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.
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]
Spider Web Glue May Prove Basis for New Bio-Based Adhesives
New studies on the glue that coats the silk of spider webs may lead to the development of “green” glues that can replace existing petroleum-based products for a range of uses. Scientists at the University of Wyoming analyzed web glue from the golden orb weaving spider, noted for spinning intricate webs. They identified two new glycoproteins in the glue and showed that domains of these proteins were produced from opposite strands of the same DNA. “Once the cloned genes are over-expressed in systems such as insect or bacterial cell cultures, large-scale production of the glycoprotein can be used to develop a new bio-based glue for a variety of purposes,” the report noted. The report appeared in the October 12 issue of Biomacromolecules published by the American Chemical Society. [Press release] [Biomacromolecules abstract]
SS DNA-Binding Protein Is Dynamic and Critical to DNA Repair
Researchers report that a single-stranded DNA-binding protein (SSB), once thought to be a static player among the many molecules that interact with DNA, actually moves back and forth along single-stranded DNA, gradually allowing other proteins to repair, recombine, or replicate the strands. In a series of experiments in E. coli, the researchers showed that SSB diffuses randomly back and forth along single-stranded DNA, and that this movement is independent of the sequence of nucleotides that make up the DNA. They also found that an important DNA repair protein in E. coli, RecA, grows along the single-stranded DNA in tandem with the movement of SSB. As the RecA protein extends along the DNA strand, it prevents the backward movement of the SSB. The researchers also found that SSB can “melt” small hairpin loops that appear in single-stranded DNA, straightening them so that the RecA protein can bind to and repair them. In this way, SSB modulates the activity of RecA and other proteins that are involved in DNA repair, recombination, and replication. “SSB may be a master coordinator of all these important processes,” said Dr. Taekjip Ha, senior author of the study, which is reported in the October 22 issue of Nature. [Press release] [Nature News & Views] [Nature abstract]
Over-Expressed Gene Produces Smarter Rat
Over-expression of a particular gene (NR2B) that lets brain cells communicate just a fraction of a second longer makes a smarter rat, according to a recent research report. The researches showed that a transgenic Long Evans rat that overexpressed NR2B was able to remember novel objects, such as a toy she played with, three times longer than the average Long Evans female rat, which is considered the smartest rat strain. The transgenic rat was also much better at more complex tasks, such as remembering which path she last traveled to find a chocolate treat. NR2B is a subunit of NMBA receptors, which are like small pores in brain cells that let in electrically-charged ions that increase the activity and communication of neurons. Dr. Joe Tsien, an author of the report, referred to NR2B as the “juvenile” form of the receptor because its levels decline after puberty and the adult counterpart, NR2A, becomes more prevalent. While the juvenile form keeps communication between brain cells open maybe just a hundred milliseconds longer, that’s enough to significantly enhance learning and memory and why young people tend to do both better, Dr. Tsien said. The report was published October 19 in PLoS ONE. [Press release] [PLoS ONE article]
Potential Anti-Melanoma Compound Synthesized
Researches at the University of Alberta in Canada have synthesized a natural compound (palmerolide A) that they believe shows exceptional potential to specifically treat melanoma, a frequently fatal form of skin cancer. “The potency of palmerolide is exceptional and melanoma is a very aggressive cancer for which there is almost no chemotherapeutic recourse,” said Dr. Dennis Hall, senior author of the report. “Natural substances like palmerolide offer real hope for such treatments. One of the problems with most cancer drugs is the lack of selectivity for cancer cells versus normal cells. Preliminary data for palmerolide A looks very promising in terms of solving this issue.” Dr. Hall emphasized that “for commercialization, the structure needs to be made more ‘drug-like;’ smaller, and more water-soluble, while preserving the potency.” The report was published in the October 14 issue of the Journal of the American Chemical Society. [Press release] [JACS abstract]
RNA Repair System Discovered in Bacteria
