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Biological Chemistry

Unraveling Thalidomide's Tragic Effects

Cell Biology: Researchers discover a protein involved in causing birth defects related to the drug

by Sarah Everts
March 11, 2010 | A version of this story appeared in Volume 88, Issue 11

Credit: Hiroshi Handa
Hiroshi Handa
Credit: Hiroshi Handa
Hiroshi Handa

More than 50 years after the discovery of thalidomide's tragic ability to stunt limbs in developing human fetuses, researchers have now identified a cellular protein involved in the drug's side effects. This first glimpse at the protein—one of many proteins expected to bind to the drug—will help unravel thalidomide's complex biological effects and could help in the design of new therapeutic analogs that don't cause birth defects.

Some 10,000 to 20,000 babies in the late 1950s and early '60s were born with thalidomide-related birth defects, primarily in Europe. Yet a precise molecular explanation of how thalidomide causes birth defects, as well as the drug's ability to halt multiple myeloma and leprosy and to act as a sedative, has eluded researchers. Scientists have proposed "more than 20 different models for how thalidomide acts in a cell," comments Lai-Ming Ching, a cell biologist at the University of Auckland, in New Zealand. Two of the most widely accepted theories link thalidomide's negative side effects and its therapeutic action to oxidative stress and its ability to block the development of blood vessels, she adds.

Now, a team of researchers in Japan led by Toshihiko Ogura, a neurobiologist at Tohoku University; Hiroshi Handa, a biochemist at Tokyo Institute of Technology; and Yoshimasa Imamura, a researcher at Astellas Pharma in Ibaraki, have identified a human thalidomide-binding protein called CRBN, which is part of a large complex that degrades proteins (Science 2010, 327, 1345). The team then engineered chickens and zebrafish to express CRBN proteins that can't bind thalidomide and exposed them to the drug during development. The engineered animals did not show the same severity of birth defects as the control animals did when exposed to the drug.

"This beautiful work is an important piece of the thalidomide puzzle and may help researchers screen out the teratogenic effects," Ching comments. "But there are certainly many other proteins" that interact with thalidomide that are still left to be discovered, she adds, especially those involved in the drug's therapeutic action.

Neil Vargesson, a development biologist at the University of Aberdeen, in Scotland, who has published research on thalidomide's ability to block blood vessel development, finds the work "interesting" but says the researchers "have not attempted to put the CRBN result into context with regard to existing models of teratogenic action of thalidomide." Vargesson would have liked the researchers to show how thalidomide's interaction with CRBN protein plays out in the cellular biology and physiology of the animals. However, he adds that the team provides a promising technique to identify more of thalidomide's protein targets.

Part of the reason a protein target for thalidomide's birth-defect-causing tendencies has been slow to come is that thalidomide is particularly tricky to study, explains W. Douglas Figg, head of the molecular pharmacology section at the National Cancer Institute. In the body both enantiomers of the drug are hydrolyzed, hydroxylated, and racemized, and these metabolic pathways vary in different organisms. For example, the drug causes birth defects in humans, chickens, and fish but not in rats or mice. "A crystal structure of the protein and drug would be exceptionally helpful," Figg says, to design analogs that may sidestep the birth defects in humans.

Imamura says the Japanese team is now working on doing just that.


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