Rocky Mountain Lab rats 

With tens of thousands of lives at stake worldwide, Hamilton scientists Frank DeLeo and Michael Otto struggle to unlock the secrets of antibiotic- resistant staph infections

Passing through the halls at Rocky Mountain Labs, a visitor can’t help notice the red and yellow biohazard signs on most of the doorways. Behind them, lab technicians work with scary-looking pipettes and beakers that glow with a fluorescent green liquid. To get this far into the federally funded research facility in Hamilton and meet the lead researchers, Dr. Frank DeLeo and Dr. Michael Otto, visitors must submit to a thorough search of their vehicle at the guardhouse, pass through airport-like security, and remain in the company of an official escort at all times. The lab currently deals mostly with Biohazard Level 2 and 3 pathogens—relatively common infectious diseases such as salmonella, plague, and Lyme disease—but later this year it will add a Level 4 lab to study some of the world’s most dangerous organisms, like Ebola and anthrax.

In the Biohazard Level 2 labs lining the Building One’s third floor hall, most of the research concerns methicillin-resistant Staphylococcus aureus (MRSA) known as USA300, the highly infectious and sometimes deadly bacteria that kills 17,000 Americans every year, according to the Center for Disease Control and Prevention (CDC). The eerie green-glowing beakers, a lab technician explains, contain millions of copies of various mutated forms of this bacterium.

In the labs, scientists and laboratory staff wear gloves, lab coats, and occasionally goggles. Bottles of disinfectant sit on every available surface in the cluttered rooms as students, research fellows, and post-graduate doctors compile data and perform countless experiments.

DeLeo, 38, and Otto, 40, control every aspect of the lab’s work on MRSA USA300. On any given day, they consult with their 24-member team to guide the day’s experiments, provide advice to collaborators in other labs across the country, and process all of the information gathered into publishable work their peers can study.

Despite the demands on their time, DeLeo and Otto take care explaining their studies of the deadly infection. Sitting in the fluorescent glow of an office filled with the sound of hissing pipes and the hum of lab electronics, including freezer units that keep mutated forms of MRSA preserved for future work, Otto and DeLeo bypass scientific jargon whenever possible to explain the basics of their research.

Essentially, they systematically destroy and mutate the MRSA infection, pushing every conceivable button on its genome to find weak points that can be exploited to save tens of thousands of lives worldwide.

Despite working around creepy critters in an unnerving, high-security setting, it’s the importance of the work, rather than spending every day around deadly bacteria, that causes the two scientists the most stress.

“That’s a lot of pressure to work under,” Otto says. “But it’s also very gratifying to know that you can impact so many lives.”


•••
Otto and DeLeo’s research into MRSA USA300 has attracted attention worldwide. Lately, they say they’re doing interviews every week for the likes of the Associated Press, The Washington Post, “60 Minutes,” and German television. It’s exciting for the scientists, but it’s a mixed blessing.

“There’s been a lot of attention given to our work lately, which is sort of gratifying, but also adds a lot of work,” says DeLeo, a Montana native with a microbiology degree from Montana State University.

The splashy coverage of MRSA increased public awareness of a highly infectious and deadly pathogen. But on the other hand, the media dubbed the bacteria a “super-bug,” which particularly irritates the meticulous researchers, because from their point of view such imprecise terminology serves only to create fear and confusion.

“Some of [the attention is] a bit, what would I say? Sensationalized,” says Otto, a German-born scientist. For example he points out that 17,000 American deaths in a year seems relatively inconsequential compared to the ravages of cancer or the perils of driving a car.

But even if MRSA gets over-hyped by the press, that doesn’t mean it’s any less exciting to study. DeLeo and Otto share an enthusiasm for their work fueled by the high stakes and a competitive drive to find the answers first.

Until three years ago, DeLeo’s only brush with staph bacteria had come in the form of a case of celluloses (a common staph infection) when he was about 19 years old.

“I remember the big problem I had with it was that I couldn’t run for a few days, and that was it,” he says. “I didn’t even realize this was such a big deal.”

DeLeo’s career had been focused on the intricacies of the body’s immune system, specifically white blood cell behavior. But a conversation with a fellow researcher at the National Institute of Health called his attention to MRSA and its emergence as a deadly, widespread infectious disease. He realized it would soon become a major public health priority, and dove into studying MRSA exclusively.

Otto came to the same conclusion from the other side of the biological equation, following the infectious agent, as opposed to the body’s response. He says he has always maintained an ongoing fascination with staph in his own studies.

“Many people probably do not find it as interesting as something like the [bubonic] plague, but I think it is something worth researching,”
he says.

