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November 11th, 2009

Preserving Ends of Chromosomes Linked to Longevity in Centenarians

Researchers at the Albert Einstein College of Medicine, and colleagues, have found a clear link between living to 100 and the inheritance of a hyperactive version of an enzyme that rebuilds telomeres. Telomeres are relatively short sections of specialized DNA that sit at the ends of all chromosomes. Telomeres have been compared to the plastic tips at the ends of shoelaces that prevent the laces from unraveling. Each time a cell divides, its telomeres erode slightly and become progressively shorter with each cell division. Eventually, telomeres become so short that their host cells stop dividing and lapse into a condition called cell senescence. As a result, vital tissues and important organs begin to fail and the classical signs of aging ensue. In investigating the role of telomeres in aging, the researchers studied Ashkenazi Jews because they are a homogeneous population that has been well studied genetically. Three groups were enrolled: 86 very old, but generally healthy, people (average age 97); 175 of their offspring; and 93 controls (offspring of parents who had lived a normal lifespan). "As we suspected, humans of exceptional longevity are better able to maintain the length of their telomeres," said Dr. Yousin Suh, senior author of the paper. "And we found that they owe their longevity, at least in part, to advantageous variants of genes involved in telomere maintenance." More specifically, the researchers found that participants who have lived to a very old age have inherited mutant genes that cause their telomerase-making system to be extra active and able to maintain telomere length more effectively. For the most part, these people were spared age-related diseases such as cardiovascular disease and diabetes, which cause most deaths among elderly people.

November 10th

Slower Pupil Response Seen in Autistic Children

Recently, University of Missouri researchers have developed a pupil response test that is 92.5 percent accurate in separating children with autism from those with typical development. The scientists used a computerized binocular infrared device, which eye doctors normally use for vision tests, to measure how pupils react to a 100-millisecond flash of light. The results showed that pupils of children diagnosed with autism were significantly slower to respond than those of a control group. "There are several potential mechanisms currently under study," said Dr. Gang Yao, senior author of the study. "If these results are successfully validated in a larger population, the pupils’ light response (PLR) might be developed into a biomarker that could have clinical implications in early screening for risks of autism. Studies have shown that early intervention will improve these children's developmental outcome." Autism is estimated to affect 1 in 150 children today, making it more common than childhood cancer, juvenile diabetes, and pediatric AIDS combined. Despite its widespread effect, autism is not well understood and there are currently no objective medical tests to diagnose it. This new report was published in the November issue of the Journal of Autism and Developmental Disorders. [Press release] [JADD article]

November 9th

Genes Distinguish Rare Long Survivors of Advanced Melanoma

Although the chances of surviving advanced melanoma are not very good with current therapies, some patients can live for years with melanoma that has spread beyond the skin to other organs. Now it may be possible to identify which patients are more likely to survive by analyzing the activity of hundreds of genes involved in the immune response and gene proliferation, according New York University Langone Medical Center scientists and collaborators. In a new study, the researchers used DNA microarray technology to find 266 genes associated with shorter or longer survival among 38 patients whose melanomas had recurred after being surgically removed. Such genetic information may someday help decide the best course of treatment for patients with advanced disease. "If we could actually understand what was happening in those patients, within the tumor itself, perhaps we'd be able to help them in terms of what therapy they might go on," said Dr. Nina Bhardwaj, the study's senior author. The collaborative study, led by graduate student Dusan Bogunovic, provided some hints about the underlying mechanism of melanoma. "We found that patients who survived longer had gene activity consistent with an immune response," Dr. Bhardwaj said. "Patients who didn't survive as long didn't have an up-regulation of those genes, but tended to have higher levels of genes associated with cell proliferation, suggesting that if your cells are growing more actively, the tumor is going to grow faster." She cautioned, however, that the study must still be validated with a much larger, independent group of patients. The study is to be published online in PNAS during the week of November 9. [Press release]

