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Organoids and a large portion of Chips!
The WORC.Community podcast and also watch (at WORC.Community) the free to join network for organoid, organ-on-a-chip & NAM researchers. Join Professors Marianna Kruithof-de Julio, University of Bern and Steven Ray Haakon Wilson, University of Oslo talking all things organoid and organ-on-a-chip! Contact us with your questions. Watch video at https://www.worc.community/channels/5753
Organoids and a large portion of Chips!
A 3Rs special of 'Organoids & a large portion of Chips!'
Also with video here. (www.WORC.Community)
This very special 3RS podcast is sponsored by:
Crown Bioscience is a Contract Research Organization (CRO) specializing in oncology and immuno-oncology drug discovery and development. 'Our preclinical and translational services offer biotech and pharmaceutical companies the opportunity to remove the guesswork from their research and development'.
This fascinating episode dives deep into the world of the Three Rs—replacement, reduction, and refinement of animal models in research—featuring three leading experts from European 3R centers.
Dr. Armand Mensen from the Swiss 3R Competence Centre explains how thoughtful experimental design forms the foundation of ethical research, allowing scientists to maintain scientific rigor while minimizing animal use. He shares a powerful perspective that good animal welfare and excellent science go hand in hand—they're complementary, not competing priorities. Professor Adrian Smith from Norway's Norecopa reveals the complex political landscape surrounding animal research and why it's crucial for scientists to step outside their comfort zones to share knowledge across disciplines. Meanwhile, Dr. Cathy Vickers from the UK's National Centre for the Three Rs showcases groundbreaking industry collaborations, including a "virtual dog" being developed to potentially eliminate certain toxicity tests and advanced organ-on-chip systems that could transform drug development.The conversation tackles major challenges facing the Three Rs movement—from implementation hurdles to misaligned academic incentives—while highlighting exciting opportunities as regulatory agencies increasingly embrace non-animal methods. We explore how technologies like organoids, microfluidic systems, and AI are creating unprecedented possibilities to study human biology directly rather than through animal proxies.
Whether you're a researcher looking to implement more ethical approaches, a policy maker interested in scientific innovation, or simply curious about how science is evolving to become more humane and human-relevant, this episode offers valuable insights into the future of biomedical research. Subscribe now and join us in exploring how the Three Rs are transforming science as we know it.
Our 3Rs special guests are:
Dr Armand Mensen.
Armand is the Scientific Officer and Deputy Director of the Swiss 3R Competence Center (3RCC).
Professor Adrian Smith
He has been the Secretary of Norecopa (Norway's consensus-platform for the 3Rs - Replacement, Reduction and Refinement of animal research)
Dr Cathy Vickers
Cathy is head of innovation at the UK National Centre for the 3Rs. She leads the CRACK IT Open innovation programme.
This very special 3RS podcast is sponsored by:
Crown Bioscience is a Contract Research Organization (CRO) specializing in oncology and immuno-oncology drug discovery and development. 'Our preclinical and translational services offer biotech and pharmaceutical companies the opportunity to remove the guesswork from their research and development'.
Hello, I'm Miles Rackliff and welcome to another edition of Organoids and a Large Portion of Chips. This is the WORC. Community podcast. So I'm here on the 11th floor of 'Organoid Towers' :-) for a very special show focusing on the three R's, that's, replacement, reduction and refinement of animal models in research, and this episode is being kindly sponsored by Crown Bioscience, who specialise in contract research services for oncology, including, of course, 3d organoid models. Well, I'm very pleased to say that we're going to be joined by some very special 3Rs guests today. But first of all, let's have a very warm welcome back for our regular hosts, professor Mariana Kruithoff- de Julio and Professor Steven Ray Wilson.
Marianna:How are you both? Hello Mariana, hi, hi Steve.
Miles:So, Mariana, what have you been up to the last few weeks?
Marianna:Oh, I feel like I've been driving planes Lots of traveling lately. I've been in many study sessions, so a of a lot of learning, uh, while I've been reviewing grants, so it's been really exciting times yeah, so what have you been learning?
Miles:dare I ask?
Marianna:oh, uh. So I learned a lot about how uh innovative some people can be in terms of uh looking how to monitor cancer with uh like hair follicles, or you know it's, it's, it's, uh, you know people people have been very creative and with things and also different ways. People are also now using organoids in terms of implantations, also in in zebrafish. So I I think you know the the field is moving towards different things and I like how creative people have have been in this, so it's really exciting, yeah oh, fantastic.