Once Otto recognized the potential significance of MRSA, like DeLeo, he saw an opportunity to get out in front of other researchers before they even became aware of the prospects, and he jumped at the chance put his knowledge of staph bacteria to work.

Melding their respective expertise—DeLeo with his understanding of white blood cells, and Otto with his familiarity with staph—the two saw an opportunity to make headway in the field and shake things up. And last month they did, publishing a paper in the Proceedings of the National Academy of Sciences debunking the conventional scientific wisdom about MRSA and revealing the method it uses to destroy the human immune system.

While not quite a perfectly efficient, indestructible germ, the USA300 bacterium gets pretty close. Its ability to lay waste to white blood cells and conceal its presence from the body’s immune system helps put it beyond the reach of modern medicine. The MRSA bacterium does have weaknesses, the scientists say, but it also possesses many features that make it difficult to treat.

“It’s an extremely ‘fit’ microbe,” DeLeo says.

USA300 starts off in an advantageous position against the body because of its ability to hide behind what Otto describes as “a wall of slime,” which produces special proteins that convince the immune system no foreign pathogen is present. The white blood cells have no idea where the prey lies, leaving the bacteria unchallenged in its instinctive drive to replicate and spread.

At the same time, the bacteria’s tough shell repels the body’s immune response, blocking natural killing agents from entering it and preventing the invasion of antibiotics.

“It has an extremely strong and resilient outer protein shell,” Otto says. “The body’s defenses cannot break in.”

The research by DeLeo and Otto also shows that the bacteria use specialized peptides that poke holes into white blood cells and destroy them. Originally researchers around the world thought a toxin produced by the bacteria caused the destruction of the immune system and created the antibiotic resistance, but DeLeo and Otto proved that thinking incorrect.

“Once again. It seems like we always have to prove this [toxin] theory wrong. Every time. The toxin does not do the damage. It is other factors of the bacteria which are the cause,” Otto says, clearly annoyed by the scientific community’s stubborn misconception.

To prove the ineffectiveness of the toxin, Otto removed it over the course of a few months using genetic manipulation. Even without the toxin-producing gene, the USA300 bacterium still caused extreme sickness in lab mice. Otto concluded it could not be the source of the infection’s indomitable strength.

After two years of further research, Otto and DeLeo found that USA300 imitates the same proteins and enzymes the white blood cells use to track infections, actually luring the body’s natural infection fighters toward them. Then, using the destructive peptides inside it, the bacteria begins punching holes in the white blood cell, tearing it apart, and thereby rendering the immune system useless against the onslaught of infection.

“There were researchers in France, another team working on the MRSA that we were working with, and they had been pushing the toxin theory for over 10 years, so they did not appreciate that we proved the toxin didn’t do anything,” Otto says, his thick German accent brimming with pride.

But even good news can cause a bad reaction. Noting Otto’s delight, DeLeo points out that he took heat for the triumph, fielding calls from French colleagues indignant about the published findings. Publicity, whether it’s focused on an exaggerated threat from MRSA or the success of the researchers investigating it, swings a double-edged sword.


•••
To illustrate how a healthy immune system responds to staph infection, a proud DeLeo shows electron microscope footage of one of his own white blood cells standing strong against several microbes of MRSA, eventually killing the invasive bacteria without much effort. But he’s equally excited when showing pictures of USA300 easily destroying a different white blood cell, almost as if in retribution for the other cell’s insolence.

In contrast to most bacteria, which die when white blood cells begin producing hydrogen peroxide, hypochlorous acid (the active component of household bleach) and other antimicrobial proteins to kill the intruders, USA300 remains mostly unharmed because of its thick outer protein shell. The USA300 also senses impending danger, allowing it to escape harm and turn the tables on the white blood cells, destroying them.

Unlike most staph infections, which occur in infectious settings like hospitals, USA300 essentially grows everywhere, even on top of many people.

According to Otto, the USA300 staph bacteria exist freely on a third of people, another third occasionally carry it, and the last third will never know the infection on a personal level.

“It’s that common,” he says, perhaps without realizing how frightening it sounds.

Otto doesn’t worry about infection however, dismissing such anxious thoughts by saying, “I wash my hands. I bathe. Really poor personal hygiene causes many of these things to be a problem.”

It does seem alarming, however, to imagine a lethal infectious bacteria may already be crawling around on a doorknob or hand, or incubating in the mucus membranes of the sinus, waiting for an open wound that will lead it deep inside its host’s body. Add in some special effects, and it becomes a full-on horror film, breeding an ample amount of fear to get people to invest in a few gallons of hand sanitizers and disinfectant soap. DeLeo and Otto agree both should be used, though every disinfectant will leave at least some of the bacteria alive.

