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5 December 2013 11:26 am ,
Vol. 342 ,
Dyslexia, a learning disability that hinders reading, hasn't been associated with deficits in vision, hearing, or...
Exotic, elusive, and dangerous, snakes have fascinated humankind for millennia. They can be hard to find, yet their...
Researchers have sequenced and analyzed the first two snake genomes, which represent two evolutionary extremes. The...
Snake venoms are remarkably complex mixtures that can stun or kill prey within minutes. But more and more researchers...
At age 30, Dutch biologist Freek Vonk has built up a respectable career as a snake scientist. But in his home country,...
Since arriving on the island of Guam in the 1940s, the brown tree snake ( Boiga irregularis ) has extirpated native...
An animal rights group known as the Nonhuman Rights Project filed lawsuits in three New York courts this week in an...
Researchers have been hot on the trail of the elusive Denisovans, a type of ancient human known only by their DNA and...
- 5 December 2013 11:26 am , Vol. 342 , #6163
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Thalidomide's Partner in Crime
11 March 2010 2:42 pm
Thalidomide ranks as one of the worst pharmaceutical disasters in modern history. Prescribed as an antinausea drug for pregnant women in the late 1950s and early 1960s, it caused severe birth defects in as many as 10,000 children before it was yanked from the market. Half a century later, scientists are still not sure exactly how the drug does so much damage, which includes shortened arms and legs, ear deformities, and malformations in the digestive system. Now, for the first time, researchers have found a specific protein that binds to thalidomide and may help explain its devastating effects on fetal development. The find could help scientists develop less-toxic versions of the drug, which has helped combat the cancer multiple myeloma and complications of leprosy.
Because of its use in those hard-to-treat diseases, thalidomide is still causing birth defects today—especially in Africa and South America where leprosy still rages. (In the United States, people given thalidomide for myeloma are instructed to use multiple forms of birth control and take frequent pregnancy tests.) Scientists are therefore eager to understand exactly how thalidomide does its damage so that they can preserve the benefits of the drug without its hazards.
Molecular and developmental biologists from Japan report in tomorrow's issue of Science that they have found a new clue. Hiroshi Handa of the Tokyo Institute of Technology and his colleagues developed tiny magnetic beads—just 200 nanometers in diameter—that can be attached to drugs and other compounds. When the bead-linked drugs are mixed with cell extracts, scientists can pick out proteins or other molecules that the drug binds to. They applied the technology to thalidomide, and their fishing expedition paid off.
Handa's team found that beads tagged with thalidomide bound to a little-known protein called cereblon, which is expressed widely in both embryonic and adult tissues. Further experiments showed that blocking production of cereblon in zebrafish can cause defects in fin development similar to those caused by thalidomide. In both zebrafish and chick embryos, adding a version of cereblon that doesn't bind to thalidomide seemed to blunt the drug's effects.
Although cereblon's role in the cell is still unknown, Handa and his colleagues think that it might be a link between the drug and better-known developmental genes that direct limb development. But given that the protein is found in so many tissues, it's puzzling that thalidomide has such specific effects on limbs, ears, eyes, gut, and kidneys. In part because of this, although the cereblon clue is interesting, it is far from the whole story, says Neil Vargesson, a developmental biologist at the University of Aberdeen in the United Kingdom. He and his colleagues have studied the activity of thalidomide in developing limbs and have shown that developing blood vessels are a primary target of the drug. The new experiments don't explain thalidomide's effects on blood vessels, he says.
Toxicologist Craig Harris of the University of Michigan, Ann Arbor, who has studied thalidomide's effects on gene expression, says that the new data are consistent with some theories of the drug's action, however. The cereblon clue will lead to new experiments that look at the protein's role in the cell, he says, key clues that may help scientists find replacement drugs. That, in turn, could finally relegate thalidomide to the history books.