The Simple Rules Bacteria Follow to Survive

Left: Football stadium. Right: Colored contoured lines showing the periodic stops in the growth of a bacterial colony
Football image credit: Stock image. The colored contoured lines show the periodic stops in the growth of a bacterial colony. Credit: Süel Lab, UCSD.

What do these images of football fans and bacterial cells have in common? By following simple rules, each individual allows the group to accomplish tasks none of them could do alone—a stadium wave that ripples through the crowd or a cell colony that rebounds after antibiotic treatment.

These collective behaviors are just a few examples of what scientists call emergent phenomena. While the reasons for the emergence of such behavior in groups of birds, fish, ants and other creatures is well understood, they’ve been less clear in bacteria. Two independent research teams have now identified some of the rules bacterial cells follow to enable the colony to persist.

Expanding circle in the movie show the periodic stops in the growth of a bacterial colony.
Expanding circle in the movie shows the periodic stops in the growth of a bacterial colony. Credit: Süel Lab, UCSD.

Like pancake batter dropping onto a warm griddle, a bacterial colony grows larger by expanding its outer edge. As it does this, the cells near the periphery have access to nutrients needed for growth but are also exposed to substances that could kill them. Meanwhile, the interior cells are starved, but safe.

“As the colony grows, the inside cells have less access to nutrients and should become dormant or even die, but this is not the case,” explains Darren Sledjeski, one of NIGMS’ experts on bacteria. The inner cells provide a reservoir of living cells that will allow the colony to rebound after the outer cells are harmed by antibiotic treatment or another assault.

How do the cells balance the need to compete for resources and cooperate for survival? It turns out that the inner and outer cells in the colony follow the same rule: restrict nutrients. A research team led by Gürol Süel Exit icon of the University of California, San Diego (UCSD), discovered this by studying the growth of Bacillus subtilis biofilms. Biofilms, which contain millions of bacterial cells, are highly resistant to chemicals. For this reason, they can lead to hard-to-treat lung, ear and tooth infections, clog medical implants and coat bathtubs and showers with a slimy residue.

Using a variety of approaches, the UCSD team learned that when the biofilm reached a certain size—about one million cells—the outer cells started consuming all the available glutamate. The starved interior cells then stopped producing ammonium, which halted the growth of the outer cells. As a result of these nutrient-limiting actions, the biofilm growth periodically fluctuated, shown in the image and video above. The results were published last month in Nature.

Other types of bacteria may follow different rules to promote the colony’s growth. Instead of restricting resources, E. coli cells seem to share them, according to a March 2015 BMC Systems Biology paper from Zaida Luthey-Schulten Exit icon and colleagues at the University of Illinois at Urbana-Champaign.

Like human muscle cells, bacteria typically use oxygen to break down glucose into the fuel needed to power cellular processes. But these resources aren’t evenly distributed across a bacterial colony. The Illinois-based studies, which used computational and experimental approaches, showed that as oxygen became less available to the interior cells, these cells broke down glucose into acetate. The acetate became the fuel source for cells with access to oxygen but not glucose. The cells’ cooperation allowed them to persist when the number of cells in the colony increased and resources became more limited.

“As both of these studies show, we’re now starting to get a deeper understanding of the simple rules that bacterial cells follow to drive their collective behavior,” says Sledjeski. “Fundamental insights like these eventually can lead to new strategies for controlling the growth of disease-causing bacteria.”

Field Focus: Progress in RNA Interference Research

Scientists first noticed what would later prove to be RNA interference when puzzling over an unexpected loss of color in petunia petals. Subsequent studies in roundworms revealed that double-stranded RNA can inactivate specific genes. Credit: Alisa Z. Machalek.

