Thalidomide Tragedy DOXA

THALIDOMIDE TRAGEDY

By Doxa

Have you ever wondered how one of the best-selling drugs in the 1950s led to one of the largest medical disasters in the world?

Thalidomide was developed and produced by the German pharmaceutical company Chemie Grunenthal in the late 1950s. It was intended as a sedative and tranquilliser initially, but soon people found it useful in treating other conditions like cold, nausea and morning sickness in pregnant women (Science Museum, 2019). There were misleading advertisements such as, “Distaval can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or child”, which was claimed by The Distillers Company Ltd in the United Kingdom, though there was no evidence from studies in humans to support their statement (MedicalNewsToday, 2020) and there was a lack of drug trials on both humans and animals. Most importantly, there had been no tests on pregnant animals. Thalidomide was seen as a very safe drug where no prescription was needed, as it would not do any harm to humans and even pregnant women could take it. As a result, thousands of pregnant women purchased this popular drug, which was widely used in 46 countries while not knowing that it could be passed through the placental barrier and could possibly do harm to their developing foetus in the womb (Science Museum, 2019). Later, the next year, over 10,000 infants worldwide were born with severe birth defects such as brain damage and Phocomelia, with nearly 40% of the affected infants having passed away (PMC, 2011). This is the Thalidomide Tragedy; an event that caused the end of many infants’ lives. It was also the start of a change in both the way drugs are tested and peoples’ views on the importance of drug trials and drug development.

At that time, not knowing what had caused the tragedy to happen in the first place and having a lack of knowledge of Thalidomide, Dr. Widukind Lenz was the first researcher who noticed a link between this drug and the birth defects. He pointed out that the mothers who gave birth to babies with birth defects had all taken Thalidomide. He therefore carried out research and many investigations to study Thalidomide in order to prove his hypothesis. In fact, Thalidomide is a chiral molecule that exists as a pair of optical isomers; pairs of molecules that are non-superimposable mirrorimages (Kerboodle.com, 2022). Through the chromatographic separation technique, scientists suggested that Thalidomide is made up of enantiomers R and S, where enantiomer R is an effective sedative medication and enantiomer S is responsible for the

teratogenic side effects (Nature, 2018 and PubMed, 2022). They are extremely hard to separate and were supplied as a racemic mixture; a mixture of equal amounts of two optical isomers of a chiral compound (Kerboodle. com, 2022). Debates on whether this man-made disaster could have been prevented have always been a popular topic to research on. Some scientists suggested that if just the enantiomer R had been used or marketed, this tragedy could have been averted, while others argued that people would have ended up with some of the S enantiomers in their bodies even though only pure R enantiomer is used, as it will eventually be converted to S-thalidomide in the human body (Kerboodle. com, 2022 and Nature, 2018). Besides, working out whether Thalidomide plays a role in causing birth defects or understanding how Thalidomide causes birth defects is also important for improving the development of drugs in the future. Although the mechanism of Thalidomide activity has remained unknown (c&en, 2014), many hypotheses have been proposed by scientists to explain the molecular mechanism of Thalidomide, particularly regarding birth defects. For instance, Scientists Jürgen Knobloch and Ulrich Ruther have carried out an experiment on human skin cells and chick embryos to identify the mechanism of Thalidomide. They focused on two specific proteins which are responsible for cell division and differentiation of neighbouring cells. They are Bone Morphogenetic Protein (BMP) and Wnt Proteins respectively. In 1962 and 1963, three studies were published by Knobloch and Ruther. They noted that the chick embryos have similarities - limb truncations - to those seen in humans, and explained that BMPs are responsible for inducing apoptosis during embryonic development and will also occur when expression of a proapoptotic factor called Dickkopf1 (Dkk1) is promoted.

While in contrast, the Wnt pathway blocks the apoptotic pathway in order to protect cells from apoptosis. They also suggested that Thalidomide generates oxidative stress, which limits upregulation of the BMP signalling pathway and causes hyperexpression on Dkk1. This leads to downregulation of Wnt signalling pathway and hence, infants’ limbs cannot develop properly in the womb (Knobloch and Rüther, 2008 andAsu. edu, 2018).

