Animal welfare: reducing lab experiments on primates

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For years, Professor Eckhard Wolf has been doing research on genetically modified pigs, which can be used as model organisms in medical studies and as potential organ donors for humans. In our interview, Wolf presents the EU-funded joint undertaking “NHPig,” which he coordinates. One of the aims of the project is to reduce animal experiments on primates through the use of such pig models. To do this, the participating research institutions and companies will have 17.5 million euros at their disposal over the coming five years.

Why is it desirable to replace primates as lab animals?

Non-human primates are our closest relatives. We share much of our evolutionary history and they are very similar to us. As such, the conclusions we derive from experiments on them transfer very well to humans. In view of their high cognitive and emotional complexity, however, primates require our special consideration. For this reason, the EU has passed regulations that limit experiments on primates as much as possible.

There are fields of study where this has just not been possible to accomplish to date. For example, I work in the field of xenotransplantation. Before we can transplant pig hearts or other organs into humans, we need to make sure that it actually works. In this context, we still have no alternative to non-human primates – in this case, baboons.

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There are people who are convinced we don’t need animal experiments at all.

I think this attitude can change very quickly when a person, or their loved ones, need a new therapy. We all have a massive stake in these therapies being effective and not having any unexpected side effects. Unfortunately, there are tragic examples from history, such as the thalidomide/Contergan scandal. Here, scientists only tested the drug on mice, rats, and rabbits, with no complications. But tragic side effects occurred in humans – and later also in tests on monkeys. In animal experiments, therefore, it’s important to choose the right target species.

But this mustn’t necessarily always be primates?

NHPig is concerned with evaluating the safety of new therapies. This can be small molecules, antibodies, RNAs, or various therapeutic modalities. When addressing such questions, experiments on pigs can certainly provide valid results. The goal of NHPig is to clarify in which areas non-human primates can actually be replaced by pig models.

To this end, we generate new reagents for the pig as model organism – for example, antibodies or other diagnostic molecules. Moreover, we want to obtain a holistic insight into the biology of pigs. We compare the results of these pig experiments with data available from primate experiments from the pharmaceutical industry to identify correspondences. The consortium is working with various mini- and micropig models to define the most valid model for each research question.

In the project, you’ve adopted the 3Rs principle. What is that?

The 3Rs principle was developed in the 1950s as a framework for research using animal experiments. The three Rs stand for replace, reduce, and refine. This means: 1) Replacing animal experiments wherever possible; 2) Reducing them in this way; and 3) Carrying out animal experiments under the best possible conditions, so that all avoidable animal suffering is avoided and results are more reliable as a consequence.

In NHPig, we also want to develop substitute models that do without animal experiments entirely. For example, we’re establishing pig cell cultures and testing how well experiments in the Petri dish compare with experiments on living pigs.

Another goal is to improve experimental procedures and the conditions in which animals are kept. There is a subproject which involves carrying out physiological measurements on the pigs without them noticing a thing. The animals are monitored with cameras and wear jackets that can measure things like blood pressure and heart rate.

What happens with the data you collect and generate in the course of the project?

There will be a large central database which will absorb many existing research findings from pharmaceutical companies and our academic partners. On top of this, it will accommodate the complex dataset that arises in the course of the project. Based on this data, we’re developing algorithms that will help evaluate the safety of new therapies and choose suitable test animals. In addition, the database is meant to ensure that experiments are not unnecessarily duplicated, because it will hold all existing information.

What is the makeup of the consortium and which institutions are involved?

The consortium is distinguished by its bringing together of many complementary kinds of expertise. The academic component is made up of nine universities and research institutions. In fact, this is a grouping which formed many years ago. I would maintain that we’ve managed to assemble the best pig researchers in Europe. In addition, all major pharmaceutical institutions are involved in the project. People in the pharma industry are very interested in evaluating and potentially using such new models.

Why is the pharma industry so interested in the project?

Commercial interests are one reason, but it’s also about the desire to keep safety research in Europe. Otherwise, research might have to be diverted to Asia in the future. In China, there are huge primate experimental facilities, where the issue of animal welfare is not necessarily as emphasized as it is in Europe. The European pharmaceutical industry is participating in the new project with a substantial financial contribution – roughly the same amount of money that the EU has awarded. Also, we shouldn’t underestimate the large treasure trove of data that the pharma industry is making available to us for the central database.

Where do you see the greatest potential for establishing pigs instead of primates as a model?

In various areas of safety research. In our consortium, for example, there’s a pig model that exhibits no defense response to certain human antibodies. This model could be used to test the safety of such antibodies, which are frequently used in tumor therapy and other areas – and might even do so better than primate models.

We ourselves have created a micropig in which the growth hormone receptor is silenced. As a result, the adult body weight of the pigs is less than 10 kilograms. This makes them particularly suitable for longitudinal studies, where it’s important that the animals do not grow as large as normal pigs, which weigh several hundred kilograms when fully grown.

Prof. Dr. med. vet. Eckhard Wolf is Chair of Molecular Animal Breeding and Biotechnology at the Gene Center Munich and the Department of Veterinary Sciences at LMU. Wolf is Director of the Center for Innovative Medical Models (CiMM) at LMU and was spokesperson of the German Research Foundation (DFG) funded Collaborative Research Centre “Biology of Xenogeneic Cell and Organ Transplantation – From Bench to Bedside.”