Marianna:I'm not sure the follicles would be much use for myself, but yes, okay, you know, maybe you have some facial hair, you have facial. We could we start plugging that?
Miles:well, you'll never need that and I'll leave my hair growing details for another episode. But yes, stephen, what have you been up to?
Steven:so I've been. I've been going bananas at the university with my, with the part of my job as professor, as a teacher, so so the last couple weeks I've had like maybe 50 oral exams, 50. So yeah, yeah, it's been crazy, but you know, but there's some really good students out there, so I've had exams and courses in biochemistry and analytical chemistry, so I'm really happy about that. But now I'm, um, I'm currently in belgium at a conference for chromatography and, uh, and just right after this talk, I'm going to be running out to to hold my, my oral presentation here. So, uh, having a great time, lots of stuff going on and listeners.
Miles:If you haven't seen, steven's got some very cool um technology in the space here, so do do check him out online and in the podcast notes afterwards thank you, miles.
Steven:Thank you, that's a free plug for you.
Miles:Excellent, all right, yeah and if anybody else has some things to advertise, feel free, that's all good. So so I was saying so we it's a very timely and this episode is focusing on the three hours, with the recent announcements by the fda, nih and, not to be outdone as well, with the eu roadmap as well, on this shift towards a human specific research and animal testing alternatives. So we have three very special three hours guests today. They are from the UK, first of all, dr Kathy Vickers, which is from the Head of Innovation at NC3Rs. From Switzerland, we have Dr Armand Mensen from the Swiss 3R Competence Centre and from Norway, professor Adrian Smith, the Norwegian 3R consensus platform called Noracopa. So I thought, first of all, it'd be nice if us, as podcast hosts, could introduce everybody more properly. So, marianna, would you be so kind and formally introduce Armand.
Marianna:It would be my pleasure. So Armand Mensen is the scientific officer and deputy director of the Swiss 3R Competence Center. Armand received his PhD in physiology in 2012 from the University of Zurich, with a variety of research fields such as sleep consciousness and stroke Very, very interesting, I must say, armand. Armand's work always focused on optimizing experimental design and developing novel statistical analytical tools. This perception, along with a strong ethical compass, brought him to join the Swiss 3R in 2018. He now manages the 3R funding scheme, the reviews on application, monitors the ongoing projects in a very strict manner, I should say, and tracks the 3R impact they might have on both on the research and public policy landscape. And, I must add, he is always very helpful and open to chat, and so I'm really glad that you decided to join us for this chat. Thank you, thank you very much.
Armand:Yeah, thanks very much for having me. So, indeed, full disclosure. We fund one of Mariana's projects, or say we fund it, it's now over. So yeah, we know each other a little bit from that.
Marianna:It was a while ago, so it was a project awarded in 2019. I think it was one of the first.
Armand:Yeah, the second year we ever did our funding scheme, so the Swiss RCC is established in 2018. Yeah, and then, yeah, your open call 2019.
Marianna:Uh, project three so it was a very successful one. That was our uh. Two nature communication papers came out of that project, so I would say it was very, very helpful and uh well, I've got to ask what was the project very quickly. So this was to set up the precision oncology platforms here at the University of Berenin, to optimizing the GU platform for generation of organoids and to reduce the amount of animals that would be used for experimental testing. So yeah.
Marianna:I think we've been quite successful in doing that, and we also generated maybe Armin doesn't know this, but we generated also a spin-off company off of this as well. So, yeah, wow.
Armand:So exactly what we're looking for.
Miles:Investment in action Marvelous. Sorry, Maria, back to you.
Marianna:Yeah. So of course we have plenty of questions for you here to ask, but you know they told me I don't have much time to just monologue with you, but here we go. Here it goes. So how can experimental design improve the use of animal models and what are the alternatives? How do you see this and what would your comment on this be?
Armand:Yeah, I mean, like you just said, like experimental design has always been a key for me, just because it's a key to any research.
Armand:I think you know, a concept can be solid, theoretical background can be there, but if the experiment is not designed in a way to produce those meaningful results so maybe it's unsuitable control groups or bias in the selection, or insufficient power it's still just a waste of time, energy and resources, as we all know, money being the one of the main resources, but not the only one.
Armand:And then, of course, as we move in the case of animal experimentation, it also becomes a further waste, of course, of an animal's life or generally their life. And so it really is such a, it's such a base factor. So, you know, with smart experimental design, we can really limit the sample sizes, or at least be precise about the sample sizes, we can define good control groups, we can already define the proper statistics that we'll need and really maintain, while maintaining the scientific rigor that we need to actually produce meaningful results. And then, even when we think about the alternative approaches, I mean one thing is that a good experimental design in the alternative arena can give a lot of those other researchers perhaps the ones using the animals, the confidence that, yes, indeed, this is a really good research project and I might be convinced now to move from my animal-based project over to this alternative. So it's such an initial key part of really any experiment, but especially ones to do with the three R's landscape.
