Scientists have finally discovered why a drug that was commonly prescribed as a quick cure for morning left thousands of babies with major birth defects.
Thalidomide was once a household name, but in the 1950s and 1960s, many women lost their pregnancies or gave birth to babies with missing or malformed limbs after taking the drug.
For decades, no one knew why, but Dana Farber Cancer Institute scientists have discovered the drug interferes with transcription proteins that can shut off a gene crucial to limb development.
One woman all but single-handedly kept thalidomide from being approved by the Food and Drug Administration (FDA), drastically minimizing the drug’s effects in the US.
But some Americans were still affected, as were scores in the UK, the rest of Europe and elsewhere around the world.
The drug was re-purposed to treat certain cancers, leprosy and lupus and may be reformulated now that researchers understand what once went horribly wrong with it.
Globally, some 100,000 babies were born with missing, short, or twisted limbs due to a birth defect related to a once-common morning sickness drug and scientists finally know why. Butch Lumpkins (pictured) is one of the few Americans affected by thalidomide
Thalidomide first appeared in west Germany in 1957 where it was prescribed as a sort of cure-all for anxiety, insomnia, upset stomach and ‘tension.’
It soon found its niche in the treatment of morning sickness, especially nausea. It quickly became an over-the-counter staple.
But it took hardly any time at all for its dangers to become clear.
Almost as soon as the drug became widespread in West Germany, between 5,000 and 7,000 babies were born with malformed legs and arms, a condition called phocomelia.
James Smith of Pound, Virginia was born with malformed hands and does not have fully functional fingers because, he says, his mother took thalidomide as late as the 1970s
Elaine Dale (right) was born without arms after her mother took thalidomide. Her children, Sarah (left) and Philip (center) were not born with the same condition
Some had no arms or legs at all. Others had extremely shortened limbs, with misshapen hands or feet, or under-developed body parts that looked more like flippers.
Another 100,000 babies were born with the same condition around the world. Just 40 percent of the West German babies and 50 percent of those born in other countries survived.
In the UK, 2,000 so-called thalidomide babies were born between 1957 and the early 1960s.
Thousands of women lost their pregnancies in the late 1950s and early 1960s, a phenomenon also attributed to the drug.
The US Food and Drug Administration steadfastly refused to approve and allow the sale of thalidomide, which distributors applied for six times but were denied for not showing adequate evidence that it was effective and safe.
Frances Oldham Kelsey, the FDA regulator who oversaw thalidomide’s case and kept it off the market, has since been hailed as a ‘heroine.’
The morning sickness drug was sold as Tensival and Distaval in West Germany. Now it is used to treat leprosy and some cancers under tightly controlled conditions
Still, the drug’s US manufacturer, Richardson-Merrell, managed to push samples past Kelsey’s regulatory blockade to the public for testing purposes.
At least 17 babies were known to have been born in the US with thalidomide-related defects.
By 1962, the horrors caused by the drug were widely known and it began to disappear from the shelves.
Doctors discovered it had some effectiveness for treating leprosy and in the 1980s it was re-purposed to treat a form of cancer, called multiple myeloma, by stopping the growth of blood vessels to feed the tumors.
This discovery cast thalidomide in a new light, suggesting it could be a powerful tool in the fight against cancer, but its mysterious and gruesome birth defects have remained a barrier to its use and the development of more related drugs.
In recent years, Researchers at Dr Eric Fischer’s lab at the Dana Farber Cancer Institute have sought to start clearing that barrier.
His mother’s thalidomide use left Mat Fraser with shortened arms, but that did not stop him from going on to become a successful actor and musician in the UK
Georgina Harrison has similar defects to those her father was born with after his mother (Georgina’s grandmother) took thalidomide
They expanded on previous work, breaking down what exactly thalidomide does to genetic material.
A gene called SALL4 is instrumental to the development of limbs during gestation, as well as coding for a network of other traits.
Thalidomide, Dr Fischer’s lab and Harvard scientists discovered tampers with proteins that control the expression of certain genes, including SALL4.
Retrospectively, they found that people with known SALL4 deletions
In people who had not taken thalidomide, people who had a deletion of SALL4 had strikingly similar defects from
– unrelated to thalidomide – had birth defects almost identical to those of thalidomide babies.
That realization set them on their course of study, and led to the newly-published finding.
In Spain, victims of thalidomide including this woman, who cannot walk or fully use her hands, protested in 2015. Most o those affected by thalidomide were born in Europe
‘Understanding the targets will help to better understand [how thalidomide effects multiple genes] and may pave the way to new applications,’ Dr Fischer told Daily Mail Online.
Now that the scientists know the part of thalidomide that causes birth defects, they can begin to reformulate a similar drug that could have all of its same cancer-fighting benefits, without the deleterious effects, and Dr Fischer wants to lead the charge.
‘My lab is deeply invested in the development of novel therapeutic strategies that build on the same mechanism of action as thalidomide, what we call “targeted protein degradation.” We are pursuing many projects that aim at better understanding and derivatizing thalidomide,’ he said.