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Archive - 2010

Date

March 13th

Arctic Reindeer Abandon Use of 24-Hour Internal Clock

In the far northern reaches of the Arctic, day versus night is often not a practical concern. During parts of the year, the sun does not set; at other times, it does not rise. A new study by an international team of researchers shows that Arctic reindeer have come up with a surprising adaptation to living under those extreme conditions: They’ve apparently abandoned use of the 24-hour internal clock that typically drives the daily biological rhythms in other organisms. “Our findings imply that evolution has come up with a means of switching off the cellular clockwork,” said Dr. Andrew Loudon of the University of Manchester in England, the senior author of the study. “Such daily clocks may be positively a hindrance in environments where there is no reliable light-dark cycle for much of the year.” Light-dark cycles drive hormone rhythms via a circuit that involves the eye and nervous system projections to structures involved in regulating hormone rhythms, in particular that of melatonin, Dr. Loudon explained. In most mammals, this wiring circuit also involves an internal clock that drives hormone levels in a rhythmic 24-hour fashion, even when there is no light-dark cycle. “In reindeer, it is this clock element that seems to be missing,” Dr. Loudon said. The reindeer show no natural internal rhythm of melatonin secretion at all. Instead, hormone levels rise and fall in direct response to light and dark. The researchers show that melatonin levels remain at or below detectable levels during daylight hours. Those hormone concentrations spike almost as soon as the light goes out, only to plunge again when light returns.

March 11th

First Whole Genome Sequencing of Entire Family

Collaborating institutions, including the Institute for Systems Biology (ISB), Complete Genomics, the University of Washington, and the University of Utah, have sequenced and analyzed the first whole genomes of a human family of four. The authors said that the benefits of sequencing an entire family include lowering DNA sequencing error rates, identifying rare genetic variants, and identifying disease-linked genes. "We were very pleased and a little surprised at how much additional information can come from examining the full genomes of the same family," said Dr. David Galas, co-corresponding author on the article and senior vice president at ISB. "Comparing the sequences of unrelated individuals is useful, but for a family the results are more accurate. We can now see all the genetic variations, including rare ones, and can construct the inheritance of every piece of the chromosomes, which is critical to understanding the traits important to health and disease. The continuing decline in the difficulty and cost of sequencing now enables us to use these new strategies for deriving genetic information that was too difficult or expensive to access in the past.” A particular family of four with two children with extremely rare genetic diseases turned out to be ideal for the study. Although the parents had no genetic abnormalities, they each carried recessive genes that resulted in their son and daughter being born with two extremely rare conditions--Miller's syndrome and primary ciliary dyskinesia (PCD). Miller's syndrome, a disorder characterized by facial and limb malformations, is thought to occur in perhaps one in one million people and has been diagnosed in only two families in the world, along with a few sporadic other cases.

Personal Genome Sequencing Hits Home for Baylor Researcher

Dr. James Lupski (photo) of the Baylor College of Medicine (BCM) came to the end of a long personal quest earlier this year when the Baylor Human Genome Sequencing Center (BHGSC) sequenced his complete genome and identified the gene and mutations involved in his own form of Charcot-Marie-Tooth syndrome, which affects the function of nerves in the body's limbs, hands, and feet. The results were published in the March 11, 2010 issue of the New England Journal of Medicine, a journal chosen, in part, because the authors believe this type of information will be crucial to physicians; as well as to the research community. The authors hope that their results will help begin a new era of clinical sequencing. The sequencing was carried out using next-generation sequencing technology, which has dramatically increased throughput and reduced costs. "This is the first time we have tried to identify a disease gene this way," said Dr. Lupski, Vice Chair of Molecular and Human Genetics at BCM. "It demonstrates that the technology is robust enough that we can find disease genes by determining the whole genome sequence. We can start to use this technology to interpret the clinical information in the context of the sequence--of the hand of cards you have been dealt. Isn't that the goal or dream of personalized genomic medicine?" According to a summary in Science Now, the BHGSC sequencing effort cost $50,000. As it turns out, the same mutations could have been found by sequencing only the protein-coding regions of the genome—a process called “exome” sequencing—for about $4,000. But full sequencing will soon be just as cheap as exome sequencing and will catch disease mutations in noncoding regions as well, said Dr. Richard Gibbs, Director of the BHGSC.