Marianna:So you would say that, basically, good planning and good statistics would be at the basics of the foundation of the generation of an experiment, of the planning of an animal experiment. Yeah, absolutely. So, moving on to something that's a little bit different, would it be maybe possible for you to give explain in a few words to somebody that is outside of science? How can they actually relate to the 3R and understand this? So how would you explain this to a non-scientist?
Armand:Yeah, so I think I mean the three R's basically as a concept started in the late 1950s. So despite that, being relatively young, we've kind of iterated over a lot of definitions. And how I would note it is that basically scientists, and science at its core is about being a problem solver. So you have a particular issue at hand and the three R's role in that is that it tries to give a sort of heuristic or set of concepts that allows researchers to be able to solve a particular problem by asking themselves a few different questions.
Armand:You know, can I solve this without any use of animals at all? And most problems, of course, that's quickly, yes, and then we move on. But when it's not okay, I need to use some animals. What's the fewest animals I need to be able to get reliable answers? And then the last is sort of okay, I really need these animals. The ones that I do need is sort of okay, I really need these animals, the ones that I do need. How can I be responsible and make sure they're as comfortable as possible and as well taken care of as possible? So really kind of just any set of principles that allows you to go through those kind of questions and sets of questions is kind of related to the three R's principle.
Marianna:Yeah, but don't you think that it's still a bit difficult for the public to actually understand and to be sure that we, as scientists, are actually using the animals appropriately and in a really necessary manner? So how can we reassure the public that it is necessary and that all we do is very well regulated?
Armand:Yeah, I mean it's such a problem. I think at the ground level, like the scientists themselves are reluctant to even talk about some of these issues, somewhat understandably, there's a lot of sort of well realistic risk in some of the pushback that exists. So very understandable but in the end really transparent reporting of research methods, you know, kind of pre-registering your studies, having independent ethical groups to review a lot of the work these are things that are already in place for the most part and as long as the public can have a sort of understanding that those processes are in place, that can build confidence. And then also just or I should say part of that understanding just relies on having really good bridges between the scientists and public so that you know good communication, good scientific publication, open honesty those are all things that can build that trust again. And I think with the trust you can point to a lot of the systems that are already in place to make sure actually you know anything that is being done is really necessary and certainly in Switzerland very, very well regulated.
Marianna:So that's really interesting. Because that brings me to the next question, which would be if you could just, you know, change how society sees one thing about the research that we do with animals, what would that be, and why would you change that, or why would you emphasize that? If not changed, maybe it's something that's already there, right, and then we just want to maybe give it like a spot of light on it, shine a light on it.
Armand:Right.
Armand:So I think what I would want people to understand is that you know, along with that definition I gave about how, like the three R's kind of, should be seen, good animal welfare and caring about the animals and the people that work with the animals and excellent science really go hand in hand.
Armand:There isn't a three R's that limits research or wants to impose restrictions and tries to do a whole lot. It's about making what is going on more reliable, relevant, ethical, and those things just go hand in hand. I mean there's sort of happy animals is good data right, or good animals good data, and I think, even though it's a short slogan, there's a lot of truth in that. And so I think if people can come to the understanding that the scientists that are doing these projects are people too I know it sounds weird that they're also people also people and for the vast majority, and certainly everyone that I've ever encountered in the field, they really deeply care about the animals they're working with and I think if that becomes kind of understandable to the, say, average public person, I think we've already come a long way in building that trust.
Marianna:Well, I like that. I think that's a very interesting and a very strong point. So, which brings me then to my last question, and that would be what does the future of animal research look like in Switzerland and maybe globally? I?
Armand:mean a bit of much, as we like to think of us in a certain isolated way.
Armand:We're certainly not isolated, you know. I hope Switzerland is, and I hope it continues to be, at the forefront of a lot of this research. I think on a practical sense, obviously, you know it involves more sophistication in models, organ on a chip, systems, organoids AI is probably going to become a big thing, and that's generally obviously, and I hope that also, whatever remaining animal research there is, it just becomes more precise through kind of these experimental designs, statistical ideas and more responsible as we continue to grow our knowledge about kind of animal welfare, how to measure animal welfare and also like what is the animal's internal experience and we can sort of guide a little bit of that. And so hopefully there still are these different bridges, all encompassed within the three hours principle, that continue to kind of grow and define. I think, as most sciences it'll be slow and steady and it may take some time, but I definitely think even in the six, seven years that I've been part of the three hours, you see, we've seen a lot of that growth already happening.
