A thousand roads to a world free of animal-testing
It is a great pleasure and honour to welcome you all to this inaugural lecture, both here in the room as well as online. The idea behind an inaugural lecture is that a professor at the university informs colleagues and the broader public about her work. I will start off by giving a brief summary in Dutch, and then continue my speech in English, because of the many international listeners.
Ik zit thuis in de vensterbank en ik voel me heel eenzaam. Ik weet dat ik er als vierde kind – wat mijn allerliefste ouders betreft – eigenlijk niet meer had hoeven te komen. Eentje teveel. Gelukkig is Frieda er voor mij, zij zit trouw naast me, onze hond die mij onvoorwaardelijke liefde schenkt. Frieda hield van mij en daardoor ben ik net als de heilige Franciscus – wiens leven wij vandaag herdenken – van dieren gaan houden en wil ik ook hun beschermer zijn waar ik dat kan. Ik ga daarom in Utrecht diergeneeskunde studeren en ontdek aan het einde van mijn studie dat er niet goed wordt omgegaan met de levens van proefdieren. Mijn missie is geboren.
Ik word wetenschapper en ga mijn leven wijden aan het voorkomen van het te veel onnodige gebruik van proefdieren. Ik probeer decennialang met wetenschappelijk onderzoek en goede argumenten een positieve bijdrage te leveren aan het vakgebied, maar zie dat het niet of nauwelijks helpt.
O ok via de politiek probeer ik mijn invloed aan te wenden en hoewel ik in de loop der jaren bijna de hele Tweede Kamer – met dank aan de Partij voor de Dieren – achter mij weet te krijgen, verandert er feitelijk heel weinig.
Alleen als onderzoekers mede op mijn initiatief systematische reviews gaan doen, leidt dit tot bewustwording van de gemiddeld slechte kwaliteit van het gepubliceerde dierproefonderzoek en de lage vertaalbaarheid ervan naar de mens. Deze bewustwording heeft enige impact en leidt tot de motivatie bij de onderzoeker om het beter te willen doen.
Inmiddels zijn er zoveel en zulke goede alternatieven voor dierproeven die beter voorspellend zijn voor de mens, dat je zou denken dat het aantal onnodige dierproeven wel snel zal verminderen, maar ook de beschikbaarheid van alternatieven helpt niet. Zelfs bij dubbel en dwars bewezen goede alternatieven duurt het nog 25 tot 30 jaar voor ze in de praktijk dierproeven vervangen. Een van de oorzaken daarvan is dat de wet- en regelgeving nogal eens achter loopt.
De alternatieven zijn inmiddels zo goed en zijn er zoveel, dat we op vele fronten meteen met dierproeven kunnen stoppen en dan bovendien waarschijnlijk meer en betere nieuwe gezondheidsbevorderende ontdekkingen doen. Kortom we kunnen en moeten zo snel mogelijk stoppen met het doen van dierproeven, en overstappen op meer mens-relevante methoden. Waarom gebeurt dat dan niet?
Enerzijds zijn er teveel gevestigde financiële belangen en anderzijds gaat het om impact-factor en onderzoeks-prestige in de bestaande academische wereld. Er is daartegenover nog te weinig druk vanuit de maatschappij.
De covid-crisis heeft geleerd dat we sneller in staat waren nieuwe effectieve medicijnen en vaccins te ontwikkelen met veel minder dierproeven en meer mens-relevante alternatieven. Moeten we wachten op een crisis nog groter dan de covid-crisis?
Overigens lijkt het erop dat deze positieve lessen geleerd uit de covid-crisis ook alweer grotendeels vergeten zijn. We zijn veelal alweer terug naar dierproeven; business as usual.
Staat hier dan een nieuwe maar pessimistische hoogleraar?
Nee, want hoewel ik de afgelopen jaren heb geleerd dat noch wetenschappelijk bewijs, noch de politiek, noch crisissen leiden tot het echt verminderen van dierproeven, heb ik ook gezien dat het burgerinitiatief in Europa, het European Citizen Initiative, wel dingen kan veranderen. Beste mensen, ik heb mijn hoop dan ook gevestigd op u, het publiek en de organisaties die de publieke opinie weten te mobiliseren, want burgers willen niet langer onnodig proefdieronderzoek. En met behulp van wetenschappelijke bewijsvoering daarnaast kunnen we samen grote stappen gaan maken.
