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Q: Didn't penicillin come from animal experimentation?

A: The fact is that animal tests sidetracked development of this important drug.

In his critique of the Greek’s fist book Dr. Michael Festing stated:

On page 73 of their book, the Greeks claim that animal testing delayed the introduction of penicillin, because Fleming used it on a rabbit and it did not work. Given that he was unable to purify the penicillin; that the use of a rabbit is not mentioned by Hare; that had Fleming had some pure penicillin, there were patients he could have tried it on; that mice would have been the natural choice of test animal, because of their small body size; and that the only references to the use of a rabbit are from anti-vivisectionist literature, I doubt whether this is true. The Greeks go on to claim that "He later had a very sick patient, and since he had nothing else to try, administered penicillin. The rest is history." In fact, Florey gave Fleming the purified penicillin. The vital part played by Chain and Florey in isolating it, proving it by using mice, and developing it, is largely ignored in their book.

The Greeks’ response is below:

There are as many stories about how penicillin came to be as there people who have written them. The hows and whys of the discovery and development of penicillin are a hotly debated story. Such is true of most medical and scientific discoveries of the past. There are some details, however, that seem to be factual:

1. Fleming re-discovered penicillin.

2. He then tested it in vitro and in vivo on rabbits and mice (he mentions the rabbits in his original paper). The in vitro results showed promise, as did topical application on rabbits. But when given systemically, the rabbits metabolized it too rapidly and led Fleming to believe it would be useless for humans when administered systemically.

3. Fleming continued to grow penicillin and even administered it to humans prior to the 1940s. Through a student of his, G. G. Paine, Fleming gave it to 4 humans suffering from ophthalmic neonatorium, 3 of whom responded well.ⁱ

4. Florey and Chain conducted research with penicillin and produced a purified product using basic chemistry.

5. The purified product was tested on mice and on more humans, all of whom did well.

6. Publicity surrounding Fleming’s patient led to funding to develop the drug. Fleming went down in history, rightly or wrongly, as the person responsible for penicillin.

We did not claim, nor did we pretend, to give the definitive historical account. Rather, we simply presented what seems clear: that regardless of how one views the history of penicillin, species differences resulted in one species leading researchers down the wrong path while another species resulted in the opposite. This draws into question the notion of trans-species extrapolation.

Under certain circumstances, penicillin kills guinea pigs and Syrian hamsters. In addition, penicillin is teratogenic in rats, causing limb malformations in offspring. Dr. Festing has derided us for ignoring certain facts. We have explained why we did not mention them: they were not relevant to our point about species differences.

The questions we want answered are: Why do Dr. Festing and others, who give unqualified support to animal experimentation, ignore the facts above? And why do these same people ignore the fact that H. W. Florey, co-winner of the Nobel Prize for penicillin, administered penicillin to a sick cat at the same time Fleming was giving it to his sick human? Florey's cat died. Who should Florey have believed, the dead cat, the rabbit, or the mice on which it worked? Neither do these individuals address the quote attributed to Fleming by his student, “How fortunate we didn't have these animal tests in the 1940s, for penicillin would probably never have been granted a license, and possibly the whole field of antibiotics might never have been realized.”ⁱⁱ They also ignore the statements of Macfarlane, another early penicillin researcher, who emphasized species differences when he stated: “Mice were used in the initial toxicity tests because of their small size, but what a lucky chance it was, for in this respect man is like the mouse and not the guinea-pig. If we had used guinea-pigs exclusively we should have said that penicillin was toxic, and we probably should not have proceeded to try and overcome the difficulties of producing the substance for trial in man.”ⁱⁱⁱ

With regard to the role of cats and rabbits: V. D. Allison (a student, lab worker, and protégé of Fleming’s), wrote in The Ulster Medical Journal in 1974:

Subsequent events are well known—the short life of the mold extract, its lack of damage to blood cells and tissues, its ability to cure certain infections in rabbits, and topically in the human eye and skin infections….

He [Florey] asked Fleming not to use it (the penicillin) until he (Florey) had injected some into the spinal canal of a cat to see if it was innocuous. However the patient was moribund with all hope given up, so Fleming decided to inject the crude penicillin into the patient’s spinal canal on the evening he received it. Fleming slept at the hospital that night and early next morning, Florey phoned Fleming and told him the cat had died. [Fleming’s patient made a complete recovery because of the penicillin.]^iv

Alison also mentions that the only disagreement Almroth Wright and Fleming ever had was over a statement that Fleming wanted to include in his original paper stating that penicillin may be useful for infections in humans. The statement was left out because of Wright.

Francis Diggins, another of Fleming’s associates, wrote to us:

Hello, nice to hear from you! Yes, he tested the crude broth extract on rabbits and mice. These were described in his original paper, sent to the British Journal of Exp. Path. on 10 May, 1929 and published in June 1929. Ref: Fleming A, Brit J Exp Path., 10 : 226, 1929. I have not got a copy of it (although I have almost every book published on the discovery, many of them with rubbish in them!) but you will find quotes from it in the book by Ronald Hare, "The Birth of Penicillin", George Allen & Unwin, 1970, p 90. "Twenty cc. injected intravenously into a rabbit were not more toxic than the same quantity of broth". Also "Half a cc. injected intraperitoneally into a mouse weighing about 20gm. induced no toxic symptoms".^v

Allen B. Weisse, Professor of Medicine at the University of Medicine and Dentistry of New Jersey, and author of Medical Odysseys: The Different and Sometimes Unexpected Pathways to Twentieth-Century Medical Discoveries, (Rutgers University Press, 1991), wrote in Hospital Practice August 15, 1991:

[Fleming was discouraged about penicillin’s possible use because first…] Third, after injection into an ear vein of a rabbit and with blood samples taken periodically thereafter for testing, it was found that penicillin was rapidly removed from the bloodstream. Samples taken at 30 minutes were found almost completely devoid of activity.

