Animals in Scientific Research
Medical Research - Diabetes
From Drs. Ray and Jean Greek in their book, Sacred Cows and Golden Geese (please refer to the book for source material).
Diabetes is a very serious disease. Even today it affects ten to fourteen million Americans. It is a leading cause of blindness, amputation, kidney failure, and premature death. Much remains mysterious about diabetes, but what is understood is that it impairs delivery of the body's main fuel, glucose.
Our digestive system breaks down food into glucose, a simple sugar. Normally, the hormone insulin (a protein composed of 51 amino acids), produced in the pancreas, ushers the glucose, or blood sugar as it is called, along through the bloodstream. Fat cells, muscle cells and other cells have insulin receptors. When insulin attaches to a receptor, it triggers chemical reactions inside the cell that allow glucose to enter.
In diabetics, blood cannot deliver glucose to cells because without insulin, cell membranes reject the glucose. When diabetes develops in childhood, it is because the pancreas, an organ of the digestive and endocrine systems, fails to produce sufficient insulin. Adult-onset diabetes is different. There is an adequate supply of insulin, but the cells stop responding to it readily. There are numerous types of diabetes, but in all types insulin receptors do not function properly, even in the presence of adequate glucose. Glucose accumulates in the bloodstream, raising blood sugar levels dangerously high.
Let us consider when and how animal studies entered into the exploration of this tragic condition.
In the first century c.e., Araeteus and Celsus described a disease of frequent urination, unquenchable thirst, and wasting. In the seventeenth century, Thomas Willis observed that the urine of people suffering from this disorder contained sugar. As early as 1788, Thomas Cawley and others performed autopsies on deceased diabetic patients and found consistent changes in the pancreas. Cawley also described other patients with pancreatic lesions who developed diabetes. Subsequent autopsies continuing into the twentieth century repeatedly confirmed Cawley's findings. In 1833, another physician named Bright discovered pancreatic cancer in a diabetic patient, establishing another link between the disease and pancreatic dysfunction. In 1869, scientists identified the Islets of Langerhans, insulin-producing pancreatic cells that are affected in diabetic patients. In short, many pancreatic conditions, such as pancreatic cancer and pancreatitis (inflammation of the pancreas) were already known to produce diabetic symptoms, reinforcing the disease's link with the pancreas well before the twentieth century with its predilection for animal experimentation.
In 1870, a physician named A. Bouchardat renounced the practice of feeding extra sugar to patients in compensation for sugar loss in the urine. By contrast, he recommended diet changes and exercise. This then-revolutionary idea continues to be a mainstay of diabetic therapy today.
In 1875, Bouchardat also noted the association of diabetes with lesions of the pancreas.
In 1895, Hansemann reviewed the literature and found seventy-two cases of diabetes accompanied by lesions of the pancreas. However, based on dog experiments he concluded that diabetes had nothing to do with the pancreas.
Dr. Pierre Marie found the association between acromegaly, a pituitary disorder, and sugar in the urine, thus connecting sugar metabolism and the pituitary gland in 1882. Another doctor, Atkinson, published data in 1938 that revealed 32.8 percent of all acromegalic patients suffered from diabetes. Bouchardat had published similar findings in 1908. For some reason, the scientist who validated this in dogs, Bernardo Houssay, ended up winning the Nobel Prize in 1947. Obviously, it is hardly fair to say dogs were responsible for his kudos, since sizable knowledge predated Houssay's experiments, and any number of human-based methods would have produced the same findings.
It was not until animal experimenters entered the picture that the hitherto nicely progressing course of knowledge regarding the pancreas and diabetes ran amok. Considerable documentation around the turn of the century confirms this. Claude Bernard conducted experiments on dogs that produced sugar in the urine. Remember, this had already been observed in humans. However, the condition in quadrupeds led Bernard to conjecture that diabetes was a liver disease, linking sugar transport to the liver and glycogen. He also conducted many experiments on animals' central nervous system in an attempt to establish a link there. Granted, the liver is involved in carbohydrate metabolism and injuries to the brain can result in hyperglycemia (elevated blood sugar levels), but this is not insulin resistance at the cellular level, or a lack of insulin production from the pancreas. These animal studies threw diabetes research off the track for many years. Because of animal studies, many scientists did not believe the pancreas to be involved in diabetes nor that a hormone such as insulin existed. One scientist, Pfluger stated that the pancreas does not "play any part at all in the origin of diabetes, whether, in fact, there is such a thing as pancreatic diabetes.''
In the 1880s, intending to "validate'' what had already been established in humans, scientists--most notably Joseph von Mering and Oskar Minkowski--feverishly began removing pancreases from dogs, cats, and pigs. Sure enough, the animals did become diabetic.
In the early 1920s, two scientists, J. J. R. Macleod and Frederick Banting, were given credit for isolating insulin by extracting it from a dog. For this they received a Nobel Prize. McCleod admitted that their contribution lay not in discovering insulin (for which they are often credited), but in providing evidence from the animal lab.
