Monday, 5 December 2016

Howard Florey and the dawn of Antibiotics

Howard Florey and the dawn of Antibiotics

I recently listened to a fascinating “Great Life”, that of Howard Florey, on BBC Radio 4.

Sir Richard Sykes championed Sir Howard Florey, a forgotten key figure in the story of penicillin.

Howard Walter Florey (1898 –1968) was an Australian pharmacologist and pathologist who shared the Nobel Prize in Physiology or Medicine in 1945 with Sir Ernst Boris Chain and Sir Alexander Fleming for his role in the development of penicillin.

I’d heard of Fleming, of course, and his accidental discovery is well know, as here explained by Dr Simon Torok:

“After World War I, Alexander Fleming was conducting an experiment with bacteria when a tear fell from his eye into a culture plate. He later noticed that a substance in his tear (which he named lysozyme) killed the bacteria, but was harmless to the body's white blood cells. Years later, Fleming was doing research on the flu when a similar coincidence occurred. While he was on holidays, a bit of mould had fallen into a discarded culture plate containing bacteria, forming a clear patch. When he returned he recognised this pattern from his previous experience with lysozyme. He concluded that the mould was producing an antibiotic substance and named the antibiotic penicillin, after the Penicillium mould that produced it.”

“His discovery was an amazing piece of luck. If Fleming hadn't left a petri dish of bacteria on his bench when he went on holidays; if he had properly disinfected the dish; if the weather had been different from the ideal conditions for bacteria and mould growth in the laboratory; and especially if Fleming hadn't the experience to recognise the importance of the observation, penicillin may not have been discovered as an antibiotic.” (1)

But Fleming wasn’t able to progress with his discovery and he left that on one side after writing up the report, and moved to other areas of interest..

Howard Florey had come over from Australia, where he assembled a team at Oxford doing research into what would be known as antibiotics. He was a great team builder, and also was good at listening to what his team told him. Chain had come over from Germany to provide biochemical support for the team.

“Florey gathered a team of scientists at Oxford University in Britain in the 1930s, when working together on scientific discoveries as a group was not at all common. Nowadays scientists work together all the time, but Florey realised that science had reached a point where a team of specialists was needed - the job was too big for one person.”

“His team commenced a careful investigation of the properties of anti-bacterial substances that are produced by mould. One member of the team, Ernst Chain, found an article about Alexander Fleming's work while flicking through a medical journal, and this prompted them to begin looking at penicillin.”

The key was to isolate the drug in a form in which it was usable for humans, something which Fleming had failed to do. And it really was a team effort:

“Individual members of the group concentrated their attention on areas in which they had the most knowledge, but they often met to exchange ideas. Chain worked on purifying penicillin with Edward Abraham. Norman Heatley improvised methods for extracting penicillin using ether and bedpans (see 'penicillin production' below). A. D. Gardner and Jena Orr-Ewing studied how penicillin reacted with other organisms. Howard Florey looked with Margaret Jennings at the impact of penicillin on animals.”

We live in a world now when drugs such as antibiotics are widespread, and it is hard to imagine that this shoestring operation, working on the smallest of budgets, managed to open up a whole new field of medicine.

What was it like before? Torok gives an example:

“How many times have you accidentally pricked your finger on a rose thorn, or perhaps a sewing needle? Nowadays, if the wound became infected you'd be cured almost immediately. But before the second half of this century, you could have been in big trouble. Infections were feared then as cancer is feared today. Your glands would swell up and require lancing to release the pus. A surgeon might even have to amputate your arm in an attempt to save your life. This was the nightmare of many infectious diseases before Howard Florey developed penicillin.”

I remember my mother was bitten by the neighbour’s cat. She washed the wound and thought nothing of it. Then her arm began to hurt; then it began to swell up, and it was a trip to casualty, where they diagnosed blood poisoning and immediately prescribed a course of antibiotics, and the swelling came down and she was fine.

Of course viruses do not respond to antibiotics, but a lot of infections do: these drugs save millions of lives every year. And while Fleming had the wit to realise what he had seen, and that it was important, it was Florey and his team which turned that into a reality.

Karl Popper used to mention critical experiments, but just as exciting as the discovery that General Relativity was right by photographing an eclipse, was the experiment Florey and his team made:

“In May, 1940 they performed one of the most important medical experiments in history. The work was so urgent that they came in to begin the experiment on the weekend, and on Saturday 25 May, Florey's team tested penicillin on eight mice injected with a lethal dose of streptococci bacteria. Four of the mice were treated with penicillin, while four were used as controls. By the next day, the treated mice had recovered and the untreated mice were dead.”

“In the early days of World War II, the lives of eight mice may seem insignificant. But their rescue by penicillin led to the treatment of Allied soldiers as early as D-Day, in June 1944, and probably influenced the outcome of the war.”

I realise that animal testing is an emotive subject, but I think these cases are ones where it is absolutely right. It is very different from cosmetics testing, which after all, when all is said and done, is a vanity project. This was a critical experiment to prove that they were correct.

“The results were so exciting Florey knew that it was time to test the drug on humans. The first patient in 1941 had been scratched by a rose thorn. Albert Alexander's whole face, eyes and scalp had swollen. He had already had an eye removed and abscesses drained; even his remaining eye had to be lanced to relieve the pain of the swelling. He was given penicillin, and within a day he began to recover.”

But as Chemical Heritage Foundation explains, the limited resources meant the test ended in failure:

“The policeman’s condition at first improved with the penicillin therapy and then relapsed. The penicillin supply had almost run out, and even retrieving penicillin from the man’s own urine (a commonly used procedure in the early clinical trials) failed to save him. Florey vowed that from then on he would always have enough penicillin to complete a treatment.”

Most British pharmaceutical companies were tied up with the war effort, so they had to go to the USA to find help:

“To increase penicillin supplies, Florey approached various British pharmaceutical firms, but only ICI considered itself in a position to accept the challenge (though many later joined the effort). British pharmaceutical firms were already committed to manufacturing other drugs needed for military and civilian populations, or, worse, their facilities had been devastated by enemy bombardment. To obtain the assistance of the United States, then still a noncombatant, in increasing production and furthering research, Florey and Heatley flew across the Atlantic in the beginning of July 1941.”

“Florey’s American connections served him well. The two English emissaries spent the Fourth of July weekend with a friend from his Rhodes year, who put Florey and Heatley in contact with the U.S. Department of Agriculture’s Northern Regional Research Laboratories (NRRL) in Peoria, Illinois, where large-scale fermentation processes were being actively studied. A. N. Richards, Florey’s old laboratory director at the University of Pennsylvania, had become chair of the Committee on Medical Research in the Office of Scientific Research and Development, which was organized to marshal the strength of the Allies. Because Richards knew Florey’s character, he decided to expedite unified action on penicillin on the basis of just one presentation.”

This meant that enough of the drug was produced to aid the war effort:

“In 1943 Florey travelled to North Africa to test the effects of penicillin on wounded soldiers. His trials were seen as a miracle. Instead of amputating wounded limbs or simply leave them to heal, he suggested soldiers' wounds be cleaned and sewn up, and that the patients then be given penicillin. Thanks to Florey and his team, the drug was available to treat Allied troops by the end of World War II. It has since revolutionised medical science, saving millions of lives.”

It is an amazing story, and one I was not aware of, only in the incomplete part which was that of Fleming. Florey and Chain both shared the Nobel prize for penicillin with Fleming, but it was Fleming whom the media latched onto, and Florey avoided media attention and even turned them away. And yet his was a truly great life.


No comments: