeds are being grown, but they’re currently not good enough,” he says, referring to the enzymes already used by the biofuel industry, which come from microbes that are easily found, easily grown and probably not the best at what they do. In that vein, Hedlund is also partnering with a Wisconsin-based biotech company, Lucigen, to identify heat-loving viruses with enzymes involved in nucleic acid (DNA and RNA) processing that have the potential to improve forensic and medical diagnostics. Not bad for a bunch of germs.

“It is this world you can’t just casually see and understand something about,” Hedlund says. “Being in microbiology, my eyes are open to more.”

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Meet Tara Edwards and Nitrospira calida
Tara Edwards is a master’s student in Brian Hedlund’s lab at UNLV. She talks about her data with the same breathless glee as someone who’s just hurled herself out of an airplane for the first time.
Her Project: Edwards' project is focused on part of the nitrogen cycle, called nitrification. Her subjects are the thermophilic bacteria Nitrospira calida, and her goal is to determine their high temperature threshold for nitrification. Basically, how hot is too hot for them to eat? The question grew from the discovery of accumulated nitrite in the hottest parts of hot springs. As far as she knows, only she and one other lab in the world are attempting to answer it.
Her Purpose: New knowledge of an organism so different from us is inherently valuable, Edwards says, and who knows what applications might emerge 20 years down the road? After all, when DNA polymerase was discovered in a hot spring, no one guessed it would help the police catch bad guys someday.
Her Microbes: Edwards tends to about 180 tinfoil-wrapped bottles of Nitrospira calida. The only way she knows they’re there is if the pink dye that stains the nitrite fades or disappears. The gloves, she says, are to protect them. If she could, she would protect the greater microbiome from its reputation, or at least tell the other side. "“There are so many stories about the negative. I would love to start seeing the same about what they do for us,” she says. “I realize there are things that are going to make you sick. My dad actually died from an infection. He had flesh-eating bacteria. … It kind of says why all of this is important.”

Serendipity is hardly the first word that comes to mind when you see an image of 9/11. Yet, had Ernesto Abel-Santos not moved to New York City a month before the attack and ensuing anthrax scare, he might never have chased that pathogen and others that threaten human health.

Originally from the Dominican Republic, Abel-Santos jokes that he was kicked out of the country because he couldn’t play baseball. While the professor’s research in UNLV’s Department of Chemistry deals with serious biohazards, his sense of humor about life and microbes is finely tuned. When I ask if pathogens, the agents of infectious disease, look evil under a microscope, he says in his dead-on Antonio Banderas baritone, “Let me show you.” The next second, I’m face-to-face with plush toys modeled after anthrax and Clostridium difficile. Lucky for us, Abel-Santos says, the threat of anthrax-related bioterrorism is small because it’s really hard to make into an airborne powder without killing yourself.

C. diff, on the other hand, is a disease of hospital patients—an unwitting creation of modern medicine. Antibiotics that blast bad microbes also blast good ones that keep common invaders like C. diff from germinating. Free to come out of hibernation and roam, the bacteria cause flu-like symptoms, violent diarrhea and about 50,000 deaths in the U.S. every year.

“This is an infection that recurs when you’re taking antibiotics. So they have to give you even stronger antibiotics. But the problem is that you’re still killing your flora,” Abel-Santos says of the beneficial microbial communities that live in our digestive systems and, as it turns out, are as unique as we are. To restore balance, some desperate patients try “fecal transplantation,” essentially consuming a healthy donor’s fecal matter (or having it inserted from the other end) in order to repopulate their systems. Chronic sufferers will be keen to know about a paper Abel-Santos recently submitted for publication, detailing the creation of patent-pending compounds that keep C. diff spores on lockdown. It’s the result of years of painstaking tests to determine the triggers of germination and then chemically disable them. “What we expect these compounds to do is basically serve as a flora surrogate,” he says. “It’s not going to cure the disease. The idea is to prevent the disease.”

