www.bprc.nl

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The Netherlands are at the top of their game whenit comes to research and development (R&D). In2009 the country spent over €10bn in the area, with

almost 10,000 people getting involved.1

Research and Development in the country is supported bythree main sources of funding: companies, the governmentand foreign entities. The government equates to 37% ofthe funding with companies making up 49%. The Ministryof Education, Culture and Science is responsible for pro-moting, funding and supporting research projects withinthe Netherlands.

Working together with universities and organisations suchas the Netherlands Organisation for Scientific Research(NWO), the Ministry distribute necessary budgets to uni-versities in order for them to excel in a certain specialismand market their knowledge.

“In the Netherlands we have an excellent knowledgeinfrastructure in which this is done at a large scale by worldclass researchers,” explains Babs van den Bergh, DirectorResearch and Policy at the Ministry of Education, Cultureand Science.

“It is important to maintain this situation and to developour knowledge further and to pass it on to the new gener-ation of inquisitive people. Only in this way will we beassured of those clever people in the Netherlands whocan help solving the big world issues and keeping oureconomy running.”2

The Ministry of Education, Culture and Science are seeinga growth in the number of public-private partnerships, with

around €90m being redistributed in the field of scienceand research. The government is supporting research andproviding incentive funding to encourage internationalcooperation in this area, because high quality researchis integral to solving social problems and boosting theeconomy.

Innovations and new products are essential for a nation togrow and gain further insights into areas of medical sciencethat are important to tackle health challenges such cancer,HIV/Aids and Malaria.

“Innovations, new products and other services are essential.However, really innovative insights are not the result ofgoal-oriented search – after all then you already know whatyou are looking for,” said Van den Bergh.

“At OBW we think along with the scientists. We help themwith organising the infrastructure, streamlining interna-tional projects, for example by taking seats on the boardsof European organisations, or by co-reading new researchagendas.”3

There are many areas of research that are conducted withinthe Netherlands, explaining to some extent why they aretop of the league when it comes to R&D.

Case study – Biomedical ResearchBiomedical research is used to deal with health issues thatcause misery to people’s lives, resulting in a desperateneed for effective medicines.

Life threatening diseases such as HIV, Aids, Tuberculosisand Malaria, require effective drugs and vaccines to help

Leading the way in researchAdjacent Digital Politics Ltd highlights the excellent research work taking place in theNetherlands and the Ministry of Education, Culture and Science…

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treat, protect and prevent deaths from occurring. Throughbiomedical research, knowledge is gained in order totackle what is seen as major health challenges aroundthe world.

For such critical research, and to help understand thehuman body and the way complex diseases affect it, it iskey for basic research to be undertaken to protect humanhealth and the environment. Due to the similarities be-tween primates and humans – this makes primates crucialfor medical research and understanding the impact thatexposure to chemicals and drugs have on the human body.

Approximately 12 million animals are used each year forscientific research and procedures in the EU. Among theseare 10,000 non-human primates (nhp’s), which are mainlymonkeys and apes. Using primates in medical research hasled to some important findings in biology and medicine.To conduct and understand such complex research (suchas brain research) and infectious diseases, primates play

a unique role. The reason for this is due to their immunesystem being very similar to that of humans. Primates areusually the species that match humans more closely interms of how drugs affect them and tests on other speciesare simply not adequate.

In the Netherlands, medical research using primates isconducted by the Biomedical Primate Research Centre(BPRC) – which is at the forefront of biomedical research.This lead in the field is helping to develop new medicines.

The BPRC works to develop medicines to treat serious anddeadly human diseases and therefore has an important butdifficult mission – to continue research to help improvehuman health.

