This month in the research journal Science a Japanese group have published evidence for a possible mechanism as to how the infamous drug thalidomide deformed a generation of babies.

This article was published in Trinity News

If ever there was an argument for the dys-teleological theory of ‘bad design’, or perhaps better worded ‘unintelligent design’, sometimes commonly referred to as atheism, thalidomide would be it. No doubt the mothers of the thalidomide babies would have asked themselves where the intelligence lies in designing an antiemetic (used to treat morning sickness) painkilling drug, that coincidentally and horribly, deforms your child, or kills it. Nevertheless, without getting too much into a theological debate, the earthly patentor of the ‘unintelligently designed’ thalidomide was aptly a German pharmaceutical company, named Chemie Grünenthal. The original packaging supplied with pharmaceutical thalidomide included the following statement.

‘In pregnancy and during the lactation period the female organism is under great strain. Sleeplessness, unrest and tension are constant complaints. The administration of a sedative and a hypnotic that will hurt neither mother nor child is often necessary’

According to Wikipedia, Chemie Grünenthal began life as “a branch of a soaps, toiletries, and cosmetics business”. And today, the company produce, you guessed it, painkillers, now for both female and male organisms. That means us. Profit for 2008 was estimated by the company to be just short of 1 billion Euros. Enough said.

In the late 50s and 60s thalidomide was prescribed as a potent painkiller and tranquiliser. However, it was through its widespread use to treat morning sickness of pregnant women that thalidomide really demonstrated its devastating capacity as a teratogenic (causing developmental defects) agent. An estimated 10,000 unborn babies were poisoned by thalidomide, with many dying, and others left with birth defects such as the trademark absence of the long bones of the legs, known as phocomelia (from the greek for seal limbs), or of the arms (amelia).

According to the website for the Irish Thalidomide Association, a group battling for proper compensation for sufferers, there are still 32 survivors of the thalidomide tragedy living in Ireland today, as well as another 18 in Northern Ireland. Whilst these people clearly cannot benefit from research into the effects of thalidomide, there is nevertheless a large body of research being conducted across the globe to try to understand how thalidomide, and similar substances, mediate their therapeutic as well as their pathogenic effects.

Today thalidomide is still prescribed to cancer patients with multiple myeloma, and also to sufferers of leprosy. These patients are strongly advised to undertake birth control measures, and clearly, the severity of these diseases warrants the use of thalidomide, particularly in the absence of any reasonable alternative therapy. Furthermore, as the research on thalidomide piles up, it is being realised that it may be a potent treatment for other diseases such as a range of cancers as well as inflammatory diseases such as Crohn’s disease and Behçet’s disease.

This month the Japanese group from the Tokyo Institute of Technology led by Hiroshi Handa report that they believe they have found the mechanism as to how thalidomide causes developmental defects.

By conjugating beads to thalidomide derivatives and exposing those beads to cellular proteins Handa’s group were able to identify two protein binding partners for thalidomide, cereblon (CRBN) and DNA binding protein 1 (DDB1). They discovered that thalidomide directly binds CRBN which is itself bound to the DDB1, and that this interaction inhibits the activity of a growth factor called fgf8. This is the first such linkage between thalidomide and this growth factor pathway.

The researchers backed up their findings with a zebrafish model of the disease. Zebrafish are commonly used to study embryonic development. When Handa’s group put zebrafish embryos into thalidomide containing medium they did not develop normal pectoral fins (see picture). They also discovered that proper growth and development of zebrafish otic vesicles and pectoral fins is dependent on the zebrafish gene equivalent of CRBN.

This groundbreaking research may allow the development of thalidomide derivative drugs that will be potent treatments for a range of diseases, but without the teratogenic risk to unborn children. Simply put, a lot of sick people could one day benefit from an earthly ‘intelligent redesign’ of the infamous thalidomide. But convincing anybody who can remember the disaster of the 50s that a thalidomide related drug is safe, that might be as difficult as convincing me of intelligent design.

photo credit: Duckwailk via photopin cc

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