Ik wil nu alvast zeggen dat ik heel blij ben bij deze Universiteit benoemd te zijn tot hoogleraar Evidence-Based Transitie Proefdiervrije Innovaties en vooral ook om weer terug te zijn bij de faculteit diergeneeskunde, alwaar ik 35 jaar geleden mijn missie ontdekte. Vanuit de geweldige afdeling IrasTox wil ik mij, samen met deze collega’s en die vanuit het SAFE consortium en de Transitie Proefdiervrije Innovaties in NL en Utrecht, met hart en ziel de komende jaren inzetten voor de Transitie Proefdiervrije Innovaties, waarbij we ook de sociale wetenschappen inschakelen om te leren hoe we deze transitie kunnen bespoedigen. Nederland is met het landelijke en Utrechtse beleid op het gebied van Transitie Proefdiervrije Innovaties uniek in de wereld.
Er wordt dan ook vanuit de hele wereld naar ons gekeken en ik beloof alles wat in mijn vermogen ligt te doen om de voorbeeldrol die we vanuit Nederland hebben, zo goed mogelijk waar te maken, want een proefdiervrije wereld …. het staat te gebeuren.
I will now continue in English.
I am sitting on the windowsill and am feeling quite lonely. As the fourth child in the family, I was not really desired anymore by my parents; three children would have been enough. Despite all the love and care of my parents, I feel most loved by our dog Frieda who is sitting next to me, and she offers unconditional love at all times. Frieda loves me and because of that I am like the holy Francis, whose live we are celebrating today, loving animals and wishing to be their protector. I decide I wish to study veterinary medicine in Utrecht. At the end of my studies I discover major shortcomings in how we deal with the science and lives of laboratory animals. My mission is born.
I become a laboratory animal scientist dedicated to preventing unnecessary use of laboratory animals, which unfortunately happens far too much. For decades I try to contribute positively to this goal through scientific research and related argumentation, but I have to conclude that this hardly helps. Also through the political scene I try to have an influence, and despite the fact that after years of lobbying, almost the entire Parliament agrees with my viewpoints on animal studies and alternatives, greatly supported by the political party Partij voor de Dieren, not much significant change is happening.
Only when researchers are stimulated by me and others to start doing systematic reviews, we see an increase in awareness on the generally too low publication quality of animal studies and the low predictivity and impact of animal studies for human health. This awareness creates some impact as it leads to the clear motivation for change, which is really important. In the meantime, science and technology have advanced so dramatically in the past decades, delivering a multitude of alternatives with better predictions for humans, that one would expect a clear decline in unnecessary animal studies. However, the number of animal studies has remained constant in the past years. Even for alternatives that have been thoroughly validated, it takes 25 to 30 years before they actually replace animal studies in the real world regulations. Regulations are lagging behind and regulatory inertia becomes transparent.
The breathtaking potential of new technologies and scientific methods is so many and so impressive, that we could easily stop most laboratory animal studies immediately, thereby also accelerating new health promoting discoveries faster and better. In short, we can and should stop lab animal studies as soon as possible and convert to better human-relevant methodologies. But why does this not happen much faster and much more?
On the one hand there are many vested financial interests; animal studies constitute big business. On the other hand there is a lot of research prestige in this field. The opposite pressure from society is not yet intensive enough. The Covid crisis has taught us that new and effective medicines and vaccines could be developed faster with more flexible approaches, with fewer animal studies and a larger role for human-relevant alternative methods. Are we going to wait for an even larger crisis than the Covid crisis before we get our act together?
By the way, it seems that many lessons learned in the Covid crisis have been forgotten again. It’s already back to animal studies too often; business as usual.
Are you listening to a new, but pessimistic professor? No, I have learned that scientific proof, politics nor crises can really lead to a substantial reduction of the total number of animal studies. But I have also seen that the European Citizen Initiative ‘Save-cruelty-free-cosmetics’ in Europe does lead to change. I have my hopes on all of you in the public and the organizations that know how to mobilize public opinion.
Citizens do not longer want unnecessary animal studies. Together with scientific evidence we can make significant steps. Soon we can expect a real change.
