The name thalidomide still summons echoes of a nightmare.
The drug, given in the 1960s as a sedative and to help pregnant women overcome nausea, resulted in noticeable and often debilitating birth defects. Thousands of children were born without arms or legs. Some babies seemed to have flippers.
It's hard to believe it's the same medication that effectively treats leprosy and that shows great promise in treating arthritis, lupus, inflammatory bowel disease, some cancers, aspects of AIDS and even tuberculosis.
The positive effects of the drug are so numerous, in fact, that scientists around the world have dedicated entire careers to try to solve the mystery of how it creates birth defects. If they can understand that, they might find a way to stop that negative side effect.
Recently, an Idaho State University biologist, Trent D. Stephens, and graduate student Brad Fillmore announced that they have unlocked at least part of the mystery.
For more than two decades, Stephens viewed it as a "backburner project," an enigma he examined from time to time. Researchers had proposed 24 or so different possible mechanisms by which thalidomide caused birth defects. He looked at them and found nothing. About two years ago, he examined 10 new proposals. It was like going to a crime scene, he said, trying to reconstruct the destruction and its cause.
What Stephens and Fillmore found may not answer all the questions. But they found that several identified proteins had been inhibited by thalidomide in a developing embryo. And other researchers had discovered that thalidomide was capable of "intercalating" into DNA.
"That means that if you look at the helix and the bases which make the flat plates in the twisted ladder structure of DNA, you see that thalidomide is a flat plate and can slide right in between the rungs of that ladder."
Thalidomide and one of the four key building blocks of DNA, guanine, are nearly identical physically. The genes involved in limb development belong to a subset of only nine percent of all human genes that have a series of guanines. So when thalidomide jumps into the DNA, it attaches to guanine and blocks limb development.
That's why the drug only affects certain embryonic tissue.
"I use the analogy of an electrical circuit board. There are six toggles, all turned on for the gene to be expressed. And you can buy three different types of switches. The drug only interferes with the function of one of those switch types, but if you have this specific type of switch, it's like pouring molasses over the toggle switch. It gums it up so it won't work," Stephens said.
That's important because most of the world banned thalidomide around 1962. It had not even been FDA-approved in America — until recently. The process had begun, and no problems were expected in getting quick Food and Drug Administration approval. But the process was stopped when the link to birth defects was found. Still, Stephens said, it never completely went away around the world. Brazil, for example, never got rid of it. And to this day, children are born there with thalidomide birth defects.
By 1964, thalidomide was recognized as a powerful treatment for leprosy, a serious public health problem in many parts of the world. Internationally, about 90 percent of all the leprosy hospitals closed, eventually, because thalidomide worked.
Yes, the drug could be extremely dangerous. It was also very therapeutic. Stephens calls it a "monstrous wonder drug."
Study has shown the drug inhibits levels of a protein in the blood that is key in the body's inflammatory reaction.
And that could be very good news when it comes to treating certain medical conditions.
Thalidomide finally won FDA approval in 1998, but it is completely unique in the level of restrictions placed on its use, Stephens said. A prescribing physician, the patient and the pharmacist all have to be registered with the FDA and the drug manufacturer. There are strict contraception requirements to avoid pregnancy while using the drug.
Now Stephens' lab hopes to create a system to test thalidomide and its breakdown products individually and look at each step carefully.
If the drug — or something similar — can be engineered so it does not produce the serious birth defects, it could change the way diseases like rheumatoid arthritis and cancer are treated.