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.
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
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
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
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
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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 , researchers used a robotic screening system to identify a compound that interferes with the delivery of proteins to mitochondria. Koehler’s team 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.
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.
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.
University of Wisconsin-Madison News Release
Learning From Bacterial Chatter Article from Inside Life Science
Bugging the Bugs Article from Findings Magazine
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.
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.
Harvard University News Release
Antibiotic-resistant strains of Staphlyococcus aureus bacteria (purple) have become the most common cause of skin infections seen in hospital emergency departments. Credit: NIH’s National Institute of Allergy and Infectious Diseases.
In the United States alone, at least 2 million people each year develop serious infections with bacteria that have become resistant to the antibiotics we use to combat them, and about 23,000 die, according to the Centers for Disease Control and Prevention. Antibiotic resistance can turn once-manageable infections into “superbug” diseases that are difficult—and sometimes impossible—to treat.
Scientists funded by the National Institutes of Health are studying many aspects of antibiotic resistance, including how it spreads. Read this Inside Life Science article for just a few research examples and how the work could aid efforts to curb the emergence of resistance.
Scientists developed a computational method that could help identify various subtypes of complex diseases. Credit: Stock image
Complex diseases such as diabetes, cancer and asthma are caused by the intricate interplay of genetic, environmental and lifestyle factors that vary among affected individuals. As a result, the same medications may not work for every patient. Now, scientists have shown that a computational method capable of analyzing more than 100 clinical variables for a large group of people can identify various subtypes of asthma, which could ultimately lead to more targeted and personalized treatments. The research team, led by Wei Wu of Carnegie Mellon University and Sally Wenzel of the University of Pittsburgh, used a computational approach developed by Wu to identify several patient clusters consistent with known subtypes of asthma, as well as a possible new subtype of severe asthma that does not respond well to conventional drug treatment. If supported by further studies, the researchers’ proposed approach could help improve the understanding, diagnosis and treatment not just of asthma but of other complex diseases.
This work also was funded by NIH’s National Heart, Lung, and Blood Institute.
Carnegie Mellon University News Release
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.