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September 23rd, 2009

Retinal Implant May Restore Some Vision

Researchers at MIT, together with collaborators, have developed a prototype retinal implant for people who have lost their vision from retinitis pigmentosa or age-related macular degeneration, two of the leading causes of blindness. The implant would help restore some vision by electrically stimulating the nerve cells that normally carry visual input from the retina to the brain. Patients who receive the implant would wear a pair of glasses with a camera that sends images to a microchip attached to the eyeball. The glasses also contain a coil that wirelessly transmits power to receiving coils surrounding the eyeball. When the microchip receives visual information, it activates electrodes that stimulate nerve cells in the areas of the retina corresponding to the features of the visual scene. The electrodes directly activate optical nerves that carry signals to the brain, bypassing the damaged layers of retina. The chip would not restore normal vision, but could help blind people more easily navigate a room or walk down a sidewalk. "Anything that could help them see a little better and let them identify objects and move around a room would be an enormous help," said Dr. Shawn Kelly, a member of the research team. The researchers hope to start testing the prototype in blind patients within the next three years, after some safety refinements are made. The work was published in the October issue of the IEEE Transactions on Biomedical Engineering. [Press release]

Whale Skeletons Home to Nine New Species

A recent Ph.D. thesis from the University of Gothenburg in Sweden, reports the identification of nine new species of bristleworm, a type of worm typically found on whale skeletons. Some previously identified species of bristleworm are so specialized in eating dead whales that they would have problems surviving elsewhere. One species uses its root system to penetrate the whale bones when searching for food. Other species specialize in eating the thick layers of bacteria that quickly form around the bones. When a whale dies, it sinks to the seafloor and becomes food for an entire ecosystem. Dead whales constitute an unpredictable food source; it is impossible to know when and where a whale is going to die, and when it does, the food source does not last forever. Nevertheless, some marine species have specialized in feeding on whale cadavers. A dead whale is an enormous source of nutrients. In fact, one cadaver offers the same amount of nutrients that normally sinks from the surface to the seafloor in 2,000 years, and this is of great benefit to innumerable species: First, the meat is eaten by, for example, sharks and hagfish, then tremendous numbers of various organisms come to feast on the skeleton. Four of the new bristleworm species were found on whale cadavers placed at a depth of 125 meters in the new national park Kosterhavet off the coast of Strömstad, Sweden. The other five species feed on whale bones in the deep waters off the coast of California. The family tree of bristleworms was explored using molecular data. The DNA analyses showed that there are several so-called “cryptic” bristleworm species, meaning species that, despite appearing identical, differ very much genetically.

September 19th

New Rabies Vaccine May Require Only One Shot

Scientists have developed a rabies vaccine that may require only one shot to prevent the fatal disease. The new vaccine is made from live virus from which a key viral gene [the matrix (M) gene] has been removed so that the virus is inhibited from reproducing in the body. This vaccine appeared safe and effective in tests in mice and non-human primates. The immune response induced with this vaccine is so substantial that only one inoculation may be sufficient, according to Dr. James McGettigan, senior author of the study. The current standard rabies vaccine is made from inactivated virus and the normal post-exposure regimen is five shots of vaccine and one of rabies immunoglobulin over a period of 28 days. Worldwide, the annual number of rabies-related deaths is estimated to be 40,000 to 70,000. The disease is endemic in developing areas, where the six-shot post-exposure regimen is not feasible for many people due to cost and availability. According to the World Health Organization, approximately 10 million people worldwide receive the post-exposure regimen, which presents a financial burden to both industrialized and developing countries. "Developing countries do not have the resources to vaccinate people six times after exposure, so many of these 10 million do not receive the full regimen," said Dr. McGettigan. "Therefore, simpler and less expensive vaccine regimens are needed. The alternative may also be to treat people pre-exposure, as they are with many of the current vaccines used. Although our vaccine was tested primarily to be a post-exposure vaccine, the data we collected show it would be effective as a pre-exposure vaccine as well." This research was published online on September 18 in the Journal of Infectious Diseases.