Marianna:Well, that's great, so I hope that that group keeps on the going in the right, in the right direction. I'm going to hand over the mic to steve. Well, thank you very much, armin sure, thanks a lot.
Steven:and uh, now we're going to be talking with adrian.
Steven:So Adrian Smith is a british veterinarian who graduated from cambridge in 1979 and emigrated to Norway in 1980. And he held the chair in the Laboratory of Animal Science at the Norwegian School of Veterinary Science from 88 until 2011. And has arranged over 50 courses for researchers and technicians and been the secretary of NORACOPA, which is Norway's consensus platform for the three R's, which are replacement, reduction and refinement of animal research, as we all know, since it was established in 2007. And he's had a special interest in three R resources for many years, which I have also had the pleasure of really being able to use in many different situations, also when preparing for talks and so forth. And he's co-authored several databases in this area and is the lead author of the PREPARE guidelines for planning animal studies.
Steven:So, adrian, it's really nice to have you here, and I also know that in Norway, you're also well known for trying to influence the policies in Norway. Could you tell a little bit about what is like the political landscape in Norway when it comes to 3R initiatives? Can you tell a little about that?
Adrian:Yeah, thanks very much for inviting me. We might just add one more disclosure. That is that I got to know you through Noricopa's 3R Prize, which we award every year for a personal group of people who have helped to advance significantly the three hours. And you have three students who were nominated last year and although they didn't win last year, I encouraged them to nominate themselves again this year and this year they won the prize. So congratulations with that. And that was for work and organize. Yeah, it's really cool.
Steven:Thank you so much for that.
Adrian:That's one of the ways in which we try and spread information about the three R's to the general public and the politicians as well, by showing that good work is being done in Norway to promote this concept. So that was maybe the initial answer to your question.
Steven:Are politicians in Norway hard to convince about 3Rs?
Adrian:Well, there's a real mystery going on here. I mean, it's a total no-brainer to be for alternatives to animal experiments. I mean, which politician would be against alternatives to animal experiments? I mean, obviously everybody is for it. Alternatives to animal experiments, I mean obviously everybody is for it.
Adrian:But um, going from that to getting them to um pass legislation or establish a proper three-hour center has been much more of an uphill battle, and my impression is that, um, every time um we've see a chance to have a really good debate about animal research, then another group of animals hits the headlines, say it's um tragedies on the pig farms, or the way we keep poultry, or whether we should forbid fur farming, this sort of thing. Each these other scenarios which the general public seem to relate more closely to have sort of taken over and swamped our debate, and therein lies the dilemma from my point of view. Norikope, which is trying to promote the three R's, is primarily targeting the scientists, and so we don't want to go out in the mass media with sort of blood dripping photos of lab animals that are suffering, because then it would alienate the group of people who we're most interested in talking to. So we keep a fairly low profile and now, at any rate in 2025, most of the animal welfare organizations are actually basically doing the same. We don't see the same level of antagonism in social media and the papers that we saw, say, 20 years ago in social media and the papers that we saw, say, 20 years ago. So, as a result, I think the general public seemed to be sort of thinking well, we rely on the fact that scientists and people like Norikopa and the local animal welfare bodies are taking care of this. We don't really want to know more about animal research and this, I think, probably influences the politicians, because there aren't a lot of people lobbying outside the parliament to abolish animal research, and the main problem from our point of view has been that we haven't managed to get sufficient majorities in Parliament for big changes.
Adrian:Noracopa is a small organisation. We would like to have a much bigger three-hour centre. We hoped that that would be proposed in a governmental report that was published just before Christmas on animal welfare, but the reports just concluded that the government would evaluate the need for a centre and how a centre could use existing resources like Noricopa. So we are now in the sort of process where we're waiting for this evaluation, and it's nice to see that Noricopa itself is clearly appreciated by the politicians, but we'd like to go one step further and have a much bigger three hour centre so we could relate more to the 80 lab animal facilities we have around Norway. There are a lot of them and it's a big country the 80 lab animal facilities we have around Norway.
Steven:There are a lot of them and it's a big country, so it's really, it's really interesting, adrian, and I'm really thinking about the point that you're making, that you know. I mean, of course animal research has there's a lot of problematic aspects with it. Of course, as we've discussed previously. I think animal research has been a clear necessity and will have a very strong role in research going forward. But, as we're talking about here, one wants to be able to do it smarter or make it more alternative models, like you say, or make it more alternative models, like you say, organoids and organoid chips. But it seems like you are.