In addition, a team of scientists led by Eric Fischer of Dana-Farber Cancer Institute, have later announced that they managed to collect evidence in their studies on identifying a potential binding target of the Thalidomide-Cereblon complex that might potentially contribute to the compound’s teratogenic actions after they have done a proteomics screen of human embryonic stem cells (c&en, 2018). They found that Thalidomide can directly bind with Cereblon, which is a highly conserved protein that forms a CRL4-type E3 ubiquitin ligase complex (CRL4CRBN) and plays a fundamental role in limb outgrowth. They suggested that Thalidomide initiates its teratogenic effects and promotes degradation of SALL4, a transcription factor when it binds to Cereblon in the human body. This mutation of SALL4 can cause Limb Deformities Syndrome, and strongly suggests how Thalidomide induces birth defects, though further investigation into the mechanism of Thalidomide is required. (c&en, 2018, eLife, 2018 and Nature, 2018).

Having spent five years finding the link between Thalidomide and the birth defects, alongside different investigations relating to Thalidomide being done by different scientists, Dr Widukind Lenz finally announced that there is a correlation between Thalidomide and birth defects, thus, Thalidomide was officially banned in 1961 (SciShow, 2017 and PMC, 2015). However back then, before carrying out any research on how Thalidomide could affect the developing foetus, the United States was in the process of having 2 million Thalidomide tablets ready to be marketed, and the drug was almost approved by the FDA (The New York Times, 2013). Fortunately, the tragedy was largely averted in the United States due to the straight continuous rejection made by the medical reviewer, Dr Frances Oldham Kelsey (FDA, 2019). Although Thalidomide had always been seen as a safe drug to take at that time, seemingly without any side effects, even in large quantities, Dr Kelsey recalled a study she performed on rabbits as a young post-doctoral pharmacologist at the University of Chicago. She had noted that there were differences between the ability to metabolise the drug by pregnant and embryonic rabbits, comparing to adult rabbits. Furthermore, she noted that the drug did pass through the placental barrier between the mother and the foetus (AMA Journal of Ethics, 2001). As a result, despite constant pressure from the company, she adamantly insisted to approve the application for Thalidomide because it lacked sufficient evidence of safety, through rigorous scientific studies and clinical trials. By refusing to compromise on exacting standards for patient safety, Dr Kelsey prevented a similar scale of tragedy from unfolding in the United States and saved thousands of children in the US, hence her remarkable achievement has been widely recognised and she was seen as the hero in American history (Washington post, 2015 and Smithsonian Magazine, 2017)

Now, even after the ban of Thalidomide, pharmacologists continued work on this drug and tried to create safer Thalidomide with fewer side effects, for instance, Lenalidomide and Pomalidomide (Kerboodle.com, 2022 and Mayo Clinic, 2021). Although Thalidomide does not appear to be useful for pregnant women, ongoing research has led the FDA to approve the use of Thalidomide for treating Leprosy. On the other hand, research has shown both Thalidomide and its immunomodulatory (IMiDs) analogs inhibit the cytokines tumour necrosis factors. It also noted that they co-stimulate primary human T lymphocytes inducing their proliferation, cytokine production and cytotoxic activity, which lead to an increase of the T cells anticancer activity (PubMed, 2005). Having indicated that Thalidomide has the activity of anticancer, it enhanced the process of approving the use of Thalidomide in the treatment for multiple myeloma. This not only brought medical research and drug development to a higher standard, but also allowed Thalidomide to be one of the potential treatments for treating cancer in the future.

In conclusion, Thalidomide has changed many people’s lives, however at the same time, it has played an important role in reminding us of the importance of drug trials and drug development in both the medical and pharmacology fields. It forced governments and medical authorities to change the way drugs are tested by tightening drug approval regulations as well as reviewing and reflecting on their pharmaceutical licensing policies regularly. These changes, as a result, could potentially save many more lives in the future.

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