Illuminating Biology

This time of year, lights brighten our homes and add sparkle to our holidays. Year-round, scientists funded by the National Institutes of Health use light to illuminate important biological processes, from the inner workings of cells to the complex activity of the brain. Here’s a look at just a few of the ways new light-based tools have deepened our understanding of living systems and set the stage for future medical advances.

RSV infected cell
A new fluorescent probe shows viral RNA (red) in an RSV-infected cell. Credit: Eric Alonas and Philip Santangelo, Georgia Institute of Technology and Emory University.

Visualizing Viral Activity

What looks like a colorful pattern produced as light enters a kaleidoscope is an image of a cell infected with respiratory syncytial virus (RSV) lit up by a new fluorescent probe called MTRIPS (multiply labeled tetravalent RNA imaging probes).

Although relatively harmless in most children, RSV can lead to bronchitis and pneumonia in others. Philip Santangelo of the Georgia Institute of Technology and Emory University, along with colleagues nationwide, used MTRIPS to gain a closer look at the life cycle of this virus.

Once introduced into RSV-infected cells, MTRIPS latched onto the genetic material of individual viral particles (in the image, red), making them glow. This enabled the researchers to follow the entry, assembly and replication of RSV inside the living cells. Continue reading “Illuminating Biology”

Forecasting Infectious Disease Spread with Web Data

Just as you might turn to Twitter or Facebook for a pulse on what’s happening around you, researchers involved in an infectious disease computational modeling project are turning to anonymized social media and other publicly available Web data to improve their ability to forecast emerging outbreaks and develop tools that can help health officials as they respond.

Mining Wikipedia Data

Screen shot of the Wikipedia site
Incorporating real-time, anonymized data from Wikipedia and other novel sources of information is aiding efforts to forecast and respond to emerging outbreaks. Credit: Stock image.

“When it comes to infectious disease forecasting, getting ahead of the curve is problematic because data from official public health sources is retrospective,” says Irene Eckstrand of the National Institutes of Health, which funds the project, called Models of Infectious Disease Agent Study (MIDAS). “Incorporating real-time, anonymized data from social media and other Web sources into disease modeling tools may be helpful, but it also presents challenges.”

To help evaluate the Web’s potential for improving infectious disease forecasting efforts, MIDAS researcher Sara Del Valle of Los Alamos National Laboratory conducted proof-of-concept experiments involving data that Wikipedia releases hourly to any interested party. Del Valle’s research group built models based on the page view histories of disease-related Wikipedia pages in seven languages. The scientists tested the new models against their other models, which rely on official health data reported from countries using those languages. By comparing the outcomes of the different modeling approaches, the Los Alamos team concluded that the Wikipedia-based modeling results for flu and dengue fever performed better than those for other diseases. Continue reading “Forecasting Infectious Disease Spread with Web Data”

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.

Improving the Odds of Surviving Sepsis

Acupuncture
A form of acupuncture—or a drug that mimics its effect—may one day lead to an anti-inflammatory therapy for people with sepsis. Credit: Stock image.

A leading cause of death in U.S. intensive care units is sepsis, an overwhelming immune response to infection that triggers body-wide inflammation and can cause organ failure.

Sepsis is challenging to diagnose and treat. Many of its early signs, such as fever and difficulty breathing, are similar to those of other conditions. When doctors do not detect sepsis until a more advanced stage, they are often unable to stop its progression or prevent its complications.

“Sepsis is a complex problem,” says Sarah Dunsmore of the National Institutes of Health (NIH). “We need more research at all levels—from the molecular to the patient—to improve sepsis diagnosis and treatment and to enhance the quality of life for sepsis survivors.”

NIH-funded scientists use a variety of tools, including blood tests and acupuncture, in their quest to detect sepsis early, treat it quickly and reduce its later effects.

Read more about sepsis research in this Inside Life Science article.

A Data Bank Built for Discovery

Dynein, a motor protein. Credit: David S. Goodsell, The Scripps Research Institute and the RCSB PDB.
The PDB archive holds structural data for dynein, a motor protein, and more than 100,000 other molecules. Credit: David S. Goodsell, The Scripps Research Institute and the RCSB PDB. Click for larger image

Meet dynein, the August Molecule of the Month presented by the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB). This motor protein travels along the cables of our cellular skeleton, delivering cargo throughout the cell. The structure of dynein’s stalk enables it to bind to regular grooves along its path.

Dynein’s shape is just one of more than 100,000 structures that scientists have deposited in the PDB archive, a freely available digital repository. Because understanding a protein’s shape helps researchers better understand its function, the structural information in the PDB can lead to additional scientific advancements. For example, scientists use the structure of HIV protease, a protein that helps the virus replicate in the body, to develop drugs that fit snugly into the protein’s center, shutting it down. And they use the shape of RNA polymerase to learn how this protein fits together with smaller ones to read our genetic code.

The PDB has doubled in size over the last 6 years. As the collection continues to grow, so does our potential for drug discovery and our understanding of basic life processes.

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How Heat-Loving Organisms Are Helping Advance Medicine

Hot spring. Credit: Stock image.
Icelandic hot springs are the natural habitat of Rhodothermus marinus, one of many species of thermophiles that the Gennis Lab studies to better understand membrane proteins. Credit: Stock image.

As the temperature climbs, most humans look for ways to cool down fast. But for some species of microorganisms, a midsummer heat wave isn’t nearly hot enough. These heat lovers, known as thermophiles, thrive at temperatures of 113°F or more. They’re often found in hot springs, geysers and even home water heaters.

