Experiment 1: Brain damaged monkeys set thousands of tests

Six macaque monkeys at Oxford University were placed in small, individual cages in front of a computer screen, where they had to identify blue squares among green ones (or vice versa) several thousand times. In return, they received small food rewards. Then four of the six had different parts of the visual cortex of their brains removed and were subsequently re-tested several thousand more times. A key purpose of this experiment was to confirm the role played by particular parts of the brain in a phenomenon known as 'priming'. This is where an advantage is conferred on a subject when undertaking subsequent repetitions of a previously learned response. This information was already known from studies in humans. The researchers here could clearly have obtained these results from scanning human brains engaged in visual tasks. It is difficult to imagine benefits from this experiment significant enough to justify the enormous suffering of the animals involved.

Funded by the Medical Research Council

'Normal discrimination performance accompanied by priming deficits in monkeys with V4 or TEO lesions'; V Walsh et al; NeuroReport 2000 Vol 11, Issue 7, p1459-62

Experiment 2: Brain damage tests last nine years

As part of a long-term study at Oxford University involving at least 20 monkeys, three macaques had part of their brains' visual cortex removed and were then tested at various times on a variety of visual tasks. The tests lasted for as long as nine years, by which time the three monkeys had died. As recognised from previous such research, the Oxford team found that the extent of visual damage varies even amongst monkeys with a similar level of deliberately inflicted brain damage. This is because the size of key parts of the brain are different in individual monkeys and different again in humans. Age when the surgical damage is inflicted and length of post-operative survival time also have an impact on the extent of the visual damage found. The results posed many more questions than answers but the researchers believed their experiments confirmed what had been already concluded from experiments by other research teams: namely, that the visual damage being studied in these surgically mutilated monkeys probably arose from differences in the number of cells in the different regions of the brain.

Human head injury victims are, sadly, all too numerous, and would clearly be the ideal research subjects to speed progress into possible treatments for their own condition. Not only may non-invasive investigation of such patients yield vital clues and enable them to help themselves and others in their condition, but countless primates could be spared years of suffering and misery.

Funded by the Medical Research Council.

'Transneuronal retrograde degeneration of retinal ganglion cells following restricted lesions of striate cortex in the monkey'; H Johnson and A Cowey; Experimental Brain Research 2000 Vol 132, Issue 2, p269-75

Experiment 3: Brain-damaged monkeys' hands immobilised with sticky tape

At Cambridge University, 12 marmosets each received ten or more separate injections of a seizure-causing chemical directly into two regions of their brains. After recovery from their post-operative seizures, they were assessed for dexterity on a battery of tasks over the course of the following nine months, before they were killed and their brains removed for analysis. Some of the tasks called for them to reach for and retrieve food 'rewards' - sometimes with one hand covered in gauze and immobilised by sticking plaster. The researchers noted that the brain damage caused 'clumsiness' and dropping of food. In other tests, the monkeys feet were bound in sticky postal labels. The researchers checked how long it took to bite and tear their way free.

The most oppressive test involved injecting the marmosets with amphetamine or apomorphine. The second drug caused the brain-damaged animals to spin uncontrollably in their cages - as many as 300 times in a 60 minute session. The drug is also believed to have provoked some of them into repeatedly licking the front panel of their cages. The researchers acknowledged that they don't know why the spinning happens but regard it as a useful measurement of brain damage.

The team says their experiments were aimed at advancing treatment of Huntington's Disease. Although they admitted that the brain damage they inflicted 'did not... replicate the pathology or the symptoms of Huntington's Disease' they have now learned how to inflict two particular types of brain damage in marmosets - one of which, they claimed, resulted in a predictable kind of impairment of movement and co-ordination. This brain-damage 'model', along with the research team's battery of tests, would be useful for future studies of potential treatments for Huntington's. These experimental treatments would include the transplantation of foetal brain cells 'harvested' from pregnant marmosets and injected into more deliberatedly brain-damaged adults.

