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Archive - Apr 3, 2015

Modified CRISPR-Cas Editing System Allows Systematic Manipulation of Candida albicans Genome; May Permit ID of New Targets for Therapy Against This Sometimes Deadlyi Fungus

By modifying the CRISPR-Cas genome editing system, Whitehead Institute researchers are now able to manipulate Candida albicans' genome systematically--an approach that could help identify novel targets for therapies against this serious pathogen for which there are a limited number of anti-fungal agents. "The ability to engineer Candida albicans with CRISPR technology has changed the playing field," says Whitehead Founding Member Dr. Gerald Fink, who is also a Professor of Biology at MIT. "We used to attack this human pathogen with our hands tied behind our back. Our findings cut these bonds, freeing us to forge ahead on problems in basic research and human health." C. albicans (image) is a commensal organism that normally lives harmlessly on the skin or in the gut. However, this yeast can grow in uncontrolled fashion--particularly in immunocompromised individuals--causing fungal infections ranging from mild to lethal. C. albicans is a hardy foe because many strains are resistant to anti-fungal drugs. To develop new anti-fungal agents, researchers need to know more about the organism’s basic biology. One tactic for identifying new drug targets in such pathogens is to knock out each of the organism's genes to determine which are essential and therefore appropriate as drug targets. The genome of C. albicans has been particularly difficult to crack because it has two copies of every gene and existing genome editing methods have been inefficient in knocking out both copies simultaneously. In 2012, a bacterial immunity system --the clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated protein 9 (Cas) system--was repurposed for genome editing. It is precise and efficient enough to edit both copies of a gene in most diploid organisms. However, C.

Geomagnetic Compass Prosthesis Permits Blind Rats to Successfully Negotiate Mazes; Implications for Aids to Blind Humans, Further Suggests Broad Expansion of Human Senses Possible

By attaching a microstimulator and geomagnetic compass to the brains of blind rats, researchers reporting online on April 2, 2015 in the Cell Press journal Current Biology found that the animals can spontaneously learn to use new information about their location to navigate through a maze nearly as well as normally sighted rats. The article is titled “Visual Cortical Prosthesis with a Geomagnetic Compass Restores Spatial Navigation in Blind Rats" Researchers say the findings suggest that a similar kind of neuroprosthesis might also help blind people walk freely through the world. Most notably, perhaps, the findings show the incredible flexibility of the mammalian brain. "The most remarkable point of this paper is to show the potential, or the latent ability, of the brain," says Dr. Yuji Ikegaya of the University of Tokyo. "That is, we demonstrated that the mammalian brain is flexible even in adulthood--enough to adaptively incorporate a novel, never-experienced, non-inherent modality into the pre-existing information sources." In other words, he says, the brains of the animals they studied were ready and willing to fill in "the 'world' drawn by the five senses" with a new sensory input. What Dr. Ikegaya and his colleague Dr. Hiroaki Norimoto set out to do was to restore not vision per se, but the blind rats' allocentric sense. That sense is what allows animals and people to recognize the position of their body within the environment. What would happen, the researchers asked, if the animals could "see" a geomagnetic signal? Could that signal fill in for the animals' lost sight? Would the animals know what to do with the information?

Chakravarti-Led Team ID’s New Pathway That Guides Development of Enteric Nervous System and May Be Key to Hirschprung’s Disease

Genetic studies in humans, zebrafish, and mice have revealed how two different types of genetic variations team up to cause a rare condition called Hirschsprung's disease. The findings add to an increasingly clear picture of how flaws in early nerve development lead to poor colon function, which must often be surgically corrected. The study also provides a window into normal nerve development and the genes that direct it. The results appear in the April 2, 2015 issue of the American Journal of Human Genetics. Approximately one in every 5,000 babies is born with Hirschsprung's disease, which causes bowel obstruction and can be fatal if not treated. The disease arises early in development when nerves that should control the colon fail to grow properly. Those nerves are part of the enteric nervous system, which is separate from the central nervous system that enables our brains to sense the world. The genetic causes of Hirschsprung's disease are complex, making it an interesting case study for researchers like Aravinda Chakravarti (photo), Ph.D., a Professor in the Johns Hopkins University School of Medicine's McKusick-Nathans Institute of Genetic Medicine, Director of the Center for Complex Genomics, and the 2008 President of the American Society of Human Genetics (ASHG). His research group took on the condition in 1990, and in 2002, it performed the first-ever genome-wide association study (GWAS) to identify common variants linked to the disease. But while Dr. Chakravarti's and other groups have identified several genetic variants associated with Hirschsprung's, those variants do not explain most cases of the disease. So Dr. Chakravarti and colleagues conducted a new GWAS of the disease, comparing the genetic markers of more than 650 people with Hirschsprung's disease, their parents, and healthy controls.

