Thalidomide
Article curated by Rowena Fletcher-Wood
In 1953, thalidomide was prescribed for morning sickness, but then over 10,000 babies were born with deformities. The molecule, it turns out, is handed, which means it comes in right-handed and left-handed versions, and the left-handed version appears to be responsible for birth defects.
Scientists first suspected only one form of thalidomide caused defects because many naturally occurring biological molecules such as proteins and sugars are left-handed only – although we don’t know why. Some scientists believe that the bias towards one chirality or the other is purely random. Other scientists, who subscribe to the theory that life on Earth was seeded from outer space, have proposed that polarized radiation bombarded the asteroids that brought the building blocks of life. In tandem, the body has developed key enzymes and receptors that only fit left-handed sugars and amino acids. Right-handed versions either do nothing – simply diluting the effect of the left-handed molecules, or they do something different… and that could be anything. We don’t know, and we don’t know how to predict where they might bind or react in the body!
2How does thalidomide cause birth defects?
In 1953, thalidomide was prescribed for morning sickness, but then over 10,000 babies were born with deformities.
There are more than 30 proposed mechanisms for how thalidomide caused these birth defects, and in fact, it looks like more than one could be true. Mechanisms include causing mutations in DNA and cartilage, interfering with neural networks, generating reactive oxygen species (which accelerate cell ageing in the body), and inhibiting some proteins[1]. It is also antiangiogenetic, which means it stops the development of new blood cells – exactly what happens when the placenta is forming between 6 and 12 weeks of pregnancy.
We do know that thalidomide binds to a target protein called cereblon, and it was this binding that eventually led scientists to prove only left-handed thalidomide caused birth defects: because they bind differently: x-rays and electron mapping showed the left-handed version binds easily, but the right-handed version is twisted and easily falls off.
To perform these experiments, scientists doped thalidomide with deuterium to stop them from interconverting[2].
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However, scientists still can’t say for certain whether right-handed thalidomide is safe. Not only does it interconvert with left-handed thalidomide, but it breaks down in the body – either by metabolism or by hydrolysis – and some of the products of these reactions are also thought to be dangerous[2].
2Can thalidomide cause autism, dyslexia, epilepsy?
The birth defects of thalidomide were first observed statistically – because 20% of “thalidomide babies” had deformities, rather than 1.5%. However, years later, higher than usual rates of dyslexia, autism, or epilepsy were also observed. Medical professionals think that thalidomide taken later in pregnancy may cause brain damage, and these conditions could also be associated with late pregnancy consumption.
Why timing effects the kinds of birth defects caused by thalidomide, we don’t know, but it does. If taken very early in pregnancy, it seems to cause miscarriage; if taken between 20 and 36 days post ovulation (3-7 weeks, when morning sickness is most common), it causes physical deformities and, if taken after that, brain damage.
Could thalidomide cure HIV?
New research on thalidomide has shown it to be anti-inflammatory, an immunomodulator, and an inhibitor of angiogenesis. As such, it’s been used successfully to treat skin conditions including leprosy, Behçet’s syndrome, lupus, and graft-versus-host disease, to shrink blood and bone cancers, and is being trialled on HIV patients – could thalidomide be a potential treatment for this disease?
It may have a terrible past, but this molecule could have a better future.
This article was written by the Things We Don’t Know editorial team, with contributions from Freya Leask, and Rowena Fletcher-Wood.
This article was first published on 2022-02-24 and was last updated on 2022-02-24.
References
why don’t all references have links?
[1] Vargesson, N., 2015. Thalidomide‐induced teratogenesis: History and mechanisms. Birth Defects Research Part C: Embryo Today: Reviews, 105(2), pp.140-156.
[2] Mori, T., Ito, T., Liu, S., Ando, H., Sakamoto, S., Yamaguchi, Y., Tokunaga, E., Shibata, N., Handa, H. and Hakoshima, T., 2018. Structural basis of thalidomide enantiomer binding to cereblon. Scientific reports, 8(1), p.1294.
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