Paper 1: Background information on theuse of non-human primates
Controls on the use of non-human primates 1.1 Controls on the use of non-human primates in research and testing in Britain
In Section 5(6) of the Animals (Scientific Procedures) Act 1986 (ASPA), which regulates the use of laboratory
animals in Britain, special mention is made of the use of non-human primates (as well as cats, dogs and equidae), in
that a project licence for use of these species will not be granted unless ‘no other species is suitable…or it is not
practicable to obtain animals of any other species that are suitable for those purposes’.
(ii) All applications for project licences to use non-human primates in procedures of substantial severity and to use
wild-caught primates must come before the Government’s statutory, independent, advisory committee on animal
experiments, the Animal Procedures Committee (APC).
(iii) During 1996, further measures on the acquisition and use of non-human primates were introduced under the terms
of the Animals (Scientific Procedures) Act, such that:
the use of wild-caught primates is banned, except where it can be exceptionally and specifically justified;
special justification is needed for the use of Old World rather than New World primates;
similarly, special justification is needed for the use of Old World primates in toxicological procedures of more
primates can only be imported from overseas breeding or supplying centres which have been approved by the
transport arrangements for such animals must also be approved by the Home Office.
(iv) In addition, a ban on the use of Great Apes was introduced in November 1997.
(v) A sub-group of the APC, the Primate Sub-Committee, advises the APC on matters relating to the acquisition,
housing, care and use of non-human primates in scientific procedures. Recently, the Sub-Committee has taken on a
more ‘strategic role’ and ‘will lead on issues such as:
how to minimise, and eventually, eliminate primate use and suffering;
acquisition of primates (availability of primates in the UK, the suitability of overseas sources and transport
the use of wild-caught primates (should this be allowed at all and, if so, what should constitute the specific and
exceptional justification needed if such use is to be authorised);
the use of primates in regulatory toxicology’ (Home Office, 1998). 1.2 Specific controls on the use of non-human primates in research and testing in the EU
The EU Directive and Council of Europe Convention for the protection of animals used for scientific purposes include
very little specific reference to the use of non-human primates. The Directive contains only two specific references,
concerning the identification of non-human primates (along with dogs and cats, they must be individually marked for
identification before weaning or as soon as possible after arrival in the establishment) and their origin (they must be
specially bred unless special exemption is made). The Convention contains no such references (see Jones, 1996). Scale of use of non-human primates in research and testing 2.1 Use of non-human primates in Britain
In 2000, 2951 non-human primates were used in scientific procedures in Britain, representing 0.11 per cent of the total number
of animals used in that year (Home Office, 2001). The primate species involved are shown in Table 1. No Great Apes have been
used since ASPA was introduced, and, as noted, the use of Great Apes has been formally banned since November 1997. Table 1: Number of non-human primates used in scientific procedures in Britain in 2000 Number of animals * In addition, in 2000, 24 squirrel, owl or spider monkeys continued to be used in procedures begun in 1998 # Baboons are used occasionally - most recently in 1998, when four baboons were used in immunology studies
The reasons for using these animals are shown in Tables 2 and 3. Seventy-six per cent of the non-human primates used
in 2000 were involved in toxicological studies on pharmaceutical substances (see details in Table 3), 7 per cent of the
animals were used in non-toxicological applied studies in human medicine or dentistry, and 16 per cent were used in
fundamental research. The last mainly comprised studies on the nervous system or special senses (49 per cent of the
fundamental research procedures), and on the reproductive system (19 per cent). Table 2: Reasons for using non-human primates in scientific procedures, Britain 2000 Species used Table 3: Number of non-human primates used in toxicology studies in Britain in 2000 Pharmaceuticals
* absorption, distribution, metabolism and excretion tests.
