Alternatives

When a disease cannot be studied in humans, scientists can induce experimental diseases in animals. The more closely the animal species is related, the better the disease processes resemble that of humans. Although this approach has led to many important discoveries and new therapies, this approach also may have an impact on the welfare of animals. We are fully aware of our responsibility to society and animals and we are only allowed to use animals when there are no other -alternative- methods available. Alternative methods are categorized along the principle of the 3Rs of Replacement, Reduction and Refinement, all of which have a place within BPRC. When alternative methods are available, Dutch law obliges researchers to use the alternatives and forbids the use of animals. However, not many of such methods are available yet. Rather than waiting, BPRC is actively testing and developing alternative methods. The 3Rs are implemented in the research of every department, as well as in the separate Unit Alternatives.

3Rs throughout BPRC

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Replacement

In 2009 BPRC-researchers developed an new in vitro assay to test drugs for anti-malaria activity. This assay replaces the use of monkeys. Last year we tested 33 new potential anti-malaria drugs with this assay. Before 2009, 33 monkeys would have been necessary to test these 33 compounds. So far, BPRC tested 999 drugs with the animal-free assay.

Reduction

Genetics; genes play an important role in infections and diseases. We have implemented new techniques to determine the genetic background of animals in the breeding and experimental colonies. This enables us to select (or deselect) appropriate animals to answer particular research questions. For example; we know that certain genes play a role in the development of AIDS after HIV infection. We now know that these genes are also present in monkeys. Selection of animals for an HIV experiment is therefore based on these genes. Proper selection reduces the variation in an experiment and therefore smaller group sizes are required to obtain statistical significant differences.

We work hard to reduce the number of animals we work with. Optimizing and standardizing in vitro laboratory tests plays an important role in this. Also in 2017 we have implemented new techniques. By using these new conditions, we aim at less variation in laboratory test that will lead to smaller group sizes in our animal experiments.

Refinement

Improving animal welfare is a continuous process in our institute and BPRC staff take part in (inter)national training programs to remain their high standards. In 2017 this resulted in

  • All animals were socially housed
  • 25 animal caretakers used positive reinforcement training (PRT). They train their animals twice per week. With this training method we were able to perform certain biotechnical techniques without sedating the animal
    • In 2017 all marmosets were trained to voluntarily jump on a scale to obtain body weight without sedation.
    • All experimentally housed animals were trained to drink from a syringe, thus voluntarily take oral medication.
  • Caretakers spent 15% of their time on (cage)-enrichment. For instance assembling food-puzzels, providing animals with toys or redecorate enclosures.
  • Further improvements were implemented in diet variation, to maximize natural feeding routines.
  • New methods were implemented to monitor stress levels;
    • Hair samples were obtained to measure cortisol levels
    • Pictures were taken to measure Alopecia
    • Round the clock camera recordings to get insight in behavior of less-compatible pair-housed animals, in the absence of a caretaker
  • In 2017 an improved version of the ‘Welzijnsevaluaties’ was implemented
  • New features were introduced in our monkey database for the registration of animals.

All animals in experiments are observed at least twice a day. During this observation different parameters are ‘scored’. Under control conditions an animal shows a broad variety of natural behaviors. In some models for (infectious) diseases the animal’s behavior changes. This is however a subjective parameter and changes are difficult to observe. We currently investigate the options for objective measurements of physical activity with telemetry that registers X-Y-Z coordinates of individual animals. With these devices it is also possible to measure body temperature, heartrate, blood pressure. This will lead to further refinement of our animal models.

In 2016 the Bill and Melinda Gates Foundation announced that the tuberculosis-research performed at BPRC is of such high standard that we will serve as one of the three central facilities for the testing of TB vaccines, world-wide. As part of this initiative the Bill and Melinda Gates Foundation initiated and funded a new line of tuberculosis-research at BPRC. For this purpose, a PET/CT scan was installed in 2017. Implementation of this novel and non-invasive technique allows screening of tuberculosis-disease progression over time. This will not only lead to new scientific insights and better understanding of tuberculosis-disease progression, it may also lead to standardizing protocols and methods that are used world-wide to evaluate vaccine candidates, and therefore minimize the number of non-human primates used for TB research.

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3Rs Alternatives Unit BPRC

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Developing in vitro methods for the central nervous system

People are getting older. In an aging population people suffer from age-related diseases. Many of these diseases, like Alzheimer’s disease, Parkinson’s disease and multiple sclerosis affect the central nervous system. BPRC works with animal models for each of these diseases. In vitro methods to complement, refine, reduce and finally replace the use of animals are therefore highly relevant. Over the years we successfully developed methods to study individual brain cells in test tubes. In 2017 we have employed a new PhD student to push this development forward and to develop better and animal-free methods to study diseases of the central nervous system.

VAC2VAC: a European initiative

Vaccines are the greatest success story of biomedical science. Vaccines have changed human life expectancy dramatically. Experimental research on animals is not only used during the development phase of vaccines, but also during the production and quality control phase. Vaccines are typically produced in batches. Every batch undergoes the same strict series of animal tests before it is released. We participate in a European initiative, VAC2VAC, that tries to change this. The idea is that every new batch of a vaccine should not be treated as an entirely new entity, but rather as one of a series. This implies that every new batch only needs to be similar to the previous batch, and should not be tested in animals. To prove similarity between batches, animal-free methods are used. By adding our panel of in-house engineered cell lines to the consortium we characterized several different vaccines and batches in 2017. Our results demonstrate that different batches are indeed highly similar according to our tests. Together with the tests that are developed in other European labs, this initiative should lead to abandoning animal testing in vaccine batch release.

Read more:

Alternatives for animal studies: BPRC participates in European project

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