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Leptin May Have Advantages Over Insulin in Type 1 Diabetes Treatment

In a mouse model, scientists at the University of Texas Southwestern Medical Center, and collaborators, have shown that administration of the hormone leptin may have multiple short- and long-term advantages over insulin monotherapy for type 1 diabetes. The scientist showed that, although the two hormones are similar in certain of their anti-diabetic effects, they differ dramatically with respect to their effects on lipid metabolism: leptin suppresses lipogenesis, whereas insulin monotherapy enhances lipogenesis and factors involved in cholesterologenesis. The researchers said that their findings indicate that recombinant leptin, either alone or combined with low-dose insulin therapy, provides equivalent or superior glycemic stability without the increase in body fat and up-regulation of cholesterologenic and lipogenic transcription factors and enzymes observed with insulin monotherapy. According to the researchers, their results raise the possibility of a role for leptin supplementation in the treatment of human type 1 diabetes. This work was published as the cover story of the March 16, 2010 issue of PNAS. [PNAS article]

Loss of Single Gene Restores Regenerative Ability in Mice

Scientists have identified a gene that may regulate regeneration in mammals. The absence of this single gene, called p21, confers a healing potential in mice that was long thought to have been lost through evolution, and reserved today only for creatures like flatworms, sponges, and some species of salamander. Researchers from The Wistar Institute and collaborating institutions have now demonstrated that mice that lack the p21 gene gain the ability to regenerate lost or damaged tissue. Unlike typical mammals, which heal wounds by forming a scar, these mice begin by forming a so-called “blastema,” a structure associated with rapid cell growth and de-differentiation as seen in amphibians. According to the researchers, the loss of p21 causes the cells of these mice to behave more like embryonic stem cells than adult mammalian cells, and the findings provide solid evidence to link tissue regeneration to the control of cell division. "Much like a newt that has lost a limb, these mice will replace missing or damaged tissue with healthy tissue that lacks any sign of scarring," said the project's lead scientist Dr. Ellen Heber-Katz, a professor in Wistar's Molecular and Cellular Oncogenesis program. "While we are just beginning to understand the repercussions of these findings, perhaps one day we'll be able to accelerate healing in humans by temporarily inactivating the p21 gene." This research was published online on March 15, 2010 in PNAS. [Press release] [PNAS abstract]

New Genetic Test for Autism Found Superior to Current Tests

A large study from Children's Hospital Boston and the Boston-based Autism Consortium, and collaborating institutions, has found that a genetic test known as chromosomal microarray analysis (CMA), which samples the entire genome, has about three times the detection rate for genetic changes related to autism spectrum disorders (ASDs) than standard tests. The authors urged that CMA become part of the first-line genetic work-up for ASDs. Because of the dramatic increase in variations identified using CMA, the Autism Consortium recommends that CMA should be included in the first tier of diagnostic testing for children with ASD symptoms that have no clear genetic cause. Expectant parents who have family members with ASDs, as well as families who already have an affected child, often request genetic testing. However, there is still only limited knowledge about actual causative genes. The currently recommended tests (karyotyping to look for chromosomal abnormalities and testing for Fragile X syndrome, the single most frequent known genetic cause of ASDs), often come up negative. CMA is a genome-wide assay that examines the chromosomes for tiny, sub-microscopic deletions or duplications of DNA sequences, known as copy-number variants. CMA offers about 100-fold greater resolution than standard karyotyping. However, because it is new, it is often considered a second-tier test. Depending on where a person lives, or what insurance he or she has, CMA may not be covered by health insurance. "Based on our findings, CMA should be considered as part of the initial clinical diagnostic evaluation of patients with ASDs," said Dr. Bai-Lin Wu, co-senior author of the report and Director of Children's Hospital Boston’s DNA Diagnostic Lab, which has offered CMA to families since 2006.

Banana Compound Blocks HIV

A potent new inhibitor of HIV infection, derived from bananas, may open the door to new treatments to prevent sexual transmission of HIV, according to a University of Michigan Medical School study. The research team discovered that BanLec, a lectin in bananas, can inhibit HIV infection by binding to the sugar-rich HIV-1 envelope protein, gp120, and blocking the virus’s entry to the body. In laboratory tests, BanLec was as potent as two current anti-HIV drugs. Based on their findings, the researchers believe that BanLec may become a less expensive new component of applied vaginal microbicides. New ways of stopping the spread of the HIV are vitally needed. The rate of new infections of HIV is outpacing the rate of new individuals getting anti-retroviral drugs by 2.5 to1, and, at present, it appears an effective vaccine is years away. "HIV is still rampant in the U.S. and the explosion in poorer countries continues to be a bad problem because of tremendous human suffering and the cost of treating it," said the study’s senior author Dr. David Markovitz, professor of internal medicine at the medical school. Although condom use is quite effective, condoms are most successful in preventing infection if used consistently and correctly, which is often not the case. "That's particularly true in developing countries where women have little control over sexual encounters, so development of a long-lasting, self-applied microbicide is very attractive," Dr. Markovitz said. Co-author Michael Swanson, a doctoral student at the medical school, is developing a process to molecularly alter BanLec to enhance its potential clinical utility. Clinical use is considered years away, but researchers say even modest success could save millions of lives.

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.

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.

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