May 21, 2022

I, Science

The science magazine of Imperial College

By Guo Wang
Autumn 2021 Magazine Feature

Medical drugs changed our understanding of life and disease. When in the past, a cold could mean a death sentence, we now take pills to address a simple morning headache, alleviating symptoms instantly without worrying too much about the possible secondary effects, the small letter. Modern drugs are pretty safe in general thanks to exhaustive drug testing. Nonetheless, this was not always the case. 75 years ago, when profits were prioritised over the lives of newborn babies. This is not a happy story, but neither is it a tragic one. It is just a very good reminder about the importance of sensibility in drug commercialisation. Because only with the wisdom of hindsight, we can avoid committing the same past mistakes in the future.

In 1952, the company Chemical Industry Basel (CIBA) synthesised thalidomide for the very first time. But the drug was tested to ‘have no effect on animals’ and was discarded in consequence. Five years later thalidomide was purchased by the German pharmaceutical company Chemical-Grünenthal, which was founded in 1946 to produce soap because post-WWII Germany was suffering a lack of antibiotics. Its Head of Research was a Nazi chemist called Heinrich Mückter, who studied the properties of thalidomide. What he and his team first found out was that thalidomide seemed to be inoffensive, at least in animal trials with mice. Many years later, the results of experiments with monkeys and rabbits would unveil the cruel truth about thalidomide. But for now, they were searching for useful applications of thalidomide that the company would be able to commercialise into ‘daily-use’ products. Initially, it was tested to be ‘harmless’ to humans.

The eureka moment arrived when they discovered certain sedative properties in thalidomide. Later, Grünenthal sent free samples to different clinics in both West Germany and Switzerland, targeting epileptic patients. Although no anticonvulsant effect was reported, the patients claimed to have a better night sleep. In consequence, without any more trials, the pharmaceutical company decided to commercialise it under the name of ‘Contergan’ to treat insomnia, colds and headaches. Because it was considered a safe drug, thalidomide was sold over the counter, which means that customers could buy it without a medical prescription. In the next following years, more and more people started using thalidomide due to its cheap prices, effectiveness and availability. The scope of the ‘miraculous’ and affordable thalidomide reached up to 46 countries under 37 different names.

In the 50s, drug testing procedures were not as strict and regulated as they are now. This lax regulation added up to the wrong belief that the placenta could protect the fetus from any drug the mother could ingest, allowing Grünenthal to communicate that thalidomide was safe for pregnant women to all German doctors in 1958. Advertising did not wait and many companies like the Distiller Company in the UK started selling the drug as if it were a panacea for treating morning sickness in pregnant women. As the consumption of thalidomide was increasing among pregnant women worldwide, the cases of a congenital malformation, characterised by undeveloped limbs attached to the trunk, called phocomelia, were rising as well. This was alarming because phocomelia was an extremely rare disease, occurring at a rate around 4 per 100,000 births.

Nobody knew exactly the causes of this global problem until 1961, when the German paediatrician Lenz and the Australian obstetrician (a medical field focused on pregnancy) McBride, independently, discovered that most of the phocomelia babies’ mothers consumed thalidomide to treat morning sickness. Thus, both doctors expressed publicly that thalidomide was indeed a teratogen (an agent that causes abnormalities in fetuses). Hence, these two doctors gained the respect and gratitude of the entire world, and thalidomide was gradually being retired from the shelves of pharmacies. This process was hampered by the mentioned fact that thalidomide had different names around the world. Canada was the last country to ban the public sale of thalidomide in 1962.

What were the dramatic consequences of thalidomide? At least 10,000 babies suffering congenital malformations without counting the families of those babies as victims. This number is already sad, but we need also to consider unfortunately two more facts: (1) the number of affected babies is surely much higher because the records are incomplete and (2) roughly 40% of the babies died before becoming adults. So many lives were destroyed due to pharmaceutical companies’ negligence. Innocent lives lost forever, and beloved mothers sunk in sadness and eternal regret. Nonetheless, in adversity, there is hope. The survivors of the thalidomide tragedy managed to become functional and successful adults. Many became an inspiration, an example of resilience. For example, Lorraine Mercer, one of the survivors, carried the Olympic torch under the motto “No limbs? NO LIMITS!” in the 2012 Olympic Games.

Why had thalidomide such horrible consequences? Firstly, we need to know that isomers are molecules with the same number and type of atoms, but these are arranged differently in space. This makes isomers have very different chemical properties. There are two main types of isomers: structural isomers, in which atoms have different chemical bonds, and stereoisomers, in which the bonds between atoms is the same but they differ in their orientations in 3D space. Stereoisomers possess the geometric property of chirality, which means that the molecules are non-superimposable mirror images of each other. An illustration of this would be your hands: they are mirror images of each other and you cannot overlap them. Indeed, etymologically, the word ‘chirality’ comes from the Greek term ‘kheir’ and it means ‘hand’.

Illustration of Thalidomide’s optical isomers | Courtesy of Wikimedia Commons

A chiral centre is an atom of the molecule connected to different substituents. The most common chiral centre, at least in organic chemistry, is carbon. If the 3D spatial orientation of the chiral centres of stereoisomers is exactly the opposite of each other, these stereoisomers are also classified as enantiomers. On the other hand, if they do not differ in all the chiral centres, these stereoisomers are called diastereoisomers. Stereoisomers are also called optical isomers; the chirality property allows them to divert polarised light to the right (dextro) or the left (levo) side. Thalidomide is both a stereoisomer and an enantiomer because it just has one chiral centre. This is the carbon atom bound to the nitrogen of the double-ring substituent. Then, thalidomide has got two forms that we call S and R (note that this applies to enantiomers in general). (R) – thalidomide has got sedative properties and help to alleviate the symptoms of morning sickness. However, (S) – thalidomide is a teratogenic agent. The reasons are still unclear, but it is suggested that it might be due to interference with genes. A possible solution would be only synthesising the harmless form of thalidomide. Nevertheless, this would be futile as human livers have got an enzyme that converts (R) – thalidomide into (S) – thalidomide in a 50-50 ratio. When the quantities of the enantiomers are equal, we call this situation a racemate.

Despite its huge side effects, there may still be a place for thalidomide in modern medicine. Nowadays, thalidomide has been found to be a surprisingly effective drug to treat cancer but not exempt from controversy, the survivors of the thalidomide catastrophe serve as a reminder, making sure that no similar episode would repeat again. Could thalidomide one day redeem itself?

This article was commissioned and written with the intention of being included in the Autumn print issue of I,Science, entitled “Spectrum”. However, due to an oversight, it is now being published as an online-exclusive feature