Thalidomide is not a drug that that impinges on just one biological pathway. That complexity could explain its multifaceted effects—from its ability to induce vascular remodeling in the adult, as outlined by Lebrin et al. in this issue (pages 420–428), to its devastating effects on the developing embryo and fetus.

It's been almost 50 years since the drug was pulled from the market for causing birth defects, but only now are researchers beginning to understand the basis for its teratogenicity. In a recent study, Takumi Ito et al. (Science 327, 1345–1350, 2010) unravel how thalidomide might cause limb deformities during embryonic development, suggesting that it acts in this context by binding a ubiquitin ligase complex.

A normally-developing chick limb, and a limb exposed to thalidomide (inset). Credit: AAAS

Using beads coated with a thalidomide derivative, the authors fished out the protein cereblon from cell lysates as a direct thalidomide target. This protein, the researchers found, is a component of a ubiquitin ligase complex. The binding of thalidomide to cereblon inhibited the activity of this complex.

In zebrafish, the authors showed that this binding is required for thalidomide to disrupt embryonic development. Knockdown of the zebrafish homolog of cereblon resulted in developmental defects similar to those caused by thalidomide treatment, and overexpression of a mutant version of cereblon, unable to bind thalidomide but still functionally active, rescued the developmental defects caused by thalidomide treatment.

The researchers observed similar mechanistic effects of thalidomide in chick embryos. Moreover, thalidomide's binding to cereblon suppressed expression of chick genes encoding two growth factors important for limb patterning, Fgf8 and Fgf10 — although exactly how is unclear.

Thalidomide may also act through other mechanisms to disrupt limb development, such as through hindering angiogenesis, as previously reported (Proc. Natl. Acad. Sci. USA 106, 8573–8578, 2009). An understanding of how thalidomide acts may spur the development of derivatives that lack teratogenicity but retain therapeutic effects.