Thalidomide: uncovering the mystery behind the disaster

31 March, 2010, Lux Fatimathas

New hope for an old drug….?

Thalidomide. The name itself is enough to spark terrible images in the minds of most people.

The prescription of thalidomide, to pregnant women in the 1950s, ranks as one of the worst pharmaceutical blunders in modern medical history. The drug, manufactured by the German company Chemie Grunenthal, was promoted as an anti-emetic and sedative. The relief from these symptoms answered the prayers of many young mothers-to-be across the globe. Prescriptions were drawn up in over forty different countries, under several different pseudonyms. Distaval in the UK, Talargan in Mexico, Poli-Gripan in Pakistan and the list goes on and on – with one noted exception. America. The ensuing tragedy was largely averted in America due to the FDA (Food and Drug Administration) not permitting licensing of the drug, stating there was insufficient evidence for its safe use in humans.[frax09alpha]

The distribution of thalidomide to the general public began in 1957 and after four years and thousands of prescriptions it was finally withdrawn. The reason is well documented and the images quite disheartening. It is not known exactly how many babies were affected by thalidomide but the numbers are thought to be in the range of ten to twenty thousand (Born Freak: Happy Birthday Thalidomide, Channel 4 Documentary, UK, 2009). The deformities observed varied according to when exactly the drug was taken by the mother. However the most well-known defect is that of phocomelia, a term which has its roots in Greek – phoke meaning seal and melos meaning limb. This literal translation quite aptly describes the appearance of the malformed limbs associated with thalidomide babies. Other defects include the loss or malformation of the ears, as well as deformities of the internal organs such as the heart, kidneys and intestinal tract.

Image: US National Cancer Institute An appearance of malformed limbs associated with thalidomide babies.

These severe side-effects understandably caused worldwide scandal and uproar, however even so these events were set to repeat themselves several years later in South America. Although thalidomide was developed as an anti-emetic and sedative, it was soon uncovered to be therapeutic in treating leprosy. It was dispensed for this purpose in the 1960s across several countries in South America, including Brazil, Argentina and Peru. No warnings were given regarding the teratogenic effect of the treatment and as such a spate of phocomelic babies were born in the following years. Sadly it appears that such cases may still be occurring in the present day, not only in South America but also in Africa, where improper monitoring of thalidomide usage is an ongoing problem.

Image: Takumi Ito (Science 12 March 2010 Vol. 327) Bone staining of the pectoral fin of zebrafish embryos treated with increasing doses of thalidomide. Upon treatment with thalidomide this structure is completely lost.

A simple solution

The devastating defects observed in newborns were later found to be attributed to one particular isomer of thalidomide called (S)-thalidomide. So perhaps there is a simple solution after all. Why not just administer the safe isomer to patients i.e. (R)-thalidomide? Unfortunately this was shown to be ineffective, as once thalidomide is present in the human body, it undergoes a process called racemisation. This process results in the production of a mixture of both the safe and harmful versions of thalidomide, irrespective of which one was administered. So the ‘easy fix’ to thalidomide remained out of reach.

Almost 50 years have passed since the damaging effects of thalidomide were uncovered and in this time little has been discovered on its precise mechanism of action. That all changed in March of this year. A seminal paper was published in Science by Takumi Ito and colleagues from the Tokyo Institute of Technology. In order to investigate the developmental effects of thalidomide, experiments were conducted in both zebrafish and chicks. Although these model organisms may seem rather far removed from humans, the highly conserved nature of many of our genes across different species means these types of investigations can yield highly informative results. In this instance it is particularly important to note that neither mice nor rats were used.

Image: Otis Historical Archives National Museum of Health & Medicine (#NCP14053) The most well-known defect is that of phocomelia, a term which has its roots in Greek – phoke meaning seal and melos meaning limb. This literal translation quite aptly describes the appearance of the malformed limbs associated with thalidomide babies.

Clinical trials on thalidomide were carried out in mice and rats in the 1950s, as these animals have long been considered good models for mimicking the human condition. However we now know that strangely thalidomide does not exert teratogenic effects in mice or rats. The Ito lab therefore chose to focus on the zebrafish, a model system that had not yet been established in the 1950s. By looking at the development of the pectoral fin, the fish equivalent of our arms if you will, Ito et al were able to pin down the interactions of thalidomide at a molecular level. As in humans, the treatment of zebrafish embryos with thalidomide interfered with limb development. These embryos failed to develop pectoral fins. Further experiments uncovered a direct interaction between thalidomide and a protein called cereblon (CRBN), of which relatively little is known. Ito et al demonstrated that when the interaction between thalidomide and cereblon is specifically abrogated pectoral fins were able to develop! It therefore appears that this interaction is essential for thalidomide to exert its harmful effects on limb development.

This study not only provides significant insight into a 50 year mystery, but may prove helpful for the future use of thalidomide in treating cancer. Although this drug was severely tainted back in the 1950s, it has proven to be a potent agent against cancer. Thalidomide is currently being used as an anti-cancer treatment in several countries including America and the UK. However women of child bearing age undergoing this treatment must also be on strict contraceptive medication and are subject to regular pregnancy tests. Now that we know one pathway through which thalidomide exerts its detrimental effects, there is hope that a new form can be designed which is safer, more targeted and ultimately more beneficial to the patients at its receiving end. Perhaps 50 years from now, the story of thalidomide will have turned from one of medical tragedy to one of medical advancement.

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