March 10th

New Drug Candidate Reduces Blood Lipids

Results of a recent clinical trial indicate that a thyroid-hormone-like substance that works specifically on the liver reduces blood cholesterol with no serious side effects. The trial was conducted by researchers from Sweden’s Karolinska Institute and collaborating institutions. Presently, high cholesterol levels in the blood are primarily treated with a group of drugs called statins, but these drugs are not always sufficiently effective and higher doses commonly cause adverse reactions. In this new clinical trial, researchers showed that a new thyroid hormone analogue called eprotirome can reduce blood cholesterol effectively in patients who have already received statins. Patients who were given supplementary medication with eprotirome demonstrated levels of harmful blood fats that were as much as 30 percent lower than those of patients who received a placebo supplementary treatment. "This drug could help patients who react adversely to statins or be used as a supplementary treatment for those who don't respond well to them," said Dr. Bo Angelin, who led the study. Eprotirome mimics the natural ability of thyroid hormone to stimulate the metabolism of cholesterol, and exerts its effects exclusively on the liver. The development of similar, non-selective drugs has previously been stopped on account of the serious adverse effects they have had on other organ systems (e.g., cardiac dilatation and osteoporosis) or on the physiological regulation of thyroid hormones. The new clinical trial results were published in the March 11, 2010 issue of the New England Journal of Medicine. [Press release] [NEJM abstract]

Familial Mutation Identified in African-Americans with Prostate Cancer

The first inherited mutation in African-American men with a family history of prostate cancer has been identified by researchers from Louisiana State University. "We detected this mutation only in African-American men with prostate cancer," noted senior author Dr. Shahriar Koochekpour. "We found it in the cell's androgen receptor (AR), a protein which interacts and responds to male sex hormones. This protein is profoundly involved in prostate cancer formation and its progression to an advanced metastatic, incurable stage. We believe that this mutation increases the risk of the development and progression of prostate cancer, in part by altering the receptor's DNA-binding ability, and by regulating the activities of other genes and proteins involved in the growth and aggressive behavior of tumors. We are hopeful that this discovery will eventually lead to a simple genetic test for prostate cancer for African-American men who are at high risk for developing prostate cancer, allowing genetic counseling and earlier, potentially life-saving treatment.” The authors noted that additional studies will be required to define the frequency and contribution of the mutation to early-onset and/or familial prostate cancer in African Americans. African-American men have a higher incidence and death rate from prostate cancer, as well as clinically more aggressive disease than Caucasians. According to the American Cancer Society's most current data for 2009-2010, prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death among American men. Between 2001 and 2005, the prostate cancer incidence rate was 59% higher in African-American men. African-American men also have the highest mortality rate for prostate cancer of any racial or ethnic group in the United States.

March 9th

Green Tea May Help Protect Against Glaucoma and Other Eye Diseases

In a rat model, Hong Kong scientists have shown that powerful antioxidants in green tea can penetrate the eye, raising the possibility that the tea may help protect against glaucoma and other common eye diseases that may be related to oxidative stress. The authors point out that so-called green tea "catechins" have been among a number of antioxidants thought capable of protecting the eye. Until now, however, nobody knew if the catechins in green tea actually passed from the stomach and gastrointestinal tract into the tissues of the eye. In this new research, the scientists resolved this uncertainty in experiments with laboratory rats that drank green tea. Analysis of eye tissues showed beyond a doubt that eye structures absorbed significant amounts of individual catechins. The retina, for example, absorbed the highest levels of gallocatechin, while the aqueous humor tended to absorb epigallocatechin. The effects of green tea catechins in reducing harmful oxidative stress in the eye lasted for up to 20 hours. "Our results indicate that green tea consumption could benefit the eye against oxidative stress," the report concluded. This new research was published on January 19, 2010 in the Journal of Agricultural and Food Chemistry, an American Chemical Society publication. [Press release] [JAFC abstract]

New Form of Prion Disease Described

NIH scientists investigating how prion diseases destroy the brain have observed a new form of the disease in mice that does not cause the hole-filled, sponge-like brain deterioration typically seen in prion diseases. Instead, the disease resembles a form of human Alzheimer's disease, cerebral amyloid angiopathy, that damages brain arteries. The study results, reported by NIH scientists at the National Institute of Allergy and Infectious Diseases (NIAID), are similar to findings from two newly reported human cases of the prion disease Gerstmann-Straussler-Scheinker syndrome (GSS). The mouse findings represent a new mechanism of prion disease brain damage, according to study lead author Dr. Bruce Chesebro, chief of the Laboratory of Persistent Viral Diseases at the NIAID’s Rocky Mountain Laboratories in Montana. The role of a specific cell anchor for prion protein is at the crux of the NIAID study. Normal prion protein uses a specific molecule, glycophosphoinositol (GPI), to fasten to host cells in the brain and other organs. In their study, the NIAID scientists genetically removed the GPI anchor from study mice, preventing the prion protein from fastening to cells and thereby enabling it to diffuse freely in the fluid outside the cells. The scientists then exposed those mice to infectious scrapie and observed the mice for up to 500 days to see if they became sick. The researchers documented signs typical of prion disease including weight loss, lack of grooming, gait abnormalities, and inactivity. But when they examined the brain tissue, they did not observe the sponge-like holes in and around nerve cells typical of prion disease.