Steven:It can get in the way if people are getting too dramatic in their way of communicating what is going on and so forth. I was just wondering, maybe Arman also, would you agree with this notion, for example? Would you agree with this notion, for example, that the way of communicating the wish to reduce animal experiments, would you agree that the way is to do it in a more of a scientific way than in a more of a dare I call it an emotional way? How does that sound, armin? Would you say?
Armand:Yeah, no, I think that has to be the way to do it too, and otherwise you get like this defensive thing coming into it and you defend your project or you defend your research career or something.
Armand:I think if you feel that that's under attack, then you're unlikely to even hear the next sentence, which is you know how and why and what resources to take you just I mean, it would just probably be a block from right there, and and I think there's, there's you know, the majority of arguments that I think one could have when there are realistic alternatives are perfectly based within science or even things. If you're a politician, perhaps your major interest might be cost, cost effectiveness, and there are great arguments within those frames too. So I think you do have to adapt your message a little bit. I think the scientific route is almost certainly going to be your best bet in most ways. But yeah, it depends on your audience. Get to know them, what they care about, perhaps what type of politician that they are in terms of where they are, in terms of the Ministry of Finance, well then, you may be talking in a different way than the Ministry of Agriculture might be interested in.
Armand:Yeah, sure, yeah Well listen Adrian, yeah, Shoot in Adrian.
Adrian:I've just come back from the big European Lab Animal Science Congress, filasa, which was held in Athens for a whole week. We were over 2,000 people there and it's very clear that the science of laboratory animal science, the field, has really advanced and we have a lot of good information there. But we are not as good at communicating with the other scientific fields. I would like to see far more outreach to the neuroscientists, the physiologists, the toxicologists, the pharmacologists, etc. I think that's really what we need now far more dialogue between these groups.
Adrian:And, as Armin mentioned, I think some of these scientists quickly feel threatened if we mention the three hours. They assume we're trying to replace an animal model which they maybe spent 30 years building and humanising and writing papers about. And who are we to come and say that? You know, scrap all that and start using organoids instead. So, but at the same time, I think there is still probably a lot of opportunities to improve and refine the animal work that has been doing is being done and I've noticed a few times I've been at these other congresses when I'm looking at a poster subscribing, say, the anesthesia that's being used that we could have been there and given them some, some better ways of doing things and I think this we need far more of this dialogue, um because animals research isn't going to disappear in in the next five minutes and we need a lot more guidelines, both species specific and situation specific guidelines, um to to improve what is being done.
Adrian:That was why NoriCorp has spent so much time developing the PREPARE guidelines for planning animal research. They were initially based on all our experiences talking with scientists, running courses for them, managing accredited facilities and realising all the practical details that can ruin an experiment which otherwise has been planned well scientifically. And I don't think all scientists are aware of all these small practical details that assume the animal facility is dealing with it. And we need to engage them from day one of planning to to make sure they have sufficient dialogue with the facility to to to plan good research, and that's where prepare comes in um, and then, at the other end of the research path, then we have reporting guidelines, which kathy will no doubt uh tell us more about. So so we need to take care of them from day one right until they submit their manuscripts.
Steven:Yeah, well, maybe that's a nice segue to Miles. Maybe we'll be hearing more from Armin and Adrian also in the last roundtable part of this. But, miles, maybe you would like to introduce Cathy to us.
Miles:Yeah, absolutely. Thank you so much both. So Cathy Vickers is a Head of Innovation at the UK National Centre for the Three Arts. Cathy received a PhD in Molecular Neurophysiology from Edinburgh University and has spent time working in Japan, the US, the UK, in both academia and industry, before joining the NC3Rs itself. She leads the Crackit Open Innovation Programme, which is funding collaborations between academia, SME, so small, medium business enterprise sector and industry scientists, and the purpose is to develop commercially available 3Rs technologies that can be used in the real world across sectors to deliver better science, improve business processes, alongside having real world impacts on the 3Rs. So thank you, Cathy, Welcome again.
Cathy:Thank you.
Miles:Nice to be here, pleasure. And so I think you know within the UK and the rest of the world the NC3Rs is very well known within the research and it's about as old as I am, so over 50 years ago I think it's been going.