September 18th

Gene Therapy Cures Color Blindness in Monkeys--Wider Applications Seen

Researchers have successfully used gene therapy to cure red-green color blindness in adult squirrel monkeys. Red-green color blindness is the most common single locus genetic disorder in humans. One in 12 men and 1 in 230 women are affected, while 1 in 6 women is a carrier of the inherited condition. “We’ve added red sensitivity to cone cells in animals that are born with a condition that is exactly like human color blindness," said Dr. William W. Hauswirth, an author of the study. “Although color blindness is only moderately life-altering, we’ve shown we can cure a cone disease in a primate, and that it can be done very safely. That’s extremely encouraging for the development of therapies for human cone diseases that really are blinding.” “People who are colorblind feel that they are missing out,” said Dr. Jay Neitz, one of the senior authors of the study. “If we could find a way to do this with complete safety in human eyes, as we did with monkeys, I think there would be a lot of people who would want it. Beyond that, we hope this technology will be useful in correcting lots of different vision disorders.” In this work, the researchers wanted to produce a substance called long-wavelength opsin in the retinas of the monkeys. This particular form of opsin is a colorless protein that works in the retina to make pigments that are sensitive to red and green. “We used human DNAs, so we won’t have to switch to human genes as we move toward clinical treatments,” said Dr. Hauswirth, who is also involved in a clinical trial with human patients to test gene therapy for the treatment of Leber congenital amaurosis, a form of blindness that strikes children. Of further note is the fact that approximately 1 in 30,000 Americans has a hereditary disease called achromatopsia, which causes nearly complete color blindness and extremely poor central vision.

SNP Variant Associated with Clearance of Hepatitis C Virus

An international research team has shown that a particular SNP genotype (C/C) near the IL28B gene appears to be associated with the ability of some people to defeat hepatitis C virus (HCV) infection and get rid of the virus with no treatment. HCV infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide. More than seventy percent of people who contract hepatitis C will live with the virus that causes it for the rest of their lives and some will develop serious liver disease including cancer. However, 30 to 40 percent of those infected somehow defeat the infection with no treatment. Previous work had shown that individuals with the C/C SNP genotype near IL28B were more likely to respond to treatment for hepatitis C, which can rid some patients of the virus. So, in the current work, the researchers investigated if the C/C variation—as opposed to the C/T or T/T alternatives—also played a role in some peoples' ability to get rid of the virus without the help of medication. To do this, the scientists assembled information from six different studies that had, over many years, collected DNA and hepatitis C infection information from people all over the world. The team then analyzed DNA in the IL28B gene vicinity from a total of 1008 patients: 620 persistently infected and 388 who had been infected but no longer carried any virus. DNA analysis revealed that of the 388 patients who no longer carried virus, 264 had the C/C variation. "This is the strongest clue to date to understanding what would constitute a successful immune response," said Dr. David Thomas, lead author of the article.

September 17th

Stem Cells Virtually Halt Rare Genetic Disease in Mouse Model

Scientists studying the rare and deadly genetic disease cystinosis, have shown that transplantation of adult bone marrow stem cells appears to virtually halt the disease in a mouse model. Cystine is a byproduct of the lysosomal breakdown of cellular components the body no longer needs. Normally, cystine is shunted out of cells, but in cystinosis a gene defect of the lysosomal cystine transporter causes cystine to build up, forming crystals that are especially damaging to the kidneys and eyes. The only available drug to treat cystinosis, cysteamine, while slowing the progression of kidney degradation, does not prevent it, and end-stage kidney failure is inevitable. "Cysteamine must be given every six hours, so children have to be woken up each night to take this drug, which has unpleasant side effects, and many others to treat various symptoms," said Dr. Stephanie Cherqui, the senior author of the study. "So although there is treatment, it is difficult treatment that does not cure the disease." In the study, the research team used bone marrow stem cell transplantation to address symptoms of cystinosis in a mouse model. The procedure virtually halted the cystine accumulation responsible for the disease and the cascade of cell death that follows. The researchers found that transplanted bone marrow stem cells carrying the normal lysosomal cystine transporter gene abundantly engrafted into every tissue of the experimental mice. This led to an average drop in cystine levels of about 80 percent in every organ. In addition to preventing kidney dysfunction, there was less deposition of cystine crystals in the cornea, less bone demineralization, and an improvement in motor function. "The results really surprised and encouraged us," said Dr. Cherqui.

