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Archive - Feb 2010

Date

February 25th

New Strategy Rapidly Identifies Two Prototype Drugs

A new and comprehensive drug development strategy that starts with extensive screening of potential targeting peptides to rapidly identify prototype small-molecule drugs has produced two that target the EGFR and VEGFR pathways in novel ways, according to a research team led by scientists at The University of Texas M.D. Anderson Cancer Center "The conceptual advance here is to demonstrate how to go rapidly from screening to structural-functional analysis to drug prototype in a few years," said co-senior author Dr. Wadih Arap, of the David H. Koch Center at M.D. Anderson. "The practical outcome is a pair of new drug candidates, one that acts as a decoy to inhibit a cancer-promoting pathway and another that blocks angiogenesis (the development of new blood vessels), which has the potential to treat both cancer and retinopathies that cause blindness," said co-senior author Dr. Renata Pasqualini, also of the David H. Koch Center. The group's approach begins by screening the target receptors with a phage display library used by Drs. Arap and Pasqualini. This method screens billions of viral particles that each display a different peptide on its outer coat to find those that fit into the receptor as a key goes into a lock. Candidate peptides are next winnowed by using structural and functional analysis. Once a peptide is identified and tested, the researchers take an additional step to synthesize a new version of the peptide more suited for use as a drug.

Stem Cells Restore Sight in Retina-Damaged Mice

Researchers have successfully used mouse embryonic stem cells to replace diseased retinal cells and restore sight in a mouse model of retinitis pigmentosa. This strategy could potentially become a new treatment for retinitis pigmentosa, a leading cause of blindness that affects approximately one in 3,000 to 4,000 people, or a total of 1.5 million people worldwide. The approach also holds promise for the treatment of other retina-damaging diseases. "This research is promising because we successfully turned stem cells into retinal cells, and these retinal cells restored vision in a mouse model of retinitis pigmentosa," said Dr. Stephen Tsang, assistant professor of ophthalmology, pathology, and cell biology at Columbia University Medical Center, and lead author of the paper. "The transplanted cells not only looked like retinal cells, but they functioned like them too." In Dr. Tsang's study, sight was restored in one-fourth of the mice that received the stem cells. However, complications of benign tumors and retinal detachments were seen in some of the mice, so Dr. Tsang and colleagues will optimize techniques to decrease the incidence of these complications in human embryonic stem cells before testing in human patients can begin. "Once the complication issues are addressed, we believe this technique could become a new therapeutic approach for not only retinitis pigmentosa, but age-related macular degeneration, Stargardt disease, and other forms of retinal disease that also feature loss of retinal cells," said Dr. Tsang. Specialized retinal cells called the retinal pigment epithelium help maintain vision.

Single-Dose HIV DNA Vaccine Produces Specific Immunity in Primates

For the first time, researchers have shown that a single-dose HIV DNA vaccine can induce a long-lasting HIV-specific immune response in nonhuman primates, a discovery that could prove significant in the development of HIV vaccines. "Our comprehensive analysis demonstrated for the first time the capacity of a single high dose of HIV DNA vaccine alone to induce long-lasting and polyfunctional T-cell responses in the nonhuman primate model, bringing new insights for the design of future HIV vaccines," said the researchers from Emory University in the United States and the Institut National de la Recherche Agronomique in France. HIV is persistently spreading at epidemic rates throughout the world, emphasizing the need for a vaccine that can substantially reduce viral loads and minimize transmission. In a previous study, the research team had successfully induced long-lasting and potent HIV-specific immune responses in mice following immunization with a single-dose SHIV DNA-based vaccine. SHIV is a virus that combines genes from HIV in a genetic background of simian immunodeficiency virus (SIV). In the current study, rhesus macaques were immunized with a single high dose of the SHIV DNA-based vaccine and monitored for vaccine-induced immune responses. Results showed that all immunized monkeys developed broad HIV-specific T-cell immune responses that persisted for months. The researchers detailed their findings in the February 2010 issue of the Journal of Virology. [Press release] [J. Virology abstract]

February 24th

Face Recognition Ability Is Heritable

Recognizing faces is an important social skill, but not all of us are equally good at it. Some people are unable to recognize even their closest friends (a condition called prosopagnosia), while others have a near-photographic memory for large numbers of faces. In a recent study of twins, researchers at MIT and in Beijing, China, have shown that face recognition ability is heritable and that it is inherited separately from IQ. This finding plays into a long-standing debate on the nature of mind and intelligence. The prevailing “generalist” theory, upon which the concept of IQ is based, holds that if people are smart in one area they tend to be smart in other areas. So if you are good in math, you are also more likely to be good at literature and history. IQ is strongly influenced by heredity, suggesting the existence of "generalist genes" for cognition. Yet some cognitive abilities seem distinct from overall IQ, as happens when a person who is brilliant with numbers or music is tone-deaf socially or linguistically. Also, many specialized cognitive skills, including recognizing faces, appear to be localized to specialized brain regions. Such evidence supports a “modularity” hypothesis, in which the mind is like a Swiss Army knife--a general-purpose tool with special-purpose devices. “Our study provides the first evidence supporting the modularity hypothesis from a genetic perspective," said senior author Dr. Jia Liu, Professor of Cognitive Neuroscience at Beijing Normal University. "That is, some cognitive abilities, like face recognition, are shaped by specialist genes rather than generalist genes." “Our finding may help explain why we see such disparities of cognitive abilities within the same person in certain heritable disorders,” added co-author Dr. Nancy Kanwisher of the McGovern Institute for Brain Research at MIT.