In less than two decades, RNA interference (RNAi)—a natural process cells use to inactivate, or silence, specific genes—has progressed from a fundamental finding to a powerful research tool and a potential therapeutic approach. To check in on this fast-moving field, I spoke to geneticists Craig Mello Exit icon of the University of Massachusetts Medical School and Michael Bender of NIGMS. Mello shared the 2006 Nobel Prize in physiology or medicine with Andrew Fire Exit icon of Stanford University School of Medicine for the discovery of RNAi. Bender manages NIGMS grants in areas that include RNAi research.

How have researchers built on the initial discovery of RNAi?

A scientific floodgate opened after the 1998 discovery that it was possible to switch off specific genes by feeding microscopic worms called C. elegans double-stranded RNA that had the same sequence of genetic building blocks as a target gene. (Double-stranded RNA is a type of RNA molecule often found in, or produced by, viruses.) Scientists investigating gene function quickly began to test RNAi as a gene-silencing technique in other organisms and found that they could use it to manipulate gene activity in many different model systems. Additional studies led the way toward getting the technique to work in cells from mammals, which scientists first demonstrated in 2001. Soon, researchers were exploring the potential of RNAi to treat human disease. Continue reading

Nature’s Medicine Cabinet

More than 70 percent of new drugs approved within the past 30 years originated from trees, sea creatures and other organisms that produce substances they need to survive. Since ancient times, people have been searching the Earth for natural products to use—from poison dart frog venom for hunting to herbs for healing wounds. Today, scientists are modifying them in the laboratory for our medicinal use. Here’s a peek at some of the products in nature’s medicine cabinet.

Vampire bat

A protein called draculin found in the saliva of vampire bats is in the last phases of clinical testing as a clot-buster for stroke patients. Vampire bats are able to drink blood from their victims because draculin keeps blood from clotting. The first phases of clinical trials have shown that the protein’s anti-coagulative properties could give doctors more time to treat stroke patients and lower the risk of bleeding in the brain.

Sea squirts

Sea squirts in the crystal waters of West Indies coral reefs and mangrove swamps are the source of an experimental cancer drug called Yondelis. The drug binds to DNA and damages specific genes, which slows cancer cell division, growth and spread. The first set of clinical studies has shown that the drug is safe for use in humans. Additional phases of clinical testing are underway to evaluate whether Yondelis effectively treats tumors of the muscles, tendons, supportive tissues and other types of cancer.

Gila monster

A hormone found in the saliva of the gila monster, a venomous lizard from the woodlands and deserts of the American Southwest, was modified to help people with type 2 diabetes maintain healthy blood sugar levels. Since gila monsters only eat about twice a year, their sugar storage hormone is active for much longer than insulin is in humans. The hormone-derived drug, Byetta, also slows the movement of food from the stomach into the small intestine, which often results in weight loss in diabetics.

Guggul tree

The guggul tree is native to India and has been used in Ayurvedic medicine since at least 600 B.C. to treat obesity and lipid disorders. Scientists are conducting preliminary studies to explore the cholesterol-lowering properties of guggulsterone, a compound in the sap of the guggul tree. Researchers think guggulsterone blocks receptors in liver cells and alters cholesterol break down. Studies have also suggested that guggulsterone has anti-inflammatory properties and can lower triglyceride levels.

Cinchona tree

The bark of the cinchona tree, found in the Amazon rainforest, is the source of the antimalarial drug quinine. Isolated by French chemists in the early 19th century, quinine treats malaria by altering the life cycle of the malaria parasite. Since then, scientists have designed other antimalarial drugs including chloroquine, mefloquine and other derivatives that are chemically similar to quinine. Another natural product, sweet wormwood plant, is the basis of the malarial treatment artemisinin.

Yew tree

A chemical produced by the Pacific yew tree is now the cancer-treating drug paclitaxel (Taxol). The plant-derived drug works by inhibiting the function of microtubules, structural elements that are needed for cell division. By preventing cancer cells from dividing, Taxol stops the cancer from growing. Taxol is used to treat a variety of cancers including breast, lung, prostate and ovarian cancer.

