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Did animal experiments delay the development of penicillin?

On Friday February 22, Good Morning Britain ran a piece on the use of dogs in medical research. In the studio was Professor Nic Wells from the Royal Veterinary College who explained how he uses dogs in his research. Opposing him in the studio was actor Peter Egan and anti-vivisection scientific advisor Andre Menache who was shown on a screen live from Paris.

Both Mr Egan and Dr Menache made a number of inaccurate claims in the interview and it’s important to understand how they might have come to make these claims. If you’re starting from a position of wanting to understand rather than dogmatically trying to prove a point the facts matter, even if they make for uncomfortable reading. Here we tackle some of their statements and see how their selective take on science history could lead them to suggest that animal experiments were bad for human health. So was penicillin really delayed for 10 years due to animal experiments? and was there any consensus in the past that diabetes was a liver disease?

Claim: Dog experiments on insulin led researchers to believe that diabetes was a disease of the liver

Where might this have come from?

Claude Bernard (the inventor of double-blind experiments) gave sweet milk soup to dogs then detected sugar in the veins that carry blood from the liver to the right atrium of the heart. In line with his ethos of avoiding assumptions, he then repeated the experiment with dogs fed only with meat but still detected sugar, leading him to conclude that the liver generates sugar. It may be that these experiments have been misunderstood as showing diabetes to be a liver-disease. As Bernard said,

“Normally there is always sugar in the blood of the heart and the liver. The sugar is formed by the liver; this is independent of the nutrition with sugar or carbohydrates.”

He was right – that sugar is called glycogen (he named it). He however made no assumptions about how various digestive processes fitted together, indeed, he is the father of not making such assumptions, an approach which led to his most important discoveries. Bernard himself performed numerous experiments to elucidate the functions of the pancreas, discovering for instance its role in processing fats. The timeline of discovery is recounted in the speech granting Banting and Macleod the 1923 Nobel Prize for Physiology.

Bernard was working primarily between 1848 and 1865, but it wasn’t until later that century, when scientists started systematically removing organs to study the effects of their absence, and testing the organ’s secretions, that the primary role of the pancreas in diabetes was confirmed. It had long been suspected by some, but many incorrect hypotheses were also entertained, such as the kidneys being key, which derived from human clinical observations. Although we can join the dots with hindsight, at the time and without proof it was impossible to tell which were correct.

The dog experiments of Joseph Von Mering  & Oskar Minkowski occurred in 1889 and settled the matter in the mind of most (but not all) scientists.  Insulin itself was hypothesized to exist before its successful isolation, following on from isolation of adrenalin and thyroxin, similarly secreted from the adrenal and thyroid glands.

Verdict:  False. The claim was not a majority view and in no way ‘held up’ science. In fact, performing the organ removal experiments earlier than 1889 would have brought greater certainty, although problems with the purification of insulin would still have led to a delay of decades.

Far from assuming the role of the liver in diabetes pathology, Claude Bernard literally invented the system by which facts are not assumed.

Claim: Penicillin was delayed by 10 years for human patients because it had no effect on rabbits

Where could this have come from?

Alexander Fleming noticed, quite by accident, that mould killed bacteria. He made a crude penicillin broth that he had extracted from the mould and demonstrated that it was non-toxic in animals at a certain dose. Based on these tests he then gave it to humans who also suffered no toxic effects. He conducted a range of tests using mice and rabbits, but also test tube samples. The mice and rabbits metabolised the broth quickly and it worked very slowly in the test tube, leading Fleming to conclude that it would only be powerful enough to be a surface antiseptic without purification. Perhaps this is the source of confusion?

Fleming tasked two of his students with producing more of the drug so there would be usable amounts and attempts would be made to purify it. He also sought out chemists who may help. However, Fleming was a famously poor communicator and struggled to convince chemists to purify his compound or the wider medical community of the benefit of his discovery. It wasn’t that he didn’t want to purify it, but that he tried and failed to find a chemist who would oblige him. He also never conducted tests on infected animals, which might have generated interest in its potential. 

Fleming and his student GG Paine continued to use it to treat humans with minor ailments like eye infections throughout the 1930s. Howard Florey and Ernst Chain, searching for potential antibiotics at Oxford University in 1940, also saw potential in a purified product and tasked their colleague Norman Heatley with creating it which he achieved using a byzantine setup involving bedpans, milk churns and bathtubs rigged together. Once created, they tested it on mice and found it protected them from infection at a non-toxic dose. 

Human trials of the purified drug started slowly with the treatment of Albert Alexander in 1941, who initially responded well until the limited supplies of penicillin ran out and he succumbed to infection.

The challenge of mass-producing this drug was daunting and Florey reached out to US drug companies. On March 14, 1942, the first patient was treated for streptococcal septicaemia with US-made penicillin produced by Merck & Co.Half of the total supply produced at the time was used just on that one patient. By June 1942, just enough US penicillin was available to treat ten survivors of a nightclub fire.In July 1943, its War Production Board drew up a plan for the mass distribution of penicillin stocks to Allied troops fighting in Europe.The results of fermentation research on corn steep liquor at the Northern Regional Research Laboratory at Peoria, Illinois, allowed the United States to produce 2.3 million doses in time for the invasion of Normandy in the spring of 1944. After a worldwide search in 1943, a mouldy cantaloupe in a Peoria, Illinois market had been found to contain the best strain of mould for production using the corn steep liquor process.

