Martijn Nolte, senior programme manager MKMD at ZonMw about the animal-free and animal-wise policy

“We need both animal-free and animal-wise testing methods to make the transition.”

Martijn Nolte is senior programme manager for More Knowledge with Fewer Animals (MKMD) at the Netherlands Organisation for Health Research and Development (ZonMw), a major funder of medical and health research. ZonMw sponsors MKMD as a partner in the Transition Programme for Innovation without the use of animals (TPI), under the direction of the Dutch Ministry of Agriculture, Fisheries, Food Security and Nature/TPI.

How would you describe the role ZonMw takes in the TPI partnership programme?

As sponsor of the programme More Knowledge with Fewer Animals (MKMD), ZonMw is making a major contribution to manifesting the basic idea of TPI by fostering efforts to develop, advance and implement new animal-free testing methods. But also by promoting animal-wise methods that cut down on the use of animal testing. With the MKMD knowledge infrastructure module, we make it possible to carry out systematic reviews, as well as to publish negative or unexpected findings. I see a really important role for ZonMw in this context. Besides the MKMD programme, as a research funder we can cast our net more widely. I believe the one follows logically from the other.

How is ZonMw, as a major funder of health research, promoting research into animal-free methods?

To make it really concrete, we send out calls for grant applications focusing on the development of innovative non-animal technologies, while the new programme offers major support for validating these methodologies. Validation is one of the insights revealed by the Knowledge Agenda that we brought out in 2023. This showed that the lack of validation was seen as an obstacle for adopting the new technologies. With both Create2Solve and ValNAM, as well as with the National Research Agenda, we are now actively promoting the advancement and validation of new non-animal technologies.

The Knowledge Agenda therefore gave rise to the new MKMD programme. Interesting insights from the Knowledge Agenda were incorporated into the new programme. For instance, no longer regarding animal testing as the gold standard for research. We now formulate programmes accordingly. Like giving researchers who receive an Off Road grant extra financial support from the MKMD programme if they conduct their study without using animal testing. Actually, then we have already achieved our goal: getting people to think through whether animal testing is in fact the right method, or whether their study can be carried out with non-animal methodologies.

ZonMw is also working on an animal-wise testing policy. Could you tell us a bit more about that?

We understand animal-wise testing to mean that research should be conducted animal-free as much as possible, but when this is not an option, we want to ensure that animal testing is done in the best and most transparent way possible. The best way possible means applying proper guidelines, such as PREPARE and the ARRIVE guidelines. These require researchers to provide as much information as possible about how animal testing has been carried out, and what the results were. As transparently as possible means that researchers have to pre-register animal testing and publish their findings in open access journals, even neutral and negative data. This new policy arose from a pilot study that we carried out last year for the Ministry of Education, Culture and Science in which we examined researchers’ use of such transparency methods. How were these instruments received? We found out for both the ARRIVE guidelines and pre-registration that many researchers were not aware of them. But that after using them, they became enthusiastic and said they would use them more often, especially ARRIVE.

We as ZonMw want to arrive at a situation where we fund many more animal-wise studies. To get there, we are currently incorporating the ARRIVE guidelines and pre-registration in all ZonMw programmes. At the moment that is not the case. So we want to even things up.

Something that was a positive surprise for me was how well the term animal-wise was received, because it also connects people. Researchers who use animal testing say that this is a realistic perspective that doesn’t shunt them off to a corner, but makes them feel included. In my position at ZonMw, I work in the interests of both sides – animal-free and animal-responsible; we need both testing methods to make the transition. It’s really important for us to get the people who use animal testing involved in the transition in a positive way too. It’s a challenge, but I believe that with animal-wise guidelines we are taking a step in the right direction.

Which ZonMw research project do you see as a good example of a breakthrough with animal-free testing?

When I see how ZonMw, and MKMD in particular, sprang into action during the Covid-19 crisis, I think that’s a really good example of how a number of very promising projects were fast-tracked for funding, for which we have now recently also seen the outcomes. One of these projects was the HepaPuff led by Theo Geijtenbeek, which used an anticoagulant, Heparine, to see whether it could prevent a virus from infecting epithelial cells in the nose. They used healthy human volunteers for this study. They gave these people nasal spray with Heparine, then collected epithelial cells from the volunteers using a nose swab to see how the drug affected the viral infection. It turned out to work really well. They are now looking at whether it only works on SARS-CoV-2, which causes Covid-19, or whether it also works on other viruses.

How important is it that society at large is involved in the transition to animal-free testing?

It’s extremely important. We have a lot of questions. For instance, how do people feel about donating extra or unused tissue from a medical test or operation for research? Or would they be willing to participate in a study like the one I just mentioned? Previous studies show that people respond very positively when asked.

If we look at the wider perspective, I myself am also really interested to know how a patient or ordinary citizen feels about a product they know has not been tested on animals. Most people will say: “Great!” But if it’s a medication that has never been tested in animals, will people still be so enthusiastic about it? Because the drug might carry health risks that they might not want. On the other hand, I think that few patients and ordinary citizens are aware of the fact that animal testing models are still being used for research into certain diseases, even though such animal tests do not translate well to humans. Do people think that’s a responsible way to develop new medicines, or should we rather be developing new NAMs, with results that translate better?

