National Anti-vivisection Society

 

National Antivisection Society

Parkinson’s Disease: Cutting through the myths

Posted: 14 April 2007

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  • The Background
  • Animal ‘models’ of Parkinson’s
  • Non-animal research
  • Imaging Techniques
  • Molecular models
  • Patient studies
  • Species Differences
  • References

As Oxford University tries to justify the construction of its new animal lab, claims about the value of animal research have been loudly trumpeted – and sadly repeated in the media with little or no critical assessment.

A TV programme last autumn publicised uncritically the work of Professor Tipu Aziz at Oxford University on Deep Brain Stimulation as a treatment for the symptoms of Parkinson’s disease (PD) and other tremor-based ailments. Prof. Aziz is using the procedure on patients at the same time as conducting experiments on monkeys. The experiments involve drilling holes into monkeys’ heads to insert electrodes, and/or administration of drugs(1).

The programme makers and vivisectionists made much of Professor Peter Singer seeming to be wrong-footed into saying that if the tests were as essential as Aziz claimed then they were morally justified. Singer has protested about how he was presented, so we must assume there was something in the edit.

What this and other programmes failed to do was to question the claims in any way. It usually goes like this: Animal researcher makes claim, cut to a patient, cut to unsympathetic shot of animal activists shouting, by way of rebuttal.

Here we provide a more rounded view of the history of Parkinson’s research, how progress has actually been made, the failings of animal models, and the non-animal methods available.

  • The Background

Current treatments for Parkinson’s disease (PD) are unsatisfactory, but none of the progress that has been made depended on animal research. The French clinical researcher Charcot developed the first drug treatments with his patients in the latter part of the nineteenth century. By 1940 a mass of unrelated biochemical research, helped by rapidly developing technology, had revealed the way in which the neurotransmitter (transmitter of nerve impulses) adrenalin was formed in living tissues; the understanding of L-dopa and dopamine; as well as decarboxylase.

Dopamine was soon found in normal brain tissue and in the early 1960s post-mortem studies showed that dopamine was depleted in the brains of PD patients. It was a short step to attempt replacement of the missing dopamine with L-dopa extracted from plants. This clinical research revolutionised the treatment of PD, but in clinical use not all of the administered L-dopa found its way into the brain. Clinical and in vitro studies showed that excess L-dopa in the body converted to dopamine, giving rise to unpleasant side effects. A drug called carbidopa was introduced, which blocks these side effects.

  • Animal ‘models’ of Parkinson’s

In the late 1970s heroin addicts suffered symptoms of PD, and this was traced to contamination of their drugs by another chemical, MPTP. In vitro research showed that this converted to a toxic form and killed brain cells. Injection of MPTP became a standard method of damaging the brains of laboratory rodents and monkeys.

However Parkinson’s is unique to humans(2), slowly progressing, whereas in the artificial lab disease ‘model’, using the drug MPTP, the disease is rapid in its course. There are differences in nerve degeneration and the transmission of nerve impulses in naturally occurring human PD and MPTP-induced PD in animals(3). Also, there are major differences at both the behavioural and neurochemical (nerve chemistry) levels between marmosets and cynomolgus monkeys when administered MPTP, making it impossible to predict with any certainty how results of macaque and marmoset experiments can be applicable to humans(4).

In 1999 the UK government advisory body, the Animal Procedures Committee, voiced concerns about the use of macaque monkeys in MPTP-induced PD. One reason was due to the differences in brain architecture between human beings and macaques, raising doubts about the transferability of results(5).

There are differences between MPTP-induced Parkinson’s in marmoset monkeys and human Parkinson’s patients, e.g., the absence of Lewy bodies in marmosets(5). Previously, the rather poor justification given by researchers for the use of marmosets was their small size. More recently they have cited the difficulty of using marmosets as being that the animals’ brains are too small(6). Despite these drawbacks, the Animal Procedures Committee approved an application relating to PD involving several hundred marmosets in 1999. The planned procedures were rated in the ‘substantial’ severity category of suffering(5).

Deliberately brain-damaged animals have also been used to study tissue transplant techniques. Adrenal tissue transplant methods were successful in rats, but failed totally in clinical use, doing more harm than good.

