Modern Drug Discovery

Two stories, not one

In September 1928 Alexander Fleming came back from holiday to his laboratory at St Marys Hospital, Paddington, and noticed that a mould had landed on a plate of staphylococcus bacteria and that the bacteria around it had died. He identified it as Penicillium, named the juice penicillin, tested it on a few patients with surface infections, published a paper in 1929 and moved on, because he could not purify it and it seemed too unstable to be a drug. For ten years almost nobody read the paper. In 1938 Howard Florey and Ernst Chain at Oxford, working through old papers for substances that killed bacteria, found it. On 25 May 1940 they infected eight mice with streptococci and gave four of them penicillin; the four treated mice lived and the others died. On 12 February 1941 they treated a policeman, Albert Alexander, dying of an infection from a scratch; he recovered for five days and died when the penicillin, recycled from his own urine, ran out. Oxford was growing the mould in bedpans, milk churns and a bath, and Britain at war had no factory to spare. In July 1941 Florey and Norman Heatley flew to the United States. A government laboratory at Peoria found a better strain on a melon in a market and a way to grow it in deep tanks, and American companies took over: production went from 21 billion units in 1943 to 1,663 billion in 1944, enough to treat every Allied casualty on D-Day. Fleming, Florey and Chain shared the Nobel Prize in 1945. AQA calls this the discovery and the development, and the grade-9 habit is to keep them apart, because different factors drove each: chance and an individual found it, science and a team made it a drug, and war and government made it a product. After 1945 the pharmaceutical industry, the NHS and the failures, thalidomide and resistance, continue the same argument. This module gives you the two stories, the industry after them, and the shapes.

Five terms with their dates

Each definition carries the date and the figure that make it usable as evidence, and names the factor behind it, because the factor is what the AQA question is about.

The penicillin story in order

Put these six events in the order they happened.

• A mould kills bacteria on a plate in a Paddington laboratory
• Four of eight infected mice survive after treatment at Oxford
• A policeman recovers and then dies when the supply runs out
• Two of the Oxford team fly to the United States to find a manufacturer
• There is enough penicillin for every Allied casualty in the Normandy landings
• Three men share the Nobel Prize for Medicine

Why did it take sixteen years?

Penicillin was found in 1928 and available in quantity in 1944. Which explanation best accounts for the gap and for what closed it?

• Different factors governed each stage: chance and an observant individual found the mould in 1928, but Fleming was a bacteriologist without the chemistry to purify it or the funds to try, so the discovery sat in a journal; science and a team at Oxford with Rockefeller money turned it into a drug in 1940 and proved it on mice and a policeman; and it was war and government that made it a product, because Britain at war could spare no factory, the American government paid for the research at Peoria and directed the companies, and the need to treat wounded soldiers justified a cost no peacetime market would have borne. Without the war the drug would have come, but later and more slowly.
• Fleming was lazy and kept the discovery secret.
• Nobody was interested in curing infection until the war.
• The Americans discovered penicillin in 1943.

Which factor did what

The factors AQA names are war, superstition and religion, chance, government, communication, science and technology, and the role of the individual. The left column attaches each to the stage of the penicillin story it drove; the right column tests the same factor against what came after 1945, which is how a judgement across the whole key element is built.

Question 1: how useful is the source?

Source A: a description of a full-page advertisement placed by Schenley Laboratories, an American penicillin manufacturer, in Life magazine in August 1944. It shows a painting of an army medic on a battlefield injecting a wounded soldier while another soldier looks on. The headline reads: Thanks to penicillin, he will come home. The text beneath says that the yellow magic of penicillin is saving lives that would have been lost in any earlier war, that the company is producing it in enormous quantities for the armed forces, and that when victory comes it will be available to every doctor and hospital. AQA Question 1 asks: How useful is Source A to a historian studying the development of penicillin? Tap the TWO details that make it most useful for that enquiry.