References

1 http://www.bladerbrochure.nl/brochure/code/63VR5q7W6v6A24oQqeieS6UVQrkins

2 (ibid)

3 (ibid)

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Animal models play an essential role in the devel-opment of new medicines, vaccines and therapiesfor the benefit of human health. Within animal

models for biomedical research, non-human primates be-long to a special group. The use of these highly developedanimals needs specific attention. The use of animals in bio-medical research raises concern by the general public, andwhen non-human primates are used this is even more so.Non-human primates are social animals and given theirhighly developed social behaviour and skills, the use ofnon-human primates in biomedical research raises ethicaland practical issues. However, in the light of the currentstate of scientific knowledge, the use of non-human pri-mates in scientific procedures is still necessary.

Within the new European Directive 63/2010, that regulatesthe use of animals for scientific purposes, there is specialattention for the use of non-human primates. They can onlybe used for biomedical research, and only in areas that areessential for human health and where no alternative mod-els are available (including other animal models such as ro-dents). Their use is only permitted for specific areas ofbasic research concerning preservation of the species, orfor biomedical research on potentially life-threatening anddebilitating diseases in humans. The use of great apes (i.e.chimpanzees), is not allowed for biomedical research inseveral European countries . The EU Directive specificallystates that great apes are only used under very specificconditions, and that the Member state claiming such aneed must provide information necessary for the Commis-sion to take a decision. In Europe, there is no chimpanzeecolony available for this purpose.

The use of non-human primates is very limited andamounts to only approximately 0.1% of the total numberof animals used for research in Europe. The majority ofnon-human primates used in research are imported fromlicensed breeding centres, mainly from Asia, and has sev-eral problems. Although care is taken that these animalsare not captured from the wild, it is regularly only the firstgeneration animals born in captivity that are used. WithinEurope, a feasibility study for the development of self-sus-taining colonies and provision of sufficient animals for theEuropean biomedical programs will be performed.

Transport of non-human primates by air is getting very dif-ficult due to both strict regulations and the refusal of manycarriers to transport non-human primates destined for bio-medical research. Pressure from animal right activists to stopanimal transport is getting stronger making transport of liveanimals difficult. Furthermore, long-distance travel is verystressful for the animals, and import of animals requires strictquarantine procedures at the host institute. In order to min-imise the need to import animals, European self-sustainingbreeding centres should be used (similar to those in theUnited States). Many of the non-human primates for re-search are bred at the National Primate Research Centres,and this provides an opportunity to further increase animalwelfare. Such self-sustaining colonies prevent much of thetransport stress and insure that all animals are bred andcared for following the local rules and guidelines. Currently,there are several non-human primate breeding colonies inthe Netherlands, Germany, France and the UK, with by farthe largest being the BPRC in the Netherlands and the DPZin Germany. Although such breeding colonies are costly

Non-human primates and health research

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compared to those in Asia, the advantages outweigh thedisadvantages, and further development of these centresin Europe would guarantee optimal care for animals. Theyare developed according to the most recent knowledge onanimal welfare and provide housing in social structures thatare as natural as possible. Other strong advantages are theguarantee of strict breeding programs, easy provision of ge-netic background, medical history of the animals, and ded-icated training and enrichment programs for the animalsthroughout their life. Over-all, this would benefit both re-search and animal welfare. Currently, the number of self-sustaining primate colonies for biomedical research inEurope that can provide animals for the scientific commu-nity, is too limited to provide all non-human primatesneeded for research.

Monkeys are divided into 2 groups: the Old World monkeys,i.e. monkeys from Asia and Africa; and the New Worldmonkeys from the America’s. The most widely used non-human primates in biomedical research are Old Worldmonkeys, mainly rhesus macaques and cynomolgusmacaques, and in specific cases baboons or vervet monkeysare used. In Europe, no great apes are used in biomedical

research. The most widely used species of New Worldmonkeys is the common marmoset.

