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The Process of Medical Discovery


By Brandon Reines, D.M.V.

 

 

 
 

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Before we can talk cogently about animal experimentation and what it's good for and not good for, we need some historical perspective on the primary function of animal experimentation. Animal experimentation has many different functions. Historically, its primary function has been as a means for a clinician to sell or dramatize hypotheses or ideas to colleagues. Because the experimental laboratory is so flexible, and because there are so many different strains in species of animals, it is almost always possible to come up with a result that will buttress a preconceived conviction. One example is the case of cigarette smoking and cancer.

 

As I looked at all the different areas of medical research — the history of physiology, therapeutics, and pathology — my ten years of historical research showed that discovery in medicine basically follows three simple steps — clinical hypothesis, lab "dramatization," and clinical testing.

 

Generally a doctor or a surgeon — someone who looks directly at human patients — identifies a series of anomalous cases, i.e., cases that do not quite fit the preconceived picture. Now, in the case of cigarette smoking and cancer, in the early part of the century, surgeons and clinicians started to notice that people who smoked cigarettes developed a very rare form of lung cancer. So this initially anomalous result was seen in human patients and on that basis, clinicians hypothesized that cigarette smoking may cause cancer. The next step was to proceed to epidemiological studies — large scale studies of human populations. This was done in both Britain and the U.S. Data was collected from many thousands of patients who smoked cigarettes, and it was found that, statistically, cigarette smoking does, indeed, cause human lung cancer.

 

The epidemiologist Ernst Winder could not convince his physician colleagues in the U.S. that cigarette smoking causes lung cancer in human beings, so Ernst Winder painted the skin of mice and rats with cigarette tars. He did this because he knew that doing it by inhalation, i.e., blowing smoke down the mouse's trachea, would never produce tumors. Inhalation was attempted in mice, rats, guinea pigs, rabbits and many other laboratory animal species, and it simply could not induce lung tumors.

 

Poor Ernst Winder kept painting the skin of different strains of rats and mice to try to induce a skin tumor, because he was unable to do it by inhalation. He finally found a strain of mouse in which he could induce tumors by skin painting, and then, in the late 1950's, he went on television and was able to convince some of his colleagues that cigarette smoking causes cancer. But again, the actual evidence came from studies of human beings.

 

Philosophers of science are now recognizing Aristotelian experimentation, the kind of experimentation in which you try to prove a point, or try to dramatize or sell a discovery that has already been made in a completely different context. Many of the great figures in the history of science were practitioners of Aristotelian experimentation.

 

One of the most renowned examples of an Aristotelian experimenter is Galileo. You've all heard the famous story in which Galileo dropped two cannon balls from the leaning tower of Pisa to see the rate of fall, in order to prove his theory of the fall of bodies and to attempt to disprove the old Aristotelian notions. Philosophers of science have shown that Galileo never actually performed the experiment. He developed his theory by thought experiment. Philosophers of science are now showing that many experiments — I think most of the animal experiments in the history of biomedical research — have actually been performed to dramatize discoveries already made by doctors, surgeons, clinicians, epidemiologists and others who study human patients directly.

 

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The father of modern medical science is a 17th century Englishman named William Harvey, who is the patron saint of thousands of researchers all over the world and has been for 300 years. The method that William Harvey used to discover that blood circulates around the body has been a subject of great debate and contention over the past 300 years.

 

Most people today think that William Harvey discovered that blood circulates through vivisection — by experimenting on about 80 species of animals. This view was doubted by an historian named Sigismund Peller, who wrote a scathing critique of the view that animal experimentation led to William Harvey's discovery, in the 1949 issue of Bulletin For the History of Medicine.

 

Historians have since shown that Harvey actually discovered the circulation of blood in two stages. In the first stage, he discovered the mechanism of the pulse. He found that the heart contracts like a pump and blows blood into passive arteries. In that first stage of Harvey's discovery, as I've elucidated in my paper called "On the Role of Clinical Anomaly in Harvey's Discovery of the Mechanism of the Pulse" (published Fall 1990 in the American medical journal Perspectives in Biology and Medicine), William Harvey did not use animals to discover how the heart and blood vessels work. He studied a single anomalous case of a nobleman whose descending aorta had been calcified into a bony tube, and he found that beyond the region of the calcification, the patient, during life, had had perfectly normal pulses in the legs.