• A private company is advertising that it produces penicillin in enormous quantities for the armed forces, which shows that by 1944 mass production had passed to American industry under military demand
• The picture is a painting rather than a photograph.
• The promise that after victory it will be available to every doctor and hospital, which shows the company preparing a civilian market and the expectation that a wartime drug would become an ordinary treatment
• It appeared in Life magazine.
• The text calls penicillin yellow magic.

After penicillin

Select the THREE statements that are accurate about treatment since 1945.

• The NHS from 1948 made prescribed drugs free at the point of use, which gave the pharmaceutical industry a market of the whole population and made the state the largest buyer of medicines in the country, with a prescription charge introduced in 1952 to contain the cost.
• Thalidomide, sold from 1958 and withdrawn in 1961 after causing severe malformations in around 2,000 British babies, led to the Committee on Safety of Drugs in 1963 and the Medicines Act of 1968, so that every new drug now has to be tested and licensed before sale.
• Resistant bacteria appeared within years of penicillin, MRSA was identified in 1961, no new class of antibiotic has reached patients since the 1980s, and a British government review in 2014 estimated 700,000 deaths a year worldwide from resistant infections.
• Antibiotics have cured all bacterial disease and resistance is not a problem.
• The NHS made patients pay the full price of every drug from 1948.
• New drugs can still be sold in Britain without testing.

Question 1: the usefulness method

AQA Question 1 on Paper 2 gives one source and asks how useful it is to a historian studying a stated enquiry, for 8 marks. The marks come from three things used together: content, what the source shows about the enquiry; provenance, who made it, when, for whom and why, and what that does to its value; and own knowledge, used to test what the source shows against what else is known. For the advertisement in Source A, the content shows a company producing penicillin in quantity for the army in 1944 and expecting a civilian market after the war. The provenance cuts both ways: it is an advertisement, made to sell the company to the public and to Congress, so its claims about saving lives are chosen for effect and it says nothing about Fleming, Oxford or the government laboratory that made the production possible; but that purpose is itself evidence, because a firm would not advertise a drug it was not making in bulk, and the date, two months after D-Day, is exactly when American output had reached the scale to supply every casualty. Own knowledge tests it: production did rise about eighty-fold between 1943 and 1944, the companies were working under government direction, and penicillin did reach British civilians through the NHS from 1948. This meant that the source is very useful for the role of war and industry in the development of penicillin, and useless for the discovery and the science, and a top-level answer says both and explains from the provenance why a piece of advertising can still be trusted for what it shows.

Four decisions, 1928 to 1943

Four moments in the penicillin story. Choose what was actually done at each, and notice which factor made the choice possible.

• September 1928. You are Fleming. The mould on your plate has killed the bacteria around it. You have tried the juice on a few surface infections with some success, but it loses its power within days and you cannot extract it. What do you do?
• February 1941. You are Florey at Oxford. Albert Alexander, a policeman with an infection spreading from a scratch, is dying. You have enough penicillin for a few days if you recover what passes through him. What do you do?
• June 1941. You are Florey. British firms are bombed, rationed and making explosives, and none will build a penicillin plant. What do you do?
• 1943. You sit on the American War Production Board. Companies are producing small amounts of penicillin for research and the army wants it in bulk for the invasion of Europe. What do you do?

From factor to outcome

Because a spore landed on a plate in 1928 and a trained eye noticed the clear ring around it, penicillin was found by _____. Because its finder could not purify it, the paper of 1929 waited nine years for a _____ at Oxford to read it. Because a team could do what one man could not, eight mice in May 1940 and a policeman in 1941 proved that it worked. Because Britain at war had no factory to spare, the mould was carried to _____, where a government laboratory and private firms multiplied output eighty times in a year. Because the _____ paid for prescriptions from 1948, the drug reached every patient in Britain and the industry that made it grew rich. And because bacteria mutate faster than laboratories find new drugs, _____ has become the problem that the discovery of 1928 left behind.

Eighty times in a year

American penicillin production was 21 billion units in 1943 and 1,663 billion units in 1944. To the nearest whole number, how many times larger was the 1944 figure?

Question 3: two similarities, marked

AQA Question 3 asks you to compare across periods, for 8 marks: Explain two ways in which the development of vaccination by Jenner and the development of penicillin were similar. Which answer reaches the top level?

