Learning More About Our Partners in Digestion

Bacteroides ovatus
Bacteroides ovatus. Credit: Eric Martens, University of Michigan Medical School.

After eating, we don’t do all the work of digestion on our own. Trillions of gut bacteria help us break food down into the simple building blocks our cells need to function. New research from an international team co-led by Eric Martens of the University of Michigan Medical School has uncovered how a strain of beneficial gut bacteria, Bacteroides ovatus, digests complex carbohydrates called xyloglucans that are found in fruits and vegetables. The researchers traced the microorganism’s digestive ability to a single piece of the genome. They also examined a publicly available set of genomic data, which included information from both humans and their resident bacteria, and found that more than 90 percent of 250 adults harbored at least one Bacteroides strain with xyloglucan-digesting capabilities. These results underscore the importance of the bacteria to human health and nutrition.

This work also was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.

Learn more:
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Gut Reactions and Other Findings About Our Resident Microbes from Inside Life Science
Body Bacteria from Findings Magazine

Resetting Our Clocks: New Details About How the Body Tells Time

VIP in time-keeping brain cells
Boosting doses of a molecule called VIP (green) in time-keeping brain cells (blue) helped mice adjust quickly to major shifts in light-dark cycles. Credit: Cristina Mazuski in the lab of Erik Herzog, Washington University in St. Louis.

Springing clocks forward by an hour this Sunday, traveling across time zones, staring at a computer screen late at night or working the third shift are just a few examples of activities that can disrupt our daily, or circadian, rhythms. These roughly 24-hour cycles influence our physiology and behavior, and they’re driven by our body’s network of tiny timekeepers. If our daily routines fall out of sync with our body clocks, sleep, metabolic and other disorders can result.

Researchers funded by the National Institutes of Health have spent decades piecing together the molecular mechanisms of our biological clocks. Now, they’re building on that basic knowledge to better understand the intricate relationship among these clocks, circadian rhythms and physiology—and ultimately, find ways to manipulate the moving parts to improve our modern-day lives.

Continue reading this new Inside Life Science article

Animal Cells ‘Reach Out and Touch’ to Communicate

Cytonemes in the fruit fly tracheal system.
Threadlike cytonemes (at right) convey signals between cells in the developing fruit fly tracheal system. Credit: Sougata Roy, University of California, San Francisco. View larger image

Scientists have long known that multicellular organisms use biological molecules produced by one cell and sensed by another to transmit messages that, for instance, guide proper development of organs and tissues. But it’s been a puzzle as to how molecules dumped out into the fluid-filled spaces between cells can precisely home in on their targets.

Using living tissue from fruit flies, a team led by Thomas Kornberg of the University of California, San Francisco, has shown that typical cells in animals can talk to each other via long, thin cell extensions called cytonemes (Latin for “cell threads”) that may span the length of 50 or 100 cells. The point of contact between a cytoneme and its target cell acts as a communications bridge between the two cells.

Until now, only nerve cells (neurons) were known to communicate this way. “This is an exciting finding,” says NIGMS’ Tanya Hoodbhoy. “Neurons are not the only ‘reach out and touch someone’ cells.”

This work also was funded by NIH’s National Heart, Lung, and Blood Institute.

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Meet Jasmine Johnson and Gabe Vela

Jasmine Johnson and Gabriel 'Gabe' Vela
Jasmine Johnson and Gabriel “Gabe” Vela
Field: genetics of sleep and obesity
Worked as researchers at: The Jackson Laboratory, Bar Harbor, Maine
Graduated from high school at: Rockdale Magnet School for Science and Technology in Conyers, Ga.
Now freshman at: Stanford University in Palo Alto, Calif. (Johnson) and Southern Polytechnic State University in Marietta, Ga. (Vela)
Fascinating fact: Johnson presented her research at the 2013 White House Science Fair
Credit: Joe Piergrossi

Jasmine Johnson and Gabe Vela might still be teenagers, but they are also seasoned scientists. It all started 3 years ago, when, as high school juniors, they took the research course Independent Studies in Computational Biology Exit icon at The Jackson Laboratory in Bar Harbor, Maine. They were hooked. They continued to do research until they graduated, working part-time for 2 academic years and full-time for 2 summers.

