Tales from the crypt are supposed to be scary, but new research from Vanderbilt University, the HudsonAlpha Institute for Biotechnology and collaborating institutions shows that crypts can be places of renewal too: intestinal crypts, that is. Intestinal crypts are small areas of the intestine where new cells are formed to continuously renew the digestive tract. By focusing on one protein expressed in our intestines called Lrig1, the researchers have identified a special population of intestinal stem cells that respond to damage and help to prevent cancer. The research, published in the March 30, 2012 issue of Cell, also shows that the diversity of stem cells in the intestines is greater than previously thought. “Identification of these cells and the role they likely play in response to injury or damage will help advance discoveries in cancer,” said Shawn Levy, Ph.D., faculty investigator at the HudsonAlpha Institute and an author on the study. The intestines and colon are normally lined with a single layer of cells to absorb nutrients from food. There are regular small pockets in the intestines called crypts, where stem cells are gathered. Rapid turnover of the lining cells and replacement by new lining cells made in the crypt, keep the intestines and colon healthy and keep damaged cells from turning into cancerous ones. The new paper demonstrates that, although the makeup of stem cells in the crypt is still controversial, one protein called Lrig1 can distinguish a group of long-lived cells at the base of the crypt. These Lrig1-positive stem cells do not regularly replace lining cells, but instead are only activated when there is damage or injury to the intestine. In addition, the researchers show that the Lrig1 protein functions to prevent cancer as a tumor suppressor molecule.
Mosquitoes infected with dengue virus experience an array of changes in the activity of genes and associated functions of their salivary glands, and these changes may lead to increased virus transmission, according to a recent study led by George Dimopoulos, Ph.D., of the Malaria Research Institute and Bloomberg School of Public Health at Johns Hopkins University. Some of these changes involve the mosquito’s immune system and affect its susceptibility to infection with the virus. Others involve factors that enhance the mosquito’s capacity to feed on blood, possibly leading to greater transmission of dengue virus to humans, the study authors write. According to the World Health Organization, each year, dengue virus infects about 50 million to 100 million people and causes between 10,000 and 15,000 deaths, most of them in children. Symptoms include high fever and pain in the muscles and joints, and in severe cases can include bleeding under the skin, damage to blood vessels, and death. The disease, which is prevalent in tropical and subtropical regions of the world, has been reported recently in parts of the United States, such as Hawaii, Puerto Rico, and Florida. There is no vaccine or drug treatment for dengue. The only way to prevent infection is to avoid being bitten by Aedes mosquitoes, which can carry the virus in their salivary glands. The Hopkins researchers sought to learn how dengue virus affects the way the glands function during virus transmission. They compared the expression of several thousand genes in Aedes aegypti mosquitoes that either were or were not infected with dengue virus.
Research from North Carolina State University shows that honey bees “self-medicate” when their colony is infected with a harmful fungus, bringing in increased amounts of antifungal plant resins to ward off the pathogen. “The colony is willing to expend the energy and effort of its worker bees to collect these resins,” says Dr. Michael Simone-Finstrom, a postdoctoral research scholar in NC State’s Department of Entomology and lead author of a paper describing the research. “So, clearly this behavior has evolved because the benefit to the colony exceeds the cost.” When faced with pathogenic fungi, bees line their hives with more propolis, a waxy, yellow substance. Wild honey bees normally line their hives with propolis, a mixture of plant resins and wax that has antifungal and antibacterial properties. Domesticated honey bees also use propolis, to fill in cracks in their hives. However, researchers found that, when faced with a fungal threat, bees bring in significantly more propolis – 45 percent more, on average. The bees also physically removed infected larvae that had been parasitized by the fungus and were being used to create fungal spores. Researchers know propolis is an effective antifungal agent because they lined some hives with a propolis extract and found that the extract significantly reduced the rate of infection. And apparently bees can sometimes distinguish harmful fungi from harmless ones, because colonies did not bring in increased amounts of propolis when infected with harmless fungal species. Instead, the colonies relied on physically removing the spores. However, the self-medicating behavior does have limits. Honey bee colonies infected with pathogenic bacteria did not bring in significantly more propolis – despite the fact that the propolis also has antibacterial properties.
