Outwitting Antibiotic Resistance

Marine scene with fish and corals
The ocean is a rich source of microbes that could yield infection-fighting natural molecules. Credit: National Oceanic and Atmospheric Administration Exit icon.

Antibiotics save countless lives and are among the most commonly prescribed drugs. But the bacteria and other microbes they’re designed to eradicate can evolve ways to evade the drugs. This antibiotic resistance, which is on the rise due to an array of factors, can make certain infections difficult—and sometimes impossible—to treat.

Read the Inside Life Science article to learn how scientists are working to combat antibiotic resistance, from efforts to discover potential new antibiotics to studies seeking more effective ways of using existing ones.

 
 

An RNA Molecule That Cues the Internal Clock

Clock
Dysfunction in our internal clocks may lead to insufficient sleep, which has been linked to an increased risk for chronic diseases. Credit: Stock image.

Our internal clocks tell us when to sleep and when to eat. Because they are sensitive to changes in daytime and nighttime cues, they can get thrown off by activities like traveling across time zones or working the late shift. Dysfunction in our internal clocks may lead to insufficient sleep, which has been linked to an increased risk for chronic diseases like high blood pressure, diabetes, depression and cancer.

Researchers led by Yi Liu Exit icon of the University of Texas Southwestern Medical Center have uncovered a previously unknown mechanism by which internal clocks run and are tuned to light cues. Using the model organism Neurospora crassa (a.k.a., bread mold), the scientists identified a type of RNA molecule called long non-coding RNA (lncRNA) that helps wind the internal clock by regulating how genes are expressed. When it’s produced, the lncRNA identified by Liu and his colleagues blocks a gene that makes a specific clock protein.

This inhibition works the other way, too: The production of the clock protein blocks the production of the lncRNA. This rhythmic gene expression helps the body stay tuned to whether it’s day or night.

The researchers suggest that a similar mechanism likely exists in the internal clocks of other organisms, including mammals. They also think that lncRNA-protein pairs may contribute to the regulation of other biologic processes.

Learn more:
University of Texas Southwestern Medical Center News Release Exit icon
Circadian Rhythms Fact Sheet
Resetting Our Clocks: New Details About How the Body Tells Time Article from Inside Life Science
Remarkable RNAs Article from Inside Life Science

Mighty Mitochondria

Mitochondria from the heart muscle cell of a rat.
Mitochondria (red) from the heart muscle cell of a rat. Nearly all our cells have these structures. Credit: Thomas Deerinck, National Center for Microscopy and Imaging Research Exit icon.

Meet mitochondria: cellular compartments, or organelles, that are best known as the powerhouses that convert energy from the food we eat into energy that runs a range of biological processes.

As you can see in this close-up of mitochondria from a rat’s heart muscle cell, the organelles have an inner membrane that folds in many places (and that appears here as striations). This folding vastly increases the surface area for energy production. Nearly all our cells have mitochondria, but cells with higher energy demands have more. For instance, a skin cell has just a few hundred, while the cell pictured here has about 5,000.

Scientists are discovering there’s more to mitochondria than meets the eye, especially when it comes to understanding and treating disease.

Read more about mitochondria in this Inside Life Science article.

Meet Scott Poethig

Scott Poethig
Fields: Plant biology, cell and developmental biology, genetics
Works at: University of Pennsylvania
Studied at: College of Wooster, Yale University
Favorite musicians: Nick Drake and Bruce Springsteen
High school job: Radio D.J.
Favorite book: “The Little Prince,” by Antoine de Saint-Exupéry

When Scott Poethig signed up for a developmental biology course in his senior year of college, he expected to learn how organisms transition from single cells to juveniles to adults. He did not expect to learn just how much scientists still didn’t know about this process.

“It was the first course I had taken as an undergraduate where I felt that I could ask a question that there wasn’t an answer to already,” he recalls. “I thought, ‘Wow! This is amazing.’”

Poethig already had an interest in plant biology and an independent research project studying corn viruses. He immediately saw the potential in combining his knowledge of plants with his questions about how organisms grow. “There seemed to be a lot of low hanging fruit in plant development,” he says.

Today, Poethig is the head of a plant development lab at the University of Pennsylvania. His work probes the complex molecular mechanisms that drive the transition from a young seedling to an adult plant that hasn’t yet produced seeds.

“The analogous period in human development is the interval between birth and puberty,” he explains. “People think of puberty as the major developmental transition in postnatal human development, but a lot of change happens before that point.”

His Findings

Poethig discovered that for the mustard plant Arabidopsis, a model organism frequently studied by geneticists, change begins early. Before these plants begin to flower—a sign of reproductive maturity—they undergo a process of vegetative maturation. In Arabidopsis, Poethig found that juvenile plants can be distinguished from adult plants by where hairs are produced on a leaf. Juvenile plants only produce hairs on the upper surface of the leaf, whereas adult plants produce leaves with hairs on both the upper and lower surfaces.