They worked with statistical geneticist Gary Churchill, using computational biology to explore the relationship between sleep and obesity. They focused on finding genes that regulate sleep and understanding how sleep affects the body. One goal of the research is to tease out a genetic explanation for why sleep deprivation increases the risk of obesity.

Working in a lab “completely changed what I thought I was going to do with my life,” said Vela. “Now I’m going to focus more on research than anything else.”

For Johnson, the experience provided the opportunity to present her research at the 2013 White House Science Fair, where she hobnobbed with some political hot shots.

“It was an amazing experience,” she said. Having “important White House officials be interested in my project … inspired me.”

Johnson and Vela visited NIH a few months ago and talked with us about their research experiences, their lives and their future goals. Jasmine Johnson & Gabriel Vela on their experience as high school researchers at The Jackson Laboratory in Bar Harbor, Maine.

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Article Exit icon about Johnson and Vela and other young researchers, from The Jackson Laboratory’s magazine The Search Exit icon.
Article about the work of Gary Churchill, from NIH’s Findings magazine.

Neanderthal DNA—Still Among Us

Map of Europe and Asia showing the presumed range of where Neanderthals lived.
For tens of thousands of years, Neanderthals lived in Europe and Asia (presumed range shown in blue) and interbred with humans, passing on some DNA to present-day people. Credit: Ryulong, Wikimedia Commons.
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Many of us have some Neanderthal genes. Before Neanderthals went extinct about 30,000 years ago, they interbred with humans living in Europe and Asia. Today’s descendants of those pairings inherited about 2 percent of their genomes from the big-brained hominids.

A research group led by David Reich at Harvard Medical School recently completed an analysis to determine the extent and identity of Neanderthal DNA in modern-day human populations. The group found that many traits in present-day people—including skin characteristics and susceptibility to various diseases—can be traced to Neanderthal DNA.

It also appears that, genetically speaking, Neanderthals and humans weren’t completely compatible. Based on the uneven distribution of Neanderthal DNA in today’s genomes, the scientists concluded that many of the male offspring of Neanderthal-human unions were infertile. In the animal world, this phenomenon is known as hybrid infertility, where the offspring of a male from one subspecies and a female from another have low or no fertility.

Studying human genes passed down through Neanderthals—as well as regions of the human genome notably devoid of Neanderthal DNA—provides an increasingly complete picture of the genetic landscape that contributed to health, disease and diversity among humans today.

Learn more:
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Evolution and Health Article from Inside Life Science
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Targeting Toxic RNA Molecules in Muscular Dystrophy

Genetic defect that causes myotonic dystrophy type 2 and used that information to design drug candidates to counteract the disease. Credit: Ilyas Yildirim, Northwestern University.
Scientists revealed a detailed image of the genetic defect that causes myotonic dystrophy type 2 and used that information to design drug candidates to counteract the disease. Credit: Ilyas Yildirim, Northwestern University. View larger image

Myotonic dystrophy type 2 (DM2) is a relatively rare, inherited form of adult-onset muscular dystrophy that has no cure. It’s caused by a genetic defect in which a short series of nucleotides—the chemical units that spell out our genetic code—is repeated more times than normal. When the defective gene is transcribed, the resulting RNA repeat forms a hairpin-like structure that binds to and disables a protein called MBNL1.

Now, research led by Matthew Disney of The Scripps Research Institute (TSRI), Florida Campus, has revealed the detailed, three-dimensional structure of the RNA defect in DM2 and used this information to design small molecules that bind to the aberrant RNA. These designer molecules, even in small amounts, significantly improved disease-associated defects in a cellular model of DM2, and thus hold potential for reversing the disorder.