Transplantation of nerve cells is being assessed in animal models of PD; lesions are made in one side of the brain so that this area is depleted of dopamine, causing the animal to rotate. The cells are grafted at various times up to 6 weeks post-surgery to see if the animal stops rotating. Transgenic mouse models are also being used in PD stem cell research. However when the results from animal experiments were used for human patients, some began to have fits(7).

Deep Brain Stimulation (DBS) is a new treatment, which involves electrical stimulation of the brain8. Contrary to the assertions about animal research made by Professor Aziz and others with a vested interest, DBS was discovered through study of humans, and by chance.

There are two claims to the discovery. The first, that a Dr A Benabid, a pioneer in neurosurgery for movement disorders, made the discovery in Grenoble, France, in the 1960s. Although monkey experiments followed this, the differences between human and monkey brains mean that the only proof that DBS works is by trying it in human patients.

The second claim is that in California in the 1980s a chemistry graduate who was catatonic and unable to move was seen by a psychiatrist. The graduate had been developing an illegal recreational drug by modifying pethidine, and supplying it to friends. One of his ‘customers’ died as a result and, when his brain was examined, it showed damage identical to PD. In the 80s, monkeys were given this so-called Parkinson’s drug and their mobility studied.

In Manchester in 1989, Prof Aziz went further. To test the hypothesis that surgically manipulating the brain’s subthalamic nucleus should benefit PD, he injected a monkey with the ‘Parkinson’s drug’. Then he implanted electrodes in the monkey’s brain, which enabled him to ‘switch off’ the Parkinson’s symptoms. This proved to be the foundation of his neurosurgical work for the next 17 years.

DBS can be used to treat a variety of neurological symptoms, such as tremor, rigidity, stiffness, and walking problems. A surgically implanted, battery-operated medical device called a neurostimulator, like a heart pacemaker, stimulates targeted areas in the brain that control movement, blocking the abnormal nerve signals that cause tremor and PD symptoms. Although most patients still need to take medication after undergoing DBS, many experience considerable reduction of their PD symptoms and are able to greatly reduce their medication. Because DBS does not appear to damage healthy nerve cells, it is hoped that when better treatments are available in the future, the DBS procedure can be reversed. It is a fairly new procedure, with only a few hundred patients treated so far and it is still in trials, as it is not suitable for everyone. It is expensive, costing between £25-£30,000 and many NHS trusts are unwilling to fund it partly because of inadequate research(9).

  • Non-animal research

Currently around one third of drug candidates fail in the first human trials. This is a huge waste. For good medical research we need the precision of modern technology and human-based study, not unreliable results produced by animal experiments. Non-animal techniques are faster, cheaper and more rigorous, such as by allowing for larger sample sizes and greater reproducibility10; highlighting the value of alternative testing for neurotoxicity in the context of regulatory needs(11).

In an opinion poll 46% said that they view medical research using monkeys as unacceptable12. Last year’s TGN1412 drug disaster confirmed such tests are both unethical and misleading. The human volunteers in the trial suffered multiple organ failure; no such effects had been seen in the lab monkeys, who had been given doses 500 times stronger. Yet a safer, non-animal alternative was available – microdosing using Accelerator mass spectrometry (AMS) analysis.

  • Imaging Techniques

Functional magnetic resonance imaging (fMRI) tracks brain activity by monitoring blood flow. This has allowed neuroscientists to understand which areas of the brain are active during specific tasks(13). This can be combined with Magnetoencephalography (MEG) to enable spatial and temporal readings of brain activity, allowing operators to track in human volunteers not just which areas of the brain are active, but when. NAVS/ADI are currently funding an fMRI facility at Aston University through our Lord Dowding Fund research wing.

Positron emission tomography (PET) allows areas of the brain that are active during a specific task, such as thinking or experiencing pain, to be identified(14).

Cortical evoked potentials (CEP) measures the electrical component of electromagnetic brain pulses and MEG measures the magnetic component. In combination, CEP and MEG accurately identify areas of the brain involved in processing information for a specific activity(15).

Transcranial magnetic stimulation (TMS) applies magnetic pulses to the brain, which then stimulate or suppress activity. This has been used to study visual attention, memory and recognition(16).