An international team led by scientists at A*STAR’s Institute of Medical Biology (IMB) has discovered that a protein, called TRIM28, normally present in the mother’s egg, is essential right after fertilization to preserve certain chemical modifications or “epigenetic marks” on a specific set of genes. The study, published in the March 23, 2012 issue of Science, paves the way for more research to explore the role that epigenetics might play in infertility. Previous studies have shown that both nuclear reprogramming as well as “imprinting” are vital for the survival and later development of the embryo. However, the underlying mechanisms governing the intricate interplay of these two processes during the early embryonic phase have not been clear, until now. Immediately after fertilization, the majority of the epigenetic marks on the DNA from the sperm and egg cells are erased. The erasure process, termed nuclear reprogramming, allows the genes from the parents to be reset so that the early embryonic cells can develop into any cell types of the body. On the other hand, certain epigenetic marks on a particular set of genes, some from the mother and some from the father must be preserved. These genes are said to be “imprinted” by their parent of origin and preservation of these marks is critical for the survival of the newly formed embryo. Expression of these imprinted genes at the appropriate levels ensures proper development of the embryo. If the epigenetic marks on the imprinted genes are not protected, severe and multiple developmental defects occur in the embryo. Using genetically identical mice from an inbred mouse strain, Drs. Davor Solter and Barbara Knowles, Senior Principal Investigators at IMB, observed that none of the embryos resulting from the fertilization of eggs lacking TRIM28 survived.
Rare mutations in a gene called XRCC2 cause increased breast cancer risk, according to a study published online on March 29, 2012 in the American Journal of Human Genetics. The study looked at families that have a history of the disease, but do not have mutations in the currently known breast cancer susceptibility genes. Sean Tavtigian, Ph.D., a Huntsman Cancer Institute (HCI) investigator and associate professor in the Department of Oncological Sciences at the University of Utah (U of U) is one of three co-principal investigators on the study, along with David Goldgar, Ph.D., professor in the Department of Dermatology at the U of U and an HCI investigator, and Melissa Southey, Ph.D., professor in the Department of Pathology at the University of Melbourne, Australia. “We have added to the list of genes that harbor mutations causing breast cancer,” said Dr. Tavtigian. “This knowledge will improve breast cancer diagnostics and add years to patients’ lives. More important, relatives who have not been affected by the disease, but carry the mutations, will benefit even more. They can find out they are at risk before they have cancer and take action to reduce their risk or catch the cancer early.” XRCC2 may also provide a new target for chemotherapy. “A type of drug called a PARP inhibitor appears to kill tumor cells that have gene mutations in a particular DNA repair pathway. XRCC2 is in this pathway, as are BRCA1 and BRCA2. It’s reasonably likely that a breast cancer patient who has a mutation in XRCC2 will respond well to treatment with PARP inhibitors,” said Dr. Tavtigian. According to Dr. Tavtigian, many breast cancer cases appear in families with a weak history of the disease.
A team of researchers led by scientists at Weill Cornell Medical College has designed what appears to be a powerful gene therapy strategy that can treat both beta-thalassemia disease and sickle cell anemia. The scientists have also developed a test to predict patient response before treatment. This study’s findings, published in online on March 27, 2012 in PLoS ONE, represent a new approach to treating these related, and serious, red blood cell disorders, say the investigators. “This gene therapy technique has the potential to cure many patients, especially if we prescreen them to predict their response using just a few of their cells in a test tube,” says the study’s lead investigator, Stefano Rivella, Ph.D., an associate professor of genetic medicine at Weill Cornell Medical College. He led a team of 17 researchers in three countries. Dr. Rivella says this is the first time investigators have been able to correlate the outcome of transferring a healthy beta-globin gene into diseased cells with increased production of normal hemoglobin — which has long been a barrier to effective treatment of these diseases. So far, only one patient, in France, has been treated with gene therapy for beta-thalassemia, and Dr. Rivella and his colleagues believe the new treatment they developed will be a significant improvement. No known patient has received gene therapy yet to treat sickle cell anemia. Beta-thalassemia is an inherited disease caused by defects in the beta-globin gene. This gene produces an essential part of the hemoglobin protein, which, within red blood cells, carries life-sustaining oxygen throughout the body. The new gene transfer technique developed by Dr. Rivella and his colleagues ensures that the beta-globin gene that is delivered will be active, and that it will also provide more curative beta-globin protein.
On March 22, 2012, Lawrence Livermore National Laboratory (LLNL) announced that it has licensed its microbial detection array technology to a St. Louis, Missouri-based company, MOgene LC, a supplier of DNA microarrays and instruments. Known formally as the Lawrence Livermore Microbial Detection Array (LLMDA), the technology could enable food safety professionals, law enforcement, medical professionals, and others to detect within 24 hours any virus or bacteria that has been sequenced and included among the array’s probes. Developed between October 2007 and February 2008, the LLMDA detects viruses and bacteria with the use of 388,000 probes that fit in a checkerboard pattern in the middle of a one-inch wide, three-inch long glass slide. The current operational version of the LLMDA contains probes that can detect more than 2,200 viruses and more than 900 bacteria. The LLMDA provides researchers with the capability of detecting pathogens over the entire range of known viruses and bacteria. Current multiplex polymerase chain reaction (PCR) techniques can at most offer detection from among 50 organisms in one test. The Livermore team plans to update probes on the array with new sequences of bacteria, viruses, and other microorganisms from GenBank and other public databases about once per year, in addition to using sequences obtained from collaborators for their probes. LLNL’s current collaborators include the University of California, San Francisco; the Blood Systems Research Institute; the University of Texas Medical Branch (Galveston); the Statens Serum Institut of Copenhagen, Denmark; the University of California, Davis; Imigene; the U.S. Food & Drug Administration; the Centers for Disease Control and Prevention; the Naval Medical Research Center; and the Marine Mammal Center of Sausalito, California.