 

This contradicted a 2,000 year old animal experiment performed by the ancient authority Galen. It absolutely contradicted what Galen had shown. The animal experiment had been wrong. In fact, it is not possible to do the experiment Galen had outlined, because it would require opening an animal and inserting a hollow reed into its artery. There would be so much hemorrhage that, without anesthesia and other supportive techniques, the experiment could not possibly have been performed effectively. But there was a "natural experiment" in which the aorta of a nobleman had been hardened into a bony tube, and that showed clearly and conclusively that the heart works like a pump and blows blood into passively expanding arteries.

 

The next stage of Harvey's discovery was performed by a thought experiment very similar to the method that Galileo, Einstein, and all the greats used. Einstein called it "Gedanken" and it is precisely what Harvey did to elucidate the circulation of the blood — a very dynamic picture and not something you could possibly have elucidated in animal experiments because in animal experiments you just get time shots, or snapshots in time.

 

What Harvey did accomplish with animals was to convince his colleagues that his theory was correct. Even at that time, during the Renaissance, because of the influence of René Descartes and Sir Frances Bacon, Harvey had to perform animal experiments to convince his colleagues that the blood circulates. He used a dead deer to convince King Charles the First of his theory. There is absolutely nothing in a dead deer that will prove that blood circulates, but it's something you can hold up in front of someone like the King and explain in very simple terms. It's a teaching tool, a way of educating students, but it has absolutely nothing to do with the process of discovery.

 

Harvey used simple clinical methods to verify his hypothesis, already worked out by thought experiment and by studying the nobleman. One such experiment, performed very late in the process, showed that blood would fill up on the side closest to the body when a ligature was placed on the arm .

 

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One feature of the animal experimental method is its drama — it is so much more dramatic than clinical discoveries that animal researchers get credit for virtually every discovery ever made in the history of medicine. A clinician will make the discovery, then an animal researcher will perform a dramatic, showy, sometimes bloody experiment and will plagiarize credit for the discovery which had already been made.

 

A very famous experimental surgeon named Alexis Carrel won the Nobel Prize in 1912, ostensibly for discovering organ transplantation and techniques of blood vessel repair. It is quite clear historically that Carrel was actually dramatizing discoveries already made by leading figures in abdominal surgery in the latter part of the 19th century. Even his technique of connecting the two severed ends of the blood vessel, which underlies modern organ transplantation, was plagiarized from the clinical surgeon Robert Tuttle Morris.

 

Carrel also received credit for performing the first bypass surgery using segments of the patient's own vein to bypass obstructed arteries. He is credited with all the modern breakthroughs in vascular surgery. In actuality, vascular and bypass surgery began to evolve in the 1700's under the influence of William Hunter, a very famous British anatomist. Hunter found that in certain anomalous human cases, there is a shunting of blood from the artery into the vein. This situation can occur from injury, or, as in former times, when a patient was purposely bled, and an artificial connection between artery and vein was created.

 

William Hunter was able to demonstrate that the person's own veins can withstand this very high blood pressure normally found in the arterial system. This finding is actually the bedrock of the bypass principle, because all modern leg and coronary artery bypasses rely on segments of the patient's own vein to bypass arteries obstructed by atherosclerotic plaques.

 

Dr. Jean Kunlin is the surgeon who, in the late 1040's, actually discovered modern bypass surgery. His work relied on the earlier discoveries of William Hunter and others who had shown that in human beings, the vein could withstand very, very high blood pressures, and, therefore, could be used for bypass.

 

To demonstrate how disastrously far off track animal experimentation can throw the entire community of medicine, in 1952 some researchers performed animal experiments using vein as bypass material to determine whether segments of the animal's own vein would withstand the very high blood pressure in the arterial system. This experiment was presented in 1952 at the annual conference of the American College of Surgeons.

