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Penicillin

– in the House of Commons at 10:30 pm on 11th May 2009.

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Motion made, and Question proposed, That this House do now adjourn. —(Steve McCabe.)

Photo of Des Browne Des Browne Labour, Kilmarnock and Loudoun 10:31 pm, 11th May 2009

It is 80 years and one day precisely since Alexander Fleming's research paper "On the antibacterial action of cultures of a Penicillium" was submitted for publication in The British Journal of Experimental Pathology. In the paper he wrote:

"While working with staphylococcus variants a number of culture plates were set aside on the laboratory bench and examined from time to time. In the examinations these plates were necessarily exposed to the air and they became contaminated with various micro-organisms. It was noticed that around a large colony of a contaminating mould the staphylococcus colonies became transparent and were obviously undergoing lysis.

Subcultures of the mould were made...it was found that broth in which the mould had been grown....had acquired marked inhibitory, bactericidal and bacteriolytic properties to many of the more common pathogenic bacteria.

In the rest of this article allusion will be made to experiments with filtrates of broth cultures of this mould. For convenience and to avoid the repetition of the rather cumbersome phrase 'Mould broth filtrate' the name 'penicillin' will be used."

Thus was born the age of antibiotics, although it was to be many years before the first practical application in treatment of bacterial infection in humans, or indeed many years before the coining of the word "antibiotics". The history tells us much about the nature of scientific discovery, the development of treatments and some of the outside factors that can influence the direction of research, development and human benefit, both positively and negatively.

On 6 August 1881, Alexander Fleming was born at Lochfield farm, near Darvel, the youngest of eight children. He received his first schooling at Loudoun Moor school, went to the village school in Darvel at the age of 10, then two years later, continued his education at Kilmarnock academy. On 24 April this year, standing in the garden of the isolated Lochfield farm, now restored by Phillip and Heather Scott, surveying the landscape that the young Fleming had crossed daily just to get to the place of his early education, I sensed the determination to learn that must have driven him on.

On the same day, examining the contemporary Kilmarnock academy school register, preserved with other Fleming memorabilia by Carole Ford, the head teacher, and Stephen King, the school librarian and archivist, and noting just how many of Fleming's contemporaries died prematurely of infections, I got a sense of what may have motivated his zeal for fighting those very infections.

Any school that boasts two Nobel laureates merits a special word of public recognition. Kilmarnock academy is entitled to that boast, because of Alexander Fleming and John Boyd Orr, the Scottish teacher, doctor, biologist and politician. When Fleming was 14 he joined an elder brother in London, where after two more years of education he commenced work as a clerk in a shipping company. Four years later, a legacy enabled him to enter St. Mary's hospital medical school, Paddington, where he excelled in his studies and in numerous sports. He qualified in 1908 and, attracted by research work, entered the laboratories of Sir Almroth Wright at St. Mary's, working on the nature of immunity and the treatment of bacterial infection.

In 1909, the German chemist-physician Paul Ehrlich developed a chemical treatment for syphilis. He had tried hundreds of compounds, and the 666th worked. It was named salvarsan, which means "that which saves by arsenic". The only previous treatments for the disease had been so toxic as often to kill the patient. Ehrlich brought news of his treatment to London, where Fleming became one of very few physicians to administer salvarsan. He did so with the new and difficult technique of intravenous injection. He soon developed such a busy practice that he got the nickname "Private 606".

That was the beginning of the age of chemotherapy of infections, with the use of salvarsan, and the beginning of Fleming's long interest in the use of chemical antiseptics in the treatment of infections, and in ways of aiding the body's natural protective mechanisms against infection. During the first world war, Fleming served in the Royal Army Medical Corps, working in a laboratory in France to study the treatment of infected war wounds. In 1921, back at St. Mary's, he discovered lysozyme,

"a substance present in the tissues and secretions of the body which is rapidly capable of dissolving certain bacteria."

