Die Once Live Twice (32 page)

Danica was with him when Phil walked in, but he also had Katharine Hepburn on his arm. “Well, I’ll be damned,” Jonathan said out loud as he laughed. After the introductions, Phil explained that Miss Hepburn was in New York to promote Hollywood, after the success last year of
Sylvia Scarlett
with Cary Grant.

“Phil is my doctor and I just had to come along and meet this doctor who works on wonder drugs,” Hepburn said.

“Phil is every actress’s doctor,” Jonathan grinned at his friend. “Some things never change. Danica, I’m so glad you’ve come. I was hoping to see you.”

“He may be every actress’s doctor, but he is this actress’s lover,” Danica laughed, and gave Jonathan a big hug.

“Katharine has a friend with pneumonia,” Phil said as they sat down. “You’re the expert on sulfa, so I thought the two of you should meet.”

“Danica told me about your wife,” Hepburn said, “but I nonetheless wondered if it is worth a try for my friend.”

“I can only partially answer that,” Jonathan sighed. “I flew to Germany to thank Domagk for his discovery and to find out how it works. Flying in one of the new DC-3 planes, with those Pullmanlike beds, was something of an adventure in itself. Of course, the main point of my trip was to try and understand why sulfa didn’t work with Marion.”

Jonathan explained about the discovery of Prontosil. “The real medical breakthrough was the discovery that drugs that did not work in a test tube might work
in vivo
. In England and the United States it is heresy to test a drug in animals that didn’t work in a test tube, but in Germany, scientists test drugs in mice also. Prontosil didn’t work in a test tube. Sulphonamides had been tested in the United States and didn’t work in test tubes. But when Domagk injected hemolytic streptococci into mice, those that also received Prontosil lived. All the controls died. Presto! A true chemotherapeutic drug that stopped infection.”

Jonathan finished the story by explaining that French scientists showed that it worked in the body because the body metabolized the drug into a sulphonamide, which rendered bacteria helpless by neutralizing an enzyme needed for their life cycle. “But that phenomenon only occurs in the body. Phil, as important as this drug is to patients, more important is the revolution in thought to our profession. Now we know that drugs which can safely work in the body might be impotent in the test tube. It changes how we will study chemicals.” It also explained to Jonathan why all his studies with pyocyanase and molds in test tubes did not yield an effective drug, even though the pyocyanase worked in Anna’s body. It meant that sometimes chemotherapeutic drugs need the body’s chemical environment to work and that the ultimate test for a drug had to happen in a living animal.

“Why didn’t it work for your wife, doctor?” Katharine looked at Jonathan with sadness in her eyes.

“I’ve thought about that a lot, and discussed it with Domagk. Her infection may have already been too overwhelming for her body to overcome, even with the drug to help. But she had a few hours of improvement so I think the drug just wasn’t powerful enough to kill all the bacteria in her body. It is not the Holy Grail we in medicine seek.”

“What should Katharine’s friend with pneumonia do?” Danica asked.

“Try it. Always try. Domagk said sulfa is not much good against pneumococcal bacteria. Pneumonia is not called Death’s Captain for no reason.”

“I wish I were a man,” Hepburn said. “I would love to play the part of the Knight who finally discovers this Holy Grail drug you refer to and then kill the evil Captain of Death.”

“Katherine, sometimes your imagination runs wild,” Phil said with a wide grin. Becoming serious, Phil turned to Jonathan. “We doctors will never have dominance over disease without a powerful drug to kill infections. Every time we operate we are at the mercy of microbes we can’t even see. They can swarm like an army through our patient’s body and all our creative work is for naught. Anyone of any age with a weak host defense may not withstand an infection—if a patient has any debilitating disease the odds are strongly against them.”

Jonathan turned to Hepburn. “We can win battles, but not the war. People can live with confidence of longevity, and doctors will truly become meaningful, if we win this war.”