Drugs that target toxic RNA molecules associated with diseases such as DM2 are few and far between, as developing such compounds is technically challenging. The “bottom-up” approach that the scientists used to design potent new drug candidates, by first studying in detail how the RNA structure interacts with small molecules, is unconventional, noted Jessica Childs-Disney of TSRI, who was lead author of the paper with Ilyas Yildirim of Northwestern University. But it may serve as an effective strategy for pioneering the use of small molecules to manipulate disease-causing RNAs—a central focus of the Disney lab.

This work also was funded by NIH’s National Cancer Institute.

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Meet Dave Cummings

Dave Cummings. Credit: Marcus Emerson, PLNU.
Dave Cummings
Field: environmental microbiology
Works at: Point Loma Nazarene University, San Diego, Calif.
Hobbies: hiking, backpacking, fly-fishing
Dream home: one that doesn’t need a lot of work
Credit: Marcus Emerson, PLNU

In college, as a pre-med student majoring in biology and chemistry, Dave Cummings grew frustrated with the traditional “cookbook” approach to doing labs in his science classes. Turned off by having to follow step-by-step lab procedures that had little to do with scientific discovery, Cummings changed his major to English literature. Studying literature, he says, “helped me find myself” and taught him to think critically.

Ultimately, Cummings says, “I came to realize that it wasn’t the practice of medicine that got me excited, but the science behind it all.” He decided to pursue a graduate degree in biology and—after “knocking on a lot of doors”—was accepted at the University of Idaho, where he earned his master’s and doctoral degrees and discovered his passion for microbiology.

Today, Cummings applies his critical thinking skills to his work as professor of biology back at his alma mater, Point Loma Nazarene University (PLNU), a small university focused on undergraduate education. There he studies the role of urban storm water in spreading genes for antibiotic resistance in natural environments, and pursues his enthusiasm for training the next generation of scientists. He enlists his students in his research, giving them what he calls “real, live, on-the-ground” research experience that relatively few undergraduate students at larger universities receive.

Cummings’ Findings

Antibiotic resistance, which can transform once-tractable bacterial infections into diseases that are difficult or impossible to treat, is a major public health challenge of the 21st century. The most common way that bacteria become drug resistant is by acquiring genes that confer antibiotic resistance from other bacteria. Often, such drug resistance genes are found on small, circular pieces of DNA called plasmids that are readily passed from one species of bacteria to another.

Urban wetlands provide ideal conditions for bacteria to mingle, swap genes and spread antibiotic resistance, notes Cummings. He focuses on the wetlands around San Diego, which act as a giant mixing bowl for storm runoff, human sewage, animal waste, naturally occurring plant and soil microorganisms, and plasmids indigenous to the wetlands.

Cummings and his students examine sediment samples from these wetlands in search of plasmids that carry resistance genes. They’ve found that during winter rains, the San Diego wetlands receive runoff containing antibiotic-resistant bacteria and plasmids, which can persist at low, but detectable, levels into the dry summer months.

“We know that urban storm water carries with it a lot of antibiotic-resistant bacteria, and along with that the DNA instructions [or genes] that code for the resistance,” says Cummings. “We have solid evidence of genes encoding resistance to clinically important antibiotics washing … into coastal wetlands in San Diego.”

“We’re trying to understand the scope of the problem, and ultimately what threat that poses to human health,” he says. His concern is that the drug-defying bacterial genes will accumulate in the wetlands, and then “[find] their way back to us, where they will augment and amplify the problem of resistance.”

Precisely how resistance genes might move from the environment into people is not yet known. One way this could occur is through direct contact with contaminated water or sediment by anglers, swimmers, surfers and other recreational users. Fish, birds and insects could also transmit resistance genes from contaminated wetlands to humans.

“There is good evidence elsewhere that birds are important vectors of drug-resistant pathogens, and this is my favorite possibility,” says Cummings. “Hopefully someday we can test that hypothesis.”