Paper 1: Background information on the use of non-humanprimates (continued)
It was reported that 99 per cent of the toxicological procedures were carried out in order to meet regulatory authority
2.2 Use of primates in elsewhere
The UK and France, together with Germany and the Netherlands, are the main users of primates in research and testing
in the EU – at least 80 per cent of reported primate use takes place in these countries (Jones 1996, Ruhdel & Sauer
1998, European Commission 1999). The species involved are mostly monkeys (see Table 4), but in 1996 (latest available
statistics), both Belgium and Austria reported using apes (species unknown), and the Netherlands reported using 1082
‘simians’, which could have included apes. Table 1: Use of non-human primates for scientific purposes in EU countries, 1996. Total number of Of which: non-human primates Prosimians used in 1996 (lemurs etc) Denmark, Finland, Greece, Spain and Sweden also used non-human primates, <60 each in 1996
The USA, together with Japan, is the main world user of non-human primates in research and testing, including Great
Apes. The United States Department of Agriculture collects annual statistics on the use of laboratory animals, but there
is considerable under-reporting. The most recent statistics show that at least 57,000 non-human primates were used in
3 Case studies in the use of monkeys in ‘fundamental’ research Three examples of the use of non-human primates in research are presented here, in order to illustrate the kinds of
fundamental and more applied benefits that might be sought from such work. Paper 5 also gives some examples of the
use of non-human primates in toxicological studies.
The case studies are summaries of presentations given by scientists using monkeys in research, who described their
work (or the work of colleagues) to the Boyd Group. Case Study 1 A university physiologist described work carried out mainly in the USA, aimed at understanding how the brain makes
perceptual decisions about the movement of visual stimuli. (British researchers collaborated in some of the studies, and
similar work is carried out in the UK).
Recordings from single neurones in the middle temporal (MT) area of the cerebral cortex of the brain (a visual area of
the brain) of conscious monkeys were made at the same time as the monkeys made decisions about the net direction of
motion of patterns of dots displayed on oscilloscope screens. The monkeys were trained to discriminate the directions
of motion of the patterns of dots (up vs. down; right vs. left), and to indicate their judgements by making an eye
movement to one of two light-emitting detectors, corresponding to the two possible directions of motion in a given
trial. When trained, the monkeys performed this task with more than 95 per cent accuracy for strong motion signals.
The patterns of dots could be manipulated by the researchers, so that the net direction of the motion was less obvious
and the monkeys had to make more considered decisions about the overall direction of the stimulus.
It was already known that more than 90 per cent of the neurones in the MT area are ‘directionally selective’, responding
only when the direction of motion of the visual stimulus is in their ‘preferred’ direction. Surprisingly, the studies
described above showed that individual MT neurones detected the direction of movement with a statistical reliability
equivalent to that of the animal’s perceptual judgement about the direction of motion. In other words, the way in which
only one neurone (or a small group of neurones acting together) responded matched the whole animal’s behaviour. Not
only this, but the researchers found that stimulating tiny groups of these neurones with extra electrical impulses could
bias an animal’s judgement. In summary, the work showed that the correlated activity of small pools of neurones in the
MT area of the brain accounted for the accuracy of the animals’ judgements about the direction of a visual stimulus.
Following from this, questions for consideration included:
where in the brain were these decisions made? – recordings from pathways that link MT to the oculomotor
planning centres of the brain could be used to investigate this;
(ii) were the neural structures underlying the decision process different in monkeys trained to indicate their decisions
Non-invasive brain imaging techniques were not suitable for this work, because they measure differential blood flow in the
brain, which is related to the total activity of the neurones in a given area of the brain, and therefore they cannot
discriminate responses at the level of individual neurones. The studies described above can be regarded as complementary
to brain imaging work, and can help to explain what the results of brain imaging mean at the neuronal level.
Other than this, no direct applications are foreseen for the work, which was primarily curiosity driven and was carried out in
order to gain scientific understanding. However, it might be envisaged that better understanding of the neurological
mechanisms involved in visual perception could provide a foundation for future advances in treatment of human visual
disorders caused by disorders of brain function. This fundamental research was described as ‘potentially Nobel prize-winning’.