I am very happy that this university, where I discovered my mission 35 years ago at the Faculty of Veterinary Medicine, has offered me this appointment as Prof. in Evidence Based Transition to Animal Free Innovations. With my wonderful and motivated colleagues from the IRAS TOX department, from the SAFE consortium and the Transition to Animal-Free Innovations group in the Netherlands and Utrecht, I wish to work on this Transition with my heart and soul. This includes working with the social sciences, in order to learn HOW we can accelerate the transition. We all know change coincides with resistance. As Pandora Pound describes so accurately in her book ‘the Rat trap’, citing the Belgian playwright Maurice Maeterlinck: “At every crossroads on the path that leads to the future, tradition has placed ten thousand men to guard the past.” I met many of them, and I still do every day. What are the hurdles and opportunities for progress? The Netherlands is unique in the world in the chosen approach for focusing on transition science, involving all stakeholders in the process. The entire world is interested in what the Netherlands is doing, and I will do everything in my power to extend this exemplary role. An animal-testing free world, it may just happen very soon.
How did I get to where I am today? It all started with performing a literature review at the Department of Laboratory Animal Science at Utrecht University on the topic of atherosclerosis in rats. It showed me how many details were not written down in publications, that methods of inducing disease were used that were quite damaging to the welfare of the animals,
leading to processes that did not resemble atherosclerosis in humans. And last, but not least, the few papers mentioning spontaneous atherosclerosis in the heart vessels of old rats were never cited.
My mission was born. I wanted to contribute to improving the quality of science and animal welfare in conjunction, to ultimately contribute to better health and medicine for humans and animals. This mission has implied that I have always kept asking critical questions, which strangely enough wasn’t always appreciated by the scientific community. I think a sound scientific environment should promote this attitude of asking critical questions and perform critical appraisals, and there is every reason to do so. I will take you through my journey of collecting evidence and keep asking new questions.
When I graduated, I still believed we needed animal studies for human and animal health, also based on our legislation, which demands animal studies in order to get medicine approved for the market. Both efficacy and safety studies need to be done in animals first, before going to humans. At least that is the intention. The efficacy is all about whether the drug will help to cure a certain disease, and the safety is to protect us from toxic side effects.
I later discovered that human studies often run in parallel or even before animal studies. I also discovered that the evidence from animal studies is not comprehensively summarized scientifically for medical ethical committees, nor in the Investigator Brochures for our medicine authorities. It is hard to believe that the evidence from animal studies in the form of systematic reviews is not required by medical ethics committees nor regulatory authorities, when these animal studies are supposed to be done with the goal to protect us.
Why do we do them then? In her book, “The Rat Trap,” Pandora Pound describes how few animal studies contribute to success in clinical practice,
with figures ranging from 1-4% (p. 90-93). It seems as if the preclinical and clinical worlds are two separate worlds, each having their own goals.
The first 20 years of my career, my focus was on the implementation of the 3Rs, which stand for Replacement, Reduction, and Refinement. My main point of attention then was Reduction and Refinement. In case we do have to use animals, we need to do it in the best possible way. Over the years, my research and practical experience have taught me that striving for the 3Rs is in itself not a fruitful way of making real changes. Researchers express they have no time nor money for the 3Rs, despite the fact that it is a legal obligation. The PhD by Judith van Luijk has revealed that searching for the 3Rs is nearly a mission impossible as there are over a hundred databases and websites with all different content and search strategies. In interviews researchers informed us that they think already existing 3R possibilities are missed in their research practises, which -strictly speaking- is illegal. But what to do when you can hardly find them?
Having been the manager of 2 animal laboratories in academia, and combining it with a professorship to implement the 3Rs makes life rather challenging. As the manager of an animal facility, you are expected to give service to researchers and make sure you have a sound financial management. This last goal often implies you have to do animal studies – as much as possible – in order to keep the finance sound, as the whole infrastructure is geared towards this process, which is in direct conflict with the 3Rs. In my times of being the manager of an animal facility with 3R-supportive university board members, then this conflict could be managed more or less. But when university board members are focused on other targets, then the tensions start to arise.
