Scientists at WorldCare Consortium™ member Dana-Farber Cancer Institute discover how thalidomide produced birth defects
Researchers from WorldCare Consortium™ member Dana-Farber Cancer Institute have found how thalidomide produced such severe fetal harm in thousands of children whose mothers took it while pregnant. The discovery not only answers a mysterious question that has been the subject of scientific curiosity for two generations, but will also be instrumental as pharmaceutical companies develop new anticancer drugs that share a basic chemical architecture with thalidomide.
Scientists found that thalidomide acts by promoting the degradation of a wide range of transcription factors (cell proteins that help switch genes on or off), including one called SALL4, resulting in the complete removal of SALL4 from cells. This interferes with limb development and other aspects of fetal growth, leading to the spectrum of complications and defects linked to thalidomide, including malformed limbs and defective organs in children whose mothers took the drug during pregnancy as treatment for morning sickness.
Individuals who carry a mutation in the gene for SALL4 are often born with underdeveloped limbs, missing thumbs, eye and ear defects and congenital heart disease, problems which parallel those in thalidomide-exposed children. “The similarities between the birth defects associated with thalidomide and those in people with a mutated SALL4 gene are striking,” stated senior author of the study Eric Fischer, PhD, of WorldCare Consortium™ member Dana-Farber Cancer Institute. “They make the case even more strongly that disruption of SALL4 is at the root of the devastation produced by thalidomide in the 1950s.”
The discovery of the mechanism by which thalidomide produces birth defects will be critical as drug developers devise and test new drugs using similar structures to thalidomide. “As new derivatives are tested, we’ll be able to explore whether they have the same potentially damaging effects as thalidomide,” Fischer added. “We know that the therapeutic effect of these drugs is based on their ability to degrade specific proteins. Our findings will help drug developers distinguish between proteins whose degradation is likely to be beneficial and whose may be harmful.”
Journal Reference: Katherine A Donovan, Jian An, Radoslaw P Nowak, Jingting C Yuan, Emma C Fink, Bethany C Berry, Benjamin L Ebert, Eric S Fischer. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome. eLife, 2018; 7 DOI: 10.7554/eLife.38430