Category: Genes

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Abnormal Mitochondria Might Cause Resistance to Radiation Therapy

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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

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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.

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Circadian Rhythms Fact Sheet

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Genetic Discovery Could Enable More Precise Prescriptions

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Prescription pad with DNA illustration on it. Credit: Jane Ades, NIH’s National Human Genome Research Institute.
New insight into the genes that affect drug responses may help doctors prescribe the medications and doses best suited for each individual. Credit: Jane Ades, NIH’s National Human Genome Research Institute.

Scientists know that variations in certain genes can affect the way a person responds to medications. New research by Wolfgang Sadee Exit icon at Ohio State University shows that drug responses also depend on previously overlooked parts of DNA—sections that regulate genes, but are not considered genes themselves. This study focused on an important enzyme abbreviated CYP2D6 that processes about one-fourth of all prescription drugs. Differences in the enzyme’s performance, which range from zilch to ultra-rapid, can dramatically alter the effectiveness and safety of certain medications. Researchers discovered two new genetic variants that impact CYP2D6 performance. One of these, located in a non-gene, regulatory region of DNA, doubles or even quadruples enzyme activity. Coupling these findings with genetic tests could help doctors better identify each patient’s CYP2D6 activity level, enabling more precise prescriptions. The findings also open up a whole new area of investigation into genetic factors that impact drug response.

This work also was funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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NIH Director Blogs About Value of Model Organisms in Drug Discovery Research

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(Left) Untreated yeast cells, (Right) Treated yeast cells. Credit: Daniel Tardiff, Whitehead Institute.
Treating yeast cells with the NAB compound reverses the toxic effects of elevated levels of alpha synuclein protein. Credit: Daniel Tardiff, Whitehead Institute. View larger image

These eye-catching images and the NIGMS-funded research that yielded them were recently featured by NIH Director Francis Collins on his blog. Scientists led by a team at the Whitehead Institute for Biomedical Research engineered yeast to produce too much of a protein, alpha synuclein. In Parkinson’s disease, elevated levels or mutated forms of this protein wreak havoc on the cell. Using the model system, the researchers tested tens of thousands of compounds to identify any that reversed the toxic effects. One did. The compound, abbreviated NAB, worked similarly in an animal model and in rat neurons grown in a lab dish. Collins described the approach as “an innovative strategy for drug hunting that will likely be extended to other conditions.”

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Using Model Organisms to Study Health and Disease Fact Sheet

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Healing Wounds, Growing Hair

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Wound healing in process. Credit: Yaron Fuchs and Samara Brown in the lab of Hermann Steller, Rockefeller University.

Credit: Yaron Fuchs and Samara Brown in the lab of Hermann Steller, Rockefeller University.

Whether injured by a scrape, minor burn or knife wound, skin goes through the same steps to heal itself. Regrowing hair over new skin is one of the final steps. All the hair you can see on your body is non-living, made up of “dead” cells and protein. It sprouts from living cells in the skin called hair follicle stem cells, shown here in red and orange. For more pictures of hair follicle stem cells—and many other stunning scientific images and videos—go to the NIGMS Image and Video Gallery.

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Flu Finds a Way In

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Influenza virus proteins in the act of self-replication. Credit: Wilson, Carragher and Potter labs, Scripps Research Institute.
Influenza virus proteins in the act of self-replication. Credit: Wilson, Carragher and Potter labs, Scripps Research Institute.

Flu viruses evolve rapidly, often staying one step ahead of efforts to vaccinate against infections or treat them with antiviral drugs. Work led by Jesse Bloom of the Fred Hutchinson Cancer Research Center has uncovered a surprising new flu mutation that allows influenza to infect cells in a novel way. Normally, a protein called hemagglutinin lets flu viruses attach to cells, and a protein called neuraminidase lets newly formed viruses escape from infected cells. Bloom’s lab has characterized a mutant flu virus where neuraminidase can enable the virus to attach to host cells even when hemagglutinin’s binding is blocked. Although the researchers generated the neuraminidase mutant studied in these experiments in their lab, the same mutation occurs naturally in strains from several recent flu outbreaks. There’s a possibility that flu viruses with such mutations may be able to escape antibodies that block the binding of hemagglutinin.

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

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New Approach Subtypes Cancers by Shared Genetic Effects

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Cancer

Cancer tumors are like snowflakes—no two ever share the same genetic mutations. Their unique characteristics make them difficult to categorize and treat. A new approach proposed by Trey Ideker and his team at the University of California, San Diego, might offer a solution. Their approach, called network-based stratification (NBS), identifies cancer subtypes by how different mutations in different cancer patients affect the same biological networks, such as genetic pathways. As proof of principle, they applied the method to ovarian, uterine and lung cancer data to obtain biological and clinical information about mutation profiles. Such cancer subtyping shows promise in helping to develop more effective, personalized treatments.

