Author: Elia Ben-Ari

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Posts by Elia Ben-Ari

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Field Focus: Progress in RNA Interference Research

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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 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.

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Unusual DNA Form May Help Virus Withstand Extreme Conditions

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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 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.”

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Field Focus: Making Chemistry Greener

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Bob Lees
NIGMS’ Bob Lees answers questions about green chemistry. Credit: National Institute of General Medical Sciences.

Chemists funded by NIGMS are working to develop “greener” processes for discovering, developing and manufacturing medicines and other molecules with therapeutic potential, as well as compounds used in biomedical research. One of our scientific experts, organic chemist Bob Lees, recently spoke to me about some of these efforts.

What is green chemistry?

Green chemistry is the design of chemical processes and products that are more environmentally friendly. Among the 12 guiding principles of green chemistry Exit icon are producing less waste, including fewer toxic byproducts; using more sustainable (renewable) or biodegradable materials; and saving energy. Continue reading “Field Focus: Making Chemistry Greener”

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Cellular ‘Cruise Control’ Systems Let Cells Sense and Adapt to Changing Demands

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Cells are the ultimate smart material. They can sense the demands being placed on them during critical life processes and then respond by strengthening, remodeling or self-repairing, for instance. To do this, cells use “mechanosensory” systems similar to the cruise control that lets a car’s engine adjust its power output when going up or down hills.

Researchers are uncovering new details on cells’ molecular cruise control systems. By learning more about the inner workings of these systems, scientists hope ultimately to devise ways to tinker with them for therapeutic purposes.

Cell Fusion

To examine how cells fine-tune their architecture and force output during the merging or fusion of cells, Elizabeth Chen and Douglas Robinson of Johns Hopkins University teamed up with Daniel Fletcher of the University of California, Berkeley. Cell fusion is critical to many developmental and physiological processes, including fertilization, placenta formation, immune response, and skeletal muscle development and regeneration.

Illustration of cell fusion

Fingerlike protrusions of one cell (pink) invade another cell prior to cell fusion. Credit: Shuo Li. Used with permission from Developmental Cell.

Using the fruit fly Drosophila melanogaster as a model system, Chen’s research group Exit icon previously found that when two muscle cells merge during muscle development, fingerlike protrusions of one cell invade the territory of the other cell to promote fusion. In the new study, led by Chen, the researchers showed that cell fusion depends on the ability of the “receiving” cell to put up resistance against the invading cell Exit icon.

In fusing fruit fly cells, the scientists saw that in areas where the invading cells drilled in, the receiving cells quickly stiffened their cell skeletons, effectively pushing back. This mechanosensory response allows the outer membranes of the two cells to be pushed together and later fuse, Chen explains.

The team then explored the mechanisms underlying the stiffening response. They found that a protein called myosin II, which is part of the cell skeleton, senses the pushing force from the invading cell. Myosin II swarms to the fusion site and binds with fibers just beneath the cell membrane to put up the necessary resistance. Continue reading “Cellular ‘Cruise Control’ Systems Let Cells Sense and Adapt to Changing Demands”

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Digging Deeply Into Data for the Causes of Disease

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Hunting for the cause of a disease can be like tracing a river back to its many sources. Myriad factors, large and small, may contribute to a condition. One approach to the search focuses on the massive amounts of genomic and other biological data that scientists are gathering in the course of their studies. To examine this data and look for meaningful patterns and other clues, scientists turn to bioinformatics, a field focused on the development of analytical methods and software tools.

Here are a few examples of how National Institutes of Health-funded scientists are using bioinformatics to dig deeply into data and learn more about the development of diseases, including Huntington’s, preeclampsia and asthma.

Huntington’s Disease

Network of proteins that interact with huntingtin

Researchers have mapped a network of 2,141 proteins that all interact either directly or through one other protein with huntingtin (red), the protein associated with Huntington’s disease. Credit: Cendrine Tourette, Buck Institute for Research on Aging, J Biol Chem 2014 Mar 7;289(10):6709-26 Exit icon.

The cause of Huntington’s disease, a degenerative neurological disorder with no known cure, may appear simple. It begins with a change in a single gene that alters the shape and functioning of the huntingtin protein. But this protein, whether in its normal or altered form, does not act alone. It interacts with other proteins, which in turn interact with others.

A research team led by Robert Hughes of the Buck Institute for Research on Aging set out to understand how this ripple effect contributes to the breakdown in normal cellular function associated with Huntington’s disease. The scientists used experimental and computational approaches to map a network of 2,141 proteins that interact with the huntingtin protein either directly or through one other protein. They found that many of these proteins were involved in cell movement and intercellular communication. Understanding how the huntingtin protein leads to mistakes in these cellular processes could help scientists pursue new approaches to developing treatments. Continue reading “Digging Deeply Into Data for the Causes of Disease”

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Remotely and Noninvasively Controlling Genes and Cells in Living Animals

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Remote control car key.
Researchers are developing a system to remotely control genes or cells in living animals with radio wave technology similar to that used to operate remote control car keys. Credit: Stock image.

