Frenemies

By Greg Breining
Bacteria: warm, fuzzy little friends that contain the answers to life and combat ills ranging from pollution to obesity? Or horrible pathogens that are out to destroy us? Bacteria are both of those things—and these Carls seek to harness their power. 

bacteria

Bacteria are everywhere, in numbers we can scarcely imagine.

They live by the hundreds of millions in an ounce of soil. They acclimate to acidic hot springs, persist in polar ice, and revel in radioactivity. They live seven miles below sea level in the ocean’s deepest trench and burrow deep in rock nearly 2,000 feet below the sea floor. They survive in the airless atmosphere of the moon, discovered in equipment left behind and later retrieved by astronauts. Freed from 30 million-year-old amber, they come back to life. They outweigh all the plants and animals on Earth. And they live inside us, outnumbering our own cells 10 to 1.

We may think of them as agents of disease and filth, the cause of cholera, syphilis, anthrax, leprosy, bubonic plague, and tuberculosis. But we can’t live without them.

 

In the Beginning . . . Bacteria!

Frasassi Caves

Our debt to bacteria goes back to a time when Earth’s early atmosphere had no oxygen, but consisted of nitrogen, carbon dioxide, and methane. Without oxygen, multicellular life wasn’t possible. The exact form of the very earliest life remains a puzzle, but the earliest fossils of life, dating back 3.5 billion years, are colonies of bacteria. “Microbes ruled the world,” says Jennifer Macalady ’91, an associate professor of geosciences at Penn State University. These bacteria took energy from waterborne chemicals, such as sulfide and iron. Sometime later, bacteria learned how to manufacture their own food through photosynthesis, probably increasing the mass of Earth’s biosphere by orders of magnitude. Cyanobacteria—photosynthetic bacteria that expel oxygen as waste—appeared more than 2.7 billion years ago, and slowly oxygen began accumulating in the atmosphere.

Macalady studies bacteria collected in the Frasassi Caves, an immense cave system in central Italy that was discovered in 1971. With the help of cave divers, she collects bacteria from regions of the cave that are flooded with water containing sulfide compounds. “This deep oxygen-free part of the aquifer illustrates how life might have existed more than 2.5 billion years ago, before microbes produced our oxygen-rich atmosphere, using sunlight,” says Macalady.

In the stable cave environment, bacteria aggregate into biofilms, sometimes several centimeters thick. “The whole ecosystem is built on energy from chemicals in the water,” says Macalady. “By forming biofilms, one bacterium will consume the waste products of another and make the other’s metabolism more efficient and energy yielding.”

In fact, the close association of dependent single-celled bacteria might have led to the birth of multicellular organisms and the incorporation of foreign cells into larger cells, becoming modern-day mitochondria. According to a researcher at the University of California–Berkeley, bacteria also had a lot to do with the origin of plants. About 1.5 billion years ago, cyanobacteria began to take up residence within certain multicellular organisms, making food for the host in return for a home—an event called endosymbiosis, which is also the origin of chloroplasts.

In addition to providing a model for early life on Earth, bacteria might help us imagine life on Mars 4 billion years ago, which likely would have existed in watery caverns and crevices without sunlight, or oxygen—much like portions of the Frasassi Caves. Using that life as a model, Macalady hopes to provide an example of what extraterrestrial life might look like to help scientists recognize other life forms that might exist in our solar system.

 

Bacteria and Plants: A Love-Hate Relationship

Raka Mitra

As a PhD student at Stanford from 1996 to 2004, Raka Mitra studied the complicated minuet between legumes, such as peas, beans, and alfalfa, and specific-soil bacteria (called Rhizobia). Farmers appreciate that legumes increase soil fertility when they are used as a cover crop by incorporating nitrogen from atmospheric sources into their tissues. Later, when legume cover crops are plowed into the soil, they increase the availability of biologically usable nitrogen compounds in the soil. Yet it is really the bacteria living in the legume root nodules that are responsible for the plant’s high nitrogen content. These bacteria convert atmospheric nitrogen into a biologically usable form, a process called nitrogen fixation.

bacteriaIn order to work together, legumes and Rhizobia must communicate effectively. The plant makes the first move by releasing a chemical signal into the soil. “If the right bacteria are present to receive the signal, they will build a novel chemical structure and send it back to the plant,” says Mitra, an assistant professor of biology at Carleton. “The plant recognizes the signal and responds by building a tumor-like structure on its roots called a nodule.” Eventually, the bacteria will inhabit the nodule, where they will fix nitrogen.