 

The researchers concluded, on the basis of their animal experiments, that it was not possible to accomplish bypass grafting with segments of the patient's own vein. Instead, the patient's artery should be used. This is because in dog experiments, when the segment of vein was inserted into the arterial tree, it ballooned out into an aneurism. The researchers were, therefore, afraid that if they placed these segments of vein into patients' arterial trees in the leg or coronary arteries, they would kill people because the vein segment simply would not hold up.

 

Because of these misleading animal experiments, most surgeons declined to use patients' own veins to bypass obstructed arteries for about ten years, at least until the early 1960's. Finally, a few surgeons began to believe the clinical data — 200 years of evidence showing that very high blood pressure did not burst veins in human beings. This evidence came from cases of arterio-venous aneurism, in which veins were used to bridge obstructions in arteries during war surgery and in other clinical contexts. It was shown very clearly that vein bypass would work. Clearly, misleading animal experiments retarded the development of modern bypass surgery by about 10 years.

 

Dr. Robert Tuttle Morris is the real pioneer of modern organ transplantation. He was already performing ovarian transplants between women by the 1890's. He discovered the endocrine function of the ovary, the theory that the ovary secretes hormones, a revolutionary theory in his time, but he never received credit for any of his theories. He also pioneered vascular surgery and developed the technique for connecting the severed ends of blood vessels. Indeed, he made so many discoveries that today, he would be awarded three or four Nobel Prizes. But he is given credit for virtually none of his discoveries. The credit went to animal researchers.

 

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To demonstrate once again that bench scientists, or animal researchers, have much more prestige around the world than clinical researchers, I suggest the case of Sir Peter Medawar, who won the Nobel Prize in 1960 for his theory of acquired immunological tolerance. This is one of the theories that underlies modern organ transplantation. In 1950, Sir Peter Medawar and the other animal researchers said that if organ transplantation were attempted in human beings, they would be doomed to death. They based this conclusion on the results of rabbit and dog experiments. The rejection response of these animals was so violent that they thought surgeons would be signing their patients' death warrants were they to attempt even kidney transplants.

 

Nonetheless, groups in Boston and France performed kidney transplants in human beings. They found that in patients with severe kidney failure, there exists a state of natural immunosuppression such that the toxins that build up in the body actually suppress the immune response. Therefore, a rapid and violent rejection of the transplanted organ as seen in normal, healthy laboratory dogs was not found. Again, this shows that animal experimentation can be quite misleading.

 

The clinical investigator who actually discovered acquired immunological tolerance, a theory attributed to Sir Peter Medawar, was a little known American country biologist named Ray David Owen. He did not study a human patient, but rather an "experiment of nature" — an animal whose condition constituted a natural experiment, similar to what Harvey did when he studied the nobleman with the calcified aorta.

 

This is probably the most extraordinary natural experiment in the annals of biology. It is called the Freemartin co-twins. Under certain conditions, cattle twins are connected in utero by a system of blood vessels, creating a free flow of stem cells, which are the bone marrow cells that are the precursors of all the blood cells that form in the body (Figure 6). During uterine life, there is a constant flux of stem cells from one fetus to the other.

 

On the basis of this natural experiment, Owen showed quite clearly that the adult cattle twins actually had each other's blood types. They had their own blood type plus the blood type of the co-twin. And, they had become tolerant to the co-twin's blood type, which is absolutely unheard of in the annals of immunology prior to Owen's time. This momentous anomaly spurred the growth of "The New Immunology," as it is now called.

 

Most of the really important breakthroughs in immunology grew out of Owen's study. It also opened the door to modern organ transplantation, because researchers felt that if nature could do it, then humans could do it. They believed that there must be some way to render an individual tolerant to donor tissue.

 

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We must return to the 1890's to demonstrate how far back this issue of plagiarism between animal researchers and clinical investigators goes. The most famous animal researcher in the 1890's in England was Sir Edward Sharpey-Schaefer. Sharpey-Schaefer has been credited with discovering how the adrenal gland — the little gland that sits on top of the kidney — works. He was also given credit for discovering adrenalin and for being the father of modern endocrinology. In fact, Sharpey-Schaefer had nothing to do with founding modern endocrinology. He plagiarized a little known country doctor who was studying human patients, a clinical investigator named George Oliver.

