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Archive - 2009 - Story

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]

October 29th

Convergent Evolution of Toxins Seen in Shrew and Lizard

Biologists at Harvard University and Massachusetts General Hospital have shown that independent, but similar, molecular changes turned a harmless digestive enzyme into a toxin in two unrelated species--a shrew and a lizard--giving each a venomous bite. "The venom is essentially an overactivation of the original digestive enzyme, amplifying its effects," said Dr. Yael T. Aminetzach, lead author of the study. "What had been a mild anticoagulant in the salivary glands of both species has become a much more extreme compound that causes paralysis and death in prey that is bitten." In the first part of the study, Dr. Aminetzach and her colleagues compared a toxin found in the salivary glands of the insectivorous North American shrew (Blarina brevicauda) to its closely related digestive enzyme kallikrein. Dr. Aminetzach found that the specific molecular differences between kallikrein and its toxic descendent are highly localized around the enzyme's active site. "Catalysis is fostered by three specific changes that increase enzyme activity," Dr. Aminetzach said. "The active site is physically opened up, and the loops surrounding it become more flexible. The area around the active site also becomes positively charged, serving to better guide the substrate directly into the active site." To further demonstrate that these molecular changes to kallikrein are related to the evolution of toxicity, Aminetzach explored the evolution of another kallikrein-like toxin in the Mexican beaded lizard (Helodermata horridum) (male and female shown in photo). She found that this toxin, while distinct from the analogous toxin in the shrew, nonetheless exhibits the same catalytic enhancement relative to the original kallikrein enzyme.

Drug-Radiation Combination Eradicates Lung Cancer in Mice

Combination of an investigative drug (BEZ235) and low-dose radiation eliminates non-small cell lung cancer (NSCLC) in mice, according to results of a recent study conducted by researchers at the University of Texas Southwestern Medical Center, and collaborators including Novartis Pharma. NSCLC is a leading cause of cancer-related deaths worldwide. The researchers found that if they administered BEZ235 before they damaged the DNA of tumor cells with otherwise nontoxic radiation, the drug blocked the pro-survival actions of a protein called PI3K, which normally springs into action to keep tumor cells alive while they repair DNA damage. The researchers tested their novel therapeutic strategy in mice transplanted with NSCLC cells obtained from patients. They found that tumors in the mice treated with BEZ235 alone were significantly smaller than those in mice not given the drug. Although the tumors stopped growing, they did not die. By contrast, tumors were completely eradicated in mice treated with a combination of BEZ235 and radiation. “These early results suggest that the drug-radiation combination might be an effective therapy in lung cancer patients,” said Dr. Pier Paolo Scaglioni, senior author of the study. The report was published in the October 1 issue of Cancer Research. [Press release] [Cancer Research abstract]

October 28th

Pumpkin Scares Off Microbes

Pumpkin rinds contain a substance with an antibacterial effect against microbes that cause millions of cases of yeast infections in adults and infants each year, according to a recent research report. The researchers noted that some disease-causing microbes are becoming resistant to existing antibiotics. As a result, scientists worldwide are searching for new antibiotics. Past studies have hinted that pumpkin, long used as a folk medicine in some countries, might have antibiotic effects. The researchers extracted proteins from pumpkin rinds to see if the proteins inhibit the growth of microbes, including Candida albicans. That fungus causes vaginal yeast infections, diaper rash in infants, and other health problems. One pumpkin protein had powerful effects in inhibiting the growth of C. albicans, in cell culture experiments, with no obvious toxic effects. The protein could be developed into a natural medicine for fighting yeast infections in humans, the report suggested. The protein also blocked the growth of several fungi that attack important plant crops and could be useful as an agricultural fungicide, the researchers added. The report was published in the October 14 issue of the Journal of Agricultural and Food Chemistry, an ACS publication. [Press release] [JAFC abstract]

October 27th

New Medical Adhesive May Come from Sandcastle Worm

Scientists questing after a long-sought new medical adhesive describe copying the natural glue secreted by a tiny sea creature called the sandcastle worm in the latest episode in the American Chemical Society's (ACS) award-winning podcast series, "Global Challenges/Chemistry Solutions." Such an adhesive is needed to repair bones shattered in battlefield injuries, car crashes, and other accidents. The traditional method of repairing shattered bones involves use of mechanical fasteners like pins and metal screws to support the bone during healing. But achieving and maintaining alignment of small bone fragments using screws and wires is challenging, according to researchers who presented their study results at the ACS 238th National Meeting in Washington, D.C. in mid-August. The podcast is available without charge at iTunes and from the ACS at www.acs.org/globalchallenges. It features audio clips of Dr. Russell Stewart, a bioengineer at the University of Utah in Salt Lake City. Dr. Stewart says this synthetic glue is based on complex coacervates, an ideal, but so far unused, method for making injectable adhesives. Coacervates are tiny spherical droplets of assorted organic molecules (specifically, lipid molecules) that are held together by hydrophobic forces from a surrounding liquid. He explains that the idea of using natural adhesives in medicine is an old one dating back to the first investigations of mussel adhesives in the 1980s. Yet almost 30 years later, there are no adhesives based on natural adhesives used in the clinic.

Tel Aviv Researchers Search for “Prozac Gene”

In an effort to develop “best-fit, personalized regimen(s)” for treating depression, researchers at Tel Aviv University in Israel are undertaking a research program designed to identify genes that are associated with extreme responses to particular antidepressants such as Prozac. "Many drugs for treating depression are on the market," said Dr. David Gurwitz, leader of the new program. "The most popular ones, including Prozac, are the selective serotonin reuptake inhibitors (SSRIs). But they only work for about 60% of people with depression. A drug from other families of antidepressants could be effective for the other 40%," he said. "We are working to move the treatment of depression from a trial-and-error approach to a best-fit, personalized regimen. We've designed an experiment to search for elements that can determine who will, and who won't, benefit from drugs such as Prozac." The researchers will explore whole-genome gene expression profiles in cell lines from healthy people. Because Prozac and similar antidepressants are known to inhibit the growth of blood cells, the researchers are now screening a large collection of cell lines to determine which have the strongest and weakest growth-inhibition responses to SSRIs like Prozac. Those cells that exhibit extreme responses will then be screened across the entire human genome, to find out which genetic make-up works best with SSRIs. "Psychiatric pharmacology remains a black box," said Dr. Gurwitz. "Nobody knows why some people respond to Prozac-type SSRI anti-depressants, while others are helped by other kinds of antidepressants. The World Health Organization predicts by the year 2020, costs and lost productivity from depression will exceed those of cardiovascular disease as the leading cause of health expenditure in developed countries.

October 26th

p16 Gene May Be Key to Cancer Absence in Naked Mole Rat

Despite a 30-year lifespan that provides ample time for cells to grow cancerous, a small rodent species called the naked mole rat has never been found with tumors of any kind—and now biologists at the University of Rochester, and colleagues, think they know why. The researchers’ findings showed that the mole rat's cells express a gene called p16 that makes the cells "claustrophobic," stopping the cells' proliferation when too many of them crowd together, cutting off runaway growth before it can start. The effect of p16 is so pronounced that when researchers mutated the cells to induce a tumor, the cells' growth barely changed, whereas regular mouse cells became fully cancerous. "We think we've found the reason these mole rats don't get cancer, and it's a bit of a surprise," said Dr. Vera Gorbunova, the senior author of the study. "It's very early to speculate about the implications, but if the effect of p16 can be simulated in humans we might have a way to halt cancer before it starts." The results were reported online on October 26 in PNAS. [Press release] [PNAS abstract]