Pfizer scientist Jasper H. Kane first suggested using a deep-tank fermentation method for producing large quantities of pharmaceutical-grade penicillin. The successful development of a deep-tank fermentation plant by chemical engineer Margaret Hutchinson Rousseau eventually resulted in full-scale production. As a direct result of the war and the War Production Board, by June 1945, over 646 billion units per year were being produced.

Verdict: False. The inability of Fleming to purify his compound or find someone who could was the major cause of the delay. Once purified, animal tests demonstrated systemic protections and safe dosages and the application to humans of this stronger compound was started, as well as meeting the challenges of mass production.

Claim: 100 vaccines against HIV tested well in animals, including NHPs, zero worked for humans

Where could this have come from?

Many animal trials have shown varying degrees of efficacy. What has been attempted are not 100 ‘cures’ but 100 different approaches, where humans might be given a similar but not identical compound to protect against a similar but not identical virus. Most of the time this has not led to prevention of infection.

HIV has a number of complicating factors however, which make creating a prophylactic an uphill task. The first is that vaccines normally provoke a natural immune response by introducing a small amount of a pathogen with its wings clipped so it cannot fully take hold. In the case of HIV, a dead version of the virus doesn’t work so humans would have to volunteer to be infected with a low dose of the live virus in the hope their immune system develops a response to it and we can discover if there is an effective exposure for a vaccination effect to occur, or if we’ve just given someone incurable HIV.

The second is that HIV has many strains and evolves more all the time. As with the flu vaccine, you have to hope that your vaccine lines up with the strain you’re exposed to.

Despite all this, there is one vaccine regimen, RV 144, that has been shown to prevent HIV in some individuals in Thailand.

Verdict: Technically false but the premise is also misleading. There are no universal vaccines for HIV yet but there is one that offers limited protection and neither should anyone expect a universal one soon. The idea of miracle cures working in animal models then failing in humans mischaracterises the research. There are, of course, very effective treatments for HIV, developed using animal research, which allow it to be a long-term managed condition rather than a short-term death sentence. 

Claim: There is no peer-regulated oversight over these experiments

Where could this have come from? 

It is very hard to imagine where this might have come from. Every single experiment undergoes peer-regulated oversight in a number of different ways. Firstly an Animal Welfare and Ethical Review Bodymade up of peers and colleagues at the scientist’s own establishment determines whether or not an experiment can take place. On these sit scientists, animal care staff, vets and lay members of the public. The Home Officealso oversees each application as the UK enjoys both national and local ethical review. Finally, the work of the responsible government minister is advised by the Animals in Science Committee, which again has a range of members including, currently, a representative from PETA and one from the RSPCA. Beyond this, every experiment is published on the Home Office websitewritten in plain English and the UK has been inspecting animal experiments since 1876. In fact, the UAR office has all of the annual returns of animals used since 1876, including the animal experiments of Alexander Fleming described above.

Verdict: Totally false. In fact, the exact opposite is true.

Claim: According to the BMJ and the US FDA, no animal can predict how a drug or chemical will 

Where could this have come from:

They are both exaggerations of a misunderstanding. The British Medical Journal (BMJ) ran an editorialin 2014 which correctly asserted that poorly designed experiments led to bad results. However, it does not follow that well designed experiments give poor results. The editorial was not focussed on the concept of using animals, and it did not claim that animals cannot predict human responses. 

A director of the US food and Drug Administration (FDA) Mike Leavitt claimedin 2006 that “Currently, nine out of ten experimental drugs fail in clinical studies because we cannot accurately predict how they will behave in people based on laboratory and animal studies”. The misunderstanding in this case centres around how animals are used in drug development because they are very goodat detecting whether a new drug is toxic at the intended dose, but not as good at predicting whether a drug is effective. Leavitt is talking about the latter and of course mentions ‘laboratoryand animal experiments’ i.e. everything that is not a human trial including computer models and cell cultures. Leavitt’s comment is also not quite accurate since there are numerous reasons that drug development is abandoned. In 32% of cases it is because the company developing it rationalised their portfolio.  

Verdict: The British Medical Journal (BMJ) did contain an editorial raising concerns over the need for good experimental design. However, the BMJ at no point endorsed the idea that animals don’t predict human reactions. The Food and Drug Administration (FDA) in the US not only says that animals canpredict human reactions, but has entire websites dedicated to demonstrating how this works. The only possible derivation of this claim is such a well-worn myth it has been corrected numerous times, most recently in “Postcards from the post-fact front line

It is fair to say that none of the points presented as fact by activists on Good Morning Britain stand up to scrutiny.

 

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Last edited: 15 March 2019 10:36

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