 

George Oliver studied patients who had tuberculous infiltration of their adrenal glands, and deduced that this condition causes Addison's disease, which results in very low blood pressure. He connected destruction of the adrenal glands with very low blood pressure in human beings, and concluded that there must be a hormone in the adrenal gland that maintains blood pressure and vitalizes the heart. He did not name the substance adrenalin, but he had already discovered and extracted it from the adrenal gland of oxen.

 

Oliver knew that his clinician colleagues and others would not believe that he had discovered something of value, even though he had already tried the extract on his son and showed that it would raise blood pressure. To convince his colleagues, he asked the famous animal researcher, Sir Sharpey-Schaefer to try this extract on cats. He felt certain it would have a dramatic effect on blood pressure and on vitalizing the heart. Sharpey-Schaefer granted Oliver's request and showed that the extract would raise blood pressure in cats. Because he went to Sharpey-Schaefer, however, he lost any claim to credit for the discovery. Oliver is now totally unknown, despite the fact that the discovery was made in the context of his clinical practice.

 

One of the most dramatic stories in the history of medicine is the discovery of the polio vaccine. The discovery and development of an effective polio vaccine has been attributed to animal experimentation alone. In fact, it's a very mixed story.

 

Dr. Simon Flexner was the head of the Rockefeller Institute for Medical Research in New York City from about 1911 to 1930. Flexner had been doing monkey experiments with the polio virus for about 20 years. He was blowing the polio virus into the nose of monkeys in an attempt to model how polio grows and spreads in the human body — an understanding absolutely essential to develop an effective vaccine. However, the model that he developed in monkeys is now known to be totally wrong, and Flexner completely mislead the entire field of polio research for about 20 or 30 years.

 

What he supposedly showed in his monkey experiments was that the polio virus will only grow in the nervous system. That finding retarded the development of a vaccine because it is not desirable to grow a vaccine in a tissue culture made from nervous tissue, since nervous tissue is extremely allergenic. If killed virus grown in nervous tissue were injected into patients, they would have all kinds of horrendous brain reactions. It had to be grown in tissue from outside the nervous system.

 

The real hero of the polio story was a Swiss epidemiologist named Ivan Wickman, who showed that polio is primarily an intestinal disease and rarely a disease of the spinal cord. John Enders won the Nobel Prize in 1949 for developing a tissue culture method of growing polio virus, which allowed him to mass produce the polio vaccine. Enders revealed in his Nobel lecture that the fact that children with polio were excreting the virus in their feces led him to hypothesize that polio virus could be grown in intestinal tissue, not in nervous tissue. On the basis of this observation in human beings, Dr. Enders began to grow the polio virus in a tissue made from human intestinal tissue. This allowed him to mass-produce the polio vaccine and led to the breakthrough.

 

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The story of the discovery of the Rhesus factor is another example of the kind of plagiarism I have been talking about. The actual discoverer of the Rhesus factor is Dr. Phillip Levine. Dr. Levine was studying a patient in a New York hospital named Mary Seno, who had had a severe transfusion reaction both to her husband's blood and to that of her unborn fetus. The fetus was born dead.

 

Based on the patient's severe transfusion reaction, Levine deduced that there had to be some factor on the surfaces of red blood cells which had not been classified yet by the ABO system of blood typing. He should have named it the Levine Factor. If he had, there wouldn't have been all this confusion. People would not have thought that the Rhesus Factor was discovered in Rhesus monkeys. But since he didn't name it, he was plagiarized by Alexander Weiner, the supposed discoverer of the Rhesus factor.

 

Alexander Weiner performed a very dramatic monkey experiment, ostensibly demonstrating the same factor that Levine had shown existed on the surface of Mary Seno's red blood cells. In fact, Philip Levine later showed that Alexander Weiner's results were erroneous.