Cathy:But just to tell me a little bit more about the, you know those important links to industry in the crack it program and how the industry is involved in these replacement efforts and maybe you have some favorite examples thank you, yes, miles, I think industry is very interested in replacement, and by industry we mean across all sectors, so that in corporate covers, pharmaceuticals, chemicals, agrochem we know the cosmetic industry already do not use animals in their regulatory testing but also CROs, the contract research organisations that support these large industries, and also a very fast growing small business sector that is growing, spinning out from universities and providing some of these real key replacement tools and technologies. Um, and I think industry's interest has always been there because obviously we've talked about it. You know, I think everybody has that ethical driver to implement this for. And if we're talking about replacement specifically, you know, I think all industries have that ethical driver to not use animals where they can avoid it. But I think what's happened recently is, I think probably for the first time, we are now in a position with iPS cells, with organoids, organoids chips and silica modelling, we can actually study human biology and disease using human biology as the model as opposed to an animal model, human biology as the model as opposed to an animal model.
Cathy:And I think many people are aware, especially for things like pharmaceuticals, that, um, failure rate or attrition of drugs failing to get to the clinic, so failing to be prescribed and available for use in humans, because the data that was generated during their testing in animals does not translate to what happens in the human.
Cathy:So it might be that it appeared to be safe in the animals and then there's an unexpected toxicity in humans, or it appeared to work in animals and doesn't seem to work as well in humans, and I think that's been a huge barrier to some, of a huge cause of attrition to especially the pharmaceutical industry, but also to other industries when they're talking about trying to ascertain whether their products are safe. And, as I was mentioning, now we've got this huge advances in biology and cells and being able to recapitulate some of human physiology better in vitro. That really does open up the opportunity to study, develop and test new medicines, for example using human biology rather than animals, and I think oh, sorry, I just wanted to highlight that all of these products, whether they come from pharmaceutical, chemical industries, etc.
Cathy:They all have to be approved by regulators and these are government agencies that look at all the data that's been provided by the company to, say, make a decision whether the, let's say, drug in this case is is effective and it's safe. And I think where that is where animal studies are still required. So a lot of pharma I'm talking pharma specifically we use a lot of in vitro complex models, human models. They're still submitting animal data for regulatory approval. But we know that the regulators are also excited about the potential of replacement with the recent FDA announcement of their roadmap, their plan to phase out animal tests for safety as a priority, preclinical safety studies, ema. We know we've got the three hours working party in the European Medicines Agency.
Cathy:So there's a lot of momentum, a lot of appetite, but I think what that generates is a huge amount of interest, a huge amount of momentum and a huge amount of promise, but I think realistically, it's about setting expectations over time. When can we get to the point where we can say you no longer, for example, need to use animals for regulatory safety studies? There are instances now where people have put submissions in for approvals, whether it's a new indication for a drug or whether it has been supported by in vitro studies, but it's absolutely. It's not the norm at the, but I think there's a huge amount of interest and engagement because of the human relevance, potentially cost and time efficiencies as well. I think it was Amal that was mentioning that you know if you can avoid doing a nine-month study in an animal because you've got advanced in vitro and in silico models that you can run from your laptop or from your bench side.
Miles:That obviously speaks to lowering costs and time as well and in terms of those projects which you're you're funding, um, how much of the innovation is maybe coming from and scientists using animal models at the moment, or is it more people looking, coming from outside, thinking maybe we? How can we change this?
Cathy:is it a bit of both or so the way we frame our graphic challenges normally is we're working with industry scientists and they are either currently using an in vivo model to address a particular scientific question, let's say, and the animal mothers are potentially very burdensome, so perhaps the animals are going to go long studies there could be some pain involved, for example, or it could be that they're not just producing human, relevant or interesting or relevant data. They could be taking a long time. And then the scientists who come to us from these industry sectors are also aware of what's emerging from the academic and SME research sectors. You know, you know IPS cells are being um, organoids are starting to show how you can address this problem. With microfluidics and engineering you can create these complex models that, with a little bit of extra funding, time and challenge, maybe could be used to replace some of the animal studies that are currently going on in R&D. And that's how they're set.
Cathy:Some of our challenges are for fall replacement, an in vitro model to look at nephrotoxicity, to replace the use of the rodent. Some of ours are looking at better, just more human, predictive biology, the development of, but we also look at in vivo challenges as well, where perhaps there's the opportunity to improve the welfare. So refine the use of animals that are being used in these studies, reduce the numbers of them that are being used. But always and again I think I'm on and agent were mentioning this it's science-led and evidence-based. We're pushing the science forward by integrating all of this new knowledge and expertise within the projects that we fund and do you, do you have a?