Like humans and other organisms, thermophiles rely on proteins to maintain normal cell function. While our protein molecules break down under intense heat, a thermophile’s proteins actually work more efficiently. They also tend to be more stable at room temperature than our own. An NIH-funded research team is taking advantage of this property of thermophiles to better understand a group of human proteins commonly targeted by today’s medicines.

Read more about the team’s thermophile research in this Inside Life Science article.

A Drug-Making Enzyme in Motion

Mutated enzyme, LovD9. Credit: Silvia Osuna and Gonzalo Jiménez-Osés, University of California, Los Angeles.
The movement of this mutated enzyme, LovD9, facilitates rapid production of the cholesterol reducing-drug simvastatin. Credit: Silvia Osuna and Gonzalo Jiménez-Osés, University of California, Los Angeles.

LovD9, a mutated version of an enzyme extracted from mold growing in soil, produces the cholesterol-reducing drug simvastatin 1,000 times faster than its natural predecessor. But scientists didn’t understand why because the enzyme’s mutations are far from the active site, where the drug is actually made. Now they do.

Yi Tang of the University of California, Los Angeles (UCLA), in partnership with the pharmaceutical company Codexis, generated LovD9 by repeatedly inducing random mutations, each time selecting the mutated versions of the enzyme with the most promise for industrial simvastatin production.

Then, the team collaborated with UCLA colleagues Kendall Houk and Todd Yeates to unlock the secret of the enzyme’s speed. Using ANTON, a special-purpose supercomputer at the Pittsburgh Supercomputing Center, they simulated how different parts of the enzyme rotate and twist when synthesizing the drug. The scientists discovered that as LovD9 moves, it forms shapes that facilitate simvastatin production more often than the natural enzyme does.

With their better understanding of how mutations far from an active site may affect an enzyme’s motion, the researchers hope to one day directly engineer enzymes with precise mutations that enhance drug production.

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Dormant Viruses Reactivate, Signaling Effect of Lingering Sepsis

Doctors with a patient
A new study finds that people with lingering sepsis may have suppressed immune systems. Credit: Stock image.

Each year, more than 200,000 people in the United States die from sepsis, a condition caused by an overwhelming immune response that can quickly lead to organ failure. While many people with sepsis survive this immediate threat, they may die days or even months later from secondary infections.

A research team that included Richard Hotchkiss, Jonathan Green and Gregory Storch of Washington University School of Medicine in St. Louis suspected that when sepsis lasts for more than a few days, it compromises the immune system. To test this hypothesis, the scientists compared viral activity in sepsis patients, other critically ill patients and healthy individuals. They looked for viruses like Epstein-Barr and herpes-simplex that are often dormant and innocuous in healthy people but can reactivate and cause problems in those with suppressed immune systems.

Of the three study groups, sepsis patients had much higher levels of these viruses, suggesting that their immune responses may be hindered. Immune suppression could make it difficult to defend against the reactivated viruses as well as new infections like pneumonia. The team now plans to test whether immune-boosting drugs can prevent deaths in people with lingering sepsis.

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Cool Video: How a Microtubule Builds and Deconstructs

A microtubule, part of the cell’s skeleton, builds and deconstructs. Credit: Eva Nogales lab, University of California, Berkeley.

In this animation, tubulin proteins snap into place like Lego blocks to build a microtubule, part of the cell’s skeleton. When construction ends, this long hollow cylinder falls to pieces from its top end. The breakdown is critical for many basic biological processes, including cell division, when rapidly shortening microtubules pull chromosomes into each daughter cell.

Until recently, scientists didn’t know exactly what drove microtubules to fall apart. A research team led by Eva Nogales of the Lawrence Berkeley National Laboratory and the University of California, Berkeley, now has an explanation.

Using high-powered microscopy, the scientists peered into the structure of a microtubule and found how a chemical reaction puts the stacking tubulin proteins under intense strain. The only thing keeping the proteins from springing apart is the pressure from the addition of more tubulin. So when assembly stops, the microtubule deconstructs.

The team also learned that Taxol, a common cancer drug, relieves this tension and allows microtubules to remain intact indefinitely. With microtubules frozen in place, a cancer cell cannot divide and eventually dies.

Because of this research, scientists now better understand both the success behind a common cancer drug and the molecular basis underlying the workings of microtubules.

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Carbohydrates as Bacterial Camouflage: How Our Immune System Responds

bacteria
Although invisible to our immune system’s antibodies, strains of a pneumonia-causing bacteria, Pseudomonas aeruginosa (orange), are easily detected by galectins. Credit: Centers for Disease Control and Prevention.

When harmful strains of bacteria invade our bodies, our immune system produces antibodies that identify the intruders by the specific carbohydrate structures coating them. Some strains, however, have coatings that mimic the carbohydrate structures found on our own cells, and this disguise allows them to evade detection by antibodies.

A team of scientists led by Richard Cummings of Emory University found that galectins, a class of proteins naturally produced by our bodies, can identify and kill these concealed bacteria without damaging our own mimicked cells. To make this discovery, the team used glass slides covered with more than 300 different carbohydrates extracted from the surface of bacterial cells. After testing the ability of galectins and antibodies to bind to specific carbohydrates on these slides, the researchers observed that the galectins easily detected the mammalian-like carbohydrates that the antibodies failed to recognize.

These findings provide a clearer understanding of the complementary roles played by galectins and antibodies in protecting us from a broad range of infections.

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

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