Another Abel-Santos project addresses American foulbrood, a highly contagious bacterial infection known to wipe out honeybee larvae. It’s a big problem for agriculture worldwide, because honeybees pollinate crops, and if their colonies are devastated so is our food supply.

UNLV doctoral student and bee whisperer Israel Alvarado is on the case, and he has already found the triggers and some inhibitors of American foulbrood’s culprit, Paenibacillus larvae. Now he’s preparing to test them on rows of tiny honeybee larvae from the hives just outside the life sciences building, but he and Abel-Santos aren’t just looking to block germination. They’re also targeting ways to encourage it because, in spore form, bacteria are impervious to pretty much everything—chlorine, heat, antibiotics—and they can lie in wait for tens of millions of years. Making them germinate also makes them vulnerable enough to kill, so the usual bonfire of contaminated beekeeping materials wouldn’t be necessary. Sometimes, preventing disease means tickling the monster.

Like Ridley Scott’s subconscious, this is too creepy. But Abel-Santos puts things in perspective by telling me about the failure of biosafety detectors.

“They work great in the lab, but they’re so sensitive that they’re false alarms. They trigger with everything,” he says, “because spores are everywhere.”

The beauty of mother nature is that’s she’s fair. As Penny Amy says, all major life forms have their own viruses. Amy is a UNLV microbiology professor, and she’s working with Abel-Santos and two other faculty members on a three-pronged solution to American foulbrood, funded by a sizable grant from the USDA. Her approach is to infect the thing that infects the bees. I ask what P. larvae does to the infant insects, and she calmly replies that it dissolves them from the inside out.

The answer is as simple as finding the right virus, or phage. But Amy says there had been two reports of such a virus, ever, and both were decades ago in Eastern Europe.

“We had no idea where the phage were, if they were active and if we could use them. So we decided to go find them,” Amy says. “We tested 98 samples—soil in and around beehives, wax, honey, dead bees, flowers, and then one day I said, ‘I wonder if Burt’s Bees products have them.’” UNLV master’s student Diane Yost found an abandoned Burt’s Bees lip balm under a park bench that day, and sure enough: of the 98 samples, 31 (including the lip balm) were positive. Amy was blown away. She and Yost have since tested all of them on eight strains of P. larvae.

Based on the patterns in the “zones of death” on their Petri dishes, a particular phage, H1P, is the microbe to beat. It’s effective on all eight strains, though Amy and Yost continue to search for candidates even better at wiping out the honeybee scourge. Once identified, several could be cloned and made into a cocktail that could be sprayed in the hive or fed to the larvae, bridging the gap to the natural immunity that comes with adulthood. And they’re looking at harnessing the power of a viral enzyme called lysin that ruptures bacterial cell walls. You might think it’s a lot of sweat over some lousy bees, but you’d be missing the huge picture. That’s what Amy tries to impress upon her students, especially those going into the health care field and those only taking biology because it’s a requirement.

“Life began with microbes. I believe life will end with microbes, if it ever ends. They are more numerous than anything on Earth. They are more adaptable than anything on Earth. They live in every single niche,” she says. “They invented every kind of metabolism that there is on Earth to this point, and other organisms made use of it. We have nearly the same metabolism as E. coli, and E. coli has been around a lot longer than we have.”

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Lucigen Corporation
Click here to explore the biotech wonders of Lucigen.

The searing hot pools that helped make Yellowstone famous are pretty old, too. Millions of people have admired the billowing steam and jewel tones of the hot springs. Tom Schoenfeld is among the few who wondered if there were viruses inside. He was digging for dinosaur bones with his son in nearby Thermopolis, Wyoming, when it hit him. It was the late ’90s, when the microbiology community was just waking up to the biological dark matter problem.