A related question is, how will the patient or ordinary citizen deal with uncertainty? We live in a world where we have to deal with uncertainties, but we want to insure ourselves against everything and people demand safety. This leads to a situation where testing for safety costs a huge amount of money and animal lives. It also raises the question of how much safety it actually provides. Maybe it’s a false sense of safety? And maybe there is also a role for the government, as a funding body, to put these questions to the ordinary citizen and have a conversation about it?

What possibilities do you see in the coming years for accelerating the transition to animal-free testing?

I think we have to get those using animal testing more involved, and I also see animal-responsible methods as a useful instrument in the transition. In parallel, it is also important to push for the validation of animal-free alternatives, because only validated methods incorporated into the guidelines will be used by big industries. I also see a great number of possibilities for us to become more active in Europe. The transition is an international phenomenon – research publications cross borders, just like the technologies used by the different researcher groups.

Money also plays a role. Our wish list is bigger than our bank account. When I look at other programmes at ZonMw, MKMD is a small programme in terms of funding. We are really happy that the Centre for Animal-Free Biomedical Translation (CPBT) will go ahead with a 124.5 million euro grant from the Growth Fund; we have a role in that too. But the CPBT has a clear focus targeting a couple of specific diseases. So that still leaves a huge number of subjects unaccounted for. Here too we have to keep an eye on what else we can do.

Across Europe there are also only a handful of programmes focusing on animal-free innovations, which surprises me. We all see the urgency for, the strength and added value of animal-free innovations, but it receives relatively little funding. I find this troubling.

How might we better exploit the Netherlands’ position as a frontrunner in Europe to advance the transition to research using non-animal methods?

To make it really concrete, I think a terrific place to start is giving TPI a place within the European Research Area (ERA) project and the roadmap for phasing out the use of animals in safety testing. I really hope that this ERA application is successful. Then the Netherlands could also take responsibility for the secretariat, which would really put us in control. We could then inspire other people to do more than they are doing now. So real active participation.

The other thing that can help is participating in meetings at the European level, also be active there. EUSAAT in particular is an extremely important platform for us, a place where we as funding body can organise sessions, which we also did last year. We can publicise the attractive projects that are underway, and explain which funding instruments can help the transition.

The mission of the TPI is making better predictions without laboratory animals. When would you feel that the mission has been a success?

A two-part answer. For me, it already is a success. Because we are already doing it – we are already making better predictions without lab animals when you see all the wonderful new technologies that have been developed in the last twenty to thirty years; one really inspiring example is the use of patient-specific organoids to determine which medication cystic-fibrosis patients will respond best to. To me this is a brilliant solution. So we are already doing that.

On the other hand, we will never be done because this is a mission without an end. I think that there will always be testing on animals. And I also think that it is always good to keep refining animal testing so that better answers are found for research questions. And in some cases – this is my prediction – we will also move towards animal testing that is a really good predictor for humans. There are already humanised mouse models where a mouse has been given a human immune system; the results of such studies seem to translate much better to humans than experiments on ordinary mice.

So the transition to animal-free innovations, as far as I’m concerned, stands on two foundations: better translation to humans, and, for ethical reasons, abolishing animal testing because it is not ethically responsible. With regard to the first, if there are animal testing models that translate really well to humans, the question is whether this is a problem. And if it is ethically responsible to conduct this kind of animal testing, then it can still be seen as part of the transition to models that make better predictions.

But then you are only looking at the element of better predictions. What about the aspect ‘without animal testing’ seen from an ethical perspective?

The Experiments on Animals Act states that animal testing is only permitted when no good alternative is available, thus the preference is always for animal-free methods – not only from an ethical but also from a legal point of view. But how well results can be translated to humans also influences ethical review. And that’s where personal considerations come in: a researcher who believes that it is never ethically responsible to use animal testing will always avoid it. But another researcher might decide – if they believe that an animal study is the right method to find an answer to the research question, and there’s no good in vitro alternative available – to submit this animal study to the CCD/DEC. If it is also clear that the outcomes of the animal study will translate well to humans, this will have an effect on the harm/benefit analysis (weighing the expected suffering of the animal against the expected importance of the results), which in turn influences the ethical review. So the development of better translatable animal studies is something I find really exciting about the transition.

You yourself worked for more than 20 years as a researcher, and now you have been a senior programme manager at ZonMw for MKMD for a couple of years. Has this changed how you view research and the subject animal-free testing?

My opinion has certainly changed, because I can now see all the things that can be done with animal-free models much better, because I have been able to look beyond my own field much more. At the same time, I also see that animal testing may still be valuable for answering certain research questions. So I still make use of my past experience as a researcher. This makes me a good discussant for people who want to conduct research using animals and make the transition to animal-responsible methods, both at ZonMw and beyond.