Sunday 20th August 2017

Banting and Best

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Banting and Best

The discovery of insulin is generally considered to have been made by Banting and Best in Toronto in 1921 when they isolated the hormone from dogs, and for this Banting and Macleod, who had assisted in the process by giving them a laboratory, received a Nobel Prize. But we know that a long series of important discoveries, useful hypotheses, precious pieces of the puzzle had paved the way before and continued to throw light on the issue after.

It is not correct to say that they discovered insulin. At the time, when the hormone theory had just been formulated, the existence of a hormone secreted by the pancreas that was capable of controlling glucose metabolism had been hypothesized. In addition, after Langerhans had discovered in the pancreas the islets (or islands) that bear his name, it was recognized that degeneration of these cells was connected with diabetes. Scientists then rightly assumed that some substance was lacking in the internal secretion of a diabetic's pancreas, which the physiologist Schafer named insulin, from insula, the Latin word for "island".

The role of chemists like Liebig, Macleod and Collip and of clinicians like Bernhard Naunyn, who applied the new advances made in chemistry to the understanding of diabetes, is also crucial in this context.

So why single out Banting and Best's contribution over all others? Because they were able to use animals to confirm hypotheses in line with the current paradigm, which states that only animal experiments can confirm or disprove a theory.

Another reason is that they isolated insulin, which had been proven difficult to do. The motive for this, Banting thought, was because, since the pancreas' other main function is the production of pancreatic juices into the gut (its external secretion), it contained many digestive enzymes that could break up proteins like insulin. Banting's idea was to ligate (tie off and block) the pancreatic ducts of a living animal and leave the pancreas where it was. The part of the gland destined to produce digestive juices would have degenerated, since the the flow of juices would have stopped, whereas the section secreting insulin into the bloodstream would have been unharmed.

In order to isolate insulin, however, the use of animals was not necessary because there were abundant human tissues. The people who purified insulin, which otherwise would have been useless for humans, were the biochemists Macleod and Collip.

In the book The Discovery of Insulin, award-winning historian Michael Bliss writes:

"Banting and Best did not discover insulin... It is particularly important to repeat that Banting's great idea, duct ligation [on dogs] played no essential part in the discovery... In Macleod's mind, the whole importance of Banting and Best's experiments had been in convincing Macleod and the others of the team that the internal secretion [insulin] was there to get." [Emphasis added]

It was not hunky-dory as the conventional storiography tries to portray. In his book just quoted, Bliss uses previously suppressed, unpublished or privately circulated documents, and his rigorous historical method corrects the myths and legends often perpetuated in the scientific literature: and mind, he is not an antivivisectionist, just a medical historian who did his job thoroughly. His work is considered the definitive history of the discovery of insulin, a significant but also controversial event.

Bliss explores a critique of Banting experiments in the British Medical Journal on 16 December 1922 penned by Dr Ffrangcon Roberts, who among other things points out that Batnting and Best's idea and experiments imply that trypsin is active even when in the pancreas, and writes:

"Now it is one of the best established facts in physiology that the proteolytic enzyme exists in the pancreas in an inactive form-trypsinogen-which is activated normally only on contact with another ferment, enterokinase, secreted by the small intestine... there was no physiological basis at all for Banting and Best's duct-ligation experiment. They had undertaken a cumbersome, time-consuming and cruel process to forestall enzyme action which would never take place."

We know that the powerful digestive enzyme trypsin, although produced in the pancreas, is inactive while in it due to inhibitors whose role is to prevent self-digestion (autolysis) of the pancreas itself. The latter can happen in a disease like acute pancreatitis, characterized by premature activation of the digestive enzymes in the pancreas. Autolysis can also make assessment of the pancreas in autopsies more difficult. Trypsin in the pancreas is present as the inactive trypsinogen, which is activated into trypsin only when it reaches the small intestine. Other pancreas digestive enzymes can only be activated through trypsinogen activation to trypsin. So Banting's idea that in the past pancreatic juices enzymes had prevented scientists from isolating insulin seems to have been incorrect.

The insulin isolated by Banting and Best was not effective on human patients as they had hoped, and had damaging effects. It was only when the biochemist Collip extracted insulin from ox pancreas and found a way to purify it using in vitro techniques, and then his and Mcleod's various pancreatic extracts were tested on diabetic patients until an extract that reduced the main symptoms of diabetes mellitus was found, that a treatment for this disease was developed.

