Nobel Prize for Powerful Microscopy Technology

Fibroblasts
The cells shown here are fibroblasts, one of the most common cells in mammalian connective tissue. These particular cells were taken from a mouse. Scientists used them to test the power of a new microscopy technique that offers vivid views of the inside of a cell. The DNA within the nucleus (blue), mitochondria (green) and cellular skeleton (red) is clearly visible. Credit: Dylan Burnette and Jennifer Lippincott-Schwartz, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.

William E. Moerner was at a conference in Brazil when he learned he’d be getting a Nobel Prize in chemistry. “I was incredibly excited and thrilled,” he said of his initial reaction.

An NIGMS grantee at Stanford University, Moerner received the honor for his role in achieving what was once thought impossible—developing super-resolution fluorescence microscopy, which is so powerful it allows researchers to see and track individual molecules in living organisms in real time.

Nobel recipients usually learn of the prize via a phone call from Stockholm, Sweden, in early October. For those in the United States, the call typically comes between 2:30 a.m. and 5:45 a.m.

Every year, the NIGMS communications office prepares for the Nobel Prize announcements in physiology or medicine and chemistry, the categories in which our grantees are most likely to be recognized. If the Institute played a significant role in funding the prize-winning research, we work quickly to provide information and context to reporters covering the story on tight deadlines. We issue a statement, identify an in-house expert on the research and arrange interviews with reporters. It’s all to help get the word out about the research and the taxpayers’ role in supporting it.

This year’s in-house expert, Cathy Lewis, shared her thoughts on the prize to Moerner in an NIGMS Feedback Loop post. You can also read this year’s statement and see a full list of NIGMS-supported Nobel laureates.

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.

 
 

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.

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The “Virtuous Cycle” of Technology and Science

A scientist looking through a  microscope. Credit: Stock image.
Whether it’s a microscope, computer program or lab technique, technology is at the heart of biomedical research. Credit: Stock image.

Whether it’s a microscope, computer program or lab technique, technology is at the heart of biomedical research. Its central role is particularly clear from this month’s posts.

Some show how different tools led to basic discoveries with important health applications. For instance, a supercomputer unlocked the secrets of a drug-making enzyme, a software tool identified disease-causing variations among family members and high-powered microscopy revealed a mechanism allowing microtubules—and a cancer drug that targets them—to work.

Another theme featured in several posts is novel uses for established technologies. The scientists behind the cool image put a new spin on a long-standing imaging technology to gain surprising insights into how some brain cells dispose of old parts. Similarly, the finding related to sepsis demonstrates yet another application of a standard lab technique called polymerase chain reaction: assessing the immune state of people with this serious medical condition.

“We need tools to answer questions,” says NIGMS’ Doug Sheeley, who oversees biomedical technology research resource grants. “When we find the answers, we ask new questions that then require new or improved tools. It’s a virtuous cycle that keeps science moving forward.”

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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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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New Compound Improves Insulin Levels in Preliminary Studies

compound
A new compound (chemical structure shown here) blocks the activity of an enzyme involved in glucose regulation.

The discovery of a compound that slows the natural degradation of insulin in mice opens up a new area of investigation in the search for drugs to treat diabetes. The research team, which included David Liu Exit icon and Alan Saghatelian Exit icon of Harvard University, Markus Seeliger of Stony Brook University School of Medicine, and Wei-Jen Tang Exit icon of the University of Chicago focused on insulin-degrading enzyme, or IDE. Using a method called DNA-templated synthesis, the scientists made 14,000 small molecules and found one that bound to the enzyme, suggesting it might modulate the enzyme’s activity. Work in test tubes and in animal models confirmed this—and showed that blocking IDE activity improved insulin levels and glucose tolerance. The researchers also learned that the enzyme is misnamed: In addition to insulin, it degrades two other hormones involved in glucose regulation.

NIGMS’ Peter Preusch says, “This is a very interesting fusion of chemical methods and biology that has uncovered new basic science findings about insulin processing with potential clinical impact.”

This work also was funded by NIH’s National Cancer Institute and the Office of the Director.

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Basic Research Fuels Medical Advances

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 change 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

This image may look complicated, but it tells a fairly straightforward tale about basic research: Learning more about basic life processes can pave the way for medical and other advances.

In this example, researchers led by Matthew Disney of the Scripps Research Institute’s Florida campus focused on better understanding the structural underpinnings of myotonic dystrophy type 2, a relatively rare, inherited form of adult-onset muscular dystrophy. While this work is still in the preliminary stages, it may hold potential for someday treating the disorder.

Some 300,000 NIH-funded scientists are working on projects aimed at improving disease diagnosis, treatment and prevention, often through increasing understanding of basic life processes.

Read the complete Inside Life Science article.

Bleach vs. Bacteria

Screenshot of the video showing how chlorine affects a bacterial protein
Exposure to hypochlorous acid causes bacterial proteins to unfold and stick to one another, leading to cell death. Credit: Video segment courtesy of the American Chemistry Council. View video

Spring cleaning often involves chlorine bleach, which has been used as a disinfectant for hundreds of years. But our bodies have been using bleach’s active component, hypochlorous acid, to help clean house for millennia. As part of our natural response to infection, certain types of immune cells produce hypochlorous acid to help kill invading microbes, including bacteria.

Researchers funded by the National Institutes of Health have made strides in understanding exactly how bleach kills bacteria—and how bacteria’s own defenses can protect against the cellular stress caused by bleach. The insights gained may lead to the development of new drugs to breach these microbial defenses, helping our bodies fight disease.

Continue reading this new Inside Life Science article.

Anti-Clotting Drugs: The Next Generation

Form of heparin
Scientists created a tailor-made form of the anti-clotting drug heparin that offers several advantages.
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The low molecular weight (LMW) form of the drug heparin is commonly used to prevent unwanted blood clots that can lead to heart attacks and strokes. It’s usually derived from pig intestines and normally cleared from the human body by the kidneys. In individuals with impaired kidney function, the drug can build up in the circulation and cause excessive bleeding. Impurities and the risk of contamination are also concerns with pig-derived heparin.

Now, Robert Linhardt of Rensselaer Polytechnic Institute and Jian Liu of the University of North Carolina at Chapel Hill have created a synthetic, tailor-made form of LMW heparin that offers several advantages over the animal-derived version, including alleviating the risk of contamination from natural sources. Studies in the test tube and in mice showed that the activity of this customized heparin molecule is easily reversible in cases of overdose or uncontrolled bleeding. And, since it is cleared from the body by the liver rather than the kidneys, this form of heparin would be safer for people with impaired kidney function. Additional research, including testing in humans, will be needed before this new version of LMW heparin can be considered for medical use.

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

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