Moral questions aside, the study is scientifically flawed since it is looking at a totally false simulation of a human condition. The same is true for similar research into Alzheimer's and Parkinson's Diseases, as in the experiment described below (Number 4). It is human-based observations that have established the biochemical basis of these neurological illnesses and which will provide targets for possible therapies in the future.

Funded by the Medical Research Council.

'The influence of excitotoxic basal ganglia lesions on motor performance in the common marmoset'; AL Kendall et al; Brain 2000 Vol 123, Part 7, p1442-58

Experiment 4: Daily injections cause nerve damage

The stated aim of this experiment - conducted at Guy's, King's and St.Thomas' School of Biomedical Sciences in London - was to investigate how chemicals in the human brain act to enhance the effects of drugs given to sufferers of Parkinson's Disease. In an attempt to mimic certain Parkinson's symptoms, 18 marmoset monkeys were nerve and brain-damaged through daily injections - over five days - of a toxic chemical. The animals suffered a range of motor dysfunctions, including freezing of movements, tremor, loss of control and unstable posture. They were also unable to vocalise.

The marmosets were then subjected to further nerve and brain damage through injections of another toxic chemical that is assumed to disrupt production of a hormone believed to work beneficially with Parkinson's drugs.

The injection of this second toxic chemical - known as NSD-1015 - caused several hours of vomiting in all the animals. Various drug treatments were then tried on the doubly-damaged monkeys to see which ones improved motor function.

The two categories of drugs being tried were L-DOPA and what are known as dopamine agonists. The monkeys' movements were monitored for up to 12 hours in tiny observation cages, to see which drugs were best at restoring some of the impaired movement. At least one of the drugs elicited reactions opposite to those produced in rats. 'The reason for this conflicting result is unclear', the authors admitted.

Given that the experiment was about complex questions as to precisely how and why certain drugs work on human beings with Parkinson's Disease, it makes no sense to be testing the drugs on another species whose chemically-induced nerve and brain damage resembles the disease in humans in only the most superficial manner.

In order to avoid such conflicting results between different species, the information being sought here could be investigated in donated human brain tissue. The Humane Research Trust funds such studies at the Cambridge Brain Bank at Addenbrooke's Hospital, using tissue from the brains of patients who - for the sake of others - wanted to help research into the condition from which they suffered.

Funded by the Parkinson's Disease Society.

'The effects of central aromatic amino acid DOPA decarboxylase inhibition on the motor actions of L-DOPA and dopamine agonists in MPTP-treated primates'; SA Treseder et al; British Journal of Pharmacology 2000 Vol 129, Issue 7, p1355-64.

Experiment 5: Food tests for brain-damaged marmosets

The Wellcome Trust and the Royal Society funded experiments at Cambridge University that involved damaging the brains of at least 15 marmoset monkeys (the total used isn't made absolutely clear) and then putting them through a series of meticulously devised and executed torments. The stated purpose was to establish which parts of the brain control functions such as choice, emotion and behaviour. Four of the monkeys were 'sham-operated controls' - meaning that they were injected in their skulls with an inert chemical. This is despite the fact that the Home Office discourages unnecessary surgical 'control' procedures.

Having inflicted 'selective lesions' to various parts of the brain, the monkeys were set three kinds of tests. In one, they were trained to reach into a transparent box and retrieve a food reward. Another called for them to make food choices. The third test involved them being trained to press a computer screen to get a food reward. But having been conditioned to expect a reward for each screen touch, the researchers, without warning, withheld the rewards and counted how many times the brain-damaged monkeys would carry on vainly pressing the screen - some of them pushed more than 50 times, it seems. In relation to all these perform-and-reward experiments, the question begs itself: How hungry were the monkeys made prior to the testing so that they would perform for their 'rewards'?