When the right match occurs, the benefits are mutual. The plant can store nitrogen and produce proteins, and the bacterium finds refuge from predatory microbes in the nodules of the plant roots.

At Carleton, Mitra studies the relationship between tomato plants and the bacterial pathogen Ralstonia solanacearum, which causes wilt, an agriculturally important disease. The bacteria “have sophisticated molecular machinery that acts like a needle that punctures the plant cell and delivers a suite of 70 proteins directly into the plant cell,” says Mitra. These injected proteins somehow assist disease progression, but very little is known about their functions. Mitra’s research team includes one Carleton graduate and six undergraduates who are investigating the role of one of these proteins, PopS, which is essential for the disease process. “If we can understand more about how this disease works,” she says, “we might be able to breed plants that are resistant to this bacterium.”

 

Contaminant Crusader

bacteria

Until about 40 years ago, scientists could observe bacterial ecosystems only by examining them under a microscope or growing them in a petri dish. And that was a problem because most bacteria won’t grow in petri dishes. Then scientists began using microbial DNA as a way of detecting organisms in an ecosystem without having to grow them.

With the arrival of high-throughput DNA sequencing, researchers were able to analyze the genetic makeup of all bacteria in a sample—such as a beaker of sewage—substantially faster and cheaper. Using a technique called metagenomics (the study of microbial genomes recovered directly from environmental samples), scientists use computers to sort through massive data sets in order to identify and characterize the genomes of individual microbial species. Metagenomics allows researchers to study how microbial communities change over time and how individual organisms function within a community.

“Communities of bacteria can have hundreds or even thousands of distinct species in them,” says Michi Taga ’98, an assistant professor of plant and microbial biology at the University of California–Berkeley. “A key ecological question is how organisms share and vie for resources in these communities.”

To simplify such a complicated picture, Taga is focusing on how bacteria compete for vitamin B12 (the same nutrient found in our multivitamins), which is essential for metabolism in many microbes. While some bacteria produce B12, others scavenge it. “From studying how this one molecule is acquired, we think we can learn general principles about how bacteria share nutrients,” says Taga.

And that’s worthwhile because knowing how to groom ecosystems of desirable bacteria can produce a wealth of benefits.

Consider bioremediation. Bacteria are great recyclers, breaking down organic compounds into elemental bits. Humans use this bacterial power in various bioreactors to break down waste. Among the largest and most familiar bioreactors are sewage treatment plants. The Twin Cities’ Metropolitan Wastewater Treatment Plant, the 10th-largest plant of its kind in the country, treats more than 200 million gallons of raw sewage each day. Incoming sewage is screened to remove trash and large chunks before running into settling ponds to remove smaller solids. In aeration ponds, managed populations of bacteria break down organics. After more settling to remove dead microbes, wastewater is sterilized with liquid chlorine before being discharged into the Mississippi. The nearly odorless effluent is often clearer than the river itself.

Rose Kantor ’10, a PhD candidate in plant and microbial biology at the University of California–Berkeley, is studying a bioreactor system that was developed to break down toxic mining waste. Initially, the mining company mixed bacterial sludge with the contaminants it wanted to eliminate and “lo and behold, some bacteria were able to break it down,” says Kantor, “but we don’t know yet what organisms are living in this soup.”

Kantor wants to learn which specific bacteria are doing the dirty work and how they function. If, for example, only a couple of species do the work and the rest are competing for resources, the system might work better without the competitors. On the other hand, it may turn out that some species are dependent on others, suggesting that balance may be key. “It would be interesting to see if we can improve the efficiency of the reactor, based on what we learn,” says Kantor. “We are using metagenomics to refine methods that could then be applied to other microbial communities.”

 

Cancer Killer

Daniel Saltzman

Daniel Saltzman, chief of pediatric surgery at the University of Minnesota, believes bacteria can deliver a warhead to human cancer cells.