Scientists supported by our Lord Dowding Fund have developed a new imaging technique known as Synthetic aperture magnetometry (SAM). By measuring electrical and magnetic pulses SAM can identify the region of the brain responsible for signals and their depth when triggered by particular stimuli. SAM is being used to study the experience of pain associated with irritable bowel syndrome and non-cardiac chest pain(17).

Patients in whom PD has been induced with MPTP have had their brains scanned using high resolution PET and the drug fluorodopa(18). Surgical lesions in the brain, located by electrodes while the patient is still conscious, are a normal, common procedure in the treatment of PD and are known to be effective19; behavioural changes in patients in whom corrective lesions for PD have been made have been studied post-surgery by MRI scans of their brains(20); microelectrodes have been used in human patients for detection of the areas where lesions need to be made in the brain, for recording and stimulating. In this way, tremor and movement cells can be located(21); the effect of patients’ movements on the lesioned brain has been assessed in human Parkinsonian patients(22); Parkinson patients have been treated by Transcranial magnetic stimulation(23).

  • Molecular models

Certain strains of Escherichia coli produce amyloid fibres similar to those that accumulate in the brains of Alzheimer’s and other degenerative brain disorder patients. E.coli is therefore used as a molecular model to study amyloid formation during the design of drugs to treat or prevent human amyloid diseases(24).

Brain cells which need dopamine to function and those that do not can be isolated from human foetal brain tissue. Using this molecular model a study was performed to understand why the degeneration of dopamine dependent brain cells occurs in neurodegenerative disorders such as Parkinson’s disease. A particular protein was identified as a causal factor in dopamine dependent brain cell death(25).

  • Patient studies

The Lord Dowding Fund has supported research using Parkinson and schizophrenia patient volunteers to investigate visual abnormalities caused by the failure of dopamine systems in the brain. The effectiveness of potential therapies is assessed by observing the effect on the patient’s vision(26).

  • Species Differences

The use of primates is often justified on the grounds of their physiological similarity to humans. Yet for all that we have in common, there are significant and insurmountable differences(27). Bear in mind that there are even significant differences between marmoset monkeys and macaque monkeys in this field.

The differences in architecture and biochemical responses between human and monkey brains means that human forms of neurological disorders cannot be completely replicated in an animal. Other primates are distinct from us in the way they express genes in the brain (’expression’ of a gene is the activity or product that the gene causes to occur in the body). There are even big differences in gene expression between humans and chimps, although gene expression between chimps and other primates is similar(28).

Criticism of primate research is long-standing. Researchers at the Salk Institute and the University of California wrote: “What is known about the neuroanatomy of the human brain? Do we have a human cortical map corresponding to that for the macaque? And what does the human equivalent of the connectional map look like? The shameful answer is that we do not have such detailed maps because, for obvious reasons, most of the experimental methods used on the macaque brain cannot be used on humans. For other cortical regions, such as the language areas, we cannot use the macaque brain even as a rough guide as it probably lacks comparable regions” (29).

Human brains have a folded cerebral cortex (a gyrencephalic brain) whereas smaller primates, such as the marmoset, have a smooth cerebral cortex (a lissencephalic brain). Not only are there anatomical differences between the two types of brain but evidence suggests that there are functional differences, too(30). In 2004, scientists discovered that entire brain areas of the rhesus monkey were “very different” to our own(31). Other researchers have reported that often, areas in the brain that appear to have one function in monkeys simply do not have the same role in humans(34). In 2005 London researchers blamed “remarkable species differences” for the failure to apply primate findings to human brains(32).

The role of the hippocampus in human memory was complicated for a time by findings from behavioural studies of monkeys and other animals with hippocampal lesions, until its role was established in 1986, from human study(35).

Researchers in Denmark and the USA compared genes found in humans to their equivalent genes in chimpanzees. They found that the genes that differ the most between humans and chimpanzees are those related to immune defence and cancer development(33). Yet the biggest area of primate research (on primates even more distant to us than apes) is in drug testing.