From the 3Rs to SR
After focusing on the 3Rs for about 20 years, I had to conclude this was not a successful road towards implementation. Asking myself the question what to do next, I heard a presentation by Malcolm Macleod on systematic reviews. THIS is what I need to do now, I thought, and started up the process. It clearly connected to my experience of my first literature review and to the fact that in the clinic the systematic review methodology had been introduced since the beginning of the 1990s already, as the routine methodology. All medical doctors think you need to do systematic reviews of clinical studies in order to summarize what evidence there is for deciding on what treatments to use. Does this treatment work or not? Is the scientific evidence of good quality? Can we trust the published results? This is all SO logical. So I thought this is just as logical for animal studies aiming to improve human health and treatments.
Together with my colleagues, we started developing the preclinical systematic reviews methodology, education, and coaching, and my group executed many SRs in cooperation with other researchers. The big advantage of SRs is that it is a truly interdisciplinary endeavor. As one of the clinicians once expressed when we planned a new SR: I have never before experienced such a wonderful research meeting examining the research question from all angles. In 2012, we organized the first international symposium in the field and founded the expertise center SYRCLE, and we started a program with the Dutch health funding organization ZonMw. This program turned out to be quite successful, and an impact study performed by Julia Menon has demonstrated that the execution of SRs has a major impact on research and researchers. What especially struck me was the interviews with researchers who really became motivated to do better jobs personally, but also wishing to influence their teams and fields of research.
As they say in the medical field: once somebody has done a SR, he/she will do all future research better. I have also experienced that medical doctors find it quite natural to do SRs of animal studies, as they are so used to this in the clinic. They say “of course we have to do this”, but for basic scientists this turned out to be quite a different ballgame.
The unfortunate benefit of SRs is that it makes everything so transparent. The quality of publications of animal studies is disappointingly low and does not seem to increase over time despite very good reporting guidelines called the ARRIVE guidelines, that are endorsed by many scientific journals. And despite the fact that this problem is now so widely recognized, 50-80% of essential experimental details are still not mentioned in publications! This makes it very difficult if not impossible to get a reliable interpretation of the results.
Moreover, a review by Cathalijn Leenaars in 2019 taught us that we cannot identify factors that can predict translational success to humans, in other words, we do not know if and what animal studies can work. I had naively thought that all researchers would think that using this systematic research methodology for animal studies is so logical and would be adopted easily.
How wrong I was.
More and more figures have become available on the low translatability of animal studies to humans. About 90% of positive results from drug tests in animal studies subsequently fail in human clinical trials. For Alzheimer’s disease, there is a failure rate reported as high as 99.6%.
More and more evidence about low translation from animal studies to the human clinic is published. Producing and presenting these results hasn’t made me popular among some researchers, the message and messenger frequently get mixed up. And abroad we have seen the same picture.
Sir Iain Chalmers, one of the founders of the Cochrane Collaboration and the James Lind Library, invited Pandora Pound and me to write a historical analysis on the developments of preclinical SRs in the UK and the Netherlands. It was a very interesting study. The parallel developments were striking. This is human nature, first resisting new things, blaming the persons introducing it, then gradual acceptance, and in the end thinking this is a normal thing to do, forgetting the initial blaming of the inventors.
Around the years 2017-2018, in the UK, the Alliance for Human-Relevant Science and in the Netherlands, the Transition to Animal-Free Innovations have been set up. Using human materials and data is a better way towards good translation to humans as compared to animal studies. We cannot deny the fact that animals and humans will never be the same.
A mouse will never become a human. Many types of cancers have been cured in mice, but not yet in humans. The UK White paper on human-relevant science also mentions that thousands of people are suffering from adverse drug reactions, although all these drugs had been tested on animals for possible toxic side effects.
On behalf of big business, often false hope and promises are provided based on positive results of animal studies and presented loudly as such in the media. This then sadly often turns out to be false hope given to patients. Jarrod Bailey examined what had happened 20 years later to 27 breakthroughs mentioned in the media: 20 were failures, 3 partially successful and 3 gave unclear results. So the success rate of very promising animal studies was only about 4% (p.91 in The Rat trap).
Great new medical treatments are often falsely claimed as the succes result from animal studies. In the book the Rat trap, several examples of this are mentioned.
I have personally experienced this with Deep Brain Stimulation treatment for Parkinson Disease, where I was told many times how important Non-human primates (monkeys) had been for developing this therapy for Parkinson. However, I discovered a publication that mentions that this treatment was actually pioneered in humans, and that clinical research into such treatments preceded the non-human primate model of Parkinson disease by decades (RAJ Pharma March 2009).
