I like December. I like the changing weather, and the cold and frost (weird, I know – I just like being able to wrap up warm and go outside!), and the anticipation of Christmas. I like excuses to stay inside curled up with the cats. And, like many people, I like Christmas specials on the tv, and the promise of new series of things in January and February. While writing this year’s Christmas cards this week (possibly a little early, but when you have family overseas, needs must!), I have been rewatching the latest series of Call the Midwife. One of the things I love about Call the Midwife is that it does not shy away from some of the more challenging aspects of recent medical history – some of the issues faced with the early versions of the contraceptive pill, for example, or the beginnings of awareness among medical professionals in the UK of female genital mutilation (FGM), both of which were covered in the last series. A story which has been ongoing over the past two series of Call the Midwife – and which I hope we may hear a little more of in the future – concerns the drug thalidomide, and the problems it caused.

(R)-Thalidomide

A molecular model of (R)-Thalidomide, a drug which acted as a sedative, and also reduced nausea and vomitting.

Thalidomide was created by German company Chemie Grünenthal in the early 1950s. It was originally developed as a sleeping tablet, and in testing was found to have remarkably few side effects. In addition to this, it was almost impossible for it to cause a lethal overdose: it seemed like a wonderdrug to many. It was licensed for sale in the UK – over the counter, without the need for a prescription – in 1958 under the brand name Distaval, and the first babies in the UK affected by the drug were born the following year. Anecdotal evidence of a surge in birth defects also started appearing in 1959, however it wasn’t until the end of 1961 that the links were made and it was withdrawn from sale.

Thalidomide, we now know, inhibits the formation of blood vessels, and interferes with cellular messaging systems. This, combined with the rapid development and growth of an embryo as it becomes a fully-formed foetus, is where the problems lie. Many women were taking thalidomide in the early days of pregnancy to help with morning sickness, however this was when their babies were developing from a ball of cells into something resembling a tiny person. It is thought that it prevented the correct formation of blood vessels, and hindered any messages sent between groups of cells which in turn led to incorrect development.

S-Thalidomide teratogenic

(S)-Thalidomide, virtually identical to (R)-Thalidomide (see below for the explanation), caused babies to be born with serious deformities to their limbs and sometimes also other organs.

The main – and most recognisable – effect for the ‘thalidomide babies’, as they became known, was that their limbs failed to develop properly. Known as phocomelia, or ‘seal limbs’, the long bones in the arms/and or legs simply didn’t develop, leaving the babies with very short limbs, and in some cases no arms or legs at all, just feet sprouting directly from the hips and hands or even just fingers from the shoulders. Less obvious were problems with the development of the eyes or ears, and major internal organs. Tens of thousands of babies were born affected by thalidomide; of those born in the UK, around 550 survived longer than their first few months. There’s a word to describe drugs which have serious effects on unborn babies: teratogenic, literally monster-producing (Greek teratos ‘monster’ plus –genes ‘born of, produced by’).

(A lot of work on early prosthetic limbs for children was done as a result of the thalidomide disaster – the London Science Museum has several examples in its collection, for example these arms and these arms.)

Of course, these properties that make thalidomide dangerous to developing embryos are the very same properties now being harnessed as a treatment for cancer. Within the past decade, thalidomide has proven very effective in improving the outcomes of people with cancer of the bone marrow, especially multiple myeloma (a specific form of bone marrow cancer, where the cells grow and divide out of control). There is no cure for multiple myeloma, in part because the way it forms means it is inoperable as there is no specific tumour that can be removed, but thalidomide inhibits the cell growth to such an extent that it added an average of 18 months to the lives of elderly patients! Thalidomide is also finding uses in treating cancer tumours, inhibiting the growth of blood vessels in the tumour and thus preventing the tumour from growing. It is also being used to treat leprosy, a disease which is still a problem in Africa and South America; the discovery of its uses here began in a hospital in Jerusalem in the 1960s. Needless to say, in the UK it is only ever approved for use on a case-by-case basis, and patients have to sign to say they are aware of the effects it can have on an unborn child and that they will take all necessary measures to prevent becoming pregnant.

Chemically, thalidomide is quite an interesting compound, as it exists in two forms. These forms are identical to each other in every respect except one: they are mirror images of each other, just like your hands are mirror images of each other. The two mirror-image forms are called enantiomers. They arise because one of the carbon atoms has 4 different groups attached to it – we say it is chiral. (Isomers are compounds which have the same chemical formula but different arrangements of atoms. Stereoisomers have the atoms arranged in the same order, but the atoms physically occupy different positions in space. This can be because they are mirror images of each other, or because there is a double bond in the molecule.)