There is simply no reason to suppose that complex human emotion and behaviour can be ascribed to the same structures as those in marmosets' brains. In fact, this study was prompted by the conflicting behavioural responses between brain-damaged macaques and humans. The only way to ascertain which brain regions are involved in specific human thought processes and abilities is to study the human brain. Functional MRI scanners can monitor the brain activity of volunteers as they undertake tests of memory and other skills, to reveal brain areas that are active during particular activities. Transcranial magnetic stimulation (TMS) is a new technique which temporarily disrupts the functioning of the brain, allowing scientists to assess the impact of 'switching off' specific regions without permanently removing them. The Dr Hadwen Trust for Humane Research is funding such studies at Oxford University.

'Inhibitory control and affective processing in the prefrontal cortex: neuropsychological studies in the common marmoset'; AC Roberts and JD Wallis; Cerebral Cortex 2000 Vol 10, Number 3, p252-62

Experiment 6: 32 brain injections with destructive chemical

At Oxford University, six cynomolgus monkeys twice underwent major brain surgery, five days or more apart. This was to inflict 16 lesions on one side of the brain, followed by 16 more to the other hemisphere. The damage was done by injecting a destructive chemical - one injection for each of the 32 lesions. The effects were assessed through literally thousands of cognitive tests that called for the animals to move a joystick or touch a screen in response to a given image. The 'reward' for a correct response was pelleted feed. One of the authors - R.E. Passingham - was a Mad Science Award winner in 1997 for another series of experiments on monkeys. This again involved the animals being seriously brain-damaged, after which they were deprived of food and set a 'frustration task', whereby food was visible to them but could not be reached. The animals resorted to biting their own limbs and licking the bar gates.

This latest experiment, first highlighted by the National Anti Vivisection Society, ended with all the animals being killed and their brains extracted for analysis. It was said to be aimed at establishing whether a part of the brain called the cerebellum plays a direct role in cognition -i.e. in the thinking, conceiving and perceiving actions of the mind. By the end of their experiment, the authors decided against the idea of the cerebellum having a cognitive role. However, the data yielded by these monkey experiments flatly contradicted results obtained in tests on brain-damaged human patients, and the authors' attempts to explain the anomalies merely strengthened the argument against using animals for such tests. One 'explanation' was that human patients might have additional difficult-to-discover brain damage, which would upset the results. But long-term studies on humans, that also included autopsies, would resolve this question. Another excuse was that people have variable IQs which affect their performance of the tests - but so do monkeys, as illustrated by the variable performance of the monkeys in the authors' own experiments. And there was the further confounding factor in these current tests - namely, the impossibility of inflicting uniform brain damage, in order to extract uniform data. The only way to investigate human brain functions is to study the human brain.

'The cerebellum and cognition: cerebellar lesions impair sequence learning but not conditional visuomotor learning in monkeys'; PD Nixon and RE Passingham; Neuropsychologia 2000 Vol 38 p1054-72

Experiment 7: Monkeys and cats in open-skull 'stroke' research

At Guy's, King's College and St. Thomas' Hospitals School of Medicine, London, SmithKline Beecham, HeadFirst and the Golden Charitable Trust sponsored 'stroke research' using five squirrel monkeys and eight cats. The animals were subjected to open-skull experiments, during which they were artificially ventilated via tracheostomy (a tube into the windpipe), while their cerebral arteries were exposed, cauterized (to simulate a stroke) and monitored for five hours. Anaesthesia throughout the experiment was maintained at a very low level. The animals were then killed with an overdose of anaesthetic.

The aim of the experiments was to investigate specific tissue changes (known as PIDs) that occur in animals in whom 'stroke' has been artificially induced, despite the fact that these particular changes might not even occur in human stroke victims.

The researchers also acknowledged that previous research showed that PID frequency varied from animal to animal and from species to species. While their own brain-damaged cats and monkeys did show individual variations, the authors had expected to find fewer PIDs in the monkey group as a whole compared with the cat group. This was because, the logic went, monkeys are more like humans, in whom PIDs don't seem to occur - or at least, can't easily be detected. In fact, the PID frequency was similar in the cat and monkey groups - an outcome the researchers struggled to explain. Their best effort was along the lines: although monkeys are like people (which is why we used them for this experiment) the particular primate species we used - squirrel monkeys - have very small brains compared with humans. In fact, their brains are about the same size as cats'. This explains why the PID frequency was similar for the cats and the squirrel monkeys. But their answer doesn't explain why they are being paid to brain-damage monkeys instead of the resources going into studying consenting human patients, before and after their deaths.