Like Fleming's discovery of penicillin, his discovery of lysozyme was the result of shrewd observation and the investigation of an unplanned event: he had a cold and observed that the drips from his nose caused lysis of bacteria where they were mixed on the culture plate. He long considered the discovery of lysozyme more important than that of penicillin.

In September 1928, Fleming discovered penicillin when he returned from a six-week holiday and observed the classic clearing or lysis of the bacterial colonies around the contaminating mould, later identified as penicillium notatum. The irony is that modern "good laboratory practice" would probably have dictated that the old culture plates would have been disposed of long since and not left lying around for the mould to grow. The discovery was made and Fleming is reported to have remarked of his observation, "That's funny."

Fleming was fortunate as a researcher to have had the freedom to follow up on the unexpected, and his classic 1929 paper includes an extensive study of the production of penicillin by the mould, and of its inhibitory effects against different species of bacteria. However, the crude penicillin was unstable, and Fleming's laboratory did not have the chemical expertise to purify it in its stable form for further study, so he was unable to pursue its development for clinical use. His later work with penicillin was mainly by using it for selective culture for the isolation of penicillin-insensitive bacteria for study.

Fleming provided samples of the mould to other laboratories, including the Sir William Dunn school of pathology at Oxford. There in 1939, Howard Florey, professor of pathology, and Ernst Chain, a biochemist and refugee from Nazi Germany, began their studies with the purely academic aims of discovering the chemical nature of penicillin and its mode of action. However, they quickly became aware of its clinical potential, and the onset of the second world war brought treatment of infected wounds back into high profile.

With the biochemist Norman Heatley, the Oxford team improvised equipment for bulk culture of the mould, and developed methods for the partial purification of penicillin. Fleming was involved in demonstrating the high potency of those penicillin preparations against cultured streptococcus and staphylococcus. By 1941, the Oxford team had purified penicillin to a stable enough form to use on a patient—an Oxford policeman dying of septicaemia. The patient improved markedly, but unfortunately the penicillin ran out, the infection strengthened and the poor man died.

However, by 1943, Fleming was able to use penicillin successfully to treat a girl with streptococcal meningitis; the rapid cure of an almost moribund patient led him to bring penicillin to the notice of the Government. That led to the setting up of the Penicillin Committee and the production of penicillin on an industrial scale, especially in the United States.

Fleming was elected a Fellow of the Royal Society in 1943, knighted in 1944, and shared the 1945 Nobel prize in physiology or medicine with Florey and Chain. In 1945, Fleming was elected the first president of the new Society for General Microbiology, which was formed to provide a common meeting ground for those interested in the study of microbes of all types—bacteria, fungi and viruses and others. The society's members came from all backgrounds, including medicine, veterinary medicine, agriculture, universities, research institutes and industry.

The society grew rapidly and still thrives today, with more than 5,000 members worldwide. Its main activities are publishing scientific journals, organising conferences, and supporting microbiology education. It is in that context that the society is sponsoring an event for school students in my constituency in November to emphasise the importance of Fleming's work in the discovery of penicillin, and how that led to an explosion in the discovery of antibiotics, which have brought tremendous benefits in terms of the control of human and animal disease. Over the years, antibiotics must have saved the lives of countless millions of human beings and animals. It is in that context that the society has offered to sponsor prizes for science in both Loudoun academy and Fleming's old school, Kilmarnock academy.

But what of the future? How secure are we in reliance on antibiotics? The next major step after the introduction of penicillin was the discovery of streptomycin in 1943 by Selman Waksman's group. He coined the term "antibiotic" for any substance produced by a micro-organism that interferes with the growth of other micro-organisms. Unlike penicillin, which is produced by a fungus, streptomycin was produced by a bacterium. In the 1950s and 1960s, many other antibacterial and anti-fungal agents were discovered in bacteria and fungi in the so-called golden age of antibiotic discovery. In the late 1960s, US Surgeon General William H. Stewart famously stated that we could

"close the book on infectious disease", and others said similar things. We now know that that is far from being the case for a number of reasons. For a start, he ignored virus diseases, which cannot be treated with antibiotics.

