1. Epidemiology (Human Population Studies)

Medical research has always sought to identify the underlying causes of human disease in order to develop effective preventive and therapeutic measures. In contrast to artificial animal model conditions that generally differ in causes and mechanisms from human conditions, human population studies have been very fruitful. For example, the identification of the major risk factors for coronary heart disease, such as smoking, elevated cholesterol and high blood pressure, which are so important for prevention techniques, derives from epidemiological studies.¹⁷⁷ Similarly, population studies have shown that prolonged cigarette smoking from early adult life triples age-specific mortality rates, but cessation at the age of 50 reduces the danger by half, and cessation at the age of 30 eliminates the danger almost completely.¹⁷⁸

Epidemiology's potential is illustrated by the growing field of molecular epidemiology. Researchers can analyze cellular and molecular characteristics of those suffering from cancer or birth defects, thereby elucidating the mechanisms and causes of DNA damage and yielding effective prevention and treatment approaches.¹⁷⁹

2. Studies on Patients

The main source of medical knowledge has always been the direct study of human disease by closely monitoring human patients. For example, cardiologist Dean Ornish has demonstrated that a low-fat vegetarian diet, regular exercise, smoking cessation and stress management can reverse heart disease.¹⁸⁰ Similarly, Caldwell Esselstyn has shown that lowering cholesterol levels with plant-based diets and medicines as needed arrests and often reverses heart disease.¹⁸¹ Henry Heimlich has relied exclusively on human clinical investigation to develop techniques and operations that have saved thousands of lives, including the Heimlich maneuver for choking and drowning victims, the Heimlich operation to replace the esophagus (throat tube), and the Heimlich chest drainage valve.^173,182

Modern noninvasive imaging devices such as CAT, MRI, PET and SPECT scans have revolutionized clinical investigation.^183-186 These devices permit the ongoing evaluation of human disease in living human patients and have contributed greatly to medical knowledge.

3. Autopsies and Biopsies

The autopsy rate in the United States and Europe has been falling steadily, much to the dismay of clinical investigators who recognize the value of this traditional research tool.^187,188 Autopsies have been crucial to our current understanding of many diseases, e.g. heart disease,¹⁸⁷ appendicitis,¹⁸⁷ diabetes^189,190 and Alzheimer's disease.¹⁰⁴ Although the usefulness of autopsies is generally limited to the disease's lethal stage, biopsies can provide information about other disease stages. Diagnostic needle and endoscopic biopsies often permit safe procurement of human tissues from living patients. For example, endoscopic biopsies have demonstrated that colon cancers derive from benign tumors called adenomas. In contrast, colon cancers in a leading animal model appear to lack this adenoma-to-carcinoma sequence.^191,192 Small skin biopsies (with intact capillaries) can be used as a tool before or during clinical trials of new drugs and could have revealed the cardiovascular risks of Vioxx, for example, before it was marketed.¹⁹³

4. Post-Marketing Surveillance

Thanks to advances in computer techniques, it is now possible to keep detailed and comprehensive records of drug side effects.¹⁹⁴ A central database with such information, derived from post-marketing surveillance, enables rapid identification of dangerous drugs.¹⁹⁵ Such a data system would also increase the likelihood that unexpected beneficial side effects of drugs would be recognized. Indeed, the anti-cancer properties of such medications as prednisone,¹⁹⁶ nitrogen mustard¹⁹⁷ and actinomycin D;¹⁹⁸ chlorpromazine's tranquilizing effect;¹⁹⁹ and the mood-elevating effect of MAO-inhibitors²⁰⁰ and tricyclic antidepressants²⁰¹ were all discovered through clinical observation of side effects.