Cone snail

Cone snails in the waters near Australia, Indonesia and the Philippines have toxin-packed venom that’s being studied as a treatment for chronic pain. Prialt, a synthetic compound modeled after a toxin in the venom, is 1,000 times more powerful than morphine in treating certain kinds of chronic pain. The snail-derived drug jams nerve transmission in the spinal cord and blocks certain pain signals from reaching the brain. It’s prescribed to help manage the pain of people suffering from multiple sclerosis, AIDS and cancer.

Bishop’s weed

Psoralen, derived from a Nile-dwelling plant called Bishop’s weed, is a key component of photodynamic therapy, which is used to treat several cancers. Once activated by light, psoralen attaches tenaciously to the DNA of rapidly dividing cancer cells and kills them. Psoralen is also prescribed to increase the ultraviolet absorptivity of skin so UV light can then be used to treat severe skin conditions like psoriasis and eczema.

Snowdrops

Galantamine, a compound extracted from the bulbs and flowers of daffodils, spider lilies and snowdrops, is prescribed to stabilize and improve cognitive function in Alzheimer’s patients. It works by preventing the breakdown of acetylcholine, a chemical that sends messages between certain nerve cells and is important for learning and memory.

The vampire bat, gila monster, bishop’s weed and snowdrop images courtesy of iStock; Sea squirt image courtesy of Pharmamar; Commiphora wightii (guggul tree) Exit icon image courtesy of Vinayaraj V R under CC BY SA 3.0; Cone snail image courtesy of Kerry Matz, University of Utah; Cinchona tree Exit icon image courtesy of U.S. Geological Survey; Pacific yew tree image courtesy of Virginia Tech, Department of Forest Resources and Environmental Conservation.

Data-Mining Study Explores Health Outcomes from Common Heartburn Drugs

Results of a data-mining study suggest a link between a common heartburn drug and heart attacks. Credit: Stock image.

Scouring through anonymized health records of millions of Americans, data-mining scientists found an association between a common heartburn drug and an elevated risk for heart attacks. Their preliminary results suggest that there may be a link between the two factors.

For 60 million Americans, heartburn is a painful and common occurrence caused by stomach acid rising through the esophagus. It’s treated by drugs such as proton-pump inhibitors (PPIs) that lower acid production in the stomach. Taken by about one in every 14 Americans, PPIs, which include Nexium and Prilosec, are the most popular class of heartburn drugs.

PPIs have long been thought to be completely safe for most users. But a preliminary laboratory study published in 2013 suggested that this may not be the case. The study, led by a team of researchers at Stanford University, showed that PPIs could affect biochemical reactions outside of their regular acid suppression action that would have harmful effects on the heart.

To find out if people who took these drugs were more likely to have a heart attack, a bioinformatics team led by Nigam Shah of the Stanford University School of Medicine used data-mining techniques that were previously tested to comb through anonymized electronic medical records of 2.9 million people.

The results, published in PLOS ONE on June 10, suggest a link between PPI use and elevated risk of heart attacks, regardless of the age of the user. The researchers didn’t find a link between another widely used family of heartburn drugs, H2 blockers, and heart attacks.

It is important to note that the results suggest only an association, not a cause-and-effect relationship—many other variables may contribute. “The association we found with PPI use and increased chances of a subsequent heart attack doesn’t in and of itself prove causation,” explains Shah in a Stanford news release Exit icon about the work.

To further explore the results, Shah and colleagues have initiated pre-clinical studies to quantify the extent to which PPIs may modify the biochemical reactions that affect vascular health.

“This research shows the value of mining large amounts of medical data that are already collected and using that information as a springboard to make new discoveries,” says NIGMS’ Rochelle Long.

It also provides an example of how a combination of experimental and data-mining studies can be used to explore, detect and analyze adverse drug events.

This work was funded in part by NIH grants R01GM101430 and U54HG004028.