Although thousands of antibiotics have been discovered, and more than 100 are currently approved for medical use, they belong mainly to a rather small number of types of chemical structure, and the rate of discovery in the golden age was followed by decades in which far fewer useful natural products were discovered. In the 1990s, drug companies invested heavily in synthetic chemistry and robotic synthesis in attempts to develop "unnatural" new drugs, and in genome sequencing of pathogens to identify genes that encode proteins not present in human cells as possible targets for newly synthesised antibiotics. Those efforts have been disappointing, and have shown little success. It appears that naturally occurring antibiotics and the interactions with their targets have been highly refined in nature over millions of years of natural selection.

More recent methods of trying to create new types of antibiotics include the genetic manipulation of natural products by altering the biosynthetic "assembly line"; the first new products are entering clinical trials. Also, sequencing the genomes of some antibiotic-producing micro-organisms such as streptomyces has shown that there may be "sleeping" antibiotic genes, used only under special conditions infrequently encountered. However, the difficulties of commercial development of any new antibiotics are immense. First, they must be devoid of side effects, unlike new anti-cancer drugs, the drawbacks of which may be considered to be outweighed by benefits. The costs are enormous, and the end product may not be profitable. Many of the antibiotics launched in the 1940s simply would not have been brought to market in the present regulatory climate.

The pressing need for new antibiotics and more types of antibiotics is due to the development of antibiotic resistance in the target pathogens. Methicillin-resistant staphylococcus aureus and multi-drug-resistant human tuberculosis are only two of many examples. Bacteria have evolved over millions of years to survive the insults of their environments, and coping with the production of antibiotics by other micro-organisms has resulted in the evolution of antibiotic resistance mechanisms. Genes for antibiotic resistance have also undoubtedly been transferred between different types of bacteria in the process of horizontal gene transfer.

If we are to maintain and expand our ability to control disease, there is a need for continued research on the fundamental biology of pathogens and their interactions with the host, and on the development of new antibiotics. We could persuade the pharmaceutical industry back to the task by re-examining some of the commercial and regulatory caveats, and develop other mechanisms for disease control such as bacteriophage therapy. The legacy of Fleming and others was the golden age of antibiotic discovery, and all the countless benefits that it brought.

The possibility of a "post-antibiotic age", brought about by widespread antibiotic resistance in pathogenic bacteria, is scary. In the words of Roy Sleator, writing in the February edition of "Microbiology Today",

"the bugs are fighting back! Moreover, the super-bugs...appear to be winning."

G

Note Mr Des Browne's point right at the end of his speech:

"back to the task by re-examining some of the commercial and regulatory caveats, and develop other mechanisms for disease control such as BACTERIOPHAGE THERAPY".

This point was missed in the ministerial reply by Dawn Primarolo at http://www.theyworkforyou.com/debate/?id=2009-05-11b.660.0#c...

Please see this Review paper:

Górski A, Miedzybrodzki R, Borysowski J, Weber-Dabrowska B, Lobocka M, Fortuna W, Letkiewicz S, Zimecki M, Filby G (August 2009). "Bacteriophage therapy for the treatment of infections". Current Opinion in Investigational Drugs (London, England : 2000) 10 (8): 766–74. PMID 19649921.
http://www.ncbi.nlm.nih.gov/pubmed/19649921

Submitted by Grace Filby

Photo of Dawn Primarolo Dawn Primarolo Minister of State (Department of Health) (Public Health) 10:45 pm, 11th May 2009

I congratulate my right hon. Friend Des Browne on securing his brief debate, and on the eloquence and knowledge that he demonstrated in reflecting the huge achievements of Alexander Fleming's contribution to modern medicine. My right hon. Friend and his constituents are of course rightly proud of the fact that Alexander Fleming is one of their own, and my right hon. Friend is right to celebrate this landmark anniversary.

