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Archive - 2010

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February 27th

Normal Version of Fusion Gene Component Is Required by Leukemia

Researchers have found that a particularly aggressive type of blood cancer called mixed lineage leukemia (MLL) requires the normal version of a translocated gene (the MLL gene) to survive. The findings were featured as the cover article in the February 17, 2010 issue of Cancer Cell. MLL develops when a piece of chromosome 11 breaks at the normal MLL gene. The chromosome piece attaches to another broken chromosome, resulting in the joining of the MLL gene to a now-neighboring gene on the other chromosome. The joined genes code for a new “fusion protein” that eventually causes uncontrolled growth of blood cells. The researchers found that the runaway growth triggered by the fusion protein is blocked when the gene for the normal MLL protein is deleted from leukemia cells. The results showed that the normal protein is required for fusion-protein generation of the leukemia and for the maintenance of transformed cells. This suggested that the normal protein cooperates with the fusion protein in the generation of the leukemia. "This research not only uncovers the crucial role of a normal protein key to the development of MLL, but also how the cancer cells stay alive in the first place," said Dr. Xianxin Hua, from the University of Pennsylvania, senior author of the article. The results point to the normal MLL gene as a potential target for new therapies, possibly through repression of the gene in leukemia stem cells. [Press release] [Cancer Cell abstract]

February 26th

Gene-Based Stem Cell Therapy Knocks Down HIV Receptor Expression

UCLA researchers have reported successfully removing CCR5 from human cells in a humanized mouse model. CCR5 is a cell receptor to which HIV-1 binds for infection, but which the human body apparently does not need. Individuals who naturally lack the CCR5 receptor have been found to be essentially resistant to HIV. In the humanized mouse model, the researchers transplanted a specific short hairpin RNA (shRNA), targeted against the CCR5 gene, into human blood stem cells, in order to inhibit the expression of CCR5 in the human immune cells arising from the stem cells. According to the authors, the positive results provide evidence that this strategy may be an effective way to treat HIV-infected individuals, i.e., by prompting the potent long-term and stable reduction of CCR5 in systemic lymphoid organs. The results of the UCLA work were published in the February 25 issue of Blood. [Press release] [Blood abstract]

Prion Protein Functions in Maintenance of Peripheral Myelin

The neuronal expression and regulated proteolysis of the normal, cellular prion protein (PrPc) are essential for the maintenance of peripheral myelin, according to an international team of researchers from institutions including Cal Tech and the University Hospital of Zurich. The integrity of peripheral nerves depends on communication between axons and the Schwann cells that produce myelin. Myelin insulates peripheral nerve axons and speeds electrical transmission. The axon signals that ensure myelin maintenance are distinct from those that direct myelination and are largely unknown, the authors wrote. The normal function of PrPc--that when misfolded into the scarpie-associated form (PrPsc) causes various transmissible fatal neurodegenerative diseases, including scrapie in sheep, mad cow disease in cattle, and Creutzfeldt-Jakob disease in humans--is also unknown. The current results appear to represent progress toward solving, at least in part, both of these puzzles. The authors showed that ablation of PrPc triggers a chronic demyelinating polyneuropathy (CDP) in four independently targeted mouse strains. CDP was triggered by depletion of PrPc specifically in neurons, but not in Schwann cells, and was suppressed by PrPc expression restricted to neurons but not to Schwann cells. CDP was prevented by PrPc variants that undergo proteolytic amino-proximal cleavage, but not by variants that are nonpermissive for cleavage, including secreted PrPc lacking its glycolipid membrane anchor. This work was published in the March issue of Nature Neuroscience. The seminal research identifying and characterizing prion proteins was recognized by the awarding of the Nobel Prize in Physiology or Medicine to Dr. Stanley Prusiner in 1997.

February 25th

Second DISC-1 Study Suggests Reason for Adolescent Onset of Schizophrenia

In a second study, researchers at Johns Hopkins and collaborating institutions have identified a mechanism whereby alterations in the DISC-1 (disrupted in schizophrenia-1) gene may underlie the adolescent onset of schizophrenia. In this second study, published in the March issue of Nature Neuroscience, the research team examined DISC-1's role in forming connections between nerve cells. The first study looked at the long-term effects of transient DISC-1 gene expression changes near the time of birth in a mouse model. This first study was published in the February 25, 2010 issue of Neuron and has previously been reported on in BioQuick News. Taken together, the results of both studies suggest that anatomical differences that seem to be influenced by the DISC-1 gene cause problems that start before birth, but surface only in young adulthood. "If we can learn more about the cascade of events that lead to these anatomical differences, we may eventually be able to alter the course of schizophrenia. During adolescence, we may be able to intervene to prevent or lessen symptoms," said second study senior author and first study co-author Dr. Akira Sawa, professor of psychiatry and director of the program in molecular psychiatry at the Johns Hopkins University School of Medicine. Numerous studies have previously suggested that schizophrenia results from abnormal connectivity. The fact that symptoms typically arise soon after adolescence, a time of massive reorganization of connections between nerve cells, supports this idea. The scientists began their second study by surveying rat nerve cells to see where DISC1 was most active. Unsurprisingly, they found the highest DISC-1 activity in connections between nerve cells.

Female Sex Hormone Found in Plant

In a finding that overturns conventional wisdom, scientists have reported the first discovery of the female sex hormone progesterone in a plant. Until now, scientists thought that only animals could make progesterone. A steroid hormone secreted by the ovaries, progesterone prepares the uterus for pregnancy and maintains pregnancy. A synthetic version, progestin, is used in birth control pills and other medications. "The significance of the unequivocal identification of progesterone cannot be overstated," the article, by Dr. Guido F. Pauli and colleagues, claimed. "While the biological role of progesterone has been extensively studied in mammals, the reason for its presence in plants is less apparent." The authors speculate that the hormone, like other steroid hormones, might be an ancient bioregulator that evolved billions of years ago, before the appearance of modern plants and animals. The new discovery may change scientific understanding of the evolution and function of progesterone in living things. Scientists had previously identified progesterone-like substances in plants and speculated that the hormone itself could exist in plants. But researchers had not found the actual hormone in plants until now. Dr. Pauli and colleagues used two powerful laboratory techniques, nuclear magnetic resonance and mass spectroscopy, to detect progesterone in leaves of the Common Walnut (or English Walnut) tree (Juglans regia). They also identified five new progesterone-related steroids in a plant belonging to the buttercup family. The discoveries were reported online on January 28, 2010 in the American Chemical Society's Journal of Natural Products. [Press release] [Journal of Natural Products abstract]

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.