Based on the confusion thrown up by such inter-species experimentation, the authors themselves admitted that it is unsurprising that clinical trials of stroke medications based on animal models 'should have proved unsuccessful to date'.

'Factors influencing the frequency of fluorescence transients as markers of peri-infarct depolarisations in focal cerebral ischemia'; AJ Strong et al; Stroke, 2000 Vol 31, Issue 1, p214-22

Experiment 8: Brain-damaged marmosets tested in plexiglass enclosures

Nine marmosets at Cambridge University were subjected to open-skull surgery to induce artificial 'strokes'. This was achieved by blocking and cutting the middle cerebral artery; hardly an accurate replication of the disease process in stroke patients, which takes many years to develop. Twenty-four hours later, four of them were operated on again to insert a mini-pump between their shoulder-blades for the delivery of an anti-stroke drug. This mini-pump device soon needed replacing, which meant a repeat operation for the animals and the introduction of another pump. In the first weeks after surgery, the monkeys often held the arm affected by the brain-damage close to their chest or left it to dangle.

Three weeks and ten weeks post-surgery the monkeys were put into small plexiglass enclosures and set various behavioural tasks, which included searching and reaching for marshmallow pieces hidden in plastic tubes. Twenty weeks after surgery all animals were killed and their brains extracted for analysis.

The stated purpose of the experiment was to test the effectiveness of a drug, chlomethiazole, on the debilitating after-affects of stroke. The authors commented that clinical trials of drugs developed through studies on rats had been hampered because 'it is inherently difficult to extrapolate the findings from rodent studies'. But there emerged obvious problems too with their primate 'model'. When the monkeys were put through their first tests three weeks after surgery, although they had problems with the thoroughly unnatural tests set them by the vivisectors, they were able to do - almost as normal - things that come naturally to a monkey: i.e. run, climb, swing and jump. This outcome makes comparisons with human stroke patients impossible, given that it is precisely their normal everyday movements with which the stroke patients have problems.

Perversely, the 'anti-stroke' medication used in the experiments had already been tested, with a positive outcome, in stroke patients in a large (1360 patients) controlled trial, whose results were published the previous year. The purpose of this study, then, was to try to reproduce in another species the protective effects of a drug which had already been reported to work beneficially in humans.

The research team combined personnel from the government's Medical Research Council and the commercial drug giant Astra Zeneca.

'Clomethiazole protects against hemineglect in a primate model of stroke'; JWB Marshall et al; Brain Research Bulletin, 2000 Vol 52, Issue 1, p21-29

Experiment 9: Marmosets as models of human fertility and reproduction

At the MRC reproductive biology unit in Edinburgh, 20 female marmosets were injected three or more times a week with antibodies or a 'control' chemical. They also had blood samples taken from their thighs three times a week - a procedure which can be very stressful for marmosets. The animals were then killed for examination of their ovaries.

The researchers say that the main purpose of the experiment was to explore the impact on the reproductive tissue of an antibody designed to suppress the production of blood vessels. The use of such antibodies and other chemicals that block blood vessel growth (known as angiogenesis inhibitors), are increasingly being investigated as a treatment for conditions as varied as cancer, rheumatoid arthritis, psoriasis and proliferation of blood vessels in the eye.

In fact, angiogenesis can be studied in human tumours in vitro; indeed, the phenomenon is currently the subject of much research supported by the Lord Dowding Fund for Humane Research and many others.

The problem with this featured experiment, as always, is applying results from one species to another. As the authors acknowledge, an angiogenesis inhibitor that, in earlier experiments, prevented pregnancy in rodents had no effect on monkeys, in whom the mechanisms regulating oestrus are 'markedly different'. Yet the basic premise of this experiment is that results from marmosets can be directly extrapolated to women.

