Today, thanks to those technologies, we are beyond the level of superficial similarities and are now studying disease at the genetic or molecular level. It is at this level that a monkey becomes a monkey and a human, a human. Does the practice of using primates or other animals as models, today, do more harm than good? Consider the following:

• Countless treatments for stroke have been developed in primates and other animals - yet all of them have failed or even harmed patients in clinical trials. (1)
• Of twenty-two drugs developed on animals as therapeutic in spinal cord injuries, none has worked in humans.
• Parkinson's Disease becomes progressively worse in patients, while the artificially induced primate version demonstrates gradual recovery.
• There is no successful animal model of Alzheimer's Disease.
• Human stroke patients often take years to recover any use of their affected limbs, while marmosets were able to run, climb, swing and jump almost as normal just three weeks following induced stroke during experiments at Cambridge University.
• To give just two quantitative examples, and to demonstrate our theory that small differences on the genetic level mean we can no longer use animals of any species to model humans, we turn to cancer research: Of 20 compounds known not to cause cancer in humans, 19 did cause cancer in animals (2) while of 19 compounds known to cause oral cancer in humans only 7 caused cancer in mice and rats using a standard National Cancer Institute (NCI) protocol. (3)
• The National Cancer Institute (NCI) tested 12 anti-cancer drugs, currently used successfully in humans, on mice. The scientists took mice that were growing 48 different kinds of human cancers and treated them with the 12 drugs. They found that 30 out of 48 times the drugs were ineffective in the mice. In other words, 63% of the time the mouse models, even with human tumours were wrong. (4)

Lewis Wolpert continues this theme in The Triumph of the Embryo:

Compare one's body to that of a chimpanzee - there are many similarities. Look, for example, at its arms or legs, which have rather different proportion to our own, but are basically the same. If we look at the internal organs, there is not much to distinguish a chimpanzee's heart or liver from our own. Even if we examined the cells in these organs, we will again find that they are very similar to ours. Yet we are different, very different from chimpanzees. Perhaps you may wish to argue, the differences lie within the brain. Perhaps there are special brain cells which we possess that chimpanzees do not. This is not so. We possess no cell types that the chimpanzee does not, nor does the chimpanzee have any cells that we do not have.
...The key changes in the evolution of form are in those genes that control the developmental programme for the spatial disposition of cells. The difference between chimpanzees and humans lies much less in the changes in the particular cell types - muscle, cartilage, skin, and so on - than in their spatial organization. Direct confirmation of this comes from studies which compare the proteins of humans and apes. If we look at the genes that code for the average 'housekeeping' proteins - proteins that function as enzymes or provide basic cell structure and movement - the similarity between chimpanzees and humans is greater than ninety-nine percent. The difference must reside not in the building blocks but in how they are arranged, and these are controlled by regulatory genes controlling pattern and growth.

Mark Ptashne and Alexander Gann write in Genes & Signals:

...it is generally believed that mammals - humans and mice, for example - contain to a large extent the same genes; it is the differences in how these genes are expressed that account for the distinctive features of the animals... a relatively small number of genes and signals have generated an astounding panoply of organisms. Thus, the regulatory machinery must be such that it readily throws up variations - new patterns of gene expression - for selection to work on.

Add-ons produce a system that is nonlinear. Nonlinearity means that the output of the system is not proportional to the input. The complex way genes are regulated is reminiscent of complexity or chaos theory, where very small differences in initial conditions lead to large and unpredictable changes in results over time. There is positive and negative feedback in a complex system, whose behaviour amounts to more than the sum of its parts. Tamas Vicsek states in Nature:

In the past, mankind has learned to understand reality through simplification and analysis. Some important simple systems are successful idealizations or primitive models of particular real situations...in other cases reductionism may lead to incorrect conclusions. In complex systems, we accept that processes that occur simultaneously on different scales or levels are important, and the intricate behaviour of the whole system depends on its units in a non-trivial way. Here, the description of the entire system's behaviour requires a qualitatively new theory, because the laws that describe its behaviour are qualitatively different from those that govern its individual units.