McCleod and Banting were not obligated to extract insulin from a dog, because certainly there was ample tissue from humans. They did so because it was a convention of the time. In that same year, Banting and another experimenter named Charles Best, gave dog insulin to a human patient, a fourteen-year-old boy, with disastrous results. When accepting the Nobel Prize, Banting stated that the dog insulin had resulted in a "marked reduction'' in the child's blood glucose level. In fact, it only went down an insignificant twenty-five percent and was accompanied by severe side effects. A second dose was not given due to the ineffectiveness and sequellae of the first. J. B. Collip, a biochemist in MacLeod's team, said that the administration of the dog insulin was "absolutely useless.''
Note what scientists said about the dog experiments in 1922: "The production of insulin originated in a wrongly conceived, wrongly conducted, and wrongly interpreted series of experiments.''
Even Banting and Best's supporters said they were "unqualified to do good work.''
Years later, scientists such as Pratt reviewed the entire insulin isolation experiments that occurred in Toronto, and concluded that Banting and Best's dog experiments had not been vital. It was the chemistry of Collip and Macleod that had isolated and purified insulin.
M. Bliss states: "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.'' Banting and Best experimented on some dogs and by sheer happenstance persuaded people who had knowledge of in vitro research to look for insulin and purify it.
Collip, Macleod and other scientists modified the process of isolating and purifying insulin using in vitro techniques, and later mass-produced insulin from pigs and cattle by reaping it in slaughterhouses. The real credit for purifying insulin should have gone to Collip, who used chemistry to purify the insulin. The existence of insulin was already well known. It was its purification that allowed harvest from slaughterhouses and administering to humans. Note what Bliss states about Macleod's opinion of the entire Banting and Best role in the purification of insulin: "In Macleod's mind, the whole importance of Banting and Best's experiments had been in convincing Macleod and the others of the team Collip that the internal secretion insulin was there to get.''
In other words, providing evidence of the existence of insulin from the dog lab was the convincing factor, another case of scientists not being convinced of something just because it was seen in humans. In the forthcoming years, scientists refined the substance. J. J. Abel, in 1926, purified pure insulin from animals. H. C. Hagedorn introduced protamine insulin, a longer lasting form, in 1936. Some lab animal work with the new insulin suggested that it caused birth defects. Fortunately for diabetics, this is not the case in humans.
Discussion of harvesting insulin from animals also introduces a very important distinction of relevance to the vivisection debate. The pro-vivisection community uses the concepts of (a) animal experimentation and (b) harvesting animal parts for use in humans interchangeably. However, these activities are not the same and do produce different risks. We do not deny that some animal parts can be made to function in humans. But what the vivisection community often understates is the risk of those organs or chemicals to humans
Animal tissue can be used for human benefit without misleading science--heart valves from pigs, insulin from cows and pigs, the production of monoclonal antibodies from mice, and so on. However these tissues and chemicals have risks, and as occurred with insulin, their ready availability delayed safer therapies.
It is true that without insulin harvested from slaughterhouses many diabetics would have lost their lives. It is also true that the harvest delayed the synthesis of far safer human insulin. Science and industry do not search for solutions to problems that are not apparent, and hence do not appear profitable. Synthetically produced human insulin might have been developed much more quickly had science and industry not decided that animal insulin was just as good. Furthermore, animal insulin's availability shrouded the discovery of important diabetes-contributing factors. Whereas animal insulin helped many diabetics, others suffered severe side effects, and its use potentially endangered many more.
Beef and pork insulin have saved lives. They also created an allergic reaction in some patients. Beef insulin has three amino acids that differ from humans, while pork insulin has only one. Although this sounds negligible, remember that it takes very little amino acid discrepancy to undermine health. (Only one deviant amino acid is enough to produce a life-threatening disease, such as cystic fibrosis or sickle cell anemia.) Injecting animal-derived insulin also presented the considerable danger of contracting zoonoses (viruses, bacteria, and other microorganisms that cross from one species to another). Had researchers then recognized these potentialities as well as the gulf of differences between ruminants and humans, the exigency for human insulin would have resulted, and it would have been developed sooner.
The ready availability of animal-derived insulin and the animal model in diabetes research has continued to encumber the investigation of diabetes throughout this century.
Whereas ample resources were devoted to studying animal models, human diabetic observation limped along with little subsidy. The ability to treat patients suffering from diabetes without giving them insulin injections was discovered entirely by chance. In 1942, M. Janbon noticed that when patients were given sulfonamides, their blood sugar dropped precipitously. In 1954 patient observation again paid off. Dr. H. Franke was giving patients a new sulfonamide when he too observed symptoms of hypoglycemia. Dr. J. Fuchs then confirmed the observation by taking the medication himself. Today, the administration of oral anti-hyperglycemics, which arose from serendipity and this human self-experimentation, entirely dispenses with the need for insulin injections in many patients.
Not until 1955 was the structure of human insulin revealed. By the 1970s scientists had established the DNA sequence of the insulin gene, and in the next decade spliced the gene into E. coli, thus creating a limitless supply of synthetically-produced human insulin. A combination of in vitro research and technological breakthrough allowed the development of human insulin and insulin preparations that last longer in the body.