As a graduate student in the mid-1990s, Saltzman studied the cancer drug Interleukin 2 (IL2), a protein that regulates white blood cells and helps the body fight cancer. “We thought it was the holy grail of cancer treatment and that it would lead to a cure,” says Saltzman, whose daughter Samantha is a junior at Carleton. “However, it became clear that, although the substance was extremely effective in fighting some cancers, it was also very toxic.” IL2 killed the cancer cells, but also 5 percent of the patients.

Saltzman and his colleagues found an ally in Salmonella, a rod-shaped bacteria that causes food poisoning. It also shows tremendous affinity for cancer cells, where it is thought to find a favorable low-oxygen environment in which to multiply. “Salmonella naturally hyperconcentrate in tumors,” says Saltzman. Building on the work of microbiologist Roy Curtiss, Saltzman and his colleagues weakened the bacteria to render it harmless and genetically engineered it as a stealthy cancer hunter—to sneak IL2 into the cancer cells—without side effects.

bacteriaIn a recent Food and Drug Administration toxicity trial, patients with advanced cancer who were given a single dose of Salmonella carrying IL2 did not demonstrate any toxic side effects from the Salmonella or
the IL2.

At about the same time as the FDA study, Saltzman and his colleagues were using the IL2 Salmonella to treat dogs whose bone cancer had spread to their lungs, an inevitably fatal condition. At present, nearly 40 percent of the dogs went into complete remission, but the study is not complete. “That’s a huge success,” says Saltzman, “but I’m not satisfied. I want 100 percent remission.”

Saltzman noted that most immune-based cancer therapies have not seen overwhelming success because cancer cells have the ability to suppress the body’s immune system in the area surrounding a tumor.  A “force field,” he calls it. “We are developing a second generation of Salmonella-based therapy that destroys that force field,” he says. “In other words, it not only stops the ability of a cancer cell to suppress the immune system, it simultaneously activates the immune system to kill the cancer.”

Research on lab mice has shown that four different proteins, including IL2, reduce the size of primary tumors, where cancers originate, and in tumors that develop subsequently as the cancer spreads.

To date, Saltzman and his colleagues have tested the treatment with breast, pancreatic, and lung cancers. Yet there is much work left to do. Because he’s had trouble finding funding for further research, Saltzman started Project Stealth to raise money. His goal is to complete within two years the preliminary studies required in order to apply to the FDA to start clinical trials on humans. (Learn more at projectstealth.org.)

Ultimately, Saltzman imagines using stealth bacteria as a tool to fight cancer worldwide—especially in poor areas that may not have access to modern cancer treatment facilities. “It’s nontoxic. It can be administered at home. And it’s cheap,” he says. “What more do you want?”

 

A Gut Reaction

Gregory Plotnikoff ’83

Researchers with the Human Microbiome Project—an international research effort led by the National Institutes of Health and involving 80 institutions—collected bacteria from 242 healthy people between 2010 and 2012. When they sequenced the samples to identify species, they found more than 33,000 species living in the volunteers’ large intestine alone. But also nearly 8,000 on their tongues, 4,200 in their throats, 2,400 behind their ears, and more than 2,000 on their inner elbows. Each person had a unique “microbiome,” a resident community of microbes consisting of only a fraction of those species.

Some were pathogens. Others were incidental to our health. But as researchers are becoming keenly aware, many species are vital to health, helping to digest our food and playing a role in making enzymes, vitamins, neurotransmitters, and nutrients. Gregory Plotnikoff ’83 says disorders of our microbiome have been implicated in disorders as diverse as obesity, autism, and cancer.

“In fact we really are not autonomous at all,” says Plotnikoff, an integrative medicine physician at Allina Health’s Penny George Institute for Health and Healing. The bacteria in our guts, he says, “can regulate our mood, behavior, metabolism, immune function, and a whole lot more. It’s clear that gut bacteria play a role in metabolic syndrome and diabetes.”

Five Things You Should Know About Bacteria

1 We eat them! For thousands of years, humans have harnessed bacteria cultures to ferment foods, resulting in, for example, yogurt, pickles, sauerkraut, and cheese.

2 Bacteria have shown promise for tasks such as recovering and concentrating valuable metals from industrial waste.

3 Bacteria have been used as relatively benign pesticides. A portion of Bacillus thuringiensis, for example, has been spliced into genetically modified crops, such as corn, to produce a protein that kills predatory insects.

4 Bacteria are adept at “horizontal gene transfer,” incorporating genetic fragments from other species of bacteria into their own genome. It’s through such transfers that many species of bacteria have quickly developed resistance to antibiotics.

