Thalidomide: The active substance in Contergan,
and its consequences
Thalidomide is the active substance in the drug Contergan, which was developed in our laboratories in 1954. The substance when taken during a certain period in pregnancy could cause deformities in unborn children known as the “Thalidomide babies”.
On this page, we provide an overview of the active substance. We explain exactly what Thalidomide is, how it was developed and how it acts in the body. We also address the question of how the medical product can cause deformities and why this was not discovered earlier. We will also provide a short overview of how Thalidomide is being used today.
Content
The chemical composition of Thalidomide
What are Thalidomide's side effects?
Thalidomide can cause deformities in unborn children
How modern science explains the action of Thalidomid
The species-specific action of Thalidomide
Polyneuritis: Thalidomide can damage nerves
Was Thalidomide developed during the Nazi era?
The chemical composition of Thalidomide
Thalidomide is a derivative of glutamic acid. It is a crystalline solid, easily soluble in water, with the structural formula C13H10N2O4.
The chemical bond in Thalidomide is chiral. That means it can come in two forms known as enantiomers. As was later discovered, one of these enantiomers is teratogenic and causes deformities in embryos.Later research has shown, however, that the two forms (enantiomers) convert into each other in the body within a few hours. Even if only the non-teratogenic form is administered, both forms are present again in the body within a few hours. In other words, the teratogenic effect of Thalidomide cannot be prevented by administering the non-teratogenic form.
How does Thalidomide work?
The active substance Thalidomide has many properties. Some of these properties are positive: Thalidomide has a sedative and sleep-triggering effect, and it also has anti-inflammatory properties and inhibits the growth of certain cancer cells.
When inventing Thalidomide in the 1950s, our researchers at the time found out that taking Thalidomide caused fatigue and sedation. They discovered that it was impossible to administer a lethal – and therefore fatal – dose. Since an overdose of all other sleep aids at that time could lead to death, Thalidomide was considered an important discovery.
How does Thalidomide trigger its sedative effect? Put simply, it appears to imitates one of the body's own messengers, which inhibits the transfer of information between nerve cells in the body. The brain therefore receives fewer signals, which has a relaxing and sleep-inducing effect on the body.1
Based on this effect, Thalidomide was used as the active substance in the medication Contergan, and similar drugs across the world. According to our information, the development and introduction of Contergan corresponded with the state of knowledge at that time and the applicable standards in the pharmaceutical industry.
What are Thalidomide’s side effects?
It has been discovered that the substance Thalidomide could cause severe side effects, including deformities known as “Thalidomide damages”. Below, we provide more precise information about the side effects of Thalidomide.Thalidomide can cause deformities in unborn children
If Thalidomide is taken during pregnancy between the 34th and 50th day following the first day of the last menstrual cycle, it leads to the deformities known as “Thalidomide damages”.
The Thalidomide damages include:
- Complete absence or shortening of arms and legs
- Deformities of the hands and feet
- Deformities of the hips, digestive tract and genitals
- Deformities or complete absence of the outer ear
How modern science explains the action of Thalidomide
The mechanism of action of Thalidomide, and thus the explanation of why these deformities occurred, remained unknown for decades. The basis for the clarification of the action was presented by the working teams of Takumi Ito and Hideki Ando from the Tokyo Institute of Technology, as well as by Yamaguchi at the Tokyo Medical University, among others, in 2010. 2 This knowledge was supplemented by various international research teams. New findings are being developed even today.3
According to the current state of knowledge, Thalidomide causes the deformities known as “Thalidomide damages” because, as a binding link, it bonds specific proteins in a child’s body that control, among other things, the formation of the extremities. This bond prevents a child’s body from being able to develop further.
Every cell in the human body contains proteins. 4 They serve as molecular “tools” and can carry out various actions, such as switching genes on and off, enabling cell movements, or acting as messengers.