Hochachka and Somero write about complexity in living systems:

...The complexity of physiological systems in multicellular organisms requires ever more complex sensing, signal transduction, and communication, as body plans attain higher levels of complexity. The control networks that have evolved are hugely complex by comparison with single-celled eukaryotes such as yeasts ...Several thousand or so genes in unicellular and multicellular organisms seem to be involved in so-called "core processes" central to cell level survival and representative of the "unity" of biochemical design. So-called "non-core" functions, such as those listed immediately above, are what a substantial fraction of the remainder of the protein-encoding regions of the large genomes of complex eukaryotes represents - these are the genes that account for physiological diversity.
...The problem (and in some senses the paradox) is that protein and gene sequences in the common chimpanzee and in humans are remarkably similar. In fact, human and chimpanzee proteins appear to be nearly 99% identical at the amino acid level, and it is widely assumed that the same percentage similarity prevails at the DNA level. Yet no one could mistake the two species as one. What these examples suggests is that only exceedingly minimal changes in genome sequences may be necessary to specify separate species, possibly with larger percentage changes in gene expression patterns. Of course, the longer any two such related lineages evolve separately from each other, the greater the genetic differences between them may become. However, in terms of the origins of unity and diversity, it is as humbling as it is surprising to realize how very small the differences in the overall genome may be between two lineages as they separate from each other and thus extend our planet's biodiversity.

Dr. J. F. Dunne stated in Textbook of Adverse Drug Reactions:

Notably in the identification of central nervous system activity, animal models are unreliable indicators...some drugs of proven value in man have negligible or paradoxical activity in laboratory animals... inconsistencies are an inevitable outcome of fundamental species-determined differences: and doubtless a number of compounds of potential therapeutic value are lost to medicine, having demonstrated little activity in an array of inappropriate animal models.

Logically, the practice of carefully scrutinizing the human who died from the actual disease is straightforward, informative, and reliable. Autopsy makes sense. Early autopsies characterized the anatomy of the brain and how that anatomy related to function. Documentation exists on many hundreds of thousands of human brain injuries that affected mobility, function, and behaviour. Until PET, MRI, and CAT scans, these copious data provided our most accurate picture of brain-activity regions. Even in the early fervour of animal models precipitated by Claude Bernard, The Lancet pointed out in 1883, "It is an interesting and noteworthy fact that pathological observation is doing more to advance our knowledge of cerebral localization than physiological [animal] experiment." In 1958, Dr. Hugh Jarvie reviewed the way in which science had since garnered knowledge concerning the location of various brain functions. He concluded,

I cannot help feeling that the answers to our questions about the functions of the human brain will not be found in that way [animal experiments], but as they always have been found - in the careful collection of clinical facts and their pathological correlations.

Also of tremendous significance were autopsies of individuals with supposed neurologic diseases in which no pathologic abnormalities could be identified. Personality disorders were characterized by the lack of pathologic changes found at autopsy. Prior to that, they had been thought to be due to pathological changes in the brain. Despite the predilection for animal models, neurology still depends heavily on the autopsy. Note what pathologists R. B. Hill and R. E. Anderson say about this:

In recent years, participants in meetings of the American Association of Neuropathologists have heard criticism about the increasing use of animal models to study human neurologic disease.... A strong cadre of diagnostic and research neuropathologists believe that only human material can provide relevant answers to many problems about human central nervous system disease. In fact, examination of the data bears out this contention. Of the 185 abstracts presented at the 1985 meeting of the American Association of Neuropathologists, 115 (62%) were presentations of human neuropathology, and an astounding 81 (43%) were based on investigations of human brains at autopsy. Among these autopsy studies were seven presentations of either the first complete description of a newly recognized human disorder, or one of the first complete descriptions of an uncommon human neurologic disease.

Most studies of humans have been done via clinical research and in vitro research using T-cell lines and cells cloned from diseased individuals. Millions of people worldwide have MS so naturally, this nightmarish problem attracts a lot of research funding. Still, though scientists have described types of MS, the exact cause of the disease has not been elucidated, nor has a cure been found. As usual, large percentages of the available resources have been directed to animal models. Many years and many millions of dollars in the animal lab have not helped MS victims. The animal "model" of MS is called experimental autoimmune encephalomyelitis (EAE). First induced in monkeys in 1933, EAE has since been induced in guinea pigs, rats, mice, and rabbits. Whereas the animals do have some of the same symptoms, the cause of the symptoms is different and, just as important, imposed. Further, there have been real problems getting EAE pathology to progress even so far as demyelination. As scientists cannot induce sickness in the animals in the same way, naturally, they haven't even begun to cure multiple sclerosis itself. Note what scientists say about the model:

In EAE, however, the inducing antigen is known, whereas the antigen specificity of the immune reaction in MS has not been identified. Furthermore, many models of EAE are characterized by perivascular inflammation without significant CNS demyelination, in contradistinction with MS in which demyelination is the primary feature. Furthermore, EAE is not a naturally occurring autoimmune disease. (6)

Those are major differences. There are numerous animal models of MS. The shaking canine pup. The shiverer mouse. The myelin-deficient rat. None replicate the human disease. Dr. Gibbs, writing in Scientific American in 1993, had this to say about animal models of MS,

To the 2.6 million people around the world afflicted with multiple sclerosis, medicine has offered more frustration than comfort. Time after time, researchers have discovered new ways to cure laboratory rats of experimental induced encephalomyelitis, the murine model of MS, only to face obstacles in bringing the treatment to humans.