Most of the work was carried out using three monkeys. Non-human primates were used because of their similarity to
humans and their ability to be trained. It was argued that there were no other suitable models for humans at the level of
cerebral and cerebellar organisation, and the work was only possible with stump-tailed monkeys and rhesus macaques,
because of their abilities to perform the tasks.
It would not have been possible to carry out the experiments on human subjects, because the work involved implanting
electrodes into the brain. The animals had to sit in primate chairs for the recording sessions and were required to hold
their eyes steady during the presentation of each visual stimulus, so that the pattern of dots was detected by the
particular ‘receptive field’ of the brain neurones from which recordings were being made. To check that this was the
case, the monkeys’ eye positions were measured using the ‘scleral search coil technique’, in which tiny magnetic coils
were inserted around the corneas of the animals’ eyes and the position of the eyes were detected using magnetic coils
Paper 1: Background information on the use of non-humanprimates (continued)
which surrounded the animals during the experiments.
It was reported that the animals participated eagerly in the experiments, climbing into the primate chairs, helping to set
up the recording apparatus on their heads, and starting the electronic tasks they were provided with. However, the
monkeys were also deprived of water before each experiment, so that they were thirsty at the start of the recording
sessions. They were ‘rewarded’ for correct choices with sips of water or fruit juice, and incorrect choices resulted in
brief ‘time out’ sessions between trials. Case Study 2 Two university researchers, one a physiologist, the other a clinician, described their long-standing research programme
on how the brain controls movement, which involved the use of rhesus monkeys. Although much of the work could be
said to be ‘fundamental’ research, all of it was carried out with a view towards improving human treatments.
work on the motor effects of temporary inactivation of the parietal cortex of the brain, studying (in particular)
how visual stimuli are converted to eye movements. (In human patients, damage to the parietal cortex causes
patients to cease to attend to visual stimuli). Serendipitously, this work had implications for the study of dyslexia,
since the resulting altered eye movements bore striking comparison to the eye movements of dyslexic children;
recording from and studying the effects of temporary inactivation of regions of the cerebellum. Again, there were
potential benefits from this basic research, in that
– dyslexic children have a mild disorder of the cerebellum (which is innervated from the parietal cortex), and
– the cerebellum and its in/outputs are frequent sites of lesions in multiple sclerosis, so the work was leading to
treatments for patients suffering movement disorders due to MS;
studying the control of movement by the brain stem, working towards better treatments for Parkinson’s disease.
MPTP-treated monkeys provided good models of human Parkinsonism, and were being used to develop
treatments involving lesioning, cooling or stimulating specific parts of the brain, so as to alleviate motor symptoms
Non-invasive brain imaging studies were not suitable at present, because the techniques were limited in their spatial and
temporal resolution, operating at a scale orders of magnitude larger than that required to examine the single cell
responses being investigated. Imaging studies did not allow study of how brain processes worked, only where the
Non-human primates were considered to be the best available animal models for this work, because their visual and
motor control is very similar to humans’. The rhesus monkeys were trained in the tasks they were required to perform
and the researchers reported that a relationship developed between researcher and monkey. Also that, since the monkeys
were required to co-operate with the researchers, it was in everyone’s interests to reduce any animal suffering as far as
possible. MPTP caused periods of discomfort for the monkeys. However, it was reported that only mild symptoms were
induced, and any further symptoms were relieved by administration of L-DOPA. Marmosets were considered less suitable
for work on Parkinson’s disease because they lack neuromelanin in their brains, resulting in unstable disease states.