 

In summary, the historical role of animal experimentation has not been primarily scientific. In certain contexts, animal research has been of value, historically, even in the case of the polio vaccine. At that time, using monkeys was the only method available to grow the polio virus. In those days, they didn't know how to grow the polio virus in a test tube, and if they wanted to determine whether or not there was polio virus in the feces of a child, the only means they had of detecting it was to inject it into the brains of monkeys. Of course, this is now outdated.

 

Historically, once again, the primary role of animal experimentation has been to sell or dramatize discoveries that were already achieved by surgeons, clinicians, and others in the actual clinical context of work with human patients.

 

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Questions

Question: You mentioned that experiments on animals actually harmed human health, because they resulted in suppression of valuable discoveries for many years, while vivisectors "dramatized" the discoveries through animal experiments. In your research, have you found any historical connection between this suppression and economic interests that were benefited by, and therefore had an incentive to encourage and support, this suppression?

 

Answer: Yes. From the standpoint of people with a vested interest, that's the beauty of animal test results. There are so many different animal strains and species that you can get virtually any result you want.

 

The case of cigarette smoking and cancer is a beautiful example. The tobacco industry hired one of the best known animal researchers of the 1950's, Clarence Cook Little, to perform their tests of tobacco on mice to determine whether or not tobacco caused cancer. Clarence Cook Little is the founder of the Bar Harbor Jackson Laboratories in Bar Harbor, Maine, one of the two major mouse breeding laboratories in the U.S. It's one of the major suppliers of in-bred mice for researchers around the world and one of the most prestigious research institutes in the U.S. So Clarence Cook Little had tremendous prestige in the 1950's.

 

The tobacco industry knew that Little was someone who would give them what they wanted to hear. So Little performed these inhalation experiments in mice, and he showed that if you force mice or any other animal to smoke cigarettes, they don't get lung tumors. So Clarence Cook Little debated epidemiologists and biostatisticians such as Winder and Irwin Bross. Little was like a hit man for the tobacco industry.

 

An epidemiologist from the American Cancer Society would say: "On the basis of a study of one million human beings in the United States, we have conclusive evidence that cigarette smoking causes cancer in human beings." And then Clarence Cook Little would say: "On the basis of a study of 1,000 mice, we have conclusive evidence that cigarette smoking does not cause cancer in human beings." Of course, he was really using a kind of Orwellian "New-speak" by saying that something that is valid for mice is valid for human beings. What he meant was that cigarette smoking does not cause cancer in mice. But by adopting this Orwellian "New-speak," that I call "Lab speak," he was able to say that on the basis of mouse experiments, cigarette smoking does not cause cancer in humans. So, yes, vested interests have long benefited from this inherent flexibility of animal test data.

 

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Question: Why do you think that clinical discoveries and discoverers are so minimized in the history of medicine?

 

Answer: There are many, many reasons. I think, probably, the simplest reason is that human beings, by their nature, tend to create icons. They tend to create very simple pictures or symbols to represent what they know about the world around them. If you ask anybody how they know current events, they say: "From watching TV." So, human beings tend to learn by looking at very dramatic images. Now, the image of a vivisected animal is a very dramatic image. It's like watching TV, or like watching a movie. It's something that's very visual and evocative and it gives you a gut feeling right off.

 

However, talking about a thought experiment or a surgeon studying an experiment of nature is different. I noticed that when I was talking about experiments of nature or statistics, or studying patients, some of you started to kind of nod off or become less interested, because it's simply not as interesting to hear about as a blood and guts animal experiment, or a cat with electrodes in its head. And I think that, fundamentally, it has to do with human psychology. The way human beings learn is by these very dramatic visual images. And science is not particularly dramatic or visual. It's actually a linguistic process. Theories are something that are written down, in language, numbers, or equations. They are quite humble and they can't be held up or patented, for that matter. So I think it's fundamentally a question of human psychology.

 

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Question: Some people say that not everything you find out in science is purposeful. Sometimes you just find something by mistake. Scientists might argue that in studying animals, we might find out something about humans. Even if it is not 100% true, it should be done anyway. They also say that humans are more important than animals. What would you tell them?