5 About 100 trillion bacteria live on or in the human body, yet because they are small, they make up only about 2 percent of our body weight.

Plotnikoff cites recent work at New York University (NYU) in which antibiotics have been implicated in weight gain, possibly by altering the natural microbiome. Lab mice that were fed antibiotics gained up to twice as much body fat as mice on the same diet without antibiotics. In other research, scientists introduced bacteria that had been removed from the guts of twin mice, one fat and the other lean, into lab mice. Mice that received bacteria from the fat twin gained weight, while the recipients of bacteria from the lean twin did not.

“Researchers have been able to make a strong case that our use of antibiotics can play a big role in who gains weight and who doesn’t,” says Plotnikoff. “This is the premise behind NYU researcher Martin Blaser’s new best seller, The Missing Microbes.”

Plotnikoff sees many “mystery patients” whose chronic maladies evade diagnosis. He has found that paying close attention to microbiome-related issues can reveal the solution to treating their conditions. “Good, friendly bacteria benefit us and can defeat bad bacteria,” he says. The good bacteria “are the folks we want on the team bus with us. But if there are empty seats, some of the bad players may come in and sit down.”

Among those bad players is Clostridium difficile, the cause of a severe gastrointestinal infection that kills an estimated 15,000 to 20,000 Americans each year. Trouble arises when antibiotics kill enough of the good microbes in a person’s gut to allow C. diff to expand and fill the void. C. diff hinders digestion and releases toxins that cause intestinal inflammation and diarrhea. The standard treatment is another round of antibiotics. But in many patients, C. diff comes roaring back once the person stops taking antibiotics.

To fight C. diff, doctors have rediscovered and are updating a treatment that was written about nearly 1,700 years ago by Ge Hong, a fourth-century Chinese alchemist who counted medicine and longevity among his many interests. After wiping out C. diff with antibiotics, doctors reintroduce “good bacteria” via a fecal transplant—introducing feces from a healthy donor into the intestine. More than 90 percent of patients recover fully within days of the transplant. (One of the treatment’s modern pioneers is Alexander Khoruts, a gastroenterologist at the University of Minnesota and one of Plotnikoff’s medical school classmates.)

We now know that humans and their bacteria are involved in a complicated relationship. One microbiologist has called the human body “an elaborate vessel optimized for the growth and spread of our microbial inhabitants.”

“It’s as if our gut bacteria are shepherds tending their flock,” says Plotnikoff. “And their flock are the cells lining our gut.”

That lining is crucial. “Good fences make good neighbors,” says Plotnikoff. “On one side are 100 trillion bacteria. On the other side is our immune system. If the fence breaks and undesirable bacteria are able to cross over, we have a lot of problems,” including inflammation, adverse food reactivity, and possibly autoimmune diseases.

Because we rely on our bacteria for our health, and quite possibly our lives, we in turn need to keep them happy and healthy, says Plotnikoff. Fortunately, we have several ways to do this. (He elaborates on many of these recommendations in his book Trust Your Gut.)

First, avoid stress: environmental stress such as frequent loud noise, physical stress such as overwork and inadequate sleep, emotional stress such as personal conflict, pharmaceutical stress such as antibiotics, and dietary stress from poor food choices. Each of these can result in an imbalanced gut ecology.

Second, exercise your mind and body to reduce stress hormone production. Plotnikoff says mindfulness exercises, such as yoga and meditation, as well as physical exercise, are especially beneficial to the body’s microbiota.

Third, be sure to include prebiotics in your diet. These are fermented or cultured foods such as sauerkraut and kimchi; cruciferous vegetables like cauliflower, cabbage, and broccoli; and fiber-rich foods such as fruit and “beans, beans, beans,” he says.

Finally, Plotnikoff recommends commercial probiotics, which contain billions of desirable species of bacteria.

By supporting the trillions of good bacteria that live inside us, we can reap the benefits of all the human biome does for us. The gut is less like a gutter than it is like a garden, Plotnikoff says—and we need to be good gardeners.

Add a comment

The following fields are not to be filled out. Skip to Submit Button.
(This is here to trap robots. Don't put any text here.)
(This is here to trap robots. Don't put any text here.)
(This is here to trap robots. Don't put any text here.)