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Archive - Sep 2, 2009

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Tbx5 Gradient Key to Development of Four-Chambered Heart

Research in turtles and lizards has revealed a tantalizing clue to the evolution of the four-chambered heart and the related ability of birds and mammals to lead a warm-blooded existence. The key appears to be varied expression of the transcription factor gene Tbx5 in the ventricles. In humans and other mammals, Tbx5 levels are high in the left ventricle and low in the right. The boundary of high and low is right at the septum, which forms to separate the two ventricles. When the researchers looked at the green anole lizard, which has just a three-chambered heart, they found that Tbx5 activity was essentially the same throughout the single ventricle and stayed the same throughout heart development. In the turtle, however, which has a primitive septum that partially separates its ventricle into left and right sides, distribution of Tbx5 was gradually restricted to the left side of the ventricle, resulting in a left-right gradient of Tbx5 activity. Further experiments in genetically engineered mice conclusively showed that a sharp line demarcating an area of high levels of Tbx5 is critical to induce formation of a septum between the two ventricles. "This is the first genetic link to the evolution of two, rather than one, pumping chamber in the heart, which is a key event in the evolution of becoming warm-blooded," said Dr. Benoit Bruneau, the senior author of the study. "The gene involved, Tbx5, is also implicated in human congenital heart disease, so our results also bring insight into human disease." The work was featured as the cover story of the September 3 issue of Nature.

Discovery of RAF Activation Mechanism May Aid Cancer Drug Development

A research team has shown that dimerization is essential for activation of the RAF protein kinase. When mutated, RAF protein kinase is responsible for more than 25 percent of human cancers. The research team believes that, by targeting the key dimerization process (specifically, the side-to-side dimerization of the kinase domain), it may be possible to develop new, more effective cancer therapies. "Protein kinases are the targets for some of the most successful anti-cancer drugs in the clinic," said Dr. Frank Sicheri, an author of the report. "Now that we have discovered how to turn off the RAF protein without interfering with other proteins, we may be able to design drugs that have unprecedented precision in targeting cancer cells while reducing the toxic side effects for patients." This work was published online in Nature on September 2. [Press release] [Nature abstract]

Teeth-Venom Combination Key to Lethality of Komodo Dragon Bite

A new study has shown that the effectiveness of the Komodo Dragon bite owes to a combination of highly specialized serrated teeth and venom. The authors dismiss the widely accepted theory that prey die from septicemia caused by toxic bacteria living in the dragon's mouth. Using sophisticated medical imaging techniques, an international team led by Dr. Bryan Fry from the University of Melbourne has shown that the Komodo Dragon has the most complex venom glands yet described for any reptile. The researchers conducted a comprehensive study of the Komodo Dragon bite, employing computer techniques to analyze stress in a dragon's jaws, and compared the results to those obtained for a crocodile. The dragons were found to have much weaker bites than crocodiles, but magnetic resonance imaging (MRI) of a preserved dragon head revealed complex venom glands and specialized serrated teeth which create deep lacerations for entry of the venom. "These large carnivorous reptiles are known to bite prey and release them, leaving the prey to bleed to death from the horrific wounds inflicted. We have now shown that it is the combined arsenal of the Komodo Dragon's tooth and venom that account for their hunting prowess," said Dr. Fry. "The combination of this specialized bite and venom seems to minimize the Dragon's contact with its prey and this allows it to take large animals." Komodo Dragons are native to the islands of Indonesia, with adult males weighing over 100 kg, and exceeding 3 meters in length. They have approximately 60 highly serrated teeth which are frequently replaced during their lifetime. The new research was published in the June 2 issue of PNAS. [Press release] [PNAS abstract]