I find Bliss's an appropriate conclusion:

"A not uncommon layman's view of the discovery holds that without the Toronto work the world might still be without insulin. This is unlikely. The internal secretion of the pancreas had been "discovered" theoretically back in 1889; its practical isolation and therapeutic use was only a matter of time, determination, ingenuity, technical skill, and resources."

 

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The Current Biomedical Paradigm

The prevailing theory at the moment says that, unless results of clinical observations, epidemiological studies and other discoveries are "confirmed" on lab animals, they are not satisfactory.

This is like the chicken and the egg. The animal-tests-as-the-heart-of-biomedical-research theory is what validates experiments like Banting and Best's over everything else. It's not the other way round, as animal experimentation apologists try to make it appear: it's not that animal research has shown itself empirically to be the fundamental, indeed irreplaceable method of research in biomedical science ("Look at all the great progresses which could never have been made without it", they say), but the theory that it is, articulated by Claude Bernard in the mid-19th century and never challenged, adjusted, argumented in favour or against or re-formulated by the biomedical community, is the only thing that gives animal experiments validation.

Animal experimentation has never adequately been put to the test, for example by comparing its results with those of other methods of research.

The statement that certain medical advances have been made because of animal experiments does not follow from the statement that they have been made after medical experiments. A correlation does not imply causation. This is particularly so in this case, since animal experiments are required by law, so we are bound to find them in the context of drug and other medical intervention development.

It is surprising that biomedical scientists, who know very well how science requires the utmost rigour both in logic and in verification, do not see that the general statements they make or support regarding animal experimentation have not been empirically confirmed. Indeed, they have never even been put to the test.

The strongest statement they make is that medical advances would not even have been possible without animal experimentation. Where is the evidence for that? How do we know what would have happened without it? There is none and we don't. The only support for that statement is theoretical, not empirical: in other words, it is an act of faith of normal scientists in their own paradigm. The strong element of dogmatism that exists in science as well as in so many human activities makes sometimes scientists blind to what appears obvious to outsiders, who have not been indoctrinated as part of the process of becoming a member of the community during the years of training and education in their discipline.

When defenders of animal experimentation list the medical advances which they think are due to it they are engaging in an activity that they would not consider appropriate in a scientific discourse, i.e. using anecdotal evidence in support of their theory.

The scientific approach to the question of animal experiments would require something completely different: comparing different methods of research to see which of them produces results which are closest to something that we already know. It's something similar to what has been done to test the validity of computer models, for example, of climate change: the tests involved using the models to see if they could "predict" past climate events.

In addition, there is also a problem of a different nature, not epistemological (of knowledge), but practical. The emphasis of animal experimentation is much more on finding a therapy than in finding a way to prevent a disease.

Clinical and epidemiological studies on man, on the other hand, are the prime tools to understand the aetiology of diseases and help preventing them from developing.

On diabetes, medical historian Michael Bliss wrote:

"Because insulin enabled diabetics to live and propagate, and because the disease had a strong hereditary component, the effect of the discovery of insulin was to cause a steady increase in the number of diabetics. Other factors, such as rising calorie intake in the twentieth century, worked in the same direction. This increase, combined with the ongoing difficulties of insulin therapy, and with the changing mix of threats to life and the incidence of infectious disease declined, meant that diabetes posed more medical problems after the discovery of insulin than before. "

The very significant fact that, while 20 to 30 percent of children are born with a genetic predisposition to diabetes, most do not develop the illness shows that other factors are important causes of the disease, like diet, exercise and maybe still unknown determinants.

Diet and exercise can reduce or eliminate the insulin necessary for many patients, and free them from the risks connected with taking insulin. Studies in which diabetics cut the amount of fat and even carbohydrates in their diet and increased exercise have shown to have remarkable effects on these patients, some of whom could stop taking anti-hyperglycaemic medications less than a month after they introduced the changes. Controlling and keeping lower blood sugar levels also enables these diabetics to reduce the risk of complications.

In practical terms, allocating more resources to experimental studies on animals, which predominantly are aimed at finding treatments, means subtracting resources to the research methods, clinical and epidemiological, which are perfectly suited to the study of prevention, which eliminates the need of cures in the first place.

 

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