Striatum Gene May Be a Key to Huntington Disease Process

The down-regulation of a key gene in the striatum, a region of the brain attacked in Huntington disease (HD), may be a defensive measure taken by striatal cells to try to avoid ultimate destruction in the HD process. The down-regulated gene (CalDAG-GEFI) is normally highly enriched in the striatal cells that are targeted in HD. An MIT research team, together with collaborators, showed that CalDAG-GEFI gene expression is dramatically down-regulated in the brains of individuals with HD, as well as in mouse models of the disease. By following mutant mice for up to nine months, the researchers further showed that this reduction occurred gradually, in parallel with the progression of the disease. These progressive changes suggested that CalDAG-GEFI is likely to play some role in the disease process. The researchers wanted to determine whether the suppression of this gene is part of the death process, or whether it represents part of the brain’s protective response. They found that the latter explanation appears to be true--when the researchers artificially blocked the expression of CalDAG-GEFI, the striatal neurons were protected from damage induced by the mutant huntingtin (Htt) protein. “So the enriched expression of CalDAG-GEFI in the striatum may explain, in part, why striatal neurons are particularly vulnerable to the expression of mutant Htt,” explained first author Dr. Jill Crittenden of the MIT McGovern Institute for Brain Research. “Switching off of the CalDAG-GEFI gene may represent the neuron’s attempt, ultimately unsuccessful, to save itself.” The researchers hope that by understanding the molecular pathway by which neurons are killed, their findings may suggest new strategies for the development of treatments that could slow or even prevent the progression of HD.

Clue to Schizophrenia Late Manifestation from Early Developmental Changes

Scientists from Johns Hopkins and collaborating institutions have discovered a clue as to how schizophrenia might develop after puberty as the result of genetic influences that occur in early development. In a new study, the researchers have manipulated (knocked down) a known schizophrenia susceptibility gene (DISC-1) in the brains of fetal mice in an attempt to unravel the complex link between prenatal brain development and the maturation of information processing and cognition in adult animals. The scientists showed that a transient reduction of DISC-1 (disrupted in schizophrenia-1) gene expression in the mouse prefrontal cortex just before or after birth led to aberrant changes in adult animals that are associated with schizophrenia--including perturbation of specific dopaminergic brain pathways, disruption of neural circuitry, and severe behavioral abnormalities. These findings are significant because they provide a concrete link between a nonlethal genetic disruption during prenatal brain development and specific abnormalities in adult brain maturation. "Prior to our study, the kinds of neurodevelopmental defects that cause the defined anatomical changes observed in schizophrenia patients--clinical onset 15+ years after birth, psychosis, impaired cognition and information processing, and aberrant dopaminergic neurotransmission--were not clear," offered Dr. Toshitaka Nabeshima, the senior author of the report. "However, the model in our study represents a majority of these characteristics.” The authors were careful to caution that while their findings shed some light on how early disease-associated events impact adult brain function, manipulation of one gene cannot fully define the complex neuropathology associated with schizophrenia.

February 23rd

Known Oncogene Discovered in Pancreatic Cancer

Researchers at the Mayo Clinic have found that protein kinase C-iota (PKCi), an oncogene known to be important in colon and lung cancers, is over-produced in pancreatic cancer and is linked to poor patient survival. They also found that genetically inhibiting PKCi in laboratory animals led to a significant decrease in pancreatic tumor growth and spread. The scientists said that their results strongly indicate that PKCi will be an effective target for pancreatic cancer therapy. The discovery is especially encouraging, they said, because an experimental agent that targets PKCi is already being tested in patients at the Mayo Clinic for other indications. "This is the first study to establish a role for PKCi in growth of pancreatic cancer, so it is exciting to know that an agent already exists that targets PKCi which we can now try in preclinical studies," said the study's senior investigator, Dr. Nicole Murray, of the Mayo Clinic’s Department of Cancer Biology. The drug, aurothiomalate, which was once used to treat rheumatoid arthritis, is now being tested in a Phase 1 clinical trial in patients with lung cancer at the Mayo Clinic's sites in Minnesota and Arizona. Based on findings to date, a Phase 2 clinical trial is being planned to combine aurothiomalate with agents targeted at other molecules involved in cancer growth. Dr. Murray stressed that her group’s new study has not yet tested aurothiomalate against pancreatic cancer, but that any treatment that targets this major cancer pathway offers a new avenue for therapy. "This is such a deadly disease. No standard treatment has shown much promise," she said. "New ideas and fresh, targeted therapies such as this are sorely needed." Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with an overall 5-year survival rate of less than 5 percent.