The events of 80 years ago are hugely significant, as my right hon. Friend demonstrated. They marked the start of a revolution in health care that no one at the time, least of all Sir Alexander Fleming, predicted. The story of penicillin's discovery is a remarkable one: an object lesson for all of us to be ready for the unexpected and to act with courage, determination and vision in seeing through the ideas that we believe in—even in the face of setbacks and disappointments. Indeed, there were some for Fleming.

Fleming's research, drawn from his observations of the way cultured mould attacked certain gram-positive bacteria, triggered a chain of events that involved an extraordinary combination of people and circumstances, and my right hon. Friend implored science and investment to build on them. Yet, as he knows and the House may be aware, we came dangerously close to losing the secret that Fleming's Petri dish had inadvertently unlocked. By 1932, Fleming had effectively abandoned his work on penicillin, believing that it would not survive long enough in the human body to kill bacteria.

It took a decade for penicillin to reach the people—perhaps the only people—capable of purifying it and doing the research that demonstrated, in record-breaking time, that it could cure deadly infections. That breakthrough ushered in the antibiotic era. Pneumonia, syphilis, gonorrhoea, diphtheria, scarlet fever and many wound and childbirth infections that killed indiscriminately suddenly became treatable. As my right hon. Friend said, millions of lives have been saved, including millions in the second world war. But, of course, penicillin was just the start. It was followed by the discovery and introduction of a steady stream of different antibiotics over the next 40 years. Those antibiotics transformed the treatment of classical infections such as meningitis and pneumonia, and invasive streptococcal infections, all of which previously carried a high mortality rate. They remain essential for modern medical practice, and, as my right hon. Friend said, it is difficult even now to comprehend the number of lives that have been saved.

The ability to treat infections and to provide antibiotic prophylaxis in surgery has unlocked other key developments in medical science. It has allowed huge advances in complex surgery, cancer therapy and transplantation, because, without those antibiotics, compromised and immuno-suppressed patients would quickly succumb to infections. The other striking fact about antibiotics is their unique status as a therapeutic agent. They are aimed at the bacteria not the patient, massively reducing the side effects that are associated with more aggressive drug treatments.

We have also come to recognise, however, that the effectiveness of the current generation of antibiotics is finite and self-limiting. Alexander Fleming was himself clear that bacteria had the ability to develop resistance—or, as my right hon. Friend said, to "fight back". The emergence of so-called superbugs such as MRSA in the past two decades has showed the potential for damage that over-reliance on antibiotic medicine can cause. The issue demands vigilance and action across the medical community.

It is absolutely imperative that while we rightly celebrate the landmark achievements made 80 years ago, we also look to the future to continue to promote the safe and proportionate use of antibiotics. We must also push the boundaries to ensure that Fleming's legacy lives on in the new forms of antibiotic treatment. As my right hon. Friend mentioned, the pharmaceutical companies, which have tended to cut back their antibiotic research programmes, have perhaps compounded the problem, creating some of the cycles that we now see. They need, with the Government, to build on the legacy now.

The new anti-infectives, which work well against MRSA, have come on stream in the past three years and research on other new anti-infective agents continues. Equally important is the emergence of novel approaches. That is the challenge that the international, big health research players in Government and industry face. We are playing our part as a Government. The Medical Research Council supports a substantial body of infection research and is currently spending £72 million a year on it. The United Kingdom clinical research collaboration has invested £16.5 million in its translational infection research initiative. That will help to boost research capacity and infrastructure and establish new career development and training programmes for scientists and researchers.

The Technology Strategy Board's new detection and identification of infectious agents platform will make £55 million available to encourage researchers to work together to produce faster diagnostic tests to identify infections in humans and animals. Like my right hon. Friend, I am utterly convinced that the potential for development of more traditional antibiotics has not been exhausted. It is absolutely vital to the future of medicine, health and humanity that we should continue to sow the seeds for future discoveries.