As it happens, about fifty percent of people with familial Alzheimer's disease have a mutation in the presenilin genes that predisposes them to the accumulation of characteristic amyloid plaques between neurons in their brains. To "validate" this finding, research with mice was immediately under way. But it had already been established so why were animal models employed at all? Here, an interesting lack of congruity between animals and humans again bungled the stream of revelation. Man-made mutations in mice can cause them not to produce presenilin 1. And as a result, the mice produce no amyloid-ß. But in humans with presenilin 1 and 2 mutations, it does the reverse. James M. Conner and Mark H. Tuszynski of the University of California, San Diego, summarized the frustration of animal models of AD in 2000, in Central Nervous System Diseases: Innovative Animal Models from Lab to Clinic,

In the case of AD, good animal models have been difficult to come by. The full spectrum of the biochemical and pathological abnormalities characterized by AD have not been found to occur spontaneously in any animal species other than the human, and the complexity of the disease has made it difficult to generate animals with a full range of experimentally induced AD pathological alterations. (11)

As for cures or vaccines, there still are none. Labs continue to try out therapies on assorted animals even though many knowledgeable scientists feel as does Dr. D. Lindholm of Uppsala University in Sweden who stated, "There is no...good animal model for the [Alzheimer's] disease process characterized by a loss of cognitive functions and memory decline." (12) Last year Dale Schenk and his colleagues buoyed the families of Alzheimer's patients with news of a suggested anti-Alzheimer's vaccine. They worked with mice that overexpress a mutant form of the human amyloid precursor protein, amyloid-ß, which in mice brings on an Alzheimer's-like condition called cerebral amyloidosis. Their prevention of this cerebral amyloidosis with vaccination was first published Nature and appeared in news media throughout the world. In an accompanying editorial in Nature, David Westaway and Peter St. George-Hyslop stated,

...all of the current animal models provide only a partial model of the human condition. So, although these animals accumulate increased levels of amyloid-ß, and have many amyloid plaque deposits, they have only subtle behavioural and electrophysiological deficits. More problematically, these animals do not develop neurofibrillary tangles or show significant neurodegeneration. (13)

No animal, aside from humans, suffers from Parkinson's. Researchers have reproduced the symptoms in animals and this has resulted in their receiving grant money to study them. These Parkinson's models include: the reserpine model, neuroleptic-induced catalepsy model, tremor model, models with degeneration of nigrostriatal dopaminergic neurons induced by using the chemicals 6-OHDA, methamphetamine, tetrahydroisoquinolines, ß-carbolines and iron, and most recently the "parkinsonian baboon." Timothy Schallert and Jennifer L. Tillerson of the University of Texas state in Central Nervous System Diseases: Innovative Animal Models from Lab to Clinic,

Many types of animal models of Parkinson's disease are available. Selecting a clinically predictive one is crucial, but has always been difficult...Although some researchers have argued that only primate models... [are useful], there is no consensus or current bias to suggest that one species is more predictive than another in the transition from research to patient. (15)

In 1983, researchers learned from clinical observation that the chemical MPTP (a by-product of synthetic heroin) could cause Parkinson's-like damage. The fact that MPTP causes PD-like symptoms was found accidentally after drug addicts injected themselves with MPTP-contaminated chemicals. The MPTP destroyed the dopamine-producing cells in the substantia nigra. So, researchers treated mice and other lab animals to infusions of MPTP. The data was merely demonstrative. Jay S. Schneider, who has worked at both Thomas Jefferson University and Drexel University, received public funds to inject MPTP into cats' brains and into two varieties of macaques. In 1997 Schneider wrote:

Some monkeys [injected with MPTP] had cognitive deficits and no motor deficits. Other monkeys had full parkinsonism that was produced after short-term high dose MPTP exposure, and some monkeys had full parkinsonism after long-term low dose MPTP exposure.