One of the items on biomedical researchers’ “to-do” list is devising noninvasive ways to control the activity of specific genes or cells in order to study what those genes or cells do and, ultimately, to treat a range of human diseases and disorders.

A team of scientists recently reported progress on a new, noninvasive system that could remotely and rapidly control biological targets in living animals. The system can be activated remotely using either low-frequency radio waves or a magnetic field. Similar radio wave technology operates automatic garage-door openers and remote control car keys and is used in medicine to control electronic pacemakers noninvasively. Magnetic fields are used to activate sensors in burglar alarm systems and to turn your laptop to hibernate mode when the cover is closed. Continue reading “Remotely and Noninvasively Controlling Genes and Cells in Living Animals”

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Correcting a Cellular Routing Error Could Treat Rare Kidney Disease

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AGT protein and peroxisomes in untreated and treated cells.
The altered AGT protein (red) and peroxisomes (green) appear in different places in untreated cells (top), but they appear together (shown in yellow) in cells treated with DECA (bottom). Credit: Carla Koehler/Reproduced with permission from Proceedings of the National Academy of Sciences USA. View larger image.

Our cells have organized systems to route newly created proteins to the places where they’re needed to do their jobs. For some people born with a rare and potentially fatal genetic kidney disorder called PH1, a genetically altered form of a particular protein mistakenly ends up in mitochondria instead of in another organelle, the peroxisome. This cellular routing error of the AGT protein results in the harmful buildup of oxalate, which leads to kidney failure and other problems at an early age.

In new work led by UCLA biochemist Carla Koehler Exit icon, researchers used a robotic screening system to identify a compound that interferes with the delivery of proteins to mitochondria. Koehler’s team Exit icon showed that adding a small amount of the compound, known as DECA, to cells grown in the laboratory prevented the altered form of the AGT protein from going to the mitochondria and sent it to the peroxisome. The compound also reduced oxalate levels in a cell model of PH1.

The team’s findings suggest that DECA, which is already approved by the Food and Drug Administration for treating certain bacterial infections, could be a promising candidate for treating children affected by PH1. And, Koehler notes, the screening strategy that she and her team used to identify DECA as a potential therapy may help researchers identify other new therapies for the disorder.

This work was funded in part by NIH under grant R01GM061721.

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Stem Cells Do Geometry

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Human embryonic cells
As seen under a microscope, human embryonic cells (colored dots) confined to circles measuring 1 millimeter across start to specialize and form distinct layers similar to those seen in early development. Credit: Aryeh Warmflash, Rockefeller University. View larger image

Each fluorescent point of light making up the multicolored rings in this image is an individual human embryonic cell in the early stages of development. Scientists seeking to understand the molecular cues responsible for early embryonic patterning found that human embryonic cells confined to areas of precisely controlled size and shape begin to specialize, migrate and organize into distinct layers just as they would under natural conditions.

Read the Inside Life Science article to learn more about this research, which has opened a new window for studying early development and could advance efforts aimed at using human stem cells to replace diseased cells and regenerate lost or injured body parts.

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Modifying Bacterial Behavior

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Biofilm
Communication through quorum sensing is key to the formation of biofilms, slimy bacterial communities that can cause infections and are often stubbornly resistant to antibiotics. Credit: P. Singh and E. Peter Greenberg.

Like a person trailing the aroma of perfume or cologne, bacteria emit chemical signals that let other bacteria of the same species know they’re there. Bacteria use this chemical communication system, called quorum sensing, to assess their own population size. When they sense a large enough group, or quorum, the microbes modify their behavior accordingly. Many disease-causing bacteria use quorum sensing to launch a coordinated attack when they’ve amassed in sufficient numbers to overwhelm the host’s immune response.

Chemist Helen Blackwell of the University of Wisconsin-Madison has been making artificial compounds that mimic natural quorum-sensing signals, as well as some that block a natural signal from binding to its protein target—a step needed to produce a change in bacterial behavior. By altering key building blocks in these protein targets one by one, Blackwell’s team found that small changes could convert an activation signal into an inhibitory signal, or vice versa, indicating that small-molecule control of quorum sensing is very finely tuned.

Improved understanding of the molecular basis of quorum sensing could help scientists design more potent compounds to disrupt these signals. Using such compounds to quiet quorum sensing may provide a new way to control disease-causing bacteria that reduces the chances an infection will become resistant to treatment.

This work was funded in part by NIH under grants R01GM109403 and T32GM008505.

Learn more:
University of Wisconsin-Madison News Release Exit icon
Blackwell Lab Exit icon

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Outwitting Antibiotic Resistance

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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.