'Suppression of luteal angiogenesis in the primate after neutralization of vascular endothelial growth factor'; HM Fraser et al; Endocrinology 2000 Vol 141, Issue 3, p995-1000

Experiment 10: Xenotransplantation of pig organs into primates

At Huntingdon Life Sciences, 14 cynomolgus macaques underwent major surgery to remove their spleens and one of two kidneys, and have them replaced with a kidney taken from young (3-4 week-old) piglets. Nine of the piglets had been been genetically altered so that their organs were less likely to be immediately rejected when transplanted into the monkeys. After the transplants, the monkeys were injected or force-fed by tube every day with a powerful cocktail of drugs designed to suppress their bodies' natural tendency to reject the foreign kidneys. The researchers monitored their symptoms until they died - and claimed the experiment was a success because not all the monkeys perished within the first few days. Maximum survival was one monkey for 78 days.

The experiment was part of a long-running organ swap programme commissioned by biotech company Imutran and carried out at Huntingdon. Hundreds of monkeys - many of them wild-caught - and thousands of pigs have been involved. The animal suffering and scientific failings of the project were exposed in a September 2000 Daily Express series of articles, based on internal company documents. Imutran subsequently went to court to gag anti-vivisection group Uncaged Campaigns which had produced a major report on the leaked documents. That legal battle continues.

The experiment featured here - one of a small number to have been published - was also designed to see whether removing the monkeys' spleens would delay the time taken for the pig organ to be rejected. Average survival time for the monkeys with kidneys from genetically altered pigs was just 35 days. The average survival time for all 14 monkeys was 24 days. And this miserable 'success' was achieved only by giving the monkeys heavy doses of three toxic anti-rejection drugs. Among the 'adverse events' logged by the authors were vomiting, diarrhoea, a build up of fluid in the body tissues, pancreatitis, gastro intestinal haemorrage, anaemia and kidney failure.

'Long-term survival of nonhuman primates receiving life-supporting transgenic porcine kidney xenografts'; E Cozzi et al; Transplantation 2000 Vol 70, Issue 1, p15-21

The cache of leaked internal documents, acquired by Uncaged Campaigns and reported from September 21, 2000 in the Daily Express, revealed much more of the story behind the supposed 'success' of the researchers responsible for the xenotransplantation experiment above. Many of the monkeys, the Express reported, had been captured from the wild and imprisoned in tropical holding camps, where some of them died. They were then transported for 35 hours or more in tiny cages in which some of them suffocated en route. After quarantine, the experiments began. Various organs from genetically manipulated pigs were transplanted into different parts of the monkeys' bodies - including hearts being stitched into their necks so that the rejection process could be easily watched. A lucky 25% of monkeys died on the operating table or shortly afterwards. In one experiment, 33 out of 61 monkeys died within 24 hours of a transplant due to 'technical failures'.

The 'survivors' were subjected to quantities of immunosuppressive drugs, in an attempt to stave off the inevitable rejection process. The drug doses were so large as to be severely poisonous. The daily log recorded their condition over their last agonising weeks. A typical entry read: 'quiet... huddled... shivering... unsteady... in spasm... vomiting... diarrhoea.'

A typical casualty was a baboon with a pig heart stitched into his neck. He was observed, during his last days, holding the swollen surgical wound from which yellow fluid seeped.

The internal company papers also pointed to serious errors and bad practice. Said the Express report:

'The documents show animals have been wrongly re-used in experiments, medicines have been left unlabelled and uncapped, and on hundreds of occasions scientists have failed to take readings and measurements from animals following operations... A monkey perished because a swab had been left inside his wound during the operation, causing his spleen to go septic. Another had to be "sacrificed" when researchers discovered the pig kidney it was to be given had been frozen by mistake.'

And a female monkey, the paper reported, had to be euthanased the day after she was given a dose of a drug four times higher than recommended.