Each animal model used to study human disease has itsown pro’s and con’s. It becomes clear that with develop-ment of our knowledge and understanding of more per-sonalised medicine, small animal models do not alwaysprovide the relevant information. Other, more sophisti-cated and/or more closely related animal models thatreflect the situation better in humans are needed. Oneof the most important reasons to use non-human pri-mates in biomedical research is their close phylogeneticrelationship with man. We share many physiological, be-havioural and genetic characteristics and susceptibilitiesfor various diseases. The genetic make-up of man andmonkeys can be similar for more than 90%, dependingon the species, and the comparability is very high forseveral important systems, including the immune sys-tem. Therefore, biomedical research in non-human pri-mates can contribute to our understanding of thesediseases and fundamental biological phenomena andare important in the development of new therapies,drugs and vaccines.

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Non-human primates are instrumental for the promotionof human health and play a critical role in the advancementof various areas in the medical field. Examples wherenon-human primates have played an essential role are: thedevelopment of bone-marrow transplantation and trans-plantation protocols; the development of vaccines againstinfectious diseases like polio; and the increase in under-standing of important diseases like yellow fever and Hep-atitis. Non-human primate models have been essential inthe identification of causative agents of infectious diseases,such as: typhoid fever, mumps, yellow fever, and SARS, andcontribute to our general knowledge of processes under-lying normal situations and disease processes.

The use of animal models to study human diseases haveadvantages in various situations. Fundamental propertiesof diseases can be studied using well-defined models,extensive sampling, and new prophylactic and therapeu-tic treatments can be studied in such models to provideproof-of-concept before advancing into clinical trials,thus limiting risk and time. In selected diseases, non-human primates provide the most suited animal modelfor such studies.

Non-human primates are susceptible to many infectiousdiseases that also affect humans, and thus provide interest-ing animal models for studying new therapies and vac-cines. One example where they play an essential role is inHIV research. Originally studied in chimpanzees – the onlyspecies beside man that can be infected with HIV, albeitwithout developing AIDS – the natural primate counterpartof HIV, i.e. simian immunodeficiency virus (SIV) is used tomimic the disease in macaques. SIV infection in macaquesresults in a disease comparable to AIDS in man. Rhesusmacaques provide an important animal model for thestudy of disease and development of therapeutics andvaccines against HIV and AIDS. Although it is often arguedthat these models still did not result in a validated, safeand reliable vaccine against HIV in man, these models havebeen essential for the development of new strategies toprotect HIV-infected people from developing AIDS.

Many of the current therapies would not have been possiblewithout the research that has been performed in macaques.Moreover, these models in macaques have been instru-mental to our understanding of disease development, andrecent studies have now provided essential information onthe early phases of the disease, something that would notbe possible to do in man.

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Although HIV research is one of the most generally knowntopics to study in non-human primates, monkeys are alsoused in research on other viral diseases. The recent fearof influenza pandemics after the H1N1 outbreak and themore avian strains that infect man directly has resulted ina resurgance in flu research. Macaques are used as an ex-perimental model to study pathogenesis and immunologyof influenza virus. These animals develop immune responsesand disease symptoms comparable to that in humans andviral replication can be detected in the nasal area and res-piratory tract. No adaptation of the virus is required and incontrast to the often used ferret model, a wide array of im-munological tools to study specifics in pathogenesis is inplace. Therefore, macaques are used to study importantquestions in influenza pathogenesis and to test new vac-cines against influenza strains from human and avian origin.

Besides influenza, our fear of new diseases and the rapidspreading of diseases due to climate change and theincreased mobility of man, for example, has led to anincrease in research on emerging infectious diseases.Examples of such diseases are West Nile virus infection,Rift Valley fever, SARS and Chikungunya (outbreaks of thesediseases have been seen over recent years). The rapid

spreading of West Nile virus in the USA and the occurrenceof this disease in the south of Europe indicates the impor-tance in the rapid development of tools to combat thesediseases. Non-human primates are used to study specificdetails of these diseases because of their natural suscepti-bility and the comparability of disease development, whichis not possible in the small animal models.