In new papers appearing in Science and PNAS, University of Illinois biochemistry professor Dr. Raven H. Huang and colleagues describe the first RNA repair system to be discovered in bacteria. This is only the second RNA repair system discovered to date (with two proteins from T4 phage, a virus that attacks bacteria, as the first). The novelty of the newly discovered bacterial RNA repair system is that, before the damaged RNA is sealed, a methyl group is added to the two-prime hydroxyl group at the cleavage site of the damaged RNA, making it impossible to cleave the site again. Thus, the repaired RNA is “better than new.” This discovery has implications for protecting cells against ribotoxins, a class of toxins that kills cells by cleaving essential RNAs involved in protein translation. Because the enzyme responsible for methylation in the newly-discovered RNA repair system is the Hen1 homolog in bacteria, the finding also has implications for the understanding of RNA interference and gene expression in plants, animals, and other eukaryotes. The eukaryotic Hen1 is one of three enzymes (along with Dicer and Argonaute) essential for the generation of small noncoding RNAs of 19-30 nucleotides in RNA interference. The new papers appear in the October 9 issue of Science and the October 12 online edition of PNAS. [Press release] [Science abstract] [PNAS abstract]
Higher Urate Levels May Slow Progression of Parkinson’s
Individuals with Parkinson’s disease who have higher levels of the antioxidant urate in their blood and cerebrospinal fluid appear to have a slower rate of disease progression, according to results of a new study funded, in part, by the National Institutes of Health. The results support similar findings of an earlier, 2008 study. Urate is a chemical that at very high levels is associated with gout. A clinical trial is under way to examine the safety and potential benefits of supplemental urate elevation for recently diagnosed Parkinson’s patients who have low urate levels. Experts emphasize there is no proof that elevating urate levels will help against Parkinson’s disease, and that it should not be attempted outside of a clinical trial, where physicians can closely monitor possible benefits and risks, such as gout and heart disease. In the new study, investigators demonstrated the link with urate by mining a repository of clinical data and tissue samples collected from Parkinson’s patients more than 20 years ago as part of a pioneering study called DATATOP, funded by the NIH’s National Institute of Neurological Disorders and Stroke (NINDS). The new study was funded primarily by the NINDS, with additional support from the Department of Defense and private organizations. “This study speaks to the value of saving data and biospecimens from large clinical studies, and making them available to the research community to pursue new, unanticipated ideas,” said Dr. Michael Schwarzschild, of Massachusetts General Hospital in Boston, senior author of the study. “These results were critically important. Only now we can be reasonably sure that the slower rate of progression in patients with higher concentrations of urate is real and not a chance occurrence,” said Dr. Alberto Ascherio of the Harvard School of Public Health and lead author of the study.
Fractal Architecture Permits Incredibly Tight Packing of Cellular DNA
Using a new technique called Hi-C, scientists have deciphered the three-dimensional structure of the human genome, paving the way for new insights into genomic function. The researchers reported two striking findings. First, the human genome is organized into two separate compartments, keeping active genes separate and accessible while sequestering unused DNA in a denser storage compartment. Chromosomes snake in and out of the two compartments repeatedly as their DNA alternates between active, gene-rich and inactive, gene-poor stretches. Second, at a finer scale, the genome adopts an unusual organization known in mathematics as a “fractal.” The specific architecture the scientists found, called a “fractal globule,” enables the cell to pack DNA incredibly tightly–the information density in the nucleus is trillions of times higher than on a computer chip–while avoiding the knots and tangles that might interfere with the cell’s ability to read its own genome. Moreover, the DNA can easily unfold and refold during gene activation, gene repression, and cell replication. The fractal globule architecture, while proposed as a theoretical possibility more than 20 years ago, has never previously been observed. “Nature’s devised a stunningly elegant solution to storing information–a super-dense, knot-free structure,” said senior author Dr. Eric Lander, director of the Broad Institute. This paper is featured on the cover of the October 9 issue of Science. [Press release]