Tiny RNA Molecule Has Big Implications for Origin of Life

The smallest RNA enzyme ever known to perform a cellular chemical reaction has been described in a paper published online on February 22 in PNAS. Scientists at the University of Colorado at Boulder (UCB) have synthesized an extremely small RNA molecule that can catalyze a key reaction needed to synthesize proteins, the building blocks of life. The findings could be a substantial step toward understanding "the very origin of earthly life," contended graduate student and first author Rebecca Turk. The research team, led by Dr. Michael Yarus, focused on a ribozyme—a form of RNA that can catalyze chemical reactions—that was made up of only five nucleotides. Because proteins are complex, one vexing question has been where the first proteins came from, said Dr. Tom Blumenthal, chairman of the Molecular, Cellular, and Developmental Biology (MCDB) department at UCB, who was not involved in the research. "It now appears that the first catalytic macromolecules could have been RNA molecules, since they are somewhat simpler, were likely to exist early in the formation of the first life forms, and are capable of catalyzing chemical reactions without proteins being present," he said. "In this paper, the Yarus group has made the amazing discovery that even an extremely tiny RNA can by itself catalyze a key reaction that would be needed to synthesize proteins," said Dr. Blumenthal. “Nobody expected an RNA molecule this small and simple to be able to do such a complicated thing as that." The finding adds weight to the "RNA World" hypothesis, which proposes that life on Earth evolved from early forms of RNA. "Mike Yarus has been one of the strongest proponents of this idea, and his lab has provided some of the strongest evidence for it over the past two decades," Dr. Blumenthal said. Dr.

Pesky Aphid Thrives Despite Weak Immune System

Pea aphids, expert survivors of the insect world, appear to lack major biological defenses, according to the first genetic analysis of their immune system. "It's surprising," said Emory University biologist Dr. Nicole Gerardo, who led the study."Aphids have some components of an immune system, but they are missing the genes that we thought were critical to insect immunity." One hypothesis is that aphids may compensate for their lack of immune defenses by focusing on reproduction. From birth, a parthenogenic female aphid contains embryos that also contain embryos. This is called "telescoping of generations." "She is born carrying her granddaughters," Dr. Gerardo said. "In a lab, a female aphid can produce up to 20 copies of herself per day. About 10 days later, those babies will start producing their own offspring." Over 50 million years, aphids have evolved complex relationships with beneficial bacteria that supply them with nutrients or protect them from predators and pathogens. It's possible that the weak immune response in aphids developed as a way to keep from killing off these beneficial microbes, Dr. Gerardo noted. "A key question is whether these microbes could have changed the aphid genome, or changed how the aphid uses its genes." Further study of how the aphid immune system interacts with microbes could yield better methods for controlling them in agriculture. Pea aphids are major agricultural pests and also important biological models for studies of insect-plant interactions, symbiosis, virus vectoring, and genetic plasticity. These resilient insects thrive despite a host of enemies, including parasitic wasps, lady bugs, fungal pathogens, and frustrated farmers and gardeners the world over.

Gene Identified for Atrial Fibrillation

By analyzing data from multiple genome-wide association studies (GWAS), scientists have identified common variants in the KCNN3 gene that are associated with a form of irregular heartbeat known as “lone atrial fibrillation” (lone AF). This is a type of AF seen in younger individuals with no other signs of heart disease. The finding may open the way to the development of innovative treatments not only for lone AF in specific, but for AF in general. The KCNN3 gene, located on chromosome 1, codes for a potassium channel protein that carries signals across cell membranes in organs including the brain and the heart. While the exact cardiac role of the protein is unknown, it may play a part in resetting the electrical activity of the atria, a process that goes awry in AF. Animal studies have suggested that a related protein, KCNN2, may help control signals originating in the atria and in the pulmonary veins, areas known to be involved in lone AF. The researchers replicated the association of KCNN3 variants with lone AF in data from two additional GWAS involving another 1,000 lone AF patients and 3,500 controls. "The genetic location we have identified could be a new drug target for the treatment of AF," said cardiologist Dr. Patrick Ellinor of the Massachusetts General Hospital Cardiovascular Research Center and Cardiac Arrhythmia Service and an assistant professor of medicine at Harvard Medical School, the first author of the report. "We also will be investigating whether these variants can help us predict patients' clinical outcomes or their response to the various treatments for AF."