September 8th

Molecular Mechanism of Rare Form of Diabetes Revealed

Researchers have uncovered the molecular mechanism underlying a rare and severe form of diabetes, i.e., permanent neonatal diabetes mellitus. Children with this genetic form of diabetes have symptoms by age six months and have a lifelong dependence on insulin to maintain proper glucose levels. To investigate the disease mechanism, researchers used animal and cellular models to focus on a mutation of the KATP gene that is known to be linked to the disease. The KATP gene codes for an ATP-sensitive potassium ion channel. "The KATP channel essentially functions as a gatekeeper for insulin secretion by pancreatic beta cells,” said Dr. Faith Kline, the lead author of the study. “Without proper regulation by this gatekeeper, the pancreatic beta cells are unable to efficiently regulate insulin secretion." The researchers showed that the chaperone molecule ankyrin is present in pancreatic beta cells and that the KATP mutation prevents most KATP channels from binding with ankyrin. This failure prevents the KATP channels from reaching their normal destination in the cell membrane. "Ankyrin proteins are like cellular taxi cabs that carry passenger channels to the cell membrane. In the case of this KATP gene mutation, the ankyrin and channels cannot interact properly, and so the channels basically 'miss their ride' and do not get to the desired location," said Dr. Peter Mohler, the article’s senior author. The team also found that the few mutant KATP channels that do reach the pancreatic cell membrane do not respond to alterations in cellular metabolism. As a result, the pancreatic beta cells do not release insulin appropriately. This work was reported in the September 8 week’s early online edition of PNAS. The findings may help identify new molecular targets for treating both rare and common forms of diabetes and hyperinsulinemia.

September 3rd

Addiction Gene Identified in Population Group

Researchers at the Yale University School of Public Health and Princeton University have identified a gene variant that is associated with addictive behaviors in white women of European origin. Genome-wide association studies revealed that a SNP variant of the PKNOX2 gene, located on chromosome 11, is associated, in these women, with multiple (two or more) dependencies involving nicotine, alcohol, marijuana, cocaine, opiates, and other drugs. While genes on other chromosomes have previously been associated with alcoholism and drug abuse in prior studies, this is believed to be the first time that the PKNOX2 gene has been associated with addiction in humans, said Dr. Heping Zhang, the paper’s senior author. The gene identified by the researchers had previously been associated with addictive behavior in mice. “This information can be used to design preventive and/or treatment strategies for addiction by controlling the environment exposure in the targeted group and/or by exploring and developing medications that modify the expression of the gene,” Dr. Zhang said. The researchers emphasized that their findings indicate that the associations are not as significant when individual outcomes for addiction are considered, underscoring the importance of considering multiple addiction types. The work was reported on August 31 in the early online edition of PNAS. [Press release] [PNAS abstract]

Epigenetic Changes Linked to Type 2 Diabetes

A research group at the Karolinska Institute in Sweden has shown that a key gene (PGC-1alpha) in the muscle cells of type 2 diabetics is chemically modified through DNA methylation. The scientists found that the gene was hypermethylated and had reduced expression in muscle cells taken from patients with early-onset type 2 diabetes. PGC-1alpha controls other genes that regulate the metabolism of glucose by the cell. DNA methylation is a form of epigenetic regulation, a process involving chemical modifications that are imposed externally on genes and that alter their activity without any change to the underlying DNA sequence. "This type of epigenetic modification might be the link that explains how environmental factors have a long-term influence on the development of type 2 diabetes," said Dr. Juleen Zierath, who led the study. "It remains to be seen whether the DNA methylation of this gene can be affected by, say, dietary factors." This work was published in the September 2 edition of Cell Metabolism. [Press release] [Cell Metabolism abstract]

September 2nd

Tbx5 Gradient Key to Development of Four-Chambered Heart

Research in turtles and lizards has revealed a tantalizing clue to the evolution of the four-chambered heart and the related ability of birds and mammals to lead a warm-blooded existence. The key appears to be varied expression of the transcription factor gene Tbx5 in the ventricles. In humans and other mammals, Tbx5 levels are high in the left ventricle and low in the right. The boundary of high and low is right at the septum, which forms to separate the two ventricles. When the researchers looked at the green anole lizard, which has just a three-chambered heart, they found that Tbx5 activity was essentially the same throughout the single ventricle and stayed the same throughout heart development. In the turtle, however, which has a primitive septum that partially separates its ventricle into left and right sides, distribution of Tbx5 was gradually restricted to the left side of the ventricle, resulting in a left-right gradient of Tbx5 activity. Further experiments in genetically engineered mice conclusively showed that a sharp line demarcating an area of high levels of Tbx5 is critical to induce formation of a septum between the two ventricles. "This is the first genetic link to the evolution of two, rather than one, pumping chamber in the heart, which is a key event in the evolution of becoming warm-blooded," said Dr. Benoit Bruneau, the senior author of the study. "The gene involved, Tbx5, is also implicated in human congenital heart disease, so our results also bring insight into human disease." The work was featured as the cover story of the September 3 issue of Nature.