Hunting the Contergan-Crooks

7. June 2010
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For half a century scientists racked their brains why thalidomide teratogenic does what it does. Many studies and wrong tracks later it seems they found the solution to the question: What could have lead to those deformities after taking Contergan pills.

The story of the meteoric rise, the deep fall and the victims and perpetrators was made a film three years ago. In 2008 this production got the German TV Award and the “Goldene Kamera” (German Golden Camera Award), after it got the prestigious “Bambi”. The bad guys: A German pharmaceutical company. The victims: Newborns with crippled arms and legs. The leading actor: A drug named Contergan. The active ingredient: Thalidomide.

Fishing with magnetic nanoparticles

Until recently it was not yet clear – despite intensive tracing – how the perpetrator attacked his victims. How could it happen that the sedative for pregnant women highly praised in the beginning became a drug leaving about 10,000 handicapped children? 40 percent of the babies born with deformities died during the first year. A Japanese working group now seems to have gotten a whole lot closer to the reconstruction of the course of events. In animal tests, Hiroshi Handa at the Tokyo Institute of Technology and his team found out that the connection of thalidomide to cereblon, a protein rarely examined so far, causes limbs not to develop properly. Just as the manufacturer Grünenthal had to discover 50 years ago, toxicological tests with mice and rats don’t always allow reliable prognoses regarding the effect on humans. So Handa’s team decided for another animal model. Embryos of the zebra danio develop in a transparent cover thus showing according defects immediately. But at first, the scientists fished for the according binding partner with magnetic nanoparticles with thalidomide bound to their surface. “We were very surprised” stated Handa, after they isolated a protein from the cell extract in their test tubes which – up to now – seemed to play no relevant role in the development of embryos. Cereblon again binds a “ubiquitin-ligase“-complex with other proteins. Thalidomide deactivates this activity.

Cereblon: Necessary for intact extremities

In fact it shows that only the binding of thalidomide to cereblon initiates deformations of fins and legs in fish and chicken. A change in the cereblon DNA of zebra danios inhibits this reaction much longer – and thus saves the limbs of the embryos despite the admission of thalidomide. When the researchers built human cereblon with the homologous mutation into the birds, it also inhibited the deformities.

Contergan-children are born – until today

These realizations don’t only have a historic value concerning the clearing of the Contergan tragedy. They might also influence the “second” career of thalidomide.

1961 Contergan vanished from the market. But until today, many babies with deformities are born every year, thalidomide during the pregnancy is responsible for: Because only three years after being banned as a sleeping pill Jacob Sheskin discovered in a French hospital that a left-over batch of the drug was effective against Erythema Nodosum Leprosum (ENL), a painful companion of leprosy. Until today people suffering from that disease in developing countries get this effective active ingredient as a treatment. Everyone not being careful with her contraception or not knowing about the other fatal attributes of thalidomide damages her children – even decades after the first Contergan victims.

Thalidomide works similarly effective against multiplen myeloma, a non-Hodgkin lymphoma. Especially with this disease there are only few therapy options thus this active ingredient and its derivates has become one of the most important parts of treatment.

Part of the key found, but puzzle not solved

Over the past half of the century, about 2000 studies were targeted to solve the mystery of the mechanism. The results: About 30 different theories about the cause of the teratogenic effect. Only last year for example, Neil Vargesson from Aberdeen in Scotland published results in the renowned “PNAS”. According to his opinion the shortened limbs result from an angiogenesia-block of thalidomide.

But the binding to cereblon does not necessarily mean that the molecular basics of the Contergan catastrophe are fully clear as well. The results are a “key part” of this puzzle – as the New York Times quotes the molecular biologist Rolf Zeller at Basel University. “But it would be premature to consider the case closed.” Because the ‘why’ of thalidomide being effective during a small time frame of pregnancy and which role cereblon has in the development of organs is something, different laboratories are currently working on intensively.

Curse and blessing of thalidomide

A few days ago, an article was published in Nature Medicine which describes thalidomide as an effective remedy against hemorrhagic teleangiectasia an inherited disorder characterized by vascular malformations and recurrent nose bleeds, which are clinically difficult to treat. Here thalidomide appears to increase the level of platelet-derived growth factor (PDGF) and thus to rescue vessel wall defects.
Thalidomide modulates the immune defense, inhibits angiogenesis and produces active oxygen bindings in the metabolism. Individually and together those reactions cause relief for cancer patients and lepers and work even for a few autoimmune diseases. If we succeeded to stop the teratogenic effect of the active ingredient in pregnant women, the serial killer of mid last century would perhaps turn into a useful hero.

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Dr. Luzian Popoviciu
Dr. Luzian Popoviciu

Excellent article. Thaks a lot for that.

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