Chapter Thirty-two

J
onathan was roaming around the offices at Rockefeller Institute passing out Christmas presents the week before Christmas, 1939, when he received a call from Doctor Warren Weaver, director of the grants committee for Rockefeller Institute. He only sporadically worked in his office any more. The yellow fever vaccine was in the production phase. He visited Boston, occasionally, where Jackson was a twenty-year-old sophomore at Harvard Medical School. It pleased Jonathan that Jackson was so enamored by the profession. Almost as enamored as the nurses were with him! “Jonathan, good morning,” Weaver began. “I have a grant proposal we’re considering from Oxford, in England. I thought you might like to review it. They’re looking for a chemical that creates bacterial antagonism. One of their studies is with bacillus pyocyaneus. you worked with that bacteria, didn’t you?”

“One more dead end to spend money on, eh Warren?” Jonathan felt little interest in the offer. He had been excited and then deflated with these investigations for forty years.

“I have a hunch about this one, Jonathan. Oxford is no fly-by-night laboratory, and Howard Florey, the director, is an impressive scientist. I want you to fly over there and evaluate their proposal. If you are hopeful, we’ll fund them and you’ll be my liaison.”

Jonathan hesitated. Traveling was not as much fun at seventy-three years of age, especially on a wild goose chase, but—
What if this is the one I’ve been searching for and I missed it?

“Okay. I’ll go after the holidays. Jackson will be home for Christmas Day and Jimmy’s family is coming to New York. I want to take his children sightseeing—George is twelve, Julie is eleven, and Patricia is eight and it’s time they saw the city. They’ll be staying until after New Year’s. So I’ll talk to you again in January.”

Europe was at war, but Weaver was able to make arrangements for Jonathan to travel to England in February. At that time the war was confined to Russia fighting Finland. After another DC-3 flight to London, he drove to Oxford and after a morning nap spent the afternoon in Florey’s laboratory at the Sir William Dunn School of Pathology. Jonathan had met Florey when he spent 1925 as a Fellow at the Rockefeller Institute, the first Australian Jonathan had ever met, and he could not resist teasing the Rhodes Scholar.

“Howard, g’day, mate.”

“Jonathan, you just would never fit in in Adelaide.”

“Ah, but you’re bloody wrong. I like the wine country there!”

“We’ll drink some of that tonight when you are my guest at dinner. I’ll bring Ernest along.” Florey proceeded to brief Jonathan on the three projects he was seeking funds for. “Our interest is the biochemical reactions of the chemical toxins a few microorganisms secrete.” Three microorganisms were proposed for study of the organism’s toxin against bacteria, but the one they were working on now was penicillium notatum, because they had some of Fleming’s original mold at Oxford. Ernest Chain, the biochemist, was working with the penicillium mold juice and his assistant, Danny Heatley, grew the mold and harvested the mold juice which had the chemical that killed bacteria.

Alexander Fleming’s chance discovery in 1928 that the mold penicillium notatum killed
staphylococcus aureus
bacteria was well known. Penicillin spores somehow landed on an agar plate of staph bacteria in Fleming’s laboratory and he observed there were no bacteria growing near the mold. He salvaged the mold, identified it, and his laboratory nourished the mold so it was continuously viable. Fleming gave samples to other research laboratories including Oxford, but because his discovery had not occurred in the course of a scientific investigation, he wasn’t prepared to study it biochemically.

“When Ernest started evaluating it he became fascinated,” Florey said. “So we have not yet done any work with the two bacteria, pyocyaneus and subtilis. I am the pathologist, the biologist,” Florey said. “If we get a chemical which acts like a chemotherapeutic agent, I will test its biologic activity. But mostly I am the leader of the team.”

“We’ve both been at this a long time,” Jonathan said ruefully.

“You’re bloody right about that.”

“I injected pyocyanase into a young girl who had anthrax twentyfive years ago and saved her life. It was the moment I truly believed in bacterial antagonism, but I never could really verify the toxicity of pyocyanase.” Jonathan threw his hands in the air.

“Almorth Wright stymied those studies. He insisted that any substance that didn’t prove its worth in a test tube was illegitimate. He was a dictator so that dictum was law. Since Fleming was a microbiologist in Wright’s laboratory, at St. Mary’s Hospital in London, he certainly wouldn’t consider studying live animals. The scientific community, you included, were straitjacketed by Almorth’s principles.”

“I certainly felt like a lunatic at times,” Jonathan laughed. “If you find a viable antibiotic, you’ll inject the chemical into what? Mice? Guinea pigs?” The word antibiotic had just been coined by Selman Waxman, who was also studying bacterial antagonism using a different mold than penicillin and would eventually discover streptomycin.

