How Did Thalidomide Cause Birth Defects?

One of the most notorious episodes in pharmaceutical history, the thalidomide disaster saw more than 10,000 babies across the globe born with phocomelia, a rare congenital deformity in which limbs are underdeveloped or absent. While the drug was marketed as a mild sleeping pill and morning sickness treatment, it later emerged the sedative was responsible for severe birth defects when taken between the fourth and eighth weeks of pregnancy.

When the link was discovered back in the 1960s little was known about how thalidomide caused the deformities. Now, scientists at the Dana-Farber Cancer Institute have uncovered the mystery and assert the defects were caused by a disruption of key proteins involved in foetal development. The results were published in the online journal eLife and build on years of research exploring the chemical architecture of thalidomide.

Pinpointing the cell degradation properties of thalidomide

Led by a team of authors, the study found that thalidomide actively degrades several C₂H₂ zinc finger transcription factors, including a cell protein known as SALL4. Without SALL4, cells are unable to fully develop which inhibits a foetus's ability to grow limbs and other important organs. As a result, many children exposed to thalidomide in the womb were born with SALL4 gene mutations, with side-effects including underdeveloped limbs and missing limbs, as well as congenital heart disease, eye defects and other developmental issues.

"The similarities between the birth defects associated with thalidomide and those in people with a mutated SALL4 gene are striking," says senior author, Eric Fischer. "They make the case even more strongly that disruption of SALL4 is at the root of the devastation produced by thalidomide in the 1950s."

Thalidomide set to emerge as cancer treatment drug

With pharmaceutical companies on the verge of launching a highly anticipated new generation of cancer treatment drugs linked to thalidomide, the study not only solves a decades-old mystery but could also help to ensure history isn't repeated.

The new anti-cancer treatment stems from research carried out in the 1980s, when scientists discovered thalidomide possessed powerful anti-angiogenic properties capable of stopping the growth of blood vessels in tumours. Today thalidomide has emerged as a popular treatment for cancers like multiple myeloma and could soon be used to tackle other abnormal cell growth conditions.

"As new derivatives are tested, we'll be able to explore whether they have the same potentially damaging effects as thalidomide," explains Fischer. "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."

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