Desert Ant Uses Stereo Odor “Landscape” Detection in Navigation

The desert ant Cataglyphis fortis, which is native to the inhospitable salt-pans of Tunisia, is already well-known for its remarkable navigational abilities. It uses a sun compass along with a step counter and visible landmarks to locate its nest (a tiny hole in the desert ground) after foraging for food. Now, researchers at the Max-Planck Institute for Chemical Ecology in Germany have shown that these ants have another tool in their navigational toolbox. After the scientists recently discovered that these ants also use olfactory cues to pinpoint their nests, they conducted new experiments that revealed that the ants cannot only locate an odor source, but they also use the distribution of different odors in the vicinity of their nests in a map-like manner. The scientists found that the ants need both their antennae for this odor-guided navigation, that is, they smell the landscape scenery in stereo. "We conducted two key experiments," said Kathrin Steck, a Ph.D. student at the Institute. "First we marked four odor sources surrounding the nest entrance with the substances methyl salicylate, decanal, nonanal, and indole, and got the ants trained on them. If these four odor points were shifted away from the nest in the original arrangement, the ants repeatedly headed for the odors, even though the nest wasn't there anymore. If we rearranged the odor sources relative to each other, the ants were completely confused." Therefore the researchers assumed that ants do not "think" one-dimensionally--i.e., they do not associate the nest with only one smell--but multi-dimensionally, i.e., they relate an odor “landscape” to their nest. Spatial perception can easily be acquired if two separate sensory organs are available, such as two eyes for visual orientation. In the case of the ants, this would be their two antennae.

Blindness Gene Therapy in Second Eye Shown Safe in Animal Studies

Gene therapy for a severe inherited blindness disorder (Leber's congenital amaurosis or LCA), which produced dramatic improvements last year in twelve children and young adults who received the treatment in a clinical trial, has cleared another hurdle. The same research team that conducted the human trial has now reported that a study in large animals has shown that a second injection of the normal gene (RPE65) into the opposite, previously untreated, eye is safe and effective, with no signs of interference from unwanted immune reactions following the earlier injection. LCA is an autosomal recessive retinal disease that progresses to total blindness by adulthood and that can be caused by mutation in any one of a variety of different genes, including the RPE65 gene. Approximately 3,000 people in the United States are estimated to have the disease. In the current study, the research team found no evidence of toxic side effects in the blood or the eyes of the ten animals—six dogs and four monkeys—that received the gene therapy (with the normal RPE65 gene). Each animal received an injection first in the right eye, then in the left eye 14 days later. All six dogs, which had been specially bred to have congenital blindness, had improved vision, in addition to showing no toxic effects from the gene therapy. The monkeys, which were not blind, also showed no toxic effects from the therapy. These new findings suggest that LCA patients who benefit from gene therapy in one eye may experience similar benefits from treatment in the other eye. Researchers had exercised caution by treating only one eye in the human trial. "We designed this study to investigate the immunological consequences of administering the gene therapy injection to the second eye after treating the first one," said senior author Dr.

March 8th

Two Dopamine Receptors Are Key to Ritalin Activity

Research reported by scientists from the University of California-San Francisco (UCSF) has shown that, in a rat model, Ritalin (methylphenidate) boosts both the ability to focus on tasks and the speed of learning by increasing the activity of the neurotransmitter dopamine through mechanisms involving two distinct dopamine receptors in the amygdala region of the brain. "We found that a dopamine receptor, known as the D2 receptor, controls the ability to stay focused on a task--the well-known benefit of Ritalin," said Dr. Patricia Janak, co-senior author of the paper. "But we also discovered that another dopamine receptor, D1, underlies learning efficiency." "Since we now know that Ritalin improves behavior through two specific types of neurotransmitter receptors, the finding could help in the development of better targeted drugs, with fewer side effects, to increase focus and learning," said Dr. Antonello Bonci, the other co-senior author of the article. The research assessed the ability of rats to learn that they could get a sugar water reward when they received a signal--a flash of light and a sound. The scientists compared the behavior of animals receiving Ritalin with those that did not receive it, and found those receiving Ritalin learned much better. However, they also found that if they blocked the dopamine D1 receptors with drugs, Ritalin was unable to enhance learning. And if they blocked D2 receptors, Ritalin failed to improve focus. The experiments established the distinct role of each of the dopamine receptors in enabling Ritalin to enhance cognitive performance.