Non-human primates are also used in non-viral infectiousresearch. Like humans, non-human primates are susceptibleto infections with the bacterium causing tuberculosis. Thisis most common in macaques, who develop a diseaseresembling human tuberculosis. Unfortunately, the currentvaccine is not very effective in adults and new vaccines areurgently needed. Worldwide, tuberculosis is still one of themain causes of death in humans. The recent occurrence ofmulti-drug resistant and extreme multi-drug resistantstrains of Mycobacterium tuberculosis, the causativeagent of tuberculosis, stresses the importance to learnmore about the pathogenesis and develop new and ef-fective therapies or vaccines. This non-human primatemodel is used for fundamental research aimed at under-standing disease processes in tuberculosis and correlatesprotection as well as the development of new vaccines.

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They contribute to rational down-selection of TB vaccinecandidates to progress to advanced clinical studies, whichis costly and time-consuming. Another recent develop-ment is the model for whooping cough in baboons. Al-though vaccines exist, a steady increase in whoopingcough cases has been observed and the current vaccinesare not sufficient to control this. The often used animalmodels, mostly mice, do not meet the need to replicatethe full spectrum of disease. In contrast, baboons havebeen observed showing the prolonged cough and trans-missibility of the causative agent, Bordetella pertussis andoffer a much more reliable model to study this disease. In-terestingly, rhesus macaques do not mimic this disease, mostlikely due to their higher body temperature, demonstratingthat it is essential to validate each disease model.

Parasites form a different and difficult group of pathogenswith respect to vaccine development. In order to developvaccines for parasites still more research is required becauseparasitic diseases are extremely challenging. One of themost serious parasitic diseases is malaria. The two majorspecies are Plasmodium falciparum, which causes the deadlymalaria tropica, and Plasmodium vivax, leading to highmorbidity in large parts of the world. There are no naturalmodels to study these malaria parasites directly, althoughAotus monkeys can be infected with blood stages. However,these animals are a protected species and only very limitednumbers are available. More importantly, there are various

primate malaria parasites that are closely related to humanmalaria parasites. Since metabolism and immune systemin macaques are highly similar to that in humans, macaquemodels in malaria research closely resembles the situationin man. Using these macaque models, researchers aregaining knowledge on malaria biology, and are beginningto overcome the major obstacles in malaria vaccine devel-opment. Based on research in non-human primates severalmalaria vaccines are currently tested in humans.

Due to the comparable immune systems between non-humanprimates, especially macaques, and humans, they are oftenused to analyse the immune responses and safety of newvaccines before they are applied in man. Moreover, thesenon-human primate models provide controlled conditionsto study and unravel complex interactions between pathogensand the host, which increases our understanding of diseasedevelopment and provides a knowledge base for rationaliseddesign and acceleration of new vaccines and therapies.

Non-human primates are also used to study many non-infectious diseases affecting humans. Various diseases withan underlying immune-related disorder are studied usingnon-human primates. Multiple sclerosis (MS) and rheuma-toid arthritis (RA) are both auto-immune diseases thataffect the life of many people. Specific non-human primatemodels provide the means to study various aspects ofthese diseases that cannot be studied in man. Althoughmany animal models used to study these diseases concernrodents, it is increasingly clear that the predictive value ofthese models is limited. Especially with respect to the morepersonalised medicine approaches and the developmentof medication that affects very specific targets in the humanbody, better and more predictive models are essential. Invarious cases, non-human primates can offer such models.Experimental models for MS and RA have been developedin non-human primates, especially macaques and commonmarmosets, to provide the bridge between rodents andman. These models are providing insight on the immuno-logical mechanisms underlying the development of MS andRA, and are instrumental in the development of new therapies.