Meet Sarkis Mazmanian and the Bacteria That Keep Us Healthy

Sarkis K. Mazmanian
Credit: New York Academy of Sciences
Sarkis K. Mazmanian, Ph.D.
Born in: The country of Lebanon, moved to Los Angeles when he was 1
Fields: Microbiology, immunology, neuroscience
Works at: California Institute of Technology
Awards won: Many, including the MacArthur Foundation “Genius” grant
Most proud of: The success of his trainees! “There’s nothing that comes close to the gratification and joy I feel when a student or research fellow goes on to be an independent scientist.”
When not in the lab or mentoring students, he’s: Spending time with his family, including his 1-year-old-son or going for an occasional run

As a child, Sarkis Mazmanian frequently took things apart to figure out how they worked. At the age of 12, he dismantled his family’s entire television set—to the dismay of his parents and the unsuccessful TV repairman.

“I wasn’t aware of this at the time, but maybe that was some sort of a foreshadowing that I would enjoy science,” Mazmanian says. “Scientists take biological systems apart to understand how they work.”

Mazmanian never thought he’d become a microbiologist, let alone a leading expert in the field. He began studying microbiology at the University of California, Los Angeles (UCLA), because it was the major that allowed him to do the most hands-on research. But as soon as he entered the field, he fell in love with the complexities of microbial organisms and the efficiency of their functions. Continue reading

Food for Thought: Nutrient-Detecting Brain Sensor in Flies

If you participated in a cupcake taste test, do you think you’d be able to distinguish a treat made with natural sugar from one made with artificial sweetener? Scientists have known for decades that animals can tell the difference, but what’s been less clear is how.

Fruit fly neurons in the brain (red) with nerve fibers (white) that extend to the gut.
For fruit flies, nutritive sugars activate a set of neurons in the brain (red) with nerve fibers (white) that extend to the gut. Credit: Jason Lai and Greg Suh, New York University School of Medicine.

Now, researchers at the New York University School of Medicine have identified a collection of specialized nerve cells in fruit flies that acts as a nutrient-detecting sensor, helping them select natural sugar over artificial sweetener to get the energy they need to survive.

“How specific sensory stimuli trigger specific behaviors is a big research question,” says NIGMS’ Mike Sesma. “Food preferences involve more than taste and hunger, and this study, which was done in an organism with many of the same cellular components as humans, gives us a glimpse of the complex interplay among the many factors.”

The study, described in the July 15 issue of Neuron, builds on the researchers’ earlier studies of feeding behavior that showed hungry fruit flies, even ones lacking the ability to taste, selected calorie-packed sugars over zero-calorie alternatives. The scientists, led by Greg Suh Exit icon and Monica Dus Exit icon, suspected that the flies had a molecular system for choosing energy-replenishing foods, especially during periods of starvation. Continue reading

From Basic Research to Bioelectronic Medicine

Kevin Tracey
Kevin J. Tracey of the Feinstein Institute for Medical Research, the research branch of the North Shore-LIJ Health System, helped launch a new discipline called bioelectronic medicine. Credit: North Shore-LIJ Studios.

By showing that our immune and nervous systems are connected, Kevin J. Tracey Exit icon of the North Shore-LIJ Health System’s Feinstein Institute for Medical Research helped launch a new discipline called bioelectronic medicine. In this field, scientists explore how to use electricity to stimulate the body to produce its own disease-fighting molecules.

I spoke with Tracey about his research, the scientific process and where bioelectronic medicine is headed next.

How did you uncover the connection between our immune and nervous systems?