Because of all of this, I decided it was urgent to make the change to more human-relevant science. For a number of years now, I am deeply involved in Replacement and the transition to animal-free innovations.
TPI in the Netherlands is a unique movement with all diverse stakeholders involved, who assemble on a regular basis to discuss how to make the transition to animal-free research really happen.
I cannot do otherwise than focus on animal-free research with this wealth of evidence on how little animal studies help and how they may even obstruct real progress in human health and medicine. So it is high time to reflect and start asking new questions.
And I started with the question, WHY do we do animal studies in the first place??? The answer is because of crises. In my research with some excellent multidisciplinary students I have discovered that we started new legislation demanding animal studies because of crises. For example, World War II. Because of the bizarre human studies performed in the concentration camps, the Nuremberg code arose after the Nuremberg trials, prescribing that there should be a sound basis of knowledge first, including all other sources of knowledge, including animal experimentation, before doing studies in human beings.
So, codes have been made to protect people from getting involved in unethical clinical studies, which can then also encompass animal studies. This in itself is a bizarre turn in history, doing animal studies to protect humans based on unethical clinical studies performed in the second world war.
Another question arose: Where is the scientific evidence in the legislation demanding animal studies?
Before World War II, the sulfanilamide elixir crisis had taken place in the US, where people had died because of this elixir. This elixer had a sweet taste, so nice to ingest but also leading to deaths.
This crisis in the 1930s resulted in the first legally demanded animal studies in the Food Drugs and Cosmetics Act in the US. In the 1960s in Europe, the Softenon / thalidomide disaster then again led to more new legislation demanding extra animal tests.
These were all crisis-based decisions without evidence of a sound scientific basis for asking these animal studies.
I wanted to find new roads towards my goal – being no more unnecessary animal studies – and I met my colleague Ingrid Visseren-Hamakers, professor in Environmental Governance and Politics, sharing as a social scientist my mission. Together we started an honors lab into the acceleration towards animal-free medical science. Ten students worked for a number of months in a co-creative interdisciplinary learning exercise on accelerating the transition. It was a fantastic experience. The students were so motivated, that they continued working on this topic during the summer holidays and many months more. And I became so proud that the honors lab students Fatima Abarkan and Rebecca van Eijden have become board members in Young TPI, together with my PhD student Julia Menon. I feel like a proud mother. Young people have the future and should have a major role in decision making in society. Ingrid and I continued our cooperation in writing a funding application on the same topic. This has resulted in obtaining funding from NWO and since April we have started a fantastic consortium called Safe, Safety Assessment through animal-free evolution. Together with 2 PhD students, one postdoc and many consortium members we are now doing research on how we can accelerate the transition to animal-free research.
I am extremely pleased to have discovered that my work was welcomed at Utrecht University and perfectly fitted in the already ongoing actions with regards to TPI. Next to my own motivation, this has really stimulated me to keep going on the current road. I meet many like-minded researchers, and it is impressive that the Groeifonds aanvraag on creating an infrastructure on animal-free research, the Center for animal-free biomedical translation, has recently received a positive advise from the Ministry of Agriculture, Nature and Food Quality.
The Role of Crises: From Frustration to Inspiration
My personal crises have led me to keep asking questions and have ultimately evolved into many positive changes for me today, for which I am extremely grateful. As my husband always says: change frustration into inspiration. And he is inspiring me continuing to do so every day.
The breathtaking developments in science and technology of the past decades make it now possible to move to animal-free testing really fast. As the global covid crisis has made clear that under pressure, we can and do make system changes in using new science and technology to produce better vaccines faster.
Many good things are already happening, showing that we are in the midst of a transition. The main example of this is the European Citizens Initiative that collected more than 1.2 million signatures. Also a European Parliament Resolution has been passed with a great majority, asking the European commission for concrete plans on phasing out and a roadmap towards animal-free research. This has recently led to a commitment statement by the European Commission to develop a roadmap towards the phasing out of animal studies and phasing in alternative methods.
Next to public pressure, there is another hopeful ongoing development. The industry has succesfully started court cases because of the regulatory inertia to incorporate new and validated non-animal methods, which is also surprising when considering the detailed content of the legislative texts, such as animal studies only to be used as a last resort.