Once geneticists located the genetic source of diabetes, genetic breeders scurried to cook up a special mouse for diabetic study. Not surprisingly, this non-obese diabetic (NOD) mouse has certain drawbacks. Unlike the human genome, the mouse genome contains two unlinked insulin genes. Drs. M. A. Atkinson and E. H. Leiter commented that,
Our understanding of the pathogenic mechanisms underlying Type 1 diabetes development in NOD mice is now quite advanced. However, this understanding has been accompanied by the realization that when this mouse is used as a surrogate for humans, genus-specific differences that restrict their interpretation are unavoidable.
In other words, the model does not work, and the differences are profound. NODs lack certain human-immune-system components. The NOD mice also resist diabetic ketoacidosis (DKA). DKA is the most serious manifestation of diabetes; it is what leads to diabetic coma and frequently to death, so the fact that that rather important clinical sign is missing is considerable.
Other models fare no better. Streptozotocin (STZ) knocks out the Islet of Langerhans cells in the pancreas in mice. B. Rodrigues et al., writing about STZ-induced diabetic lab animal in Experimental Models of Diabetes state:
In conclusion, numerous types of experimental diabetes are available. However, with the different animal models of diabetes, there will always be physiological, pathological, and morphological differences between models. Moreover, an unavoidable reality is that none of these animal models of diabetes are perfectly equivalent to the human disease state.
Scientists attempt to pass off the STZ-induced rat as a twin of the human diabetic. Yet problems very quickly arise. For example, the STZ rat does not require insulin to survive as humans do. Nor is it sensitive to renal toxicity brought about by exposure to the antibiotic gentamycin. But physicians discovered that humans are, particularly diabetics who have compromised renal function to begin with. Sharma and colleagues noted that "this model does not exactly reproduce the structural hallmark of diabetic nephropathy kidney disease.''
"Not exactly?" Remember, most of the people we quote have a vested interest in animal experimentation. "Not exactly'' is really sciencespeak for "this does not predict anything for humans.''
The animal models actually differ dramatically. The STZ injected rat does not require insulin to survive, and other diabetes models, the Zucker rat for one, do not even suffer from elevated blood glucose.
C. Ioannides et al., state:
None of these models of insulin-dependent diabetes mellitus (IDDM) mimics all the characteristics encountered in the human form of the disease. Animals in which diabetes has been chemically induced may survive for several months in the absence of an exogenous supply of insulin, and in this respect they differ markedly from the human disease.
Humans cannot survive months without insulin. Certainly this suggests some very substantial discrepancies. Likewise referring to IDDM experimental models, another authority writes: "No animal model of diabetes mellitus is a perfect model of the disease; hence a wide variety of models continue to be employed.''
Nonhuman models misled the development of non-insulin therapies, such as oral antihyperglycemics, for diabetes.
The FDA recently approved troglitazone and Parke Davis marketed it as Rezulin. Troglitazone has been linked to severe hepatotoxicity and liver failure, and has been associated with as many as 155 deaths. This is not an isolated incidence. Repeatedly, the animal model has thwarted diabetes research, due to the great differences in digestion and metabolic processes between species. The pancreas continues to be a difficult organ for animal experimenters today, but this has not slowed animal-modeled attempts. In 1992, researchers had this to say about animal models of pancreatitis:
The most important role of experimental models in animals is their use in investigating aspects of pathogenesis, morphology and diagnosis. Whether the induction of experimental acute pancreatitis by whatever means imitates the etiology in humans seems to be most doubtful. As long as we do not know the true causative factors and their pathogenic principles in human acute pancreatitis, it remains speculative whether these models have a comparable pathogenesis. Finally, human acute pancreatitis seems to be a different disease than the one induced in experimental animals.
Due in part to dollars misallocated to animal labs, diabetes is still stunningly enigmatic. Most clinicians believe that strict glucose control though insulin injections offers advantages over a less regimented treatment plan, and we agree. However, insulin is a treatment, not a cure, for diabetes. The exact biochemical process through which insulin regulates blood sugar is still not known. Neither have researchers discovered how that lack of regulation results in diabetes. As one scientist has stated: "Since the discovery of insulin in 1921, many physicians and patients alike have had the erroneous impression that the horrific disease diabetes mellitus has been conquered.''
Even in the 1920s, after insulin had been purified and was being given to diabetics, many heralded it as a cure. The insulin-centric nature of our investigation and treatment of diabetics may have produced a forest-for-the-trees kind of oversight. Importantly, even though as many as twenty to thirty percent of children are genetically predisposed to diabetes, most do not develop the disease. That is a pretty staggering discovery. It means other factors such as diet, exercise, and as yet unknown determinants bear significantly on susceptibility.
The availability of insulin obfuscated more important and other factors. Clearly, diet and exercise can decrease or eliminate the amount of insulin needed for many patients and relieve them of the risks associated with taking insulin. Programs that reduce fat in the diet and increase exercise show dramatic benefits and enable some patients to get off antihyperglycemic medications in less than a month. By controlling glucose levels and maintaining lower blood sugar, these diabetes patients also decrease the risk of complications.
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