Furthermore, they could not be trained like Old World monkeys. Thus, although marmosets were considered useful in
studying acute, pharmacological, interventions, they were not regarded as suitable for this kind of surgical work. Case study 3 A clinician and academic researcher described his studies on the effects of increased maternal steroids (specifically the
‘stress’ hormones, glucocorticoids) on later disease in low birth weight babies. Widescale, worldwide, epidemiological
studies had shown that lower birth weight babies had increased risk of developing hypertension, diabetes and a whole range
of other diseases later in life. Long-term excess of glucocorticoids (Cushing’s syndrome) also caused such diseases, and
increased maternal glucocorticoids were known to reduce birth weights. Taken together with many other data, these
findings suggested (i) that the practice of routine administration of glucocorticoid (specifically, long-acting dexamethasone)
to prevent premature delivery in at-risk mothers could lead to later disorders and (ii) that deficiency of the natural enzyme
‘barrier’ in the placenta to maternal glucocorticoids may explain the link between low birth weight and later disease. In vivo
experimental work supported this suggestion: when mother rats were given dexamethasone or inhibitors of the placental
enzyme barrier they produced low birth weight young, which grew rapidly to catch up with their peers, but always remained
hypertensive and had high blood glucose levels. (Malnourishment produced the same results and reduced levels of the
placental barrier enzyme.) Further studies with rats helped unravel possible molecular mechanisms for this effect.
It was difficult, however, to persuade obstetricians to consider changing their practices, since administration of
glucocorticoid saved babies. There was thus a need for further work to confirm and explain the effects in humans, but
research involving human subjects was limited to observational studies. Studies of causation, involving sampling during
infancy, and interventional studies to examine the mechanisms by which the effects were exerted, would not meet with
ethical approval. Furthermore, no controls were possible because steroids (the conventional treatment) had to be given
when pre-term delivery was threatened; therapeutic manipulations would not be possible without strong animal data.
A wide range of possible animal models was considered for this work, and it was concluded that Old World monkeys were
the only possible model. These animals had appropriate glucocorticoids, long gestations with single fetuses, and similar
relevant behaviour. By contrast, rats and mice, for example, had the ‘wrong’ glucocorticoid, short gestations producing
multiple fetuses, and showed key behavioural differences; sheep had ‘odd’ glucocorticoid biology and major placental
differences; whilst New World primates crucially were glucocorticoid resistant and many produced multiple fetuses.
Against this background, the work in non-human primates was considered justified by the researcher, on the grounds
that it was novel and important – a critical issue for human health related to a variety of diseases which affected many
people in both developed and developing countries. The studies would provide a rapid means of determining the longer-
term safety of an ‘established’ human therapy. References Ruhdel, I.W. & Sauer, U.H. (Eds., on behalf of European Coalition to End Animal Experiments) (undated, probably 1998). Primate experimentation. A report on the housing conditions of primates used for scientific purposes within the EuropeanUnion. Deutscher Tierschutzbund e.V. Akademie Fur Tierschutz.
European Commission (1999). Second report from the Commission to the Council and the European Parliament on the statisticson the number of animals used for experimental and other scientific purposes in the member states of the European Union.
COM(1999)191 final. Office for the Official Publications of the European Communities: Luxembourg.
Home Office (1998). Report of the Animal Procedures Committee for 1997. London: TSO.
Home Office (2001). Statistics of scientific procedures on living animals, Great Britain 2000. Command 5244. London: TSO.
Jones, B. (1996). Current standards in Europe for the care of non-human primates in laboratories. RSPCA and Advocates
for Animals. Horsham, West Sussex. RSPCA.
PUBLICATIONS Dr. R.A. De Abreu (until April- 2006) 1. Berns AW, De Abreu RA, Kraaikamp M van, Benedetti EL, Bloemendal H. Synthesis of lens protein in vitro. V. Isolation of messenger-like RNA from lens by high resolution zonal centrifugation. FEBS letters 1971; 18: 159-163. 2. Lommen EJP, De Abreu RA, Trijbels JMF and Schretlen EDAM. The IMP dehydrogena-se catalysed reaction in erythrocyt
C2-Symmetric Bicyclo[2.2.2]octadienes as Chiral Ligands: Their High Performance in Rhodium-Catalyzed Asymmetric Arylation of N-Tosylarylimines Norihito Tokunaga, Yusuke Otomaru, Kazuhiro Okamoto, Kazuhito Ueyama, Ryo Shintani, and Department of Chemistry, Graduate School of Science, Kyoto Uni V ersity, Sakyo, Kyoto 606-8502, Japan Received August 29, 2004; E-mail: email@example.com-