 

stereoisomers optical isomerism chiral carbon mirror images

A simple example showing the two mirror image molecules. You can build a similar pair of models yourself using marshmallows, cocktail sticks, and four different colours of sweets (fruit pastilles or jelly tots, for example). No matter how you rotate them, you cannot superimpose one on the other.

cis trans e z isomers stereoisomers isomerism double bond

Another example of stereoisomerism. The carbon-carbon double bond cannot rotate, so it makes a difference how the groups on ether side are oriented (see dotted lines).

 

R S isomerism stereoisomers chiral carbon thalidomide optical isomers

R- and S- Thalidomide. Look at the hydrogen near the middle nitrogen – on one diagram it is drawn with a wedge, showing that in 3D it would be coming out of the page towards you, while on the other it is drawn with a dashed line, showing that in 3D it is underneath. A very small different, but one of huge consequence.

Switching any two groups on a chiral carbon will lead to a pair of mirror image molecules. They are identical in every way, except you cannot superimpose one on top of the other. Chemists denote the difference between the two enantiomers with the prefixes (R)- and (S)-.*

(R)-thalidomide is a sedative and antiemetic (antiemetics are drugs which treat nausea and vomiting), while (S)-thalidomide is teratogenic. Sometimes, medicines which exist in enantiomeric forms can be successfully separated and used in the pure R or S form. In the case of thalidomide, it has been established that the two forms interconvert in the body, and so either form given pure leads to the effects of both. Hence, a lot of care is taken when prescribing thalidomide these days. (It is worth noting though, that less care is taken in developing countries, and new generations of thalidomide children are still being born.)

 

 

R-Thalidomide optical isomers stereoisomerism

Molecular models to show (R)-Thalidomide, which is a sedative and antiemetic.

(S)-Thalidomide optical isomers stereoisomerism

(S)-Thalidomide, on the other hand, is teratogenic. Look to the middle of the models to spot the tiny difference which had such drastic effects.

The case of thalidomide is unarguably a huge tragedy which could have been prevented. Thankfully though, lessons were learnt and changes were made. Drugs are regulated in every country by national authorities, and these had their powers greatly increased. A lot of changes were also made to the stages of testing drugs have to go through before they can be marketed.

  • Simulations are used, based on what we already know about how similar chemicals behave in the human body, and the drugs are tested on human cells in laboratories.
  • If the drugs pass the first stage (many don’t), they are then tested on animals. This testing is much more extensive than it used to be, and includes testing to see whether the drugs cross the placenta and the effects they have if they do.
  • If a drug passes through all the stages of testing on animals, it starts first trials in humans, generally on very small groups of healthy volunteers and purely to look for side effects.
  • If there are no issues, the clinical trials start to involve more people, and to look at whether the drug treats the condition it was developed for.
  • Only when it has passed through all of these stages can it be considered for approval, and even then there is still ‘post-marketing surveillance’, where people prescribed the drug are monitored by doctors, and there is a process for doctors to raise any concerns they or their patients may have.

Obviously this is a very lengthy process, and a lot of potential medicines fail at some point and are discarded. For this reason, drug development is hugely expensive and takes a very long time. During the ebola outbreak in 2014, vaccine trials were accelerated considerably to try and get an effective vaccine sorted and approved more quickly. It was decided that the risks to people of there being an issue with the vaccine, given the stages of testing it had already gone through, were lower than the risks of the disease. Drugs companies are also encouraged to test both enantiomers of compounds which are chiral separately, to ensure that there are no negative side effects or differences in efficacy of each form.

 

In the Classroom

Students are always fascinated by the effects of thalidomide, and there are lots of excellent pictures available online to illustrate this. There are so many ways it can be useful as well.

  • The ethics of testing on animals.
  • How drug development has changed, which can be tied into the more recent ebola outbreak as well – at what point should drug development be accelerated to try to combat a disease?
  • Biologial action of different molecules, and how the same property can be harmful in one situation and useful in another ((S)-Thalidomide and developing embryos vs cancer tumours); this could also be linked in to enzymes, specificity, and the lock-and-key idea.
  • Isomerism, something which students can find quite dry, and why it is important.
  • The interdependence of different branches of science (why chemistry is important for biology, and why drug development isn’t just about the molecules, for example).

 

*If you want to know more about how chemists determine which is the R form and which is the S form, look up the Cahn-Ingold-Prelog rules. Of course, chemists also use L- and D- to differentiate between enantiomers, which are assigned in a very different way…

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