My lab was testing whether a chemical we developed called CNI-1493 could stop immune cells from producing inflammation-inducing molecules called TNFs in the brain of rats during a stroke. It does. But we were surprised to find that this chemical also affects neurons, or brain cells. The neurons sense the chemical and respond by sending an electrical signal along the vagus nerve, which runs from the brain to the internal organs. The vagus nerve then releases molecules that tell immune cells throughout the body to make less TNF. I’ve named this neural circuit the inflammatory reflex. Today, scientists in bioelectronic medicine are exploring ways to use tiny electrical devices to stimulate this reflex to treat diseases ranging from rheumatoid arthritis to cancer. Continue reading

Elements That Keep Us Alive Also Give Color to Fireworks

Looking up at the night sky this Fourth of July, you might wonder what gives fireworks their vivid colors. The bright hues result from chemical elements that are also essential for life. Chemists and other researchers have been uncovering their roles in a range of important biological processes.

By mass, about 96 percent of our bodies are made of four key elements: oxygen (65 percent), carbon (18.5 percent), hydrogen (9.5 percent) and nitrogen (3.3 percent). These elements do not give color to fireworks, but they are found in our body’s most abundant and important molecules, including water, proteins and DNA.

A dozen or so other elements—mostly metals—make up the remaining 4 percent. Present in minuscule amounts, these elements are involved in everything from transporting oxygen and releasing hormones to regulating blood pressure and maintaining bone strength. They also add a burst of color when put in to a fireworks recipe. Here are several examples. Continue reading

Designing Drugs That Kill Invasive Fungi Without Harming Humans

Top to bottom: Cryptococcus, Candida, Aspergillus, Pneumocystis
Invasive fungal infections kill more than 1 million people worldwide every year. Almost all of these deaths are due to fungi in one of these four groups. Credit: Centers for Disease Control and Prevention.

Invasive fungal infections—the kind that infect the bloodstream, lung and brain—are inordinately deadly. A big part of the problem is the lack of drugs that are both effective against the fungi and nontoxic to humans.

The situation might change in the future though, thanks to the work of a multidisciplinary research team led by chemist Martin Burke at the University of Illinois. For years, the team has focused on an antifungal agent called amphotericin B (AmB for short). Although impressively lethal to fungi, AmB is also notoriously toxic to human cells.

Most recently, the research team chemically modified the drug to create compounds that kill fungi, but don’t disrupt human cells. The scientists explain it all in the latest issue of Nature Chemical Biology.

Invasive fungal infections are so intractable because most antifungal drugs aren’t completely effective. Plus, fungi have a tendency to develop resistance to them. AmB is a notable exception. Isolated 50 years ago from Venezuelan dirt, AmB has evaded resistance and remains highly effective. Unfortunately, it causes side effects so debilitating that some doctors call it “ampho-terrible.” At high doses, it is fatal.

For decades, scientists believed that AmB molecules kill fungal cells by forming membrane-piercing pores, or ion channels, through which the cells’ innards leak out. Last year, Burke’s group overturned this well-established concept using evidence from nuclear magnetic resonance, chemistry and cell-based experiments. The researchers showed that AmB molecules assemble outside cells into lattice-like structures. These structures act as powerful sponges, sucking vital lipid molecules, called ergosterol, right out of the fungal cell membrane, destroying the cell. Continue reading

Unusual DNA Form May Help Virus Withstand Extreme Conditions

A, B and Z DNA.
DNA comes in three forms: A, B and Z. Credit: A-DNA, B-DNA and Z-DNA by Zephyris (Richard Wheeler) under CC BY-SA 3.0.

DNA researcher Rosalind Franklin Exit icon first described an unusual form of DNA called the A-form in the early 1950s (Franklin, who died in 1958, would have turned 95 next month). New research on a heat- and acid-loving virus has revealed surprising information about this DNA form, which is one of three known forms of DNA: A, B and Z.

“Many people have felt that this A-form of DNA is only found in the laboratory under very non-biological conditions, when DNA is dehydrated or dry,” says Edward Egelman Exit icon in a University of Virginia news release Exit icon about the recent study. But considered with earlier studies on bacteria by other researchers, the new findings suggest that the A-form “appears to be a general mechanism in biology for protecting DNA.” Continue reading