Vaccines, of course, play a huge part in our strategy for combating infections—prevention is better than cure—but we are a long way from removing the need for antibiotics. The basic researches and determinations of Alexander Fleming have profoundly shaped the development of medical science and treatment across all health care systems. It is right that we should be celebrating his life and contribution today. As my right hon. Friend implored, we should also recognise that just a fraction of the potential that Fleming identified has been exploited to date. There are new ideas and ways of operating and of treatment. The legacy is not only about the past standing us in good stead, but about the past still shaping our future. It gives me great pleasure to join my right hon. Friend in recognising the achievements of this great scientist and in making sure that we, as a Government, play our part in funding the great scientists who continue to build on that legacy.

Question put and agreed to.

House adjourned.

G

If only the Government had played its part in funding the great scientists who discovered bacteriophages. These ultra-microscopic entities which Mr Des Browne was referring to at the very end of his speech, destroy bacteria naturally. I think you will find that the current level of funding of bacteriophage therapy is extremely low (or even non-existent) as a proportion of the public money spent on infection research in the UK. The excellent human research initiatives I am aware of in the UK are privately funded.

Long before the golden age of antibiotics began, a contemporary of Fleming's was Dr F W Twort. Dr Twort had published his pioneering discovery back in December 1915 in The Lancet - nearly 100 years ago. In Twort's historic archives donated by the family to the Wellcome Trust for posterity, there is correspondence showing that bacteriophages were being used successfully for treating bacterial infections e.g. streptococcus viridans in endocarditis in 1931 and many other success stories, some of them on a large scale overseas. There is also correspondence between Fleming and Twort in London over several decades.

Yet, whereas antibiotics were soon receiving masses of media coverage worldwide, there was a neglect and 'cover-up' of bacteriophage science and therapy. Dr Twort's valiant efforts to raise the subject of the need for Government financial support with the Prime Minister, Parliament and the Establishment were thwarted over and over again. This noble doctor, professor, Fellow of the Royal Society and leading British microbiologist died in poverty and despair (1877-1950), his pioneering work and great vision largely ignored and so many opportunities lost. Yet now we know that bacteriophages have many immensely valuable applications in industry and medicine, in the environment and in bio-security - and indeed played a vital role in the discovery of DNA.

To give just one medical example: in 1961, movie star Elizabeth Taylor was given phages for staphylococcal pneumonia; 20 small vials were flown over specially from New York to the London Clinic to save her life. Yet some members of the press and scientific establishment did not publish that part of the story. Fortunately some diligent research in US publications has enabled the writing of a detailed account (see http://www.amazingphage.info).

Now in the 21st century we are only too well aware of the challenges of antibiotic resistance, allergies and the miserable adverse effects of antibiotics (sometimes fatal).

As well as celebrating the 80 years of undoubted achievement with antibiotics, I hope that the Dept of Health will now rise to these remaining challenges which cannot be ignored. Will our Ministers nobly accept their responsibility to put things right, and generously offer to fund British phage science in a spirit of international collaboration?

I hope that the great scientific institutions such as the Science Museum and the Wellcome Trust will now offer to enlighten the public about these opportunities for the future of science and medicine, perhaps as a start, alongside their prominent features on antibiotics. The educational examining boards could simply introduce bacteriophages and phage therapy into the GCSE curriculum. It is such an inspiring subject for science students, history students, art students and even maths students because they are so symmetrical and robotic in their shape yet of immense diversity in nature. As medicine, phages offer real hope to those whose infections have failed to respond to antibiotics.

Besides, research shows that it's much less expensive!

I agree with Mr Browne:

"back to the task by re-examining some of the commercial and regulatory caveats, and develop other mechanisms for disease control such as *bacteriophage* therapy."

Submitted by Grace Filby Read 3 more annotations