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RESEARCH BRIEFS
Gene Shown to Determine Brain SizeHMS researchers report that they have uncovered part of the mechanism that may control the size of the cerebral cortex--and possibly how smart humans are--in a paper published in the Aug. 19 Science.
At left is a normal, smooth mouse brain; at right is an enlarged brain from a mouse injected with beta-catenin, which has folds resembling human brain. (Photo courtesy of Anjen Chenn and Christopher Walsh) Eighty percent of the human brain is cerebral cortex, and it is this large size that distinguishes humans from other animals by making them more intelligent. "There is a lot of speculation about how evolution acts on the cerebral cortex, causing mice to have a small, flat cerebral cortex and humans to have a great big cerebral cortex," said study leader Christopher A. Walsh, HMS professor of neurology at Beth Israel Deaconess Medical Center. Previous research had shown that the beta-catenin protein is involved in Wnt signaling, which plays a role in brain cell development and proliferation. Beta-catenin is expressed in many of the body's tissues and is known to regulate cell proliferation and tissue growth. Walsh and his team, therefore, thought that the gene might be involved in determining the size of the cortex by acting as a switch to control the cell's decision to divide or not. "Beta-catenin probably tells the cells to not differentiate, to keep dividing," Walsh said. To test whether beta-catenin does affect the size of the cortex, Anjen Chenn, a postdoctoral fellow in Walsh's lab and lead author of the study, designed DNA that overexpresses the beta-catenin protein. This DNA was injected into the nuclei of fertilized mouse eggs, where it became incorporated into the DNA and was expressed as the embryo grew. Chenn examined the mouse brains on embryonic day 16, three days before the end of normal gestation. Brain sections showed not only that the cerebral cortex was larger than normal, but that it had developed grooves (sulci) and bumps (gyri) characteristic of the human brain. The sulci and gyri are nature's way of squeezing a large cerebral cortex into a relatively compact skull. "This gives us some idea of how, during evolution, nature may have put together a bigger brain," Chenn said. Though the study demonstrates that the size of the cortex can be controlled by beta-catenin, it does not establish that this is the mechanism nature uses, Walsh said. The researchers now are investigating whether people born with smaller or bigger brains have beta-catenin abnormalities. --Sena Desai
System Devised to Construct More Versatile AntibioticBy mimicking the natural biosynthetic pathway, HMS researchers have synthesized an analogue of the cyclic peptide antibiotic, tyrocidine A, that is more active and less toxic than the natural product. Macrocyclic antibiotics are synthesized by a system of non-ribosomal peptide and polyketide synthetases, an enzymatic assembly line that is nature's way of doing solid phase chemistry. First, linear peptides are synthesized by stepwise addition of building blocks with intermediates always tethered to the carrier protein; then the linear peptides are formed into a ring, or macrocyclized, by an enzyme, which completes the synthesis of the antibiotic. Tyrocidine A acts by disrupting the osmotic and ionic regulation of cell membranes. It is toxic, however, and used only topically since it acts on not only bacterial but human cells. About three years ago, a team of researchers led by Christopher T. Walsh, HMS professor of biological chemistry and molecular pharmacology, identified the enzyme that catalyzes the macrocyclization step for this antibiotic as the thioesterase domain from the synthetase. "We studied the limits of this enzyme--how tolerant it would be to substrate substitutions," said Rahul Kohli, a graduate student working with Walsh and the lead author on the study. The researchers found that thioesterase was versatile and could be used to cyclize variants of the natural linear peptide, producing a range of analogues of the natural tyrocidine A. "Solid phase chemistry is the accepted way of making peptides today," Walsh said. For tyrocidine A, his team first used a solid phase resin--polyethylene glycol amide--that mimicked the natural carrier protein. They then carried out solid phase synthesis to build a range of linear peptides. The thioesterase was excised from the synthetase by cloning the isolated domain, and it was used as a catalyst to convert the linear peptides to variants of the natural antibiotic. From their library of analogues, Walsh's team isolated a variant that is both more selective and more active than the natural antibiotic. It is 30 times more selective for bacterial over human cells and acts against not only gram-positive bacteria, like the natural product, but also gram-negative bacteria. The work can be used to understand these biosynthetic pathways better and to synthesize a range of variants of important natural pharmacological products that have broader activity and less toxicity. The study appears in the Aug. 8 Nature. --Sena Desai |