Of what use might be an antibacterial agent that took several hours to act but was removed from the body within 30 minutes and inhibited by the blood with which it would obviously be mixing?^vi

Craig H Steffee of Bowman Gray School of Medicine, writing in the North Carolina Medical Journal states:

Flemming considered penicillin a potential chemotherapeutic agent, but his early in-vivo investigations were discouraging. In rabbits, serum levels of penicillin dropped rapidly after parenteral administration, too fast to allow the several hours of contact with bacteria required for an effect in vitro.

Steffee defends Fleming’s laying penicillin aside based on the rabbit work stating:

…how many therapeutic modalities with the poor in vivo results of Fleming’s early penicillin trials would be offered continued funding today?^vii

Note also, that Weisse defends Fleming’s decision not to use more animals:

One might well wonder why, given the uncontrolled devastation of bacterial diseases, no further experiments on animals or humans were undertaken. The rapid disappearance from the blood has already been mentioned…. Even the choice not to use animal experiments more extensively, a routine practice of investigators on the continent, could be defended by Fleming and his group. After all, there might be differences between humans and other animals in resistance or susceptibility to different infections.

While researching Sacred Cows, we easily discovered that Fleming used a rabbit and concluded from it that penicillin would not be effective in humans. The general public does not understand the differences between t ½α and t ½β and t ½π (and perhaps neither do some of the readers) but they do understand what is meant when someone says, “it doesn’t work.” We stand by our statement.

Weisse continues:

In August 1942, a close personal friend of Fleming had contracted streptococcal meningitis. When conventional therapy failed and death seemed imminent, Fleming turned to Florey for help. The latter personally delivered his remaining supply of penicillin to Flemming and instructed him in the initial use of it. A dramatic cure was obtained, even the more so since penicillin was administered into the spinal canal for the first time to enhance its effectiveness. This “miracle” at St. Mary’s was reported in the London Times and the following day a letter from Almroth Wright identified Fleming as the one on whose brow the laurel wreath should sit.

Because of the prestige of Wright, Fleming was largely credited in the press with the miracle of penicillin. (That Florey avoided the press like the plague did not help clarify the situation. Then, as now, once the press has awarded credit to a single individual, that eclipses the important contributions of his colleagues.) Regardless of the truth of the press’s claim that Fleming was the brains behind the drug, the reason money was then poured into penicillin was Fleming’s successful administration to his friend and the publicity surrounding it. (Others confirm that Fleming routinely gave penicillin to humans with infections for years after 1929.^viii)

Human observation also encouraged Florey to continue the penicillin purification process. As John Warren Henderson wrote in the Mayo Clinic Proceedings:

About that time, Florey who had been at Sheffield before his appointment at Oxford, recalled Paine’s (previously mentioned) successful topical treatment of ophthalmic neonatorium with a crude broth of penicillin. All these factors gave Florey and Chain hope that systematically administered penicillin might have therapeutic potential in humans.^ix

Granted, Fleming obtained the more pure form of penicillin, which he gave to his friend in 1942, from Florey who tested it on mice. But that is irrelevant. To say that the purification process, which produced the penicillin, was dependent upon testing it in the mice is another example of fallacious reasoning, a non sequitur. The purification process was classic in vitro research, based on knowledge of chemistry. If Florey gained the confidence to proceed, based on tests in mice, that does not mean that animals were incumbent for the development of the drug. If he had used guinea pigs, who knows what would have happened?

The true story of how penicillin came to be is probably known only to God. The point of our passage is that Fleming received data from rabbits, which led him to abandon penicillin as a systemic antibacterial agent. Many references support this. We do not deny that penicillin can be used in many species. We do deny that animals can be used as predictors for humans because, as the penicillin story illustrates, animals vary in their reactions and a reaction in animals does not mean the same will occur in humans. Thalidomide, cyclosporin, the statins, the SSRIs, and scores of more recent drugs attest to this. The penicillin saga is, again, an example of using animals as causal analogical models (CAMs). The practice proved ineffective in the 1920s and is even less effective today. (We will shortly explore why this is so.) A related criticism that has been leveled against us is that because clinical trials did not uncover adverse side effects, we cannot blame animal tests for not doing so either. Again, this is fallacious. The medical community has long criticized the drug industry for its abbreviated clinical trials. Clinical trials assume approximately 60% of the cost of bringing a drug to market. Because studies on animals are cheaper and still offer liability protection in the USA and Europe, Big Pharma is reluctant to extend costly clinical trials to the numbers that are needed to ensure safety upon release. Dr. Festing cannot justify the failure of animal models by citing the failures of the drug industry. (In light of current research in pharmacogenomics, Big Pharma should be, and in some cases is, developing multiple drugs to treat the same disease rather than focusing on the blockbuster.)

Notes:

i. See Mayo Clinic Proceeding 1997;72:683-7 and Antibiotics vol 2 Florey, Chain et al. Oxford U Press.1949.

ii. ATLA 1994:207-209.

iii. Koppanyi, T. and Avery, M. A. Clinical Pharmacology and Therapeutics vol. 7, 1966 p250-270.

iv. The Ulster Medical Journal 1974;43:89-98.

v. Personal communication (email) January 2002.

vi. Hospital Practice (Of Ed) August 15, 1991 p 93-118.

vii. NCMJ June 1992, volume 53 number 6, pp 308-310.

viii. See multiple references (20-23) in The mystery of the plate: Fleming’s discovery and contribution to the early development of penicillin by Milton Wainwright in the Journal of Medical Biography 1993;1:59-65 and Br J Biomed Sci 1999;56:83-93.

ix. Mayo Clinic Proceeding 1997;72:683-7