The first miracle drug

Some idiot on a bicycle slammed into me yesterday. Fortunately I did not break anything, but the bruises are giving me an ucomfortable time since then. After rinsing both knees with chlorhexidine and iodine, I was not concerned; if there was an infection, antibiotics would take care of it.

But it wouldn't have been that way seventy years ago, when the most you could do to prevent a wound from getting infected...was wait, and perhaps apply some crude remedies. That was how it had been for two hundred years. For all the progress we had made, bad bugs still mostly got the better of us. It is appalling that about fifty percent of deaths in WW1 were from infections that riddled shrapnel wounds, and not from explosives or gunfire themselves. Once infection set in and gas gangrene made its hideous appearance, all one could do was wait, and maybe hope that the suffering would end soon...until sulfa drugs appeared on the scene.

That era of sulfa drugs, and not the one of penicillin, was the first heroic age of antibiotics. Most of us, if asked to name the first wonder-drug antibiotic, would name penicillin. But long before penicillin, sulfa saved thousands of lives. Without sulfa around, Hoover's son died. With sulfa, FDR's son, and Winston Churchill, survived. Thomas Hager has done an excellent job in bringing this forgotten but extremely important story to life in "The Demon Under the Microscope". The former biographer of Linus Pauling has shown us how different it was to suddenly have a drug that cured infections that previously would have almost certainly killed you. The time until the 1930s was a scary time, with every kind of Strep and Staph waiting to kill you after entering your body through the slightest cut, and diseases whose names we don't even remember now were rampant and much feared. It was sulfa that first declared war on and largely eradicated all these infections.

At the center of the sulfa story is the remarkable doctor and biochemist Gerhard Domagk. Domagk was an officer in WW1 and saw thousands needlessly die around him in agony, all because nobody could prevent the infection that set in after they were hit. After the war, Domagk went through a succession of jobs and finally ended up at Bayer, where he had a trailblazing career in the discovery of new cures for old infections. Building upon Paul Ehrlich's convictions about azo dyes as bacteriocidal agents, he and his colleagues tested hundreds of analogs, until he hit on the right one. This was the beginning of SAR as we know it today. And here, we can see the chemist's tragedy. Domagk tested the compounds, but it were two chemists who actually made them. Yet, they were excluded from the prize that Domagk would gather. This was not his fault, but really the workings of the Swedish committee, which did not behave this way for the first and last time. Patriotic and yet conscientious, Domagk stayed put after Hitler came to power, losing himself in his work to distract himself from the injustice that was taking place around him. In 1939, he was awarded the Nobel prize, but the Nazis did not allow him to accept it. Bayer itself became connected with the notorious IG Farben, which designed hydrogen cyanide vials (Zyklon B) for the gas chambers.

There is much in the book that is eye-opening, and sulfa is only one chapter in a book that also deals with medical history and the social history of science. There were several things I was unaware of; one revelation was that the modern American university model is based on the German model. The Germans were the world leaders in both industry and academia, and the modern and highly successful trend of close collaboration between industry and academia was already widespread in Germany. For all their philosophical bent, the Germans never saw any contradiction between pure and applied research, and the university-industry collaboration and connection led to very fruitful research in engineering and medicine. The modern patent regime too was pioneered by German industry.

The most important fact which I was not aware of was the pivotal albeit unfortunate role that sulfa played in revitalizing the FDA and granting it powers to implement laws that made it mandatory for manufacturers to display warnings and ingredients labels on their products. Before that, almost anyone could set up shop and sell metals, elixirs, and liquids that promised cures for everything from syphilis to baldness, a practice that went back two hundred years. But in the 1930s, through a series of unfortunate events, a concoction of sulfa in, of all the things, ethylene glycol, was sold extensively in many states. Today, we would be horrified at such large-scale use of an industrial solvent for mixing a drug. But at the time, there were almost no laws that required manufacturers to list such petty things as solvents on their bottles. The FDA was a skimpy and ineffectual agency at the time, with a few dozen agents scuttling around to mainly keep a check on excessive profit making. After the sulfa-ethylene glycol concoction was sold, a wave of death began that did not stop until several hundred people died, and public outrage changed the face of the FDA- and the way in which drugs are developed, manufactured and sold in the US- forever. After the tragedy, the FDA acquired new powers that it could have only dreamt of before. Of course, it took the thalidomide tragedy to have the kind of strict FDA regime that we have today, but the sulfa tragedy started it all, and made drugs substantially safer for the public.

An amusing and ironic chemical fact also accompanies the discovery of sulfa. Even though it were the Germans who pioneered its development, it was a French group that discovered the most important fact about the drug; that it was not the azo linkage, but the aryl sulfonamide group that was key to the action of the drug. Once they discovered this fact, all bets were off for the Germans, because the potent part of sulfa turned out to be benzene sulfonamide, a bulk chemical that could not be patented! Even if the Germans tried to quickly get past this handicap by synthesizing new derivatives at a terrific pace to outnumber their French colleagues, the cat was out of the bag, and they could never top their initial success.

Gradually, sulfa made it everywhere, and into the United States through the perspicacity and interest of two Johns Hopkins researchers. It began to be marketed in every form and colour and flavour, as every derivative and analog. In the 1930s, it became the drug of choice for treating every imaginable kind of Strep or Staph infection, most of which it effectively tackled. Cure by sulfa was touted as a miracle cure, with its relentless and wondrous effect on cases that only ten years ago would have been totally hopeless. But as a drug, sulfa had already fallen behind. Penicillin had arived on the scene. In due course, resistance would develop to both drugs, albeit relatively gradually to sulfa.

Domagk spent the last days of his life in gloomy peace, distraught by his country's destruction, and somewhat validated by the thousands of lives he had saved. Sulfa is still used for topical purposes.

We now know that sulfa competes with PABA for the synthesis of dihydrofolate. Sulfa and further related research led to, among other things, Methotrexate, a widely used current drug in cancer therapy. But in the end, what befell sulfa has befallen other antibiotics. The bugs have become resistant. When sulfa and penicillin were discovered, they were regarded as miracles. Perhaps we need another miracle for bad bugs today, and the age of fervent antibiotic research might be coming back to haunt us. But it should not be forgotten that sulfa was the first miracle drug, before penicillin.