Miles:if you could, uh, single out a couple of examples, or maybe just one which you think yes.
Cathy:So one of the ones we have running at the moment is uh, we are funding the development of a virtual dog. So, um dog, so when their medicine is going to be approved or when you're testing the toxicity of a new medicine, without getting too technical, this is mainly in small molecules we're looking at here you have to do toxicity in a rodent and a non-rodent species. The rodent is normally the rat and the non-rodent species is normally the dog. And you will do again. It varies. It's going to regulatory guidelines. You'll do a short term and a longer term study in both species.
Cathy:We have worked through some of our other programmes at NC3Rs to identify that actually retrospectively, looking at data and decisions that have previously been made, we analysed a data set that showed that the use of the chronic study did not change a decision that would have been made based solely on the short-term study.
Cathy:So what they're saying is the regulators required to do a short-term and a long-term study in the dog, and retrospective analysis suggested that there were times and opportunities that the long-term study in the dog didn't alter the decision around the safety or the information around the molecule.
Cathy:So what we're doing so getting regulatory requirements to shift. To say that you don't need a chronic toxicity in the dog would take a very long time and needs a lot of evidence, and part of that evidence we're trying to generate through the creation of this virtual dog. So this is trying to use advanced in silica modelling and machine learning to create a suite of virtual dog. So this is trying to use advanced in silica modeling and machine learning to create a suite of virtual dog organs so that you could make a decision that you would normally make following a chronic toxicity, chronic toxicological study using a dog, using our in silica model. Now it's very ambitious. I'm not sure the dog will have a waggy tail and ears, but what we're doing is and how many different parties are involved in this we have seven pharmaceutical companies.
Cathy:We collaborated with the recent imr project, e-trans safe, and we're working with the german sme esq labs, collaborating with fraunhofer to deliver the work this is quite a big project.
Cathy:It's got quite a way to go.
Cathy:It's a big challenge but again, just really excited to say that awareness of the capabilities that are coming out in the scientific research base and matching them up with some big needs from industry can actually deliver really exciting and innovative tools that can really have an impact.
Cathy:And we've got a similar bigger challenge is looking at organ-on-a-chips. So looking at connecting organ-on-a-chips or what they are we know this for organ-on-a-chips podcast but what we're looking at is reducing some of the barriers for their sort of rapid uptake and integration into industrial workflows by getting that confidence, making them more automated. So we've got a big challenge called SensorChip that's looking to develop real-time multi-parametric monitoring of these connected organs on chips and also combine them with some advanced data interrogation and machine learning so that you can get that robustness, reproducibility and reliability which is perhaps lacking from some current organ-honoured chip systems because of their complexity and you need to be pretty skilled at doing your organ-honoured chip experiment and reducing some of the barriers to their incorporation into sort of R&D. But also looking to say can we get as much high-quality, reproducible scientific knowledge out of these chips as we can by collecting all the as we can, by collecting all the information we can and doing some really thorough analysis on them fantastic.
Miles:That's really exciting and for everybody listening. We will be putting some links at the bottom of the podcast as well on smith's, crack it and other challenges. So thank you so much, kathy. That's wonderful. Um, we're going to move on now have a bit of a round table discussion, so I'm gonna have a few questions um gonna pop out there and I think one of the main ones is you know what are the biggest challenges but also the opportunities um armand, adrian and kathy that the the three hours face today. So really the challenges and opportunities which are faced by everybody.
Armand:Maybe um armand, sure, um although I'd love to defer to my better knowing colleagues, but I think certainly one of the biggest challenges we face actually in the three RCC at least, but I'd be very interested to know if my colleagues have the same which is simply a lot of good science already exists, already exists. So there's a lot of really good like individual kind of papers that are out there. You can look for them on a number of topics, whether it's organoids or organ on a chips, a lot of the really good basis science has been done and then the paper kind of sits there by itself a little bit and we don't have this widespread outreach by the scientists. Well, one could ask, is it really their job to do this? They've done so much of the work already. But to get that to neighboring systems, maybe a colleague of theirs uses it, maybe someone picked it up at a conference somewhere, but it's not as widespread as it should be or could be somewhere, but it's not as widespread as it should be or could be.
Armand:So there's a lot of this low hanging implementation fruit that I think can be had. So that's the challenge. But because it's this low hanging fruit, we also see it as this opportunity where, man, the five years of hard work and the publications that you have to get through the system, that part's over and there's probably just these little niche things that maybe aren't as convincing. Perhaps that's understanding, perhaps that's, you know, maybe detailed costs or really one of the biggest hurdles and opportunities for us.