“There’s a big travertine formation there, this deep chasm of clear water that looks like a swimming pool, but you could cook hot dogs in there. It’s boiling hot. It just seemed to go on forever and looked like a portal to the netherworld. I just thought there must be something cool in there,” Schoenfeld says.

Due to his work with pioneering biotech companies Promega and Epicentre, he already knew it was possible that viral “extremophiles” were present. For Lucigen, a company he helped move out of a basement and into the booming biotech industry, he hoped to find one with an enzyme that could enable rapid diagnostic testing.

That enzyme is DNA polymerase. It’s what all cells and many viruses use to replicate their genetic material. Schoenfeld needed one that could replicate viral RNA, the theory being that it could be used to amplify, or make thousands or millions of copies of a target pathogen to make it easier to detect. Some viruses are treatable, if you catch them fast enough.

“Ironically, in the middle of writing the grant that funded all this research I got pneumonia. It was actually kind of instructive. … The window for treating, you’ve got to get that within 24 hours of presenting with a fever. By the time the answer gets back it’s too late,” he says. “So the idea that we’re working on is a point-of-care test, something that could be done in the clinic. Hopefully we’ll have a result in 30 or 40 minutes so that you can be sent home with the right drug. That’s something that came from our research in the hot springs.”

The “something” is called PyroPhage, and Lucigen is using its special enzyme to amplify and detect various RNA viruses, everything from SARS and HIV to bird flu and swine flu, which have trumped DNA viruses over the last couple decades when it comes to annihilating humans. PyroPhage works just as well on both, and it has been shown to be faster, cheaper and more stable in quantifying a patient’s viral load than the two-enzyme industry standard.

You wouldn’t expect the VP of a major biotech player to still be mucking around in the field, but just last month Schoenfeld was with Hedlund at the Great Boiling Spring. They’re working on what could be the most complete picture of an ecosystem ever painted, a 360-degree view of the hot spring microbiome that could shed serious light on evolution writ large.

For fun, I ask Schoenfeld what he makes of my germophobia. He mentions Louis Pasteur and Robert Koch, the fathers of microbiology. Their insights revolutionized medicine, but they also deeply ingrained an idea in the public mind-set that Schoenfeld calls “misleading.”

“The way I think people picture the human body is that it’s a sterile canister, where suddenly influenza pops up or salmonella pops up. And that’s not it. It’s not a question of you getting a disease. The microbial populations get out of balance,” he says. “People who are paranoid about viruses probably aren’t realizing that every cup of water has a million of them in it.”

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Magnetotaxis in action
Click here for a YouTube video of magnetotactic bacteria responding to a switching magnetic field (set to appropriately dramatic music).

By the time I get to Dennis Bazylinski’s office in the manmade jungle in the heart of UNLV’s School of Life Sciences, the world looks different. It’s weird and kind of wonderful knowing that my belly button is an oasis.

In addition to directing the School of Life Sciences, Bazylinski is a veteran professor and microbial biogeochemist (I sincerely hope he plays Scrabble). His “bugs” are water dwellers, and while he finds them in lakes, ponds and springs in the middle of Nevada’s deserts, much of his fieldwork has been in the oceans. He has even been aboard Alvin, a deep-sea submersible that can withstand the crushing pressure nearly 15,000 feet below the surface. That’s how he was able to view the Gulf of California’s Guaymas Basin, where, at a depth of more than 6,500 feet, hydrothermal vents shoot from cracks in the sea floor. Some believe such geysers are where life really started.

He doesn’t say whether he believes it. In fact, he’s sure that the “truth” so many scientists seek is out of reach. We can’t escape our internal biases, he says, and we can’t time warp in order to prove our inferences no matter how much data is behind them. What we can do is ask questions as objectively as possible and chip away at the answers.

Bazylinski has been working on two fundamental questions for his entire career. As a result, he’s one of the foremost experts on magnetotactic bacteria, so named because they form “the smallest permanent magnets that can be made of two materials” and ride them along the magnetic field lines of the Earth.