The processes involved in behavioural responses in humans are known to be more complex than in other species(36), and no animal species reacts to behaviour altering drugs in the same way as a human being would37. For example caffeine, which can induce panic attacks in people, has conflicting results in animal models of anxiety(38).

An anti-Parkinson’s disease drug, tolcapone (Tasmar) was withdrawn from the market in 1998 after links to deaths from liver disease(39). Clinical trials of a potential Alzheimer’s vaccine were suspended when participating patients began experiencing nervous system side effects(40). The vaccine had been hailed as “revolutionary ..following encouraging tests on animals” (41).

Next time you hear a vivisector making spurious claims about their work, check out our website and challenge them on the facts.

  • References:

1. The Guardian, 4 March 2006.
2. Br. Journal Hosp Medicine, 1990, 43:327)
3. MRMC. Perspectives on Medical Research, 1991, 3:35-46
4. Br J Pharmacology, 1992. Vol 107, Proceedings suppl. 300P
5. Report of the Animal Procedures Committee 1999: The Stationery Office
6. The great primate debate. Nature, 13 June 2002; 417:684-687
7. Stem Cells, Royal Society Conference, 21,22 June 2001
8. Brain and Cognition, Mar 2000, 42 (2); 231-52 and 268-93
9. Saga, Sept 2004
10. Coecke S. et al. (2006)
11. Environmental Toxicology and Pharmacology 21: 153-167
12. UK MORI poll (2002) http://www.mori.com/polls/2002/pdf/cmp.pdf
13. Nature, 417, 9 May 2002: 114-116
14. The Campaigner, September to December 2000: 98-99 & Strange PG, Brain Biochemistry and Brain Disorders, Oxford University Press 1992: 151-154
15. The Campaigner, September to December 2000: 98-99
16. Nature, 417, 9 May 2002: 114-116
17. The Campaigner, September to December 2001: 81.
18. J Neurology, Neurosurgery and Psychiatry, Mar 2000, 68 (3):276
19 J Neuroscience Methods, Mar 15 2000; 96(2):113-117
20. Movement Disorders, Sep 1999; 14 (5): 780-9
21. Neurosurgery, Mar 2000; 46 (3) 613-624
22. Brain, a Journal of Neurology, Apr 2000; 123: 746-58
23. Journal of Neuroscience Research, Sep 15 1999; 57 (6): 935-40
24. SCRIP, 2719, 8 February 2002: 26
25. Nature Medicine, 8(6), June 2002: 600-606
26. Lord Dowding Fund Summary of Research Projects 1973-1993
27. Bailey J., Knight A and Balcome J (2005). The future of tereatology research is in vitro. Biogenic Amines 19(2): 97-145
28. Pennisi, E. Science, 12.04.02; 233-235
29. Crick, F and Jones, E. Nature, 1993; 361: 109-110.
30. Smith, JM et al. Journal of Anatomy 2001; 198: 537-554
31. Orban GA, Van Essen D& Vanduffel W (2004). Comparative mapping of higher visual areas in monkeys and humans. Trends Cogn. Sci. 8:315-324 & Denys K et al (2004). Visual activation in prefrontal cortex is stronger in monkeys than in humans. J. Cogn. Neurosci. 16:1505-1516
32. Lemon R.N. and Griffiths J. (2005) Comparing the function of the corticospinal system in different species: Organizational differences for motor specialization? Muscle & Nerve 32 (3): 261-279
33. Nielsen R. et al. (2005), A Scan for positively selected genes in the genomes of humans and chimpanzees PLoS Biology, June; 3(6): e 170
34. Scientific American, editorial, March 2000: 11-12
35. Squire, LR & Zola-Morgan, S. Science 1991; 253: 1380-86
36. Russell, WR (1963) The Lancet 1: 1173-77
37. Brimblecombe, RW. In: Modern Trends in Toxicology, Vol.1, Eds. Boyland, E; Goulding, R. Butterworths 1968: 157-158
38. Nadel, RA et al. (1993) Behavioural Pharmacology 4: 501-508
39. SCRIP, November 1998: 6-7
40. SCRIP 2724, 27 February 2002: 23 & SCRIP 2726, 6 March 2002: 23
41. Liverpool Daily Post, 7 June 2001: 18

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