November 8th

Deletion of a Nicotinic Receptor Gene Could Lead to Learning Defects

The loss of a particular gene (CHRNA7) through deletion of genetic material on chromosome 15 appears to be associated with significant abnormalities in learning and behavior, according to a recent report by Baylor College of Medicine (BCM) researchers and colleagues. "This research goes about 95 percent of the way to pinning these problems in a specific group of individuals to this gene," said Dr. Arthur Beaudet, chair of molecular and human genetics at BCM and an author of the report. Dr. Beaudet believes that the deletion will be identified in other people with behavioral problems, as well as schizophrenia, developmental delay, and epilepsy. The gene's role in schizophrenia has been under study for some time. "This gene encodes a subunit of a nicotinic receptor," Dr. Beaudet said. "It is a gene that mediates the response to nicotine via a receptor whose normal ligand is acetylcholine." The gene encodes a protein called an ion channel, which allows ions to flow in and out of neurons in the brain. Defects in ion channels have previously been associated with forms of epilepsy or seizure disorder. "If insufficient expression of the nicotinic receptor causes most or all of the problems associated with deletions in this particular area of chromosome 15, then it offers a target for drug treatment," said Dr. Pawel Stankiewicz, senior author of the report. One such drug mentioned in the paper is Chantix, a medicine now used in smoking cessation efforts. This work was published online on November 8 in Nature Genetics. [Press release] [Nature Genetics abstract]

November 6th

Simple Blood Test May Identify Women at Risk of Alzheimer’s

Middle-aged women with high levels of a specific amino acid (homocysteine) in their blood are twice as likely to suffer from Alzheimer's disease many years later, according to a recent thesis from the Sahlgrenska Academy at the University of Gothenburg, Sweden. This discovery could lead to a new and simple way of determining who is at risk long before there are any signs of the illness. The thesis is based on the Prospective Population Study of Women in Gothenburg, which was started at the end of the 1960s when almost 1,500 women between the ages of 38 and 60 were examined, asked questions about their health, and had blood samples taken. Nearly all of the samples have now been analyzed and compared with information on who went on to suffer from Alzheimer's and dementia much later. "Alzheimer's disease was more than twice as common among the women with the highest levels of homocysteine than among those with the lowest, and the risk for any kind of dementia was 70 per cent higher," said Dr. Dimitri Zylberstein, author of the thesis. Historically, elevated homocysteine levels have been related to certain vitamin deficiencies (B12 and folate). Today we know that high homocysteine levels might be present even with perfectly normal vitamin status. "These days we in our clinical practice use homocysteine analyses mainly for assessment of vitamin status. However, our results mean that we could use the very same analysis for assessment of an individual's risk profile for dementia development. This opens the possibility for future preventive treatment at a very early stage," said Dr. Zylberstein. [Press release]

November 4th

Scientists Target DNA Quadruplexes in Battle Against Cancer

Some designers of anti-cancer drugs are investigating mysterious chunks of the genetic material DNA that may play a key role in preventing the growth and spread of cancer cells, according to an article in the November 2 issue of Chemical & Engineering News, the weekly newsmagazine of the American Chemical Society. In the article, C&EN Deputy Assistant Managing editor Stu Borman notes that the DNA structures, which scientists term "quadruplexes" because they have four-sided structures, are a genre of folded DNA that may help control whether genes are switched on or off. Quadruplexes sometimes form near genes that foster the growth of cancer cells. Some scientists thus regard them as promising targets for developing new anti-cancer drugs. Drugs that interact with quadruplexes could help kill cancer cells without harming healthy cells. In addition, they may side-step the serious problem of drug resistance, in which some drugs gradually lose their effectiveness against cancer. The C&EN article describes research on quadruplex-targeted drugs and explores the mysteries about how quadruplexes form, disappear, and function. [Press release] [C&EN article]