By studying mutant Arabidopsis plants where the adult pattern of hair development is either delayed or advanced, Poethig identified microRNAs as key players in this developmental transition.

MicroRNA molecules commonly block the expression of specific genes. Poethig found that in Arabidopsis, a type of microRNA prevents development. Young plants have high levels of this microRNA and cannot fully mature. When those levels drop, plants progress to adulthood.

MicroRNAs similarly control development in the nematode C. elegans. Scientists study the genetics of this tiny worm to better understand related developmental processes in more complex organisms. Because plants also use microRNAs to regulate development, Poethig’s discoveries may contribute to our understanding of how these molecules govern development in animals, including humans.

Poethig now wants to learn what determines the timing of developmental changes. He asks: “Why do microRNA levels drop? What’s the signal that causes that? What is the plant measuring?” His current hypothesis: sugar.

In a recent study, he found that giving plants additional sugar reduced microRNA levels and sped up development. Meanwhile, mutant plants that couldn’t produce enough sugar on their own through photosynthesis had increased microRNA levels and delayed development compared to normal plants.

This research may one day advance our understanding of how nutrition and genetics interact to affect human development. “In essentially all organisms, aging and the timing of developmental processes are strongly affected by nutrition,” Poethig explains. “In humans, childhood obesity is sometimes associated with early puberty, and it is important to understand the molecular basis for this effect.”

Poethig believes that studying microRNAs in plants may also lead to discoveries in human genetics outside of developmental biology. “MicroRNAs control a wide range of gene activity in plants and animals,” Poethig explains. “In humans, these molecules control the activity of as many as 30 percent of our genes. So understanding how microRNAs work in plants could help us understand their function in humans.”

Besides studying the Arabidopsis plants in his lab, Poethig also studies the plants in his kitchen, and uses his fascination with the history, culture and politics of food to excite others about science. Watch video.

Field Focus: Precision Gene Editing with CRISPR

Bacterial cells infected by viruses.
Bacterial cells can be infected by viruses (shown in red and purple) and have evolved ways to defend themselves. Credit: Stock image.

Like humans, bacteria can be infected by viruses and have evolved ways to defend themselves. Researchers are now adapting this bacterial “immune system” to precisely and efficiently edit genes in cells from humans and a wide range of other organisms. Scientists are excited about the tremendous potential of this powerful tool for advancing biomedical research and treating diseases.

The bacterial defense system is called CRISPR, for clustered regularly interspaced short palindromic repeats. A breakthrough in understanding CRISPR came from examining bacteria used by the dairy industry for the production of yogurt and cheese. In a study published in 2007, researchers showed that these bacteria insert viral DNA sequences into their own genomes and use that information to disarm the virus when it attacks again. Subsequent research has shown that the CRISPR system consists of small RNA molecules that target specific viral DNA sequences and proteins that cut the DNA, thus destroying the virus.

Researchers have already adapted CRISPR into a gene-editing tool that’s quicker, cheaper and more precise than existing methods. Researchers can use CRISPR to add, delete, rev up or tone down certain genes as well as create animal models for studying human diseases. The ability to precisely target genes in human cells is expected to speed progress in the development of gene-based therapies.

Although much is known about CRISPR, we still have a lot to learn. For example, how do bacterial cells obtain and insert the viral DNA into their genome? What triggers production of the CRISPR RNA molecules? How are invading viral DNAs targeted for destruction? This last question is answered in part by a pair of findings described in an earlier post, A Crisper View of the CRISPR Gene-Editing Mechanism. We also want to figure out how we can make the CRISPR gene-editing tool even more versatile and precise.

The CRISPR story offers a good example of how studying basic biological processes leads to new—and sometimes unexpected—insights and applications.

Emily Carlson also contributed to this blog post.

A Crisper View of the CRISPR Gene-Editing Mechanism

Structural model of the Cascade surveillance machine
Structural model of the Cascade surveillance machine. Credit: Ryan Jackson, Montana State University. Click for larger image

To dismantle the viruses that infect them, bacteria have evolved an immune system that identifies invading viral DNA and signals for its destruction. This gene-editing system is called CRISPR, and it’s being harnessed as a tool for modifying human genes associated with disease.

Taking another important step toward this potential application, researchers now know the structure of a key CRISPR component: a multi-subunit surveillance machine called Cascade that identifies the viral DNA. Shaped like a sea horse, Cascade is composed of 11 proteins and CRISPR-related RNA. A research team led by Blake Wiedenheft Exit icon of Montana State University used X-ray crystallography and computational analysis to determine Cascade’s configuration. In a complementary study, Scott Bailey Exit icon of Johns Hopkins University and his colleagues determined the structure of the complex bound to a viral DNA target.