Although the average person may see plenty of cause for concern, DeLeo and Otto joke when asked if they ever worry about an infection.

“[It’s] nothing to really worry about though, unless you’ve got some open wound you’re picking your nose and then touching,” DeLeo says.

Otto balks at the possibility as well.
“Your odds of ever actually getting the staph infection, and then dying from it, are not very high,” he says. “The majority of time the body deals with the infection just fine.”

Even in the lab, they say, there is a very small chance of an infection. Maybe because lab work, especially around dangerous infectious substances, isn’t much of a full contact sport.

“I will tell you that the majority of people who need to worry are those in situation where wounds, or abrasions are common. Like football,” DeLeo says.

He’s referring specifically to a 2005 outbreak of USA300 that, according to the New England Journal of Medicine, sickened over a dozen players who shared a communal whirlpool an infected player had used.

“They play hard and they get these open wounds where the bacteria just goes crazy,” DeLeo says.

Otto says with the new fear surrounding the bacteria, Rocky Mountain Labs gets calls from coaches and athletic directors all the time asking how they should disinfect a locker room containing the bacteria. “Some of them think they need to go and have the entire place bleached again and again. But really all they need is to clean the place and make sure everyone washes themselves,” he advises.

But despite the reassurances, when standing near glowing green beakers full of the infectious bacteria, one cannot help but picture what can happen when just a few hundred of these buggers invade a wound on the body.

•••

Most people with common staph infections develop pus-filled sores, or abscesses that look like pimples or boils, but which can grow as large as softballs if left untreated. Antibiotics easily clear up the sores and the person goes on living a normal life without serious complications, or even remnants of the infection. It’s the most common ailment to strike a sick individual in a hospital, according to the CDC.

USA300, however, is a different creature all together. It can stay in a person’s body, killing white blood cells, expanding its territory and devastating the immune system in its wake.

Both Otto and DeLeo talk about it in strict scientific terms, repeating again and again that the bacterium is just that: a bacteria. It seeks nothing other than survival. It darts behind its cloak of slime and hides, a reminder that although not a sentient being, it fights to live, and kills only inadvertently. DeLeo even expresses amazement that the bacteria’s habit of causing death seems out of character for such an organism, because when the host dies, so does the infection.

“Most of the time bacteria live symbiotically with their host because it needs the host for survival,” he says.

But USA300 can and does kill. Photos of the sores it causes differ dramatically from those of weaker versions of staph infection. The USA300 pictures show areas of dead flesh where a boil once erupted, leaving an ugly crater of gore that eventually scars, a memory of the dead flesh forever emblazoned on the patient.

At first, a MRSA infection acts like any other staph infection. Patients display the same fever and lethargy commonly associated with other bacterial infections. But soon, left to grow, the USA300 bacteria can invade the lung and heart tissues, causing suffocation or cardiac arrest.

Despite its deadly nature, photos of USA300 make the bacteria seem rather innocent, mild, or bland. Bunched together in fluorescent dyed images taken by electron microscopes, the USA300 appear more like grapes on a vine ready for the
harvest than death inducing microbes.

But DeLeo and Otto know better. They say the number of infections in America may have reached its pinnacle, but the number of infections worldwide is likely to grow, and in developing countries where medicine may not be readily available, the bacteria could kill thousands more.

“I’d say we’re not quite at the top of the curve yet as how many people will be part of this epidemic, though I don’t exactly think that’s the term for it,” Otto says.

For now the research continues. Every day scientists working with DeLeo and Otto from around the globe purposefully mutate the USA300 to find out how it works, and what gives it strength.

Did it evolve because of the widespread use of antibiotics used in modern medicine? That’s one possibility they’re researching. Another could be that the organism simply mutated as it passed from person to person, learning new ways to dodge the human immune system while becoming more hostile toward it.

To find the answers, Otto and DeLeo, along with other research teams around the world, are tearing apart the bacteria’s DNA to discover its vulnerabilities to provide a genetic map for other scientists to target with new antibiotics, or at least new treatment options for infected patients.

“That’s what needs to happen,” DeLeo says, “we haven’t had new types of antibiotics for years. That may be what’s needed here.”

So everyday he and Otto show up at the lab, check with their teams of scientists, and guide the research that may lead to an effective treatment for MRSA.

“There is definitely a solution to this,” a confident Otto says. “Sickness, bacteria like this, pathogens like this, they come up from time to time and make a big splash. But science always finds a solution.”

And that’s something both men take seriously.
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