The way in which the brains of non-human primates andhumans are organised is highly similar. The use of non-human primates in brain research is important to understandthe functioning of the brain, and provides knowledge onfunctioning under normal conditions and in brain-relateddiseases. Like humans, common marmosets are susceptibleto an agent that induces Parkinson’s Disease like symptoms

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in both species. Because marmosets, can handle complexbehavioural tasks that enable testing cognitive functionsin Parkinson’s Disease, this model is used to study diseasetherapies and neuroprotective methods. Unlike rodents,marmosets with induced Parkinson’s Disease show a widerange of Parkinsonian behaviour that is also present inhumans, which makes this primate model very valuable todevelop new interventions therapies. Research using brainsobtained from deceased macaques and great apes in com-parison with humans is used to study evolutionary aspectsof aging for example. Studies have identified interestingaspects of potentially involved mechanisms.

In auto-immune diseases like MS, and neurodegenerativedisease like Alzheimers and Parkinson’s Disease, non-humanprimate models are used to study new treatment. A recentand exiting development is the use of stem cells. Thepotential of such cells as therapy is currently studied inrelevant non-human primate models. This will certainly resultin new insights with respect to disease development andthe development of curative or preventive therapies.

Another field of neuroscience where monkeys play an es-sential role is in the development of new ways to deal withprosthetics. It has been shown that by specific research andmapping of brain areas, new devices have been developedthat could be steered by the monkey solely using its‘thoughts’. This opens the pathway to new applications ofneuro-based steering of prosthetics by patients. Monkeysare used to map the brain in more detail and to study anumber of aspects involved in brain development.

Non-human primates are also used to understand moreabout various aspects of human evolution. Research usingbrains of deceased macaques and great apes, and thencompared with human brains, is used to study evolutionaryaspects of aging, and recent studies have shown interestingmechanisms that might be involved. Comparisons of severalcomponents of the immune systems are used to learn moreabout evolution. Non-human primates are also used to studysocial evolution by looking at aspects of cooperation,bonding, altruism and sexual behaviour. Comparison ofthese aspects between man and their closest relatives leadto interesting insights into our own behaviour.

These examples of the use of non-human primates demon-strate that they provide important models for various areasin biomedical research. Because of their close phylogeneticrelation with humans, non-human primate models have

been, and are still, providing essential knowledge in ourstruggle against life-threatening and debilitating diseases.

One of the promising advances has been the sequencingof the genome of various non-human primate speciesthat are used in biomedical research. This knowledge ofthe genome and genes involved in immune regulationtogether with the developed animal models in the variousdisease areas will increase our understanding of themechanisms involved in these diseases and/or protectionagainst them.

The use of non-human primates in research is a continuousmatter of debate. Although many scientists are convincedthat they are useful in several areas of research to answerspecific questions, we also have the obligation to alwaysbe able to justify this use for the general public. Further-more, if we decide to use non-human primates in biomedicalresearch, this also comes with the obligation to take optimalcare for these highly developed animals and to recognisetheir specific needs with respect to housing and care. It isessential that these animals are housed and treated in sucha way that meets their natural behavioural, environmentaland social needs as much as possible. During the pastdecades many things have changed for the better, andunder the new Directive, all animals will be socially housedin large cages. Furthermore, the animals need to be men-tally stimulated during the day, for example, giving themthe opportunity to search for food. For all primates en-gaged in biomedical research, enrichment programmeshave to be in place and carried out carefully. To preventside effects of enrichment, e.g. overfeeding, specificguidelines for enrichment have been developed. More re-cent developments also include training protocols for theanimals – to cooperate with procedures voluntarily in orderto prevent stress and sedation as much as possible. Non-human primates react very well to positive reinforcementtraining (PRT). Besides learning to cooperate with certainprocedures, PRT also provides enrichment. It is stronglyadvocated that all facilities working with non-human pri-mates also include PRT training. This addition will benefitboth the animals and research.

It is clear that non-human primates have been and stillare essential in the advancement of biomedical research.However, we have to realise that each individual has itsown intrinsic value and if we decide to use these animalsfor our own benefit, we also have the obligation to treatthese animals in the best way we can.

BPRC. Lange Kleiweg 161, 2288 GJ Rijswijk, The Netherlands. tel: +31 15 284 2500 fax: +31 15 284 2600

www.bprc.nl