Like blueprints, these structural models help scientists understand how Cascade assembles into an efficient surveillance machine and, more broadly, how the CRISPR system functions and how to adapt it as a tool for basic and clinical research.

Learn more:
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New Research Sheds Light on Drug-Induced Salivary Issues

Open human mouth
Scientists have discovered a possible mechanism behind the bad taste and dry mouth caused by some drugs. Credit: Stock image.

The effects some medicines have on our salivary glands can at times extend beyond the fleeting flavor we experience upon ingesting them. Sometimes drugs cause a prolonged bad taste or dryness in the mouth, both of which can discourage people from taking medicines they need. Now, a research team led by Joanne Wang of the University of Washington has discovered a possible mechanism behind this phenomenon. Working primarily with mice and using a commonly prescribed antidiabetic drug known to impair taste, the scientists identified a protein in salivary gland cells that takes up the drug from the bloodstream and secretes it in saliva. Wang and her colleagues were also able to pinpoint a specific gene that, when removed, hindered this process. They hope their new insights will aid efforts to develop medicines that do not cause salivary issues.

This work also was funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Learn more:
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Aspirin’s Dual Action

Aspirin
Aspirin can help reverse inflammation as well as prevent it from occurring. Credit: Stock image.

Ever wonder how aspirin knocks out aches? Scientists have known that medicine prevents an enzyme called cyclooxygenase from producing compounds linked to pain and inflammation, but they recently made another discovery about how aspirin works.

Edward Dennis and colleagues at the University of California, San Diego School of Medicine researched aspirin’s effect on macrophages–white blood cells that play a role in the body’s immune response to injury. They found that in addition to killing cyclooxygenase, aspirin causes the enzyme to make a product called 15-HETE. During infection and inflammation, 15-HETE can get converted by another enzyme into lipoxin, a compound that terminates and reverses inflammation.

Researchers will likely use lipoxin and similar compounds to develop new anti-inflammatory drugs.

Learn more:
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Cool Image: Training Cells to Devour Dying Neighbors

A healthy cell that has ingested dying cells.
A healthy cell (green) that has ingested dying cells (purple). Credit: Toru Komatsu, University of Tokyo.

In this image, a healthy cell (green) has engulfed a number of dying cells (purple) just as a predator might ingest wounded or dying prey. A team of researchers is hoping to use this same strategy at the cellular level to help treat infection, neurodegenerative diseases or cancer.

Our bodies routinely use a process called phagocytosis to rid themselves of unhealthy cells. Takanari Inoue Exit icon at Johns Hopkins University and collaborators at the University of Tokyo set out to investigate the molecular underpinnings of phagocytosis. Their goal was to endow laboratory-grown human cells with phagocytotic skills, namely the ability to recognize, swallow and digest dying cells. The scientists tried to do this by inserting into the cells two molecules known to play a role in phagocytosis.

The engineered cells accomplished the first two tasks—they recognized and surrounded dying cells. But they didn’t digest what they’d engulfed. Now the researchers are looking for a molecular trigger to get the engineered cells to complete this last task.

Eventually, the scientific team aims to build artificial cells that are programmed to target and destroy abnormal cells, such as those ravaged by bacteria, cancer or other diseases.

Learn more:
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How Cells Take Out the Trash Article from Inside Life Science
Cellular Suicide: An Essential Part of Life Article from Inside Life Science

Say Cheese

Assorted cheeses
A biofilm of bacteria and fungi, commonly known as a rind, forms on the surface of traditionally aged cheeses. Credit: Elia Ben-Ari.

Biofilms—multispecies communities of microbes that live in and on us, and in the environment—are important for human health and the function of ecosystems. But studying these microbial metropolises can be challenging because many of the environments where they’re found are hard to replicate in the lab.

Enter cheese rinds. These biofilms of bacteria and fungi form on the surface of traditionally aged cheeses, and could serve as a system for understanding how microbial communities form and function. By sequencing DNA from the rinds of 137 artisan cheese varieties collected in 10 countries, Rachel Dutton and her colleagues at Harvard University identified three general types of microbial communities that live on their tasty study subjects. After individually culturing representatives of all the species found in the rind communities the scientists added them to a growth medium that included cheese curd. This approach allowed them to recreate the communities in the lab and use them to detect numerous bacterial-fungal interactions and patterns of community composition over time.

The scientists plan to use their lab-grown cheese rinds to study whether and how various microbes compete or cooperate as they form communities, as well as what molecules and mechanisms are involved. In addition to answering fundamental questions about microbial ecology, this cheesy research might ultimately yield insights that help fight infection-causing biofilms or lead to the discovery of new antibiotics.

Learn more:
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