Three types of proteins play a role in the mechanism of action of Thalidomide 5
- The protein cereblon can attract other proteins, almost like a magnet 6 These proteins are then “marked” by cereblon and broken down (destroyed)7
- The proteins Sall 4 and p63 are known as transcription factors. They can turn genes on and off like a switch. Sall 4 and p63 control growth, as well as the development of extremities and specific organs in a child's body.
The structures of cereblon and Sall 4 or p63 are so different that they do not fit together in their original states. They exist alongside each other. In this state, Sall 4 and p63 can stimulate the growth of extremities and control the formation of organs.
If Thalidomide is taken during a specific period in pregnancy, the active substance can reach the child’s body through the mother’s metabolism. Once it gets there, Thalidomide first docks to cereblon. At this point, a partially different novel structure is formed that can dock with Sall 4 and p63.
Thalidomide docks to the protein cereblon and can prevent the healthy development of the child.
As soon as Sall 4 and p63 dock to the cereblon-Thalidomide complex, cereblon can mark the two other proteins and thus signal to the body that they should be broken down. With the elimination of these two proteins, the signal that stimulates the growth of extremities and specific organs in the child’s body is also lost. Depending on when this mechanism is triggered, the child's extremities are not formed at all or are formed incompletely.
The video from the Dana Farber Cancer Institute explains the processes. However, the statement in the film that the medication was developed for morning sickness is inaccurate.
The species-specific action of Thalidomide
After Contergan was withdrawn from the market, researchers first attempted to prove the suspicion regarding the teratogenic effect in lab animals, using typical drug tests for that time, i.e. rats, rabbits and mice. The results were negative at first. This is because of the species-specific action of Thalidomide. The substance does not affect all animals, just certain species. Teratogenic effects in pregnant animals could therefore only be observed in 1962 (after the withdrawal) when Thalidomide was specifically tested on a certain breed of rabbit, the White New Zealand Rabbit (NZW).
Polyneuritis: Thalidomide can damage nerves
Thalidomide can cause polyneuritis, an inflammatory disease of the nervous system, in people who use the drug. Symptoms include a sensation of numbness in the tips of the fingers and feet. It can also be very painful. In the case of longer-lasting complaints, polyneuritis also leads to a change in the nerve tissue that can be demonstrated by pathology.
Was Thalidomide developed during the Nazi era?
Grünenthal strongly condemns the atrocities of the Nazi regime and has repeatedly engaged in initiatives against the radical right. As is the case for many other companies, however, people worked at Grünenthal in the post-war period who had previously held positions within the NSDAP [National Socialist German Workers' Party].
Some conspiracy theorists have concluded that Thalidomide was developed during the Nazi era by Nazi chemists and was tested on concentration camp prisoners as an antidote to chemical warfare agents. There is no dependable evidence for these speculations 8 We examine two repeatedly expressed theories in greater detail below:
- There is a rumour that Thalidomide was developed before 1954, in the era of the Third Reich. Original documents (Lab report of Keller, Lab report of Kunz) and witness testimony under oath of Grünenthal researchers Dr. Kunz and Dr. Keller in the Thalidomide trials9 prove, however, that the two scientists developed the active substance Thalidomide in the Grünenthal lab in 1954. The first patent was applied for in 1954.
- Even so, attempts are repeatedly made to create a link between the development of the active substance Thalidomide and the Nazi past of Dr. Otto Ambros, later a member of the Advisory Board. However, Dr. Ambros was never an employee of the Grünenthal company. He joined the Grünenthal Advisory Board in 1972, which is eleven years after Contergan was withdrawn from the market.
In a research report that appeared in 2016, historian Dr. Niklas Lenhard-Schramm was investigating a possible connection between Thalidomide and the Third Reich, as well as the plausibility of the theories presented. He came to the conclusion that the conspiracy theory allegations that Thalidomide had already been developed before 1954 lacked credible evidence.10
Was Thalidomide also sold in other countries?
After Contergan was put on the market in Germany in 1957, licensees and distribution partners gradually distributed Thalidomide-containing medications worldwide in many countries. The products were available on the market under different brand names, such as Distaval and Softenon.