“We’ll use mice too, like Domagk. Let me take you to Ernest and he can summarize our chemical studies for you. I think you will understand, from the complexity of our work, the reason I requested a grant.”

Jonathan was immediately attracted to Ernest Chain. Chain was a gregarious Russian-Jewish immigrant to Britain. Within an hour Jonathan knew he was one of those brilliant minds that change history. Chain sat down with Jonathan in the laboratory and told their story. After Fleming, those who studied penicillin gave up quickly because the chemical was so unstable it just disappeared when they tried to purify it out of the mold juice. Penicillin was dismissed as clinically useless and penicillin studies had been discontinued. Chain decided to characterize the chemical within the mold juice, find out its structure and nature.

“I was sure it was an enzyme because enzymes are unstable,” Chain said. “But I was wrong! When I filtered the chemical, the molecules passed through which meant it was not an enzyme. Enzymes’ molecules are too large to pass through the filter. It was a strange chemical of low molecular structure. Now I was hooked. I had to characterize this substance.”

Chain purified the chemical from the mold, but it was stable only in an alkaline medium and at a temperature of 0 degrees centigrade. Although he could prevent the chemical from disappearing in its liquid state, he could not form crystals from the ether the chemical was in. Finally he tried a new technique being used for blood. He freeze-dried the mixture and the chemical formed a dry brown powder.

“My God man, you’ve stabilized penicillin!” Jonathan exulted.
He has a genius that none of the other researchers had
, Jonathan thought. “If it’s not toxic, you’ve got the first biologic antibiotic. One microorganism killing another. Not an inert dye. Bacterial antagonism!”

“Easy now, Jonathan. We’re nearing the watershed moment, but all we have now is untested brown powder.”

“Yes, but....” This was the only time in history that an unstable chemical that was toxic to bacteria had ever been stabilized. Jonathan was more excited than he had been about anything—anything at all—since Marion died. “I am going to stay in England to see what happens.”

“Heatley is helping me collect enough powder—we only get a few milligrams every time. When we have enough we’ll test its antibacterial activity in the test tube to be sure we retained penicillin in the crystals, then inject it into mice to see if it kills them. If it kills them the chemical is worthless.”

At dinner that night, Jonathan presented Florey with a check. “This is a grant of $5,000, which will be given yearly, to your laboratory from the Rockefeller Foundation. We must see your investigation through!”

While the experiments in the Oxford lab became more and more important, the war was becoming dangerous for England. In March, 1940, the Germans invaded Norway and the Russians defeated Finland. British soldiers were in Norway fighting Germans. In the laboratory, the conversation was about the war every day, but the work was about testing brown powder. The first test was startling. The powder killed bacteria in a test tube at a dilution of one part of penicillin in a million parts of water. This was twenty times more powerful than sulfa. Chain became excited and he pushed Heatley to produce more powder for toxicity tests.

It seemed success in the laboratory paralleled success by the Germans in the war. By the end of April, the Germans had conquered Norway, and British troops retreated. There was no retreat in the laboratory. The brown powder crystals were dissolved in saline and injected into mice in an excessively large dose. The mice lived. Florey wanted the test repeated. Penicillin was beginning to be too good to be true. The mice lived again. Not only did the mice live, Jonathan observed, but their urine was brown. “Ernest, this is really important. The penicillin passed through the body’s organs and is excreted still in an active form. If it’s active in body fluids, then it’s a chemotherapeutic drug. An antibiotic
in vivo
!”

“Jonathan. Before you die of excitement—you are an old man you know—let’s do the real test.” Ernest said, teasing Jonathan. “Let’s infect some mice and see if the penicillin saves them.”

During the wet month of May, Jonathan could only reflect on the irony of the times. Britain’s politicians had sent their military to stop Germany’s attempt to rule the world, but in a small laboratory in Oxford, a university town at the edge of the idyllic countryside of the Cotswolds, a biologic war was being waged that would change the world. If Florey and Chain had indeed found the magic potion, every society would be healthier and life expectancy would rise. Elective surgery would become possible, viruses could be identified because antibiotics in the cultures would prevent bacterial overgrowth, and deaths from infection could be prevented. A blockbuster!
I suspect history will judge one war just as important as the other.