“And they’re inside the cells. So the cells are actually magnetic,” Bazylinski says. “They’re like living compass needles.”

While an Italian scientist named Salvatore Bellini discovered the organisms in 1963, it was Richard Blakemore who got them widespread attention with a publication in the esteemed journal Science in 1975. Bazylinski was his first Ph.D. student on the project. Blakemore had recently joined the faculty at the University of New Hampshire, where Bazylinski was interviewing for a position in another professor’s lab. The position was already filled, so the department chair took him to meet Blakemore. Below his lab’s window were 25 bottles of muddy water. Blakemore extracted a single drop and put it on a slide under a weak dissecting microscope, with the lighting set to dark-field.

“Under those conditions you can’t really see the shape of bacteria, but anything that’s alive and moving you see as a bright star swimming around,” Bazylinksi says. “He just put a magnet next to it, and they all started swimming to the edge of the drop. … To this day I sit up under the microscope sometimes, and I look at that and think, my God, this thing is just so damned amazing.”

He shows me looped video of the bacteria swimming one way and then rushing back when the magnetic field is switched. It is damned amazing. Despite his “black thumb,” meaning he’s been able to grow and study organisms no one else could, he still isn’t entirely sure why or how they make magnetosomes, crystals of magnetite that line up along the cell wall. He and his peers in the small, international group focused on these questions believe they’ve zeroed in on some of the genes and proteins involved, but it’s not clear how they fit together at the molecular level. What Bazylinski does know is how the magnets serve microbes in nature. And with the help of many grad students over the years, he has mapped their habitats, discovered extremophilic strains and expanded the picture of how their ability to sense magnetic fields evolved.

“I’m starting to get worried that maybe there’s not going to be enough time to figure it all out. We’ve had a couple hints, but there’s been no smoking gun,” he says. Not even when NASA asked him to collaborate on several papers addressing the significance of magnetite particles found on the ALH84001 meteorite. It came from Mars, and the structure of the particles was almost identical to those found inside a bacterium soon-to-be-named Magnetovibrio blakemorei, in honor of Blakemore. The papers were well received, but they weren’t enough to draw grand conclusions about our intergalactic roots.

One by one, the lines of evidence for life on Mars laid out in the 1996 Science publication that started the frenzy—Search for Past Life on Mars—have been dismissed by the bulk of the research community. Bazylinski is not one of its authors, but he is one its defenders when it comes to overall impact.

“Before that paper came out, whether it be right or wrong, there was no such thing as astrobiology, and now there is. Everybody started to think, ‘Well maybe there is life on other planets, and maybe it’s microbial.’ And the odds of that happening are probably so much greater than little green men coming down here from space,” he says, adding that life on Earth would not even be possible without its microbiome. “It’s a fine line. The same bugs that help you, if your immune system changes slightly or something goes awry, they’re your worst enemy. ... [But] the planet couldn’t exist without them—not just us, the whole planet would be gone. The gas percentages, what makes up air, would not be correct if microbes weren’t controlling that.”

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UNLV School of Life Sciences
Click here to learn more about fascinating research going on in the School of Life Sciences.

Funny how thinking about the smallest creatures makes me feel small. From Hedlund’s dark matter to Bazylinski’s magnetic stars, I have a new appreciation for what’s growing in the “garden,” as The New York Times put it in a June story about the Human Microbiome Project. The story labeled microbial ecologists “wildlife managers,” tasked with finding ways to address the threats some microbes pose without napalming the entire ecosystem. Kill the weeds; save the grass. Because right now, there are tiny living things clearing my skin of residue, making vitamins that enable my blood to clot and keeping lids on those renegade intestinal spores. We need each other. And even if they never reveal the origin of the life we inescapably share, they have already changed its course.

“If the asteroid theory is correct, it’s the same as the poker chip,” Hedlund reflects. “There’s an object loaded with seeds, and it comes into contact.”

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