Cummings’ studies, done in collaboration with Ryan Botts at PLNU and Eva Top at the University of Idaho, could reveal antibiotic resistance genes with the potential to move into new species of disease-causing bacteria and back into human populations. By identifying these genes and raising awareness of the problem, he hopes to aid future efforts to mitigate the spread of antibiotic resistance.

One Mutation Leads to Another—At Least in Yeast

DNA mutation. Credit: Stock image.
Newly discovered genetic effect in yeast could shed light on carcinogenesis. Credit: Stock image.

Cancer cells typically include many gene mutations, extra or missing genes, or even the wrong number of chromosomes. Scientists know that certain genetic changes lead to ones elsewhere. But they’ve had a chicken-and-egg problem trying to figure out which changes trigger which others—or whether mutations accumulate randomly in tumors.

New research led by J. Marie Hardwick Exit icon of Johns Hopkins University sheds light on the issue. She found that incapacitating a single gene in yeast cells—regardless of which gene it was—spurred mutations in one or two other genes. The process was anything but random: If, say, gene X was knocked out, yeast cells almost always developed a secondary mutation in gene Y. It’s as if knocking out one gene disrupts the genomic balance enough that the cell must alter a different gene to compensate.

Significantly, the secondary mutations—but not the original ones—caused altered yeast cell characteristics, including traits linked to cancer. Also, many of the secondary mutations occurred in genes associated with cancer in humans, further suggesting that these secondary changes might play a role in carcinogenesis.

This new information will help researchers better understand the chain of genetic events that lead to cancer. It might also prompt scientists to reevaluate years of research that attributed changes in cell behavior or appearance to a given gene knockout.

This work also was funded by NIH’s National Institute of Neurological Disorders and Stroke.

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Abnormal Mitochondria Might Cause Resistance to Radiation Therapy

Mitochondria. Credit: Judith Stoffer.
Bean-shaped mitochondria are cells’ power plants. The highly folded inner membranes are the site of energy generation. Credit: Judith Stoffer. View larger image

Why some cancers are resistant to radiation therapy has baffled scientists, but research on abnormalities in mitochondria, often described as cells’ power plants, could offer new details. A research team led by Maxim Frolov Exit icon of the University of Illinois at Chicago learned that the E2F gene, which plays a role in the natural process of cell death, contributes to the function of mitochondria. Fruit flies with a mutant version of the E2F gene had misshapen mitochondria that produced less energy than normal ones. Flies with severely damaged mitochondria were more resistant to radiation-induced cell death. Studies using human cells revealed similar effects. The work could help explain why people with cancer respond differently to radiation therapy and might aid the development of drugs that enhance mitochondrial function, thereby improving the effectiveness of radiation therapy.

This work also was funded by NIH’s National Cancer Institute.

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Stop the (Biological) Clock

Molecular structure of the three proteins in blue-green algae’s circadian clock.  Credit: Johnson Lab, Vanderbilt University.
Molecular structure of the three proteins in blue-green algae’s circadian clock. Credit: Johnson Lab, Vanderbilt University.

Many microorganisms can sense whether it’s day or night and adjust their activity accordingly. In tiny blue-green algae, the “quartz-crystal” of the time-keeping circadian clock consists of only three proteins, making it the simplest clock found in nature. Researchers led by Carl Johnson of Vanderbilt University recently found that, by manipulating these clock proteins, they could lock the algae into continuously expressing its daytime genes, even during the nighttime.

Why would one want algae to act like it’s always daytime? The kind used in Johnson’s study is widely harnessed to produce commercial products, from drugs to biofuels. But even when grown in constant light, algae with a normal circadian clock typically decrease production of biomolecules when nighttime genes are expressed. When the researchers grew the algae with the daytime genes locked “on” in constant light, the microorganism’s output increased by as much as 700 percent. This proof of concept experiment may be applicable to improving the commercial production of compounds such as insulin and some anti-cancer drugs.

Learn more:

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Circadian Rhythms Fact Sheet
The Rhythms of Life Article from Inside Life Science