Inconsistent, coerced rather than acquired symptoms, which in aggregate Schneider calls "parkinsonism," are hardly a true model of this still little understood human disease. Simranjit Kaur and Ian Creese of the Centre for Molecular and Behavioural Neuroscience, Rutgers stated in Central Nervous System Diseases: Innovative Animal Models from Lab to Clinic,

The best model of PD to date, is the 1-meth-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. The neurotoxicity produced by 1-methyl-4-phenylpyridinium ion (MPP+), a metabolite of MPTP, is thought to mimic human PD. MPTP reduces the levels of dopamine and its metabolites in the striatum. However, this model is far from ideal owing to the high cost of using primates (MPTP is ineffective in rats) and unlike human PD, which is progressive, the neurotoxic damage produced by MPTP is reversible...In these models, it is difficult to ascertain the roles played by individual dopamine receptors in the pathology as well as the therapy of PD.

And is the ability to give animals the Parkinson's-like agitated movement in any way helping real Parkinson's victims? These animal models can only reproduce data already gleaned from humans. Their predictive value is negligible. The problem is, that while it is relatively easy to kill the substantia nigra with these substances and make animals shake, the reason the cells in the substantia nigra die in the animal is not the same as in Parkinson's. Furthermore, none of the models reflects the progression of Parkinson's symptoms as it occurs in humans. Philippe Hantraye of Service Hospitalier, France, wrote:

However, it is essential to understand that animal models only represent an imperfect replica of human disorders [of PD], and this is so for several reasons. First, animal models are generally developed in beings (rodents, nonhuman primates) that are subjects with behavioural repertoires and anatomical characteristics very different from humans. These species differences are known to play a role in the clinical expression as well as in the cellular specificity of the lesions. For example, striatal degeneration in humans is frequently associated with dyskinesia, whereas in rat or nonhuman primates, striatal excitotoxic lesions alone are not sufficient to induce dyskinesia or chorea. Second, in addition to these species differences, the time course evolution of the nerve cell degeneration, which normally evolves over several years in neurodegenerative diseases in humans is for practical reasons, being replaced over a much shorter period of time in animal models. (16)

As an example, take a look at one cause of epilepsy, cortical dysplasia, which is a result of brain damage that occurs in utero. (Cortical means "brain-related," and dysplasia has to do with abnormal cell growth.) The connection between this brain malformation and epilepsy was known in the 1800s, however no one could act on the knowledge until recently. Cortical dysplasia researcher N. Chevassus-au-Louis and his colleagues are in favour of the animal model. Yet, when they summarized the three most meaningful contributions to our understanding of epilepsy in the 1990s, they made no mention of animal models:

• Development and widespread use of modern brain-imaging techniques, specifically magnetic resonance imaging (MRI).
• The ability to detect malformations during life has opened the door for surgical resection of the malformed areas. Indeed surgery can reduce or abolish seizures or both in most patients, suggesting the existence of at least a causal link between malformation and epilepsy. Moreover, neuropathologic analysis of resected tissue has frequently demonstrated the presence of more subtle malformations that were not identified in vivo.
• Recent progress in human molecular genetics has allowed the identification of several genes whose mutation leads to both malformations and epilepsy. (18)

Felbamate was one of the first modern AEDs to be approved in the US. It was thoroughly tested on animals and subsequently underwent an aggressive marketing campaign. Time magazine even ran an article titled "Taming the Brainstorms." Within months after its launch, in the early 1990s, reports of aplastic anaemia began surfacing. Cases of liver failure and death ensued. Commenting on the side effects, physicians John Pellock and Martin Brodie stressed the exigency for more patient evaluations prior to giving drugs to the general public and thorough post-marketing drug surveillance after drugs are on the market. They did not call for more animal studies. Tragedies due to animal models are far bigger news than putative successes, but they get very little press. Meijer and colleagues stated in 1983,

Unfortunately many AEDs [antiepileptic drugs] show marked pharmacological differences between animals and man... (22)

The National Institutes of Health is using human brain tissue of epileptic patients, obtained during palliative surgeries for this disorder, to study why seizures occur and what medications can be used to treat them. The director of a leading epilepsy research facility in Europe said,

As a scientist, I am of the opinion that animal experiments bring no progress in the diagnosis and therapy of epilepsies. I have a well-founded suspicion that similar facts apply in other areas of medicine.