In some countries like Spain, Italy, and Brazil, companies distributed medications with the active substance of Thalidomide without the participation or authorization of Grünenthal.
In the United States, Thalidomide was not sold because the FDA did not issue an approval to the drug.
Grünenthal stopped sales of its Thalidomide-containing products in November 1961 and informed its distribution partners and licensees in the respective countries in which they had distributed the medications.
Is Thalidomide still used today?
Research is still being conducted on Thalidomide. It was found that Thalidomide shows positive properties in severe diseases, such as leprosy, bone marrow cancer, and some autoimmune diseases.11,12,13
Our company no longer produces any Thalidomide-containing products. Thalidomide is, however, relatively easy to produce and is not subject to patent protection. Grünenthal has no connection to third parties who offer Thalidomide-containing products. Of course, science, industry, and regulatory authorities now know about the serious side effects Thalidomide can produce. The manufacture and use of the active substance are therefore subject to strict regulations. The product may be prescribed and dispensed only in accordance with a special programme to prevent deformities in unborn children.14
1 https://www.netdoktor.de/medikamente/thalidomid/
2 Takumi Ito, Hideki Ando et al (2010): “Identification of a Primary Target of Thalidomide Teratogenicity”, in: Science (327 / 5971), pages1345-1350, available at https://science.sciencemag.org/content/327/5971/1345.
3Tomoko Asatsuma-Okumura, Hideki AndoNature et al (2019): “p63 is a cereblon substrate involved in Thalidomide teratogenicity”, in: Nature Chemical Biology (15), pages 1077–1084, available at https://www.nature.com/articles/s41589-019-0366-7.
4 A protein is a biological macromolecule that can contain several hundred amino acids, which are joined together by peptide bonds. Cereblon contains around 440 amino acids, for example.
5 The p63 proteins are ∆Np63α and TAp63α. The breakdown of the protein ∆Np63α causes damage to the extremities, while the breakdown of the protein TAp63α is responsible for damage to the ears. (Nature Chemical BIOLOGY | VOL 15 | NOVEMBER 2019 | 1077–1084
6 Cereblon acts as a substrate receptor within the E3-ubiquitin-ligase family.
7 Cereblon is part of the E3-ubiquitin family. Every E3-ubiquitin-ligase can mark certain proteins with ubiquitin, which signalises to the cells that these marked protein should be broken down or destroyed. This marks proteins that contain errors or that have changed. This mechanism manages the life cycle of proteins in this way.
8 Niklas Lenhard-Schramm (2016): „Die Haltung des Landes Nordrhein-Westfalen zu Contergan und den Folgen“, research paper from the WWU Münster for the Ministry for Health, Emancipation, Care and Ageing of the German State of North-Rhine Westphalia page 26f.
9 Dagmar and Karl-Heinz Wenzel (1968): „Bericht und Protokollauszüge vom 51.-100. Verhandlungstag“, in: Der Conterganprozess (II); Keller page 56ff, Kunz page 71ff.
10 Niklas Lenhard-Schramm (2016): „Die Haltung des Landes Nordrhein-Westfalen zu Contergan und den Folgen“, research paper for the WWU Münster for the Ministry for Health, Emancipation, Care and Ageing of the German State of North-Rhine Westphalia, page 26f.
11 https://www.emedicinehealth.com/drug-thalidomide/article_em.htm
12 David Millrine, Tadamitsu Kishimoto (2017): “A Brighter Side to Thalidomide: Its Potential Use in Immunological Disorders”, in: Trends in Molecular Medicine, (23 / 4), page 348 ff, available at https://www.cell.com/trends/molecular-medicine/pdf/S1471-4914(17)30025-4.pdf
13 https://www.netdoktor.de/medikamente/thalidomid
14 https://www.ema.europa.eu/en/medicines/human/EPAR/thalidomide-celgenehttps://www.ema.europa.eu/en/documents/overview/thalidomide-celgene-epar-medicine-overview_de.pdf