From the 1000 roads toward animal-free research that are currently already there, the main road seems to me the road of the public. Citizens can make a difference, and combining this with the scientific evidence on what steps to take, this must be most effective in accelerating the change for real. Based on my scientific work I will, together with colleagues support this kind of initiatives wherever and whenever I can. For the benefit of all living beings, that is what I promise.
I like to start by saying that I am very grateful to Bert van Zutphen, Anton Beynen and Vera Baumans, and other colleagues from the Department of Laboratory Animal Science, who have taught me crucial lessons about quality of science, laboratory animal welfare and striving for an open dialogue at all times.
A few years ago conversations about my possible move to Utrecht University started and I have been impressed by the numerous people who expressed how welcome my work is at this university: a big thank you especially to Wim de Leeuw, Frank Miedema, Anton Pijpers, Dick Heederik and Debbie Jaarsma.
Especially Wim de Leeuw, your tireless endeavours and patience to make this work have been impressive.
Juliette Legler, there was no hesitation whatsoever to accept me in your department and you and all IRAS tox colleagues have made me feel so welcome. Juliette, the way you manage so many projects and people in such a fantastic manner is an example to the academic world and beyond.
Ingrid Visseren-Hamakers: your unconditional support in very challenging circumstances was essential, and the honours lab and the NWO funding application have been a wonderful cooperation. The cooperation in the SAFE consortium with you, all participants and Justine Watkins, Love Hansell and Kristie O’Neill is really stimulating and united by our wish to make this world a better place. A special thanks to Paul Carmichael and Bart Spee for co- supervising Justine’s PhD, and Hanna Dusza for being her mentor. Thank you to Thomas Hartung and Janneke Hogervorst for co-supervising Love Hansell’s PhD. The cooperation with Unilever feels quite special, as it feels a bit like coming home again. Julia Fentem, Paul Carmichael and colleagues, it is impressive what you are accomplishing towards methods of replacing animal studies. I really love your slogan “use science not animals”.
Also in challenging times coaches are of utmost importance and I wish to thank Sheila van de Sande, and Margreet van Rixtel and Heleen Brinkman, of Leading Academic, for letting me re-discover my own strengths and mission again and again.
I am deeply grateful to Esther Ouwehand and Frank Wassenberg from the Partij voor de Dieren, who have given a lot of support throughout the years.
Cathalijn Leenaars, your drive in teaching and researching systematic reviews is impressive. I hope our cooperation will continue for many years, just like our ongoing cooperation with Franck Meijboom and Rens van de Schoot.
Julia Menon, I am happy you have become registered as my external PhD student, with Martijn Nolte from ZonMw as co-supervisor to study what funders can do to improve quality of science, both nationally as well as globally in the Ensuring Value in Research Funder Forum. Thank you to Tineke Kleinhout-Vliek for being Julia’s mentor and giving excellent input in the qualitative research part.
I also want to thank the colleagues involved in driving TPI UU forward, especially Daniela Salvatori for taking the initiative.
I thank Ronette Gehring for inviting me as the second promotor of Tom Roos’s PhD, with the aim of developing alternatives for cardiotoxicity testing.
A special thanks to Pandora Pound, Jan Turner and the Safer Medicines Trust in the UK, for always stimulating scientific discussions. I feel deeply honoured by the Pioneer Award by Animal-free research UK.
There are some people that have always provided me with friendship and good advice throughout the years: Netty van Lookeren Campagne, Sir Iain Chalmers and Jeremy Grimshaw. I am happy to be board member of Evidence Synthesis International.
A special thanks to Aarhus University, to Gregers Wegener and Birgitte Kousholt, where I have been appointed as honorary Skou professor. Tusind tak for godt samarbejde!
I would like to thank a number of people that have plaid a key role in my working life, and because of time constraints I will mention their names only: Kees Hagenaar, Rob de Vries, Laura Visee, Wynand Alkema, Rafael Frias, Emile Lohman, Dirk Ruiter, Roelof de Wijkerslooth, Yari Barella, Inke Looman, Doortje Swaters, Wim van Meurs, Brett Lidbury, Jennifer Stone and Carel van Os. There are many more, and I apologize for not being able to mention you all here.
Rients – you have taught me Zen meditation and that means a lot to me. Thank you for your never ending support. I hope we can continue this exciting road together for many more years. Dedicated to the benefit of all living beings.
Ik heb gezegd.