Pharmacologists learned that iproniazid exerted its effects by inhibiting mono-amine oxidase. Mono-amine oxidase is an enzyme that breaks down norepinephrine. Too little norephinephrine can lead to depression. The class of drugs called mono-amine oxidase inhibitors (MAOI) work because they increase the presence of norepinephrine. Reserpine, a derivative of snakeroot, helped to elucidate the pathophysiology of mental health. Physicians noted that high blood pressure patients who received reserpine became depressed or had mood swings. When they stopped taking reserpine their moods returned to normal. This helped elucidate depression's biochemical basis. But when researchers successfully interrupted reserpine's depressive effects in animals using MAOI and tricyclic antidepressants, it created two monsters: one, the conclusion that depression was a simple matter of depleted monoamines and two, the reserpine animal model. According to scientists who wrestled with these "monsters,"

Most of the approximately one hundred compounds that reached some stage of clinical trials in the last 25 years did so because they could "qualify" on these tests. Gamfexine was the first drug that failed to show a correlation between animal tests and human trials. Its effect on cats was exceptional but it worsened the clinical status of human patients, two of whom had to be prevented from committing suicide. Gamfexine was first in a long line of failures.
...Whether the "censorship" practised by these animal models prevented us from developing chemically novel antidepressants remains an unanswered question. We do know that in the last 25 years not a single compound has been discovered which is unequivocally better in clinical efficacy than the very first drug of this class. It was the very failure of these animal models in screening out ineffective compounds that ushered in the next stage of psychopharmacologic research. (23)

Not all antidepressants work on all depressed people. For instance distinct brain differences, revealed in brain scans, showed that although Prozac reached the right brain areas, the shift in brain metabolism never occurred in some people. This is important, not just to the afflicted, but also to our argument. If subtleties like this affect organisms within one species - humans - why would anything we can borrow from animal models be substantive? Many scientists have recognized and spoken out on the issue of animal testing of psychiatric medications:

Two major points emerge from our reading; the surprisingly poor track record of most if not all animal models to date (a) in accurately predicting clinically effective antidepressants and (b) in generating new and conceptually liberating hypotheses of the pathophysiology of depression. These observations are highlighted by the fact that almost every significant advance in antidepressant drug treatment from the discovery of iproniazid and imipramine to the recently introduced "second generation" class of antidepressants has resulted either from astute clinical observations or serendipity; a far cry from a planned, predictive, screening test. In fact many second generation antidepressants such as iprindol, mianserin, trazodone and salbutamol should be classified as false negatives on the conventional drug screening models (i.e. ineffective during preclinical screening but clinically efficacious). Conversely, a series of compounds, predicted to be at least as effective as imipramine, were reported to be clinically ineffective (i.e. false positives). (24)

Anomalies in research for other psychiatric conditions reinforce the ineptitude of animal models. Scientists have attempted to learn more about panic attacks, for example, by making mice panicky. Consider the following definition from the DSM-IV, which is used by psychiatrists to describe mental-health disorders:

A panic attack is...the sudden onset of intense apprehension, fearfulness, or terror, often associated with feelings of impending doom. During these attacks, symptoms such as shortness of breath, palpitations, chest pain or discomfort, choking or smothering sensations, and fear of "going crazy" or losing control are present.

Now imagine looking for these symptoms in a caged mouse or monkey.

As seen, beneficial research, which has actually helped people with mental illness, historically issues from nonanimal based research. As a direct result of the ineffectiveness of animal modelling of mental illness, clinical psychologists largely ignore studies on animals. (25) A study in 1979 revealed that only 7.5 percent of the articles referenced by scientists contained experiments on animals. A similar study in 1986 revealed that only 33 out of 4425 (0.75 percent) references in the clinical psychology literature were animal studies. In reviewing the 1984 volume of the Journal of Consulting and Clinical Psychology, Kelly found only 0.3 percent of references were animal-based. In reviewing the 1984 volume of Behaviour Therapy, a journal that one would expect to use animal data, Kelly found only two percent of references cited referred to animal models. (26) A study published in the November 1996 issue of American Psychologist reported that only 5.7 percent of clinical psychologists felt that completely banning animal experimentation would be detrimental to their practice. (27) However, the funnelling of grant monies earmarked for mental illness study into animal labs continues. As one scientist sums up,

Many of the psychotropic drugs were discovered by chance when they were administered for one indication and observed to be helpful for an entirely different condition. The history of the development of both the major antidepressants and the antipsychotic drugs points up the fact that major scientific discoveries can evolve as a consequence of clinical investigation, rather than deductions from basic animal [-modelled] research.