5. Other Nonanimal Methods

Between the mid-1950s and mid-1980s, the NCI screened 400,000 chemicals as possible anti-cancer agents, mostly on mice who had been infected with mouse leukemia.²⁰² The few compounds that were effective against mouse leukemia had little effect on the major human cancer killers.²⁰³ More recently, researchers have favored grafting human cancers onto animals with impaired immune systems that do not reject grafts. However, few drugs found promising in these models have been clinically effective, and drugs with known effectiveness in humans often fail to show efficacy in these models.²⁰⁴  

By contrast, in vitro cell and tissue cultures have proven to be powerful investigative tools. The NCI has now switched to 60 in vitro human cancer cell lines, a more reliable and much less costly alternative.²⁰⁵ Similarly, in vitro tests using cells with human DNA can detect DNA damage much more readily than animal tests.²⁰⁶

New drugs can be tested in human tissues. This could have predicted the catastrophic reaction to the drug TGN1412 in the clinical trial in London in 2006.¹³⁸ Companies such as Biopta and Asterand work exclusively with human tissue because, contrary to animal tissue, the results obtained can be directly extrapolated to humans.²⁰⁷

Regarding vaccines, researchers discovered already in 1949 that vaccines made from human tissue cultures not only were more effective, safer and less expensive than vaccines produced from monkey tissue,^208,209 but also completely eliminated the serious danger of contamination with animal viruses.²¹⁰  Likewise, many animal tests for viral vaccine safety have been replaced by far more sensitive and reliable cell culture techniques.^211,212

Microfluidic circuits provide the nearest thing to a human body on a chip. They comprise tiny channels with cells from various human organs and are linked by a circulating blood substitute. Using these circuits, new drugs can be tested on a "whole system", where they encounter human cells in the same order as they would encounter them in the human body. Sensors in the chip then feed back information for computer analysis. Microfluidic circuits promise to deliver, early in the preclinical phase, data of dramatically improved predictive relevancy to the human organism.²¹³

Computer modeling is now so sophisticated that scientists can simulate in silico in minutes or hours experiments that would take months or years to perform in animals. Drugs can be rationally designed on computers and then tested on virtual organs or in virtual clinical trials. Research teams around the world are working on a "virtual human" which will predict human responses more accurately than would ever be possible with any animal model.²¹⁴

Microdosing is a tremendously exciting breakthrough in drug development based on the principle that the best model for man is man. Human microdosing relies on ultra-sensitive analytical techniques and permits the safe introduction of miniscule doses (amounting to only 1% of the normal full dose) of new drugs into subjects in order to evaluate drug activity in the human body. The technique has proven quite accurate, with the results from microdosing studies showing a 70% correspondence with those from full-dose studies.²¹⁵ Microdosing should replace misleading, unreliable animal testing and become part of phase 0 preclinical trials for every drug. Both the FDA and the European Agency for the Evaluation of Medicinal Products have endorsed the use of microdosing to accelerate and improve the safety of drug development.²¹⁶

Why Animal Experimentation Persists

If animal experimentation is so flawed, why does it persist? There are several likely explanations.

1. For the chemical and pharmaceutical industries, animal experiments provide an important legal sanctuary. In cases of death or disability caused by chemical products or adverse drug reactions, the responsible companies claim due diligence by pointing out that they performed the legally prescribed "safety tests" on animals and are therefore not accountable. As a result, the victims or their families most often come away empty-handed after suing for damages.¹⁴

2. Animal experimentation is easily published. In the "publish or perish" world of academic science, it requires little originality or insight to take an already well-defined animal model, change a variable or the species being used, and obtain "new" and "interesting" findings within a short period of time. In contrast, clinical research, while directly applicable to humans, is more difficult, expensive and time-consuming. In addition, the many species available and the nearly infinite possible manipulations offer researchers the opportunity to "prove" almost any theory that serves their economic, professional or political needs. For example, researchers have "proven" in animals that cigarettes both do and do not cause cancer – depending on the funding source.^217,218

3. Animal experimentation is self-perpetuating. Scientists' salaries and professional status are often tied to grants, and a critical element of success in grant applications is proof of prior experience and expertise. Researchers trained in animal experimentation techniques find it difficult or inconvenient to adopt new methods such as tissue cultures.

4. Animal experimentation is lucrative. Its traditionally respected place in modern medicine results in secure financial support, which is often an integral component of a university's budget. Many medical centers receive several hundred million dollars annually in direct grants for animal research, and an average of over 40% more for overhead costs that are supposedly related to that research. Since many medical centers faced with declining clinical revenues depend on this financial windfall for much of their administrative costs, construction and building maintenance, they perpetuate animal experimentation by praising it in the media and to legislators.

