Syndicate content

Archive - Mar 2010

Date

March 14th

Opium Poppy Yields Secrets to Codeine and Morphine Synthesis

Researchers at the University of Calgary in Canada have discovered the unique genes that allow the opium poppy to make codeine and morphine, thus opening doors to alternate methods of producing these effective painkillers either by manufacturing them in a lab or controlling their production in the plant. "The enzymes encoded by these two genes have eluded plant biochemists for a half-century," said co-author Dr. Peter Facchini, professor in the Department of Biological Sciences, who has dedicated his career to studying the unique properties of the opium poppy. "In finding not only the enzymes but also the genes, we've made a major step forward," said Dr. Facchini. "It's equivalent to finding a gene involved in cancer or other genetic disorders. With this discovery, we can potentially create plants that will stop production at codeine. We are also working toward the synthesis of codeine and other opiate drugs more efficiently and economically in controlled bioprocessing facilities. Our discovery now makes it possible to use microorganisms to produce opiate drugs and other important pharmaceuticals." One of the next steps for the research team is using the codeine gene to produce pharmaceuticals in yeast or bacteria. The other co-author, Dr. Jillian Hagel, a post-doctoral scientist in Dr. Facchini's lab, was assigned the task of finding the key genes as part of her Ph.D. research. She succeeded using cutting-edge genomics techniques that helped her sort through up to 23,000 different genes and ultimately find a single gene called thebaine 6-O-demethylase (T6ODM) that codes for the plant enzyme that converts thebaine to codeinone, which is then converted to codeine by a known enzyme. She then went on to find the gene coding for the enzyme called codeine O-demethylase (CODM) that converts codeine to morphine.

Hydra Genome May Offer Clues to Huntington’s and Alzheimer’s Diseases

An international team of scientists has reported sequencing the genome of the Hydra, a freshwater organism that has been a staple of biological research for 300 years. The organism is currently used in research on regeneration, stem cells, and patterning. The research team discovered that the Hydra has approximately the same number of genes as humans and seems to share many of the same genes. Interestingly, the team also found that the Hydra has genes linked with Huntington's disease and with the beta-amyloid plaque formation seen in Alzheimer's disease, suggesting the possible use of Hydra as a research model for these two diseases. "Having the Hydra genome sequenced also enhances our ability to use it to learn more about the basic biology of stem cells, which are showing great promise for new treatments for a host of injuries and diseases," said Dr. Robert Steele, associate professor and interim chair in biological chemistry at the University of California-Irvine and senior author of the report. The Hydra genome sequence was reported online on March 14, 2010 in Nature. [Press release] [Nature abstract]

Possible Impact of Direct Physical Force on Cancer

A possible new therapeutic avenue may have been opened up with scientific evidence for a never-seen-before way in which cells can sense and respond to physical forces. A team of researchers has shown that the biochemical activity of a cellular protein system, which plays a key role in cancer metastasis, can be altered by the application of a direct physical force. This discovery sheds important new light on how the protein signaling complex known as EphA2/ephrin-A1 contributes to the initiation, growth, and progression of cancerous cells, and also suggests how the activity of cancer cells can be affected by surrounding tissue. EphA2 is a member of the receptor tyrosine kinase (RTK) family of enzymes that are key regulators of cellular processes. The over-expression of EphA2 has been linked to a number of human cancers, including melanoma, lung, colon, and prostate, but is especially prominent in breast cancer. Some 40 percent of all breast cancer patients show an over-abundance of EphA2, with the highest levels found in the most aggressive cancer cells. Ephrin-A1 is a signaling protein that is tethered to the surface of a cell’s outer membrane. It binds to EphA2 in a neighboring cell like a key fitted into a lock. When ephrin-A1 binds with EphA2, the newly bound complexes become activated and gather in a cluster. “The host cell will then literally give the clusters a distinctive tug, applying a force that pulls the clusters across the surface of the cell to a centralized location,” Dr. Groves said. “What we found is that by applying an opposing force, we could alter the cell’s biochemical activity. When we applied a big opposing force we were able to convert highly invasive cells into well-behaved cells.

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.