November 3rd

Reconstitution of Enzyme Synthesizing Lovastatin Precursor

Researchers from UCLA, and colleagues, have for the first time successfully reconstituted in the laboratory the enzyme responsible for producing the blockbuster cholesterol-lowering drug lovastatin. "In this study, we studied the enzyme that makes a small-molecule precursor to lovastatin. And what's really different about this enzyme, compared to all other enzymes people have studied, is that this enzyme is extraordinarily large," said Dr. Yi Tang, senior author of the study. "It's one of the largest enzymes ever to be reconstituted in a test tube. It is ten times the size of most enzymes people study." The enzyme used in Dr. Tang's study has seven active sites and catalyzes more than 40 different reactions that eventually result in an important precursor to lovastatin. Dr. Tang's team has been able to recapture all of the steps needed to make the lovastatin precursor molecule. "It's like having an assembly line with seven stations, and in one round you have to go through a combination of these seven stations. Remarkably, this enzyme uses the assembly line eight times to make this small molecule—every time, it uses a different combination of the individual stations," Dr. Tang said. "So the large enzyme is programmed to utilize these stations differentially at every cycle, in different combinations, and now we can do it in a test tube." And with this, Dr. Tang hopes they will be able to disrupt, tweak, and change some of the steps to make slightly different molecules that can be just as beneficial. "It's biosynthetic engineering of an assembly line to make a molecule that nature doesn't make,” Dr. Tang said.

Agent Inhibits Breast Cancer Metastasis to Bone

Researchers have reduced breast cancer metastasis to bone by using an experimental agent to inhibit ROCK (Rho-associated kinase), a protein that was found to be over-expressed in metastatic breast cancer. In a study in mice, a team of researchers from Tufts University reported that inhibiting ROCK in the earliest stages of breast cancer decreased metastatic tumor mass in bone by 77 percent and overall frequency of metastasis by 36 percent. The results suggest that ROCK may be a target for new drug therapies to reduce breast cancer metastasis. "While the primary tumor causes significant illness and requires treatment, metastasis accounts for over 90 percent of breast cancer-related deaths. There are no treatments to eradicate metastasis. Establishing ROCK's role in the spread of breast cancer and identifying agents to inhibit ROCK brings us one step closer to an approach that might reduce metastasis in the future," said senior author Dr. Michael Rosenblatt. Breast cancer is the second leading fatal cancer in women, and affects just under one in eight women in the United States. Bone is the most common site of breast cancer metastasis, affected three times more often than the lungs or liver. The study was published online on November 3 in Cancer Research. [Press release] [Cancer Research abstract]

October 31st

Antibody Gene Therapy Shows Promise in Mouse Models of Huntington’s Disease

Researchers at the California Institute of Technology have shown that a highly specific intrabody (an antibody fragment that works against a target inside a cell) is capable of stalling the development of Huntington's disease in a variety of mouse models. "Gene therapy in these models successfully attenuated the symptoms of Huntington's disease and increased life span," noted Dr. Paul Patterson, the senior author of the study. The intrabody, called Happ1, targets an amino acid sequence unique to the huntingtin protein that is rich in the amino acid proline. Because of this, the action of Happ1 is expected to be extremely specific. "Our studies show that the use of intrabodies can block the parts of mutant huntingtin that cause its toxicity without affecting the wild type, or normal, huntingtin—or any other proteins," said Dr. Patterson. In other words, he said, this approach has the potential to be the kind of "silver-bullet therapy" that many medical researchers look for. With regard to future work, Dr. Patterson said, “we need to improve the efficacy of the intrabody, and we need to build a viral vector that can be controlled—induced and turned off—in case of unexpected side effects. This is a general goal shared by all types of experimental gene therapies." This work was published in the October 28 issue of the Journal of Neuroscience. [Press release] [Journal of Neuroscience abstract]

October 30th

Blood-Starved Retinal Cells May Regain Function

Researchers at Johns Hopkins, together with collaborators, have found that when some cells in the mouse retina are not properly fed by blood vessels, they can remain alive for many months and can later recover some or all of their normal function, suggesting that similar conditions in people may also be reversible. "This finding is intriguing," said Dr. Jeremy Nathans, senior author of the study, and a professor of molecular biology and genetics, neuroscience, and ophthalmology at Johns Hopkins and a Howard Hughes Medical Institute investigator. "It suggests that neurons in the retina can survive for an extended period of time even though they have been functionally silenced. If the human retina responds to a decrease in blood supply in the same way that the mouse retina responds, then these results may have relevance for those patients with vision loss due to vascular defects," said Dr. Nathans. "In particular, these experiments suggest that if a region of the retina has been deprived of its normal blood supply, then completely or partially restoring that supply may also restore some visual function, even if this happens weeks or months later.” The report appeared in the October 16 issue of Cell. [Press release] [Cell abstract]