5. Animal experimentation appears more "scientific" than clinical research. Researchers often assert that laboratory experiments are "controlled" because they can change one variable at a time. This control, however, is illusory. Any animal model differs in myriad ways from human physiology and pathology. In addition, the laboratory setting itself creates confounding variables – for example, stress and undesired or unrecognized pathology in the animals. Such variables can have system-wide effects, skew experimental results, and undermine extrapolation of findings to humans.

6. The morality of animal experimentation is rarely questioned by researchers, who generally choose to defend the practice dogmatically, rather than confront the obvious moral issues it raises.^219-222 Animal experimenters’ language betrays their efforts to avoid morality. For example, they "sacrifice" animals rather than kill them, and they may note animal "distress", but they rarely acknowledge pain or other suffering.²²³ Young scientists quickly learn to adopt such a mind-set from their superiors, as sociologist Arnold Arluke explains: "One message – almost a warning – that newcomers got was that it was controversial or risky to admit to having ethical concerns, because to do so was tantamount to admitting that there really was something morally wrong with animal experimentation, thereby giving ‘ammunition to the enemy’."²²³ Physician E. J. Moore also observes: "Sadly, young doctors must say nothing, at least in public, about the abuse of laboratory animals, for fear of jeopardizing their career prospects."²²⁴

Evidence indicates that many animal experimenters fail to acknowledge – or even perceive – animal pain and suffering. For example, sociologist Mary Phillips observed animal experimenters kill rats in acute toxicity tests, induce cancer in rodents, subject animals to major surgery with no postoperative analgesia, and perform numerous other painful procedures without administering anesthesia or analgesia to the animals. Nevertheless, in their annual reports to the U.S. Department of Agriculture (USDA), none of the researchers acknowledged that any animals had experienced unrelieved pain or distress.²²⁵ Phillips reported: "Over and over, researchers assured me that in their laboratories, animals were never hurt… 'Pain' meant the acute pain of surgery on conscious animals, and almost nothing else… [When I asked] about psychological or emotional suffering, many researchers were at a loss to answer."²²⁵

Similarly, a study published in the British Medical Journal found that Canadian neurologists who spent a year of their training experimenting on animals "had so hardened themselves to animal suffering that they were no longer capable of recognizing suffering in their patients for quite a while after returning to clinical work".²²⁶

Animal experimenters' ethical defense of the practice has been superficial and self-serving. Usually, they simply point to the supposed human benefits and argue that the ends justify the means,^227,228 though they rarely substantiate their claims with scientific evidence.²²⁹ Often, they add that nonhuman animals are "inferior", lacking certain attributes compared to humans, such as intelligence, family structure, social bonding, communication skills and altruism. However, numerous nonhuman animals – among them rats, pigs, dogs, monkeys and great apes – reason and/or display altruism. There is accumulating evidence that many animals experience the same range of emotions as humans.^230-232 For example, mice have been shown to exhibit empathy with cage mates suffering pain.²³³ Chimpanzees and gorillas can be taught human sign language and to communicate with one another using signs even without humans being present.^234,235

The general public, which cares about animal welfare, has been led to believe that animals rarely suffer in laboratories. Animal experimenters often cite USDA statistics (derived from researchers themselves) which claim that only 6-8% of animals used in animal experimentation experience pain unrelieved by anesthesia or analgesia.²³⁶ However, mice, rats and birds, who in the United States constitute over 90% of all animals used in animal experimentation, receive absolutely no protection from the Animal Welfare Act.²³⁷  

The general public is clearly uneasy about animal experimentation. In a 2006 poll in the United Kingdom, for example, 51% of nearly one million voters said they are not in favor of animal testing.²³⁸ Since medical research is conducted for the benefit of the public and is financed largely with their taxes and charitable donations, their concerns should be respected and addressed.

The tens of millions of animals used and killed each year in American laboratories generally suffer enormously, often from fear and physical pain, and nearly always from the deprivation inflicted by their confinement which denies their most basic psychological and physical needs.