Finding out how to cause bacteria to dye

A new book by Thomas Hager titled "The Demon Under The Microscope" is reviewed in today's WSJ ("Medicine's First Miracle Drug" by Paul McHugh). It's a description of how the first miralce drug was discovered. All along I thought this was penicillin, but the drug here -- sulfa drugs -- actually came first.

From the the 1870s, thanks to the work of scientists Louis Pasteur, Joseph Lister and Robert Koch, the germ theory (that germs cause infections and disease) was becoming accepted, but nobody had a clue of how to prevent or stop germs. At the turn of the century, a German scientist named Paul Ehrlich "proposed that chemical compounds -- "magic bullets" -- must exist with a selective capacity to kill germs in the body. After all, he noted, certain dyes selectively stained bacteria. Why couldn't certain dyes be made to kill them, too?"

Then a group of German physician-scientists who believed in the truth of Ehrlich's theory, perhaps for lack of a better alternative theory, began working during the post-WWI period at the "dye conglomerate IG Farben."

Year after year the team infected mice with streptococci, the bacteria responsible for so many deadly infections in humans. The researchers then treated the mice with various dyes but had to watch as thousands upon thousands of them died despite such treatment. Nothing seemed to work. The 1920s turned into the '30s, and still Domagk and his team held to Ehrlich's idea. There was simply no better idea around.

Then one of the old hands at IG Farben mentioned that he could get dyes to stick to wool and to fade less by attaching molecular side-chains containing sulfur to them. Maybe what worked for wool would work for bacteria by making the dye adhere to the bacteria long enough to kill it.

Sulfanilamide, called sulfa by the chemists who synthesized it around 1900, sat on all dyers' shelves, the proprietary patents having long expired. In October 1932 Domagk began using dyes with sulfa attachments and promptly his mice began to survive -- indeed many started "jumping up and down very lively," he noted. At first the investigators couldn't believe the results. But repeated experiments showed again and again that sulfa-augmented dyes protected the mice from infection.

In February 1935, after a variety of trials on humans, Domagk announced to the medical world his discovery of the drug he called Prontosil. It was a common nitrogen-based azo dye with a sulfa side-chain, and it cured bacterial infections. The news spread quickly.

It's amazing that such a simple theory, that is not intuitive and certainly unconventional (even today people would find it hard to believe that a dye can kill bacteria), worked. What's even more amazing is the serendipity involved, for it wasn't the dye that did the deed.

The German scientists -- all of them Ehrlich disciples -- thought that the power to cure infection rested in the dye, with the sulfa side-chain merely holding the killer dye to the bacteria. The scientists at the Pasteur Institute, though, showed that the sulfa side-chain alone worked against infection just as well as the Prontosil compound. In fact, the dye fraction of the compound was useless. You could have Ehrlich's magic bullet without Ehrlich's big idea! This bombshell rendered the German patents worthless. The life-saver "drug" turned out to be a simple, unpatentable chemical available in bulk everywhere.

Still, the lesson of this story (as in so many, especially in medical science) is that being determined about and working hard for a goal may yield big results, even if it's not due to the belief you had behind the goal. "Gerhard Domagk was embarrassed that he missed the final analytic step, allowing the French to carry the day. But without his dedication to Ehrlich's idea, no one -- German or French -- would have used sulfa in a medicine, let alone fought infections with it. Domagk deservedly won the Nobel Prize in 1939."