"The partisans have ampicillin". Really?

The Russian covert antibiotic program must have been hugely successful



In an effort to stave off the boredom that inevitably accompanies adjustment to a new environment, I was watching the WW2-era movie "Defiance" yesterday. The movie is based on an astounding true story about two Jewish brothers (played by Daniel Craig and Liev Schreiber) who hide and lead a band of Jewish refugees through the forests of Belorussia for two years and thwart the Nazis' plans for their extermination. Surviving on food killed and obtained in the jungle, defending themselves with stolen small firearms and occasionally seeking the help of partisans from the Red Army, the Bielski brothers and their group provide one of the most exemplary stories of resistance against the Nazis during the war.

So far so good, and the movie is not bad at all. But during one scene my ears suddenly perked up. There is a winter epidemic of typhus threatening to wipe out the population. A nurse tells Craig that the disease is spread by lice and without medical attention the patients will certainly die. To prevent this, she says, Craig and his group must borrow ampicillin from the Red Army. "The partisans have ampicillin", she says with hope and concern.

Which is all fine, except that ampicillin was not even known in 1942. It was introduced only in 1961. Even penicillin was a closely guarded secret in 1942. Plus I am not even sure if typhus is properly treated with beta-lactam antibiotics of the penicillin type.

I was further chagrined when in order to confirm this I visited the Wikipedia page on penicillin. While it otherwise looked ok, it also said that the first total synthesis of penicillin was achieved by the legendary chemist Robert Burns Woodward at Harvard. Again, not true. Woodward synthesized cephalosporin. It was John Sheehan from MIT who synthesized penicillin after a mammoth effort of 15 years. The error is now rectified.

Seems the directors of Defiance and the editors of the Wikipedia penicillin page have the same problem of fact-checking.

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 chemical linkage, but the benzene 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 cheap 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.

MORE IMPORTANT THAN THE BOMB

If you think the most important and key invention to come out of the war was the atomic bomb, think again.

Rudolf Peierls was an outstanding German physicist then living as an "enemy alien" emigre in England. He wanted to work on physics, but most of the physicists were then engaged in war work, and being an alien, he was barred from participating in this work. However, insiders knew his special abilities all too well, and Marc Oliphant, an Australian born British scientist, decided to invite Peierls to the University of Birmingham to work on 'pure' physics- microwaves. What possible war use could a discussion on microwaves have? But, as the war made clear, and as mathematician Stanislaw Ulam said later, it is revealing to say the least, what influence a group of people sitting at a table and scribbling on a piece of paper or a blackboard can have on world history. So it was with the men and women who discovered atomic energy, and so it was with Peierls and his microwaves.

The seemingly 'pure' discussion about microwaves that Peierls had with Oliphant resulted in possibly the most important secret of the war- Radar. For Peierls, a man who is not known outside select physics and history circles, this was a double crowning achievement. Because it was Peierls who worked on radar, and more importantly, supplied the first concrete proof of the feasibility of an atomic bomb.

This BBC article nicely and concisely documents the secret that saved England and possibly the world. The atomic bomb might have ended the war, but radar has the greatest claim to have shaped the war in a way that it could actually end in favour of the Allies. It was the everyday use of radar that dealt the decisive blow to the Luftwaffe. This remarkable invention, along with the German Enigma code-breaking efforts at Bletchley Park, was one of the best kept secrets of all time.

There is one more invention which was equally important in winning the war; penicllin. Its efficacy can be speculated from the fact that, because of it, half of the ten million soldiers who died in World War 2 could have been saved (all of them died from infection and not directly from wounds). Penicillin too, was a closely guarded secret, and the world can but be thankful to the unknown souls who toiled in secrecy on its production. Penicillin, code-breaking, radar, and the atomic bomb- four secrets that saved civilisation as we know it.