After a long, L-O-N-G time, I found something that really excited me. I mean, really. The New York Times recently reported on a study published in Science which highlights a series of efforts in which scientists begin to figure out how exactly Thalidomide caused the congenital defects in limb development. The well written, insightful and informative NYT article, a pleasure to read, was written by Ex-ScienceBlogger, Science Writer and author Carl Zimmer.
In the late fifties, pregnant women in Europe were taking Thalidomide, then-considered safe, for morning sickness. By 1962, when the drug was officially banned for its teratogenicity (i.e. the ability to induce malformations in developing embryo/fetus), almost ten thousand children were born with Thalidomide-induced congenital defects in limb development, in which the long bones of the arms (humerus, radius and ulna), and sometimes legs (femur, tibia and fibula), failed to develop, though bones of palms (carpal and metacarpal) and feet (tarsal and metatarsal), and of fingers (phalanges) grew, producing a fin or flipper like appearance. Thalidomide, however, was not a problem when used in adults to control inflammation associated with leprosy, or for multiple myeloma; it is even being tested for HIV infection and Crohn’s Disease.
All this while, developmental biologists did not know how exactly Thalidomide produced that effect. Theories abounded ranging from the drug being neurotoxic in growing limbs to its causing apoptosis in the developing limb cells.
Collaborative studies by researchers from the National Cancer Institute of the NIH, Imperial College London and University of Aberdeen have revealed that anti-angiogenic properties of CPS49, a single metabolite of Thalidomide, causes limb defects in chick embryos. The paper indicates:
Both in vitro and in vivo, outgrowth and remodeling of more mature blood vessels is blocked temporarily, whereas newly formed, rapidly developing, angiogenic vessels are lost. Such vessel loss occurs upstream of changes in limb morphogenesis and gene expression and, depending on the timing of drug application, results in either embryonic death or developmental defects.
This model is important in accounting for the action of Thalidomide in causing defects in limbs but not anywhere else, because limbs begin to develop relatively late compared to the rest of the body, which makes the growing blood vessels in them vulnerable to Thalidomide – given the timing of its use by pregnant mothers. The damage to already mature blood vessels is relatively less.
The Science paper by a Japanese group found a protein of unknown function called ‘cereblon’ binding to Thalidomide. In Zebrafish embryos, cereblon was found to contribute to fin development (controlled by a set of genes remarkably similar to those responsible for human limb development), making it equally vulnerable to Thalidomide. Genetically modified cereblon, that no longer bound to Thalidomide, was able to allow normal wing development in chick embryos even in presence of Thalidomide.
Of course, much remains to be done, including identification of other putative molecules that can bind to Thalidomide. But this is a good beginning; a modified Thalidomide that perhaps doesn’t bind to strange proteins would be very useful for diseases, such as cancer, which involve significant angiogenesis.
I encourage you all to take a gander the NYT article, as well as the Science paper. I found it very satisfying. This is what good, old science is all about: an everlasting spirit of enquiry, a critical analysis of observations, and the will and the tenacity to solve puzzle after puzzle. Great stuff!