 

Answer: Your question has two parts and I'll try to answer both of them. Your first point involves this idea of luck or chance, that you really just have to do a zillion experiments so that serendipitously you'll make some sort of discovery. You've hit upon the central argument of the father of experimental medicine, Claude Bernard, the French physiologist. In Bernard's An Introduction to the Study of Experimental Medicine, he claims that all of his discoveries were made by accident, in the laboratory setting.

 

I've just written a very esoteric paper that debunks that whole notion. Actually, Claude Bernard read autopsy reports. For instance, while he was "discovering" that pancreatic juice digests fat, he read a paper written 20 years before he began any of his laboratory experiments. He read several papers on autopsy reports of patients who had pancreatic ducts obstructed by carcinoma and who also had very fatty feces, and on that basis, he deduced that the pancreatic juice must split fat.

 

Instead of reporting the actual sequence of events in his book An Introduction to the Study of Experimental Medicine, Claude Bernard said "I discovered that pancreatic juice splits fat by accident, in rabbit experiments." Saying that the discovery was by accident severs the laboratory from the clinic. It's a way of saying: "I didn't get any inspiration from the clinic, from other doctors, from anything I ever read. It came solely from that dramatic event in the laboratory setting, solely by that accident in the laboratory, full-blown like a picture."

 

Since that time, most of the books about biomedical discoveries present them as simply a succession of laboratory accidents. Pasteur's rediscovery of vaccination supposedly happened because he accidentally left some flasks out on his laboratory table containing some cholera organisms that became naturally attenuated. When he returned from vacation, he injected them into some chickens and, lo and behold, the chickens didn't die and were vaccinated against subsequent injections.

 

In fact, Pasteur was building on Jenner's prior work in the 1700's in human beings. Jenner is the actual father of vaccination. He showed that you could vaccinate against one disease by using an attenuated form of another disease.

So invoking laboratory accident is simply a way for the animal researcher to divorce his discovery from its actual moorings and origin in the clinic. And I've demonstrated this time after time. It will be documented in my upcoming book. It's simply a ruse, a way of plagiarizing a discovery that has already been made.

 

Your second point was that humans come first. I agree totally that humans come first and that public health comes first. But, when I started looking into this whole issue about 10 years ago, being a very curious and thoughtful person, I didn't want to take a stand on any issue until I really understood the ins and outs of it. So being someone who does care for human beings first and foremost, I really wanted to have the issue down before I started making any kind of public statements or analyses.

 

What I found, again, is that, historically, animal research really served a very small productive function. Primarily, animal research was useful in the early days of infectious disease research, when they needed some system in which to grow bacteria, viruses, or parasites. They didn't have tissue cultures, so they absolutely needed the animals in those days.

 

Today, when most diseases are non-infectious — cancer, heart disease, stroke, mental illness — when most diseases are really a breakdown of the patient's own body and tissues, you simply can't extrapolate from animals. You don't have that simple analogy of a living test tube — an animal infected with a germ is like a test tube infected with a germ is like a human with an infectious disease.

 

In the non-infectious diseases, the analogy breaks down. You simply cannot extrapolate from a mouse tumor to a rat tumor or from a rat tumor to a human tumor. So on purely public health grounds, the National Cancer Institute has now switched from using mice to search for cures for cancer to growing the patient's own tumors in the test tube. And that's how the National Cancer Institute is now screening for potential drugs for the treatment of cancer, by testing on these human tumors grown in the test tube. It's an attempt to overcome the extrapolation problem which the U.S. Federal Research Bureaucracy is finally facing.

 


References

1. Reines, B. P.: On the role of clinical anomaly in Harvey's discovery of the mechanism of the pulse. Perspectives in Biology and Medicine 34(1):128–133, 1990.

2. Reines, B. P.: On the locus of medical discovery. The Journal of Medicine and Philosophy 16:183–209, 1991.

3. Reines, B. P.: Masked Men of Medicine. Unpublished Manuscript.

 

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