A Different Stride Against Glioblastoma Multiforme; Brain Delivery via SNAs Shows miR-182 Inhibits Oncogenes in Animal Model of This Lethal Cancer

On Sunday, March 29, 2015, the television program 60 Minutes outlined a phase 1 trial underway at the Duke University Medical Center that uses a modified polio virus injected directly into glioblastoma tumors in the brain as a way to mobilize the immune system to attack, and hopefully eradicate, the normally fatal brain tumor. Two persons in the 22-person phase 1 trial at Duke have been declared “cancer-free” after three years. Eleven patients, however, have died. The Duke story is written up in BioQuick News at The BioQuick article includes a link to a peer-reviewed Duke article describing how the polio virus has been modified so as to replicate in glioblastoma cells, but not in normal cells—something that was not detailed in the 60 Minutes story. Now, on the heels of the breaking glioblastoma news from Duke, comes a report from Northwestern University’s Feinberg School of Medicine that scientists there have identified a microRNA molecule called miR-182 that can suppress the expression of cancer-causing genes in mice with glioblastoma multiforme (GBM), a deadly and incurable type of brain tumor. While standard chemotherapy drugs damage DNA to stop cancer cells from reproducing, the new method stops the source that creates those cancer cells: genes that are overexpressing certain proteins. "Our study identified miR-182 as a glioblastoma tumor suppressor that reduces the expression of several oncogenes that promote cancer development," said senior author of the study Dr. Alexander Stegh, an Assistant Professor in the Ken and Ruth Davee Department of Neurology and of Medicine at Northwestern University Feinberg School of Medicine.

Mayo-Clinic-Led Team Develops 77-SNP-Based Risk Factor Score to Identify Women at Increased Risk of Breast Cancer

Recent large-scale genomic analyses have uncovered dozens of common genetic variants that are associated with breast cancer. Each variant, however, contributes only a tiny amount to a person's overall risk of developing the disease. A Mayo Clinic-led team of international researchers has now combined 77 of these common genetic variants into a single risk factor that can be used to improve the identification of women with an elevated risk of breast cancer. This factor, known as a polygenic risk score, was built from the genetic data of more than 67,000 women. The results of the research were published online on April 2, 2015, in the Journal of the National Cancer Institute (JNCI). A companion study has extended this finding to show that this measure of genetic variation can be combined with traditional predictors of breast cancer risk such as breast density and family history to improve personalized estimates of breast cancer risk. These latter findings appeared in JNCI last month. "This genetic risk factor adds valuable information to what we already know can affect a woman's chances of developing breast cancer," says study co-author Celine Vachon, Ph.D., an epidemiologist at the Mayo Clinic. "We are currently developing a test based on these results, and though it isn't ready for clinical use yet, I think that within the next few years we will be using this approach for better personalized screening and prevention strategies for our patients." Scientists have known for decades that genetics can play a role in breast cancer. For example, inheriting a mutation in BRCA1 or BRCA2 genes greatly increase a woman's risk of developing the disease, but these mutations are rare and account for less than five percent of all breast cancers.

UCSF Team Finds Lung Cancer Tumor That Activates NF-Kappa-B Pathway to Resist Effects of EGFR-Targeted Drugs Like Erlotinib; Experimental Drug Exists to Block NF-Kappa-B Pathway and, If Used with Erlotinib, Might Prove Highly Effective

Capitalizing on a rare opportunity to thoroughly analyze a tumor from a lung cancer patient who had developed resistance to targeted drug treatment, UC-San Francisco (UCSF) scientists identified a biological escape hatch that explains the resistance, and developed a strategy in mice for shutting it down. In experiments that combined the drug the patient had taken with a second compound that blocks off this newly discovered resistance pathway, the researchers were able to durably wipe out cancer cells in mice implanted with cells from the drug-resistant human tumor. "Even in cancers that are responding to targeted therapy by conventional criteria, resistance is already developing," said the senior author of the new study, Trever Bivona, M.D., Ph.D., Assistant Professor of Medicine and member of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC). "In this work we have begun to crack open the question of why residual disease persists after targeted therapy." Between 10 and 35 percent of non-small cell lung cancer (NSCLC) patients carry mutations in a gene that codes for a cell-surface protein called the epidermal growth factor receptor (EGFR). As its name suggests, under normal circumstances, when a growth factor protein locks onto the EGFR, the receptor sends signals that prompt cells to divide and proliferate. But the EGFR mutations seen in NSCLC cause the receptor to be stuck in an "on" position, leading to rampant cell proliferation. Over the past decade, medications such as erlotinib (trade name Tarceva), which precisely targets the EGFR and tamps down its activity, have advanced the treatment of EFGR-mutant NSCLC beyond chemotherapy, but significant challenges remain.