UCLA researchers and colleagues have pinpointed a new mechanism that potently activates T-cells, the group of white blood cells that plays a major role in fighting infections. In work published March 25, 2012 online in Nature Medicine, the team specifically studied how dendritic cells, immune cells located at the site of infection, become more specialized to fight the leprosy pathogen known as Mycobacterium leprae. Dendritic cells, like scouts in the field of a military operation, deliver key information about an invading pathogen that helps activate the T-cells in launching a more effective attack. It was previously known that dendritic cells were important for a strong immune response and the number of such cells at an infection site positively correlated with a robust reaction. However, until now it was poorly understood how dendritic cells become more specialized to address specific types of infections. The researchers found that a protein called NOD2 triggers a cell-signaling molecule called interleukin-32 that induces general immune cells called monocytes to become specialized information-carrying dendritic cells. “This is the first time that this potent infection-fighting pathway with dendritic cells has been identified, and demonstrated to be important in fighting human disease,” said the study’s first author Dr. Mirjam Schenk, postdoctoral scholar, division of dermatology, David Geffen School of Medicine at UCLA. In conducting the study, scientists used monocytes taken from the blood of healthy donors and leprosy patients and incubated the cells with the pathogen M. leprae or specific parts of the mycobacteria, known to trigger NOD2 and TLR2, both associated with immune system activation.
An intra-tumor injection of a virus prevented further growth of some pancreatic tumors and eradicated others in mouse models of pancreatic ductal adenocarcinoma. However, some tumors continued growing despite this treatment, proving resistant to the viruses. The research is published in the March 2012 Journal of Virology. About 95 percent of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAs). PDA is considered to be one of the most lethal malignancies, resulting in a five-year survival rate of only 8-20 percent. In this study, the researchers, led by Dr. Valery Z. Grdzelishvili of the University of North Carolina, Charlotte, tested several species of virus against pancreatic tumors, most notably vesicular stomatitis virus (VSV), a type of virus that is commonly used in the laboratory. Previous studies had demonstrated that some other viruses, including adenoviruses, herpesviruses, and reoviruses, could be used to kill pancreatic cancer cells in some animal models of pancreatic cancer. VSV has several qualities which make it attractive as a potential oncolytic (cancer killing) agent. First, unlike some other viruses (including adenoviruses), VSV replication does not require the cancer cell to express a specific receptor in order to infect that cell, and therefore it can infect most any cancer cell. Second, replication occurs in the cytoplasm of host cells, which means that there is no risk that it will cause healthy host cells to become cancerous, says Dr. Grdzelishvili. Third, this virus’s genome is easily manipulated, which would make it fairly practical to adjust levels of foreign gene expression to enhance the virus’s specificity for particular cancers, and its ability to kill them. Fourth, unlike with some other viruses, humans have no preexisting immunity to VSV.
A growing body of evidence underscores the importance of human gut bacteria in modulating human health, metabolism, and disease. Yet bacteria are only part of the story. Viruses that infect those bacteria also shape who we are. Frederic D. Bushman, Ph.D., professor of Microbiology at the Perelman School of Medicine at the University of Pennsylvania, led a study published March 6, 2012 in the PNAS that sequenced the DNA of viruses — the virome — present in the gut of healthy people. Nearly 48 billion bases of DNA, the genetic building blocks, were collected in the stools of 12 individuals. The researchers then assembled the blocks like puzzle pieces to recreate whole virus genomes. Hundreds to thousands of likely distinct viruses were assembled per individual, of which all but one type were bacteriophages — viruses that infect bacteria — which the team expected. The other was a human pathogen, a human papillomavirus found in a single individual. Bacteriophages are responsible for the toxic effects of many bacteria, but their role in the human microbiome has only recently started to be studied. To assess variability in the viral populations among the 12 individuals studied, Dr. Bushman’s team, led by graduate student Samuel Minot, looked for stretches of bases that varied the most. Their survey identified 51 hypervariable regions among the 12 people studied, which, to the team’s surprise, were associated with reverse transcriptase genes. Reverse transcriptase enzymes, more commonly associated with replication of retroviruses such as HIV, copy RNA into DNA. Of the 51 regions, 29 bore sequence and structural similarity to one well-studied reverse transcriptase, a hypervariable region in the Bordetella bacteriophage BPP-1. Bordetella is the microbe that causes kennel cough in dogs.