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How Some Bacteria Colonize the Gut

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A section of mouse colon with gut bacteria (center, in green). Credit: S. Melanie Lee, Caltech; Zbigniew Mikulski and Klaus Ley, La Jolla Institute for Allergy and Immunology.
A section of mouse colon with gut bacteria (center, in green) residing within a protective pocket. Credit: S. Melanie Lee, Caltech; Zbigniew Mikulski and Klaus Ley, La Jolla Institute for Allergy and Immunology.

Have you ever felt that your gut was trying to tell you something? The guts of germ-free mice have told scientists a few new things about our resident microorganisms. By studying a genus of bacteria called Bacteriodes that live in the gastrointestinal tract, Sarkis Mazmanian of the California Institute of Technology discovered how Bacteriodes species stake their claim in a mouse’s gut. Mazmanian and his colleagues introduced different species of Bacteriodes into germ-free mice to learn how the microbes competed and found that most of them peacefully co-existed. However, when microbes of a species that was already present were introduced, they couldn’t take up residence. Further investigation revealed that Bacteriodes species, due to a set of specific genes, can live in tiny pockets or “crypts” of the colon, where they are sheltered from antibiotics and infectious microbes passing through. Understanding how these microorganisms colonize could help devise ways to correct for abnormal changes in bacterial communities that are associated with disorders like inflammatory bowel disease.

This work also was funded by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases.

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Making Strides in Genomic Engineering of Human Stem Cells

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Genetically engineered human stem cells. Credit: Jeff Miller, University of Wisconsin-Madison.
Genetically engineered human stem cells hold promise for basic biomedical research as well as for regenerative medicine. Credit: Jeff Miller, University of Wisconsin-Madison.

Human pluripotent stem cells (hPSCs) can multiply indefinitely and give rise to virtually all human cell types. Manipulating the genomes of these cells in order to remove, replace or correct specific genes holds promise for basic biomedical research as well as medical applications. But precisely engineering the genomes of hPSCs is a challenge. A research team led by Erik Sontheimer of Northwestern University and James Thomson of the Morgridge Institute for Research at the University of Wisconsin-Madison developed a technique that could be a great improvement over existing, labor-intensive methods. Their approach uses an RNA-guided enzyme from Neisseria meningitidis bacteria—part of a recently discovered bacterial immune system—to efficiently target and modify specific DNA sequences in the genome of hPSCs. The technique could eventually enable the repair or replacement of diseased or injured cells in people with some types of cancer, Parkinson’s disease and other illnesses.

This work also was funded by NIH’s National Center for Advancing Translational Sciences.

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Meet Galina Lepesheva

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Galina Lepesheva
Galina Lepesheva
Field: Biochemistry
Works at: Vanderbilt University, Nashville, TN
Born, raised and studied in: Belarus
To unwind, she: Reads, travels, spends time with her family

Galina Lepesheva knows that kissing bugs are anything but romantic. When the lights get low, these blood-sucking insects begin feasting—and defecating—on the faces of their sleeping victims. Their feces are often infected with a protozoan (a single-celled, eukaryotic parasite) called Trypanosoma cruzi that causes Chagas disease. Lepesheva has developed a compound that might be an effective treatment for Chagas. She has also tested the substance, called VNI, as a treatment for two related diseases—African sleeping sickness and leishmaniasis.

“This particular research is mainly driven by one notion: Why should people suffer from these terrible illnesses if there could be a relatively easy solution?” she says.

Lepesheva’s Findings

Currently, most cases of Chagas disease occur in rural parts of Mexico, Central America and South America. According to some estimates, up to 1 million people in the U.S. could have Chagas disease, and most of them don’t realize it. If left untreated, the infection is lifelong and can be deadly.

The initial, acute stage of the disease is usually mild and lasts 4 to 8 weeks. Then the disease goes dormant for a decade or two. In about one in three people, Chagas re-emerges in its life-threatening, chronic stage, which can affect the heart, digestive system or both. Once chronic Chagas disease develops, about 60 percent of people die from it within 2 years.

The Centers for Disease Control and Prevention (CDC) has targeted Chagas disease as one of five “neglected parasitic infections,” indicating that it warrants special public health action.

“Chagas disease does not attract much attention from pharmaceutical companies,” Lepesheva says. Right now, there are only two medicines to treat it. They are only available by special request from the CDC, aren’t always effective and can cause severe side effects.

Lepesheva’s research focuses on a particular enzyme, CYP51, that is the target of some anti-fungal medicines. If CYP51 can also act as an effective drug target for the parasites that cause Chagas, her work might help meet an important public health need.

CYP51 is found in all kingdoms of life. It helps produce molecules called sterols, which are essential for the development and viability of eukaryotic cells. Lepesheva and her colleagues are studying VNI and related compounds to examine whether they can block the activity of CYP51 in human pathogens such as protozoa, but do no harm to the enzyme in mammals. In other words, her goal is to cripple disease-causing organisms without creating side effects in infected humans or other mammals.

Lepesheva has tested the effectiveness of VNI on Chagas-infected mice. Remarkably, it has worked 100 percent of the time, curing both the acute and chronic stages of the disease. It acts by preventing the protozoan from establishing itself in the host’s body. If it is similarly effective in humans, VNI could become the first reliable treatment for Chagas disease.