• One similarity is that both began with an observation by an individual who could not explain it: Jenner noticed in the 1790s that milkmaids who had caught cowpox did not catch smallpox and tested it on James Phipps in 1796 without any idea of germs, and Fleming noticed in 1928 that a mould had killed the bacteria on his plate and published in 1929 without being able to purify it, so that in both cases the science that explained the discovery came later. A second similarity is that both depended on government to reach the population: Parliament gave Jenner 10,000 pounds in 1802 and made vaccination free in 1840 and compulsory in 1853, and the American government funded and directed the mass production of penicillin from 1943 while the NHS paid for it in Britain from 1948, because neither a country doctor nor an Oxford laboratory could supply a nation alone.
• Both were discovered by clever men.
• Vaccination prevents disease but penicillin cures it.
• Both involved chance, individuals, government, opposition, testing and fame.

Question 2: significance, marked

Question 2: Explain the significance of penicillin for the treatment of disease. At the time, penicillin was significant because it was the first drug that killed the bacteria behind the commonest killers, blood poisoning, pneumonia and infected wounds, without harming the patient. The Oxford trial of 25 May 1940 showed the four treated mice living and the four untreated dying, the policeman Albert Alexander showed in February 1941 that it worked in a human being and that quantity was the only obstacle, and by D-Day in June 1944 American production of 1,663 billion units a year meant that every Allied casualty could be treated; this meant that soldiers who would have died of infection in 1918 came home in 1945, and the death rate from pneumonia and from infected wounds fell sharply within a decade. In the longer term its significance was larger, because it created the model for modern treatment: the deliberate search for antibiotics that produced streptomycin against tuberculosis in 1943 and a dozen more by 1960, the pharmaceutical industry that grew from the companies which had learned deep fermentation in the war, and the expectation, met by the NHS from 1948, that a cure would exist and be paid for. The limit of the significance is twofold: penicillin does nothing against viruses, so that influenza, polio and HIV needed vaccines and different drugs, and bacteria began to resist it within years, so that MRSA appeared in 1961 and a review in 2014 counted 700,000 deaths a year from infections that antibiotics no longer cure. Penicillin matters most for having made infection curable for the first time in history, and for the warning, visible from the start, that the cure would not last unless it was guarded. What earned the marks: significance at the time with dates and figures; significance in the longer term, distinguished from the first and traced through industry and the NHS; the limit stated plainly with evidence; and a closing judgement on what it matters most for. That three-part shape, at the time, longer term, limit, is what the 8-mark significance question rewards.

Question 4: the factor judgement

Has the role of the individual been the main factor in the development of the treatment of disease since 1900? Explain your answer with reference to the role of the individual and other factors.

• Make the case for the individual with evidence: Fleming in 1928, Florey and Chain at Oxford, and what each contributed and could not do alone
• Set other factors against it: chance in the mould, war and government in the American production of 1943 to 1944, science and technology in deep fermentation and the drugs since, industry and the NHS after 1948

Question 4: the judgement, tested

A student has argued that the role of the individual was the main factor because Fleming discovered penicillin, Florey and Chain developed it, and all three won the Nobel Prize. Which is the strongest point to set AGAINST that judgement, in the way the top level of Question 4 requires?

• The individuals could discover but not deliver: Fleming published in 1929 and nothing happened for nine years because he lacked the chemistry and the money, Oxford could treat one policeman and not save him because it could grow the drug only in bedpans, and the drug reached patients only when the American government funded Peoria and directed the companies in 1943, multiplying output eighty-fold in a year for the army; since 1945 the pattern has hardened, with drugs found by teams screening thousands of compounds, tested for a decade under the Medicines Act, and paid for by the NHS, so that a judgement across the period should rank war, government and industry above the individual for the delivery of treatment, and keep the individual for the moment of discovery only.
• Fleming was a genius, so the individual must have been the main factor.
• No individual matters because science is done by everyone.
• Chance was the main factor because the mould blew in through a window.