Back in the early 1960s, one of the most notorious medical scandals of all time left thousands of newborn babies with severe deformities, after a compound called thalidomide was marketed as a sedative for pregnant women. Though the drug was quickly pulled from pharmacies across the world, it has taken more than half a century for researchers to figure how the substance produced its horrific side effects. Finally, a paper published last week in the Journal Nature Medicine appears to have got to the bottom of the mystery.
The first clues as to how thalidomide works on a molecular level came when it was discovered that some of its derivatives – such as lenalidomide and pomalidomide – can be effectively used to treat certain types of tumor by preventing cancerous cells from proliferating. Research on these compounds revealed that they work by preventing two proteins – known as CD147 and MCT1 – from joining together to form a complex.
Crucially, the CD147-MCT1 complex is known to promote a number of biological functions, such as the proliferation of cells and the formation of blood vessels. While these are obviously very beneficial to the development of a fetus, an overabundance of this key complex can cause cells to multiply excessively, leading to the formation of tumors.
By treating cells with thalidomide and a number of its derivatives, the authors of this latest study found that these drugs outcompete a protein called cereblon, which plays a pivotal role in helping CD147 and MCT1 to combine, thereby preventing the formation of the CD147-MCT1 complex.
While this explains the anti-cancer properties of thalidomide-related drugs, the researchers suspected that it may also somehow lead to the formation of birth defects. To investigate, they treated pregnant zebrafish with thalidomide, noting that this caused their embryos to develop abnormally small heads, fins and eyes.
They then created a line of genetically engineered zebrafish that lacked CD147, finding that these fish displayed the exact same deformities as those that had been treated with the drug. As such, they conclude that such defects must indeed be caused by a disruption to the formation of the CD147-MCT1 complex – which is exactly what thalidomide appears to do.
Image: Thousands of people around the world have had to suffer the consequences of thalidomide, and have been demanding answers for some time. Peter Bischoff / Stringer / Getty
Comparing the drug’s cancer-fighting properties to its side effects, lead researcher Florian Bassermann explained that “the mechanisms are identical,” adding that “a specific inactivation of the protein complex resulted in the same developmental defects observed after thalidomide treatment.” Based on this discovery, the researchers can conclude with some confidence that the deformities associated with thalidomide are due to the way that the drug prevents the formation of blood vessels and proliferation of cells in the developing fetus.
Therefore, despite the fact that drugs like lenalidomide and pomalidomide have been found to produce less severe side effects than thalidomide itself, such chemicals clearly carry a potential for danger, and should certainly be avoided during pregnancy.