Miles:So that's really sort of a communication and engagement point of view.
Armand:Yeah, there may also be sort of you know, minor research questions that prevent kind of a full uptake like oh, will that work in this particular thing.
Miles:But by and large I think it is a little bit of just communication understanding I mean, do you think these questions go on directly to the author, or do you think somebody reads a paper and then it gets lost and they move on to something else, or I think I think there's a lot of reasons that I mean.
Armand:I mean happy to hear from from k, from Kathy, what kind of things she most often comes across in this space.
Steven:Maybe Kathy first and then Adrian has a comment after that.
Cathy:Okay, Okay, I mean, I just wanted to add, you know we set ourselves quite a task. We have three ambitions replacement, reduction, reduction and refinement. And we want to implement them across the whole of basic life sciences research pharmaceutical r&d, agrochemical, petrochemical, veterinary medicine. You know, and so we. It's huge, right, the whole fields and the whole areas of life science research is huge and I completely agree with armon, you kind of sometimes can feel frustrated that you know these models, alternatives or well refined models or experimental, that this out there it should be and they should be. They are easily accessible. It should be more, whether it's communication, whether it's better a dissemination of these approaches, but that encouragement to drive or incentivize in vivo researchers to move away from that. But I think we have to be a little kind to ourselves in realizing the size of what we're trying to change, just in the disciplines and the research areas as well. But just before I hand over to adrian, I also wanted to say it's about expectations as well, and I sort of alluded to some of that when I was talking about some of the regulatory sites organ on chips and organoids. They're really exciting, of course they are.
Cathy:We can do things, as I say, model human biology like we've never modeled it before. But we can't replicate a human in a dish at the moment. We can't replicate where a drug travels in one heartbeat, its exposure, its metabolism to all the different organs and all the different. And so I think sometimes the we can't replicate where a drug travels in one heartbeat, its exposure, its metabolism to all the different organs and all the different. And so I think sometimes the expectations can be too high from these technologies.
Cathy:Right now they are so good at doing what they're designed to do, but the expectation that they could solve every scientific question or deliver data against every hypothesis, right now it's not there yet. The important thing is to make sure they're implemented and replacing animals right now where they are able to do so, which is across a lot of disciplines and types of research, and then building that confidence in them so they can be further developed and combined with other approaches to then tackle some of the larger whole body, if you like, or systemic um physiological questions in the future. But sorry, I'll be quite hand over to adrian now yeah, hi, thanks, that's great.
Adrian:um, this is a fascinating area.
Adrian:It was actually something that russell and birch um were conscious of right back in the mid 1950s when they wrote a letter of introduction to scientists who they were going to interview and they were asked to take out the word alternative from the letter because they were afraid that the UFO was afraid that the scientists would react negatively to that.
Adrian:And we talk often about two different types of alternatives NATs and NAMs NATs being the non-animal technology and NAMs being new approach methodologies, and the definitions are debatable, but the point is that these new approach methodologies they are often not replacements to animal research at all there, and people may not even be aware they're using or developing a technique that might replace animal research, and this is yet another reason why I think we need to get out of our comfort zones and visit the other scientific societies, go to their meetings, because they don't seem particularly inclined to come to lab animal science meetings.
Adrian:We need to invite ourselves to them and and have more dialogue to to break down these barriers and show that you know we're all working towards the same scientific aims and there may be alternative methods that they haven't thought about, not as a threat to their work, but as a way of advancing the science, and so I'm really a fan of more respectful dialogue between the different scientific disciplines, getting out of our comfort zone, going to those who maybe don't know as much about lab animal science as the specialists in that field, and that's one of the reasons why NoriCorp spends a lot of time building up a comprehensive website on TRIA alternatives, so that the resources are easily available for people who are curious about that. But there's no substitute, in my opinion, to to going to their other meetings and having these, these informal discussions about the way ahead, to to remove the the, the sense that we're threatening scientists who have been using animal models for years.
Armand:Yeah, I think more sort of like knowledge transfers between labs that are planned right from the beginning. You know we're going to do this and then in stage two we've already organized that you know, an expert from here and here is going to visit our lab and also the trainees are going to visit these other labs, and have that integrated within the time scope of the scientific project itself would be, I mean, usually advantageous, although time, time, who has the time for these things? But still, I think that's the communication. Knowledge transfer should be kind of baked into the scientific program along with the hundred other things I just, I just wanted to add something.
Marianna:I mean, I think this is, uh, this is a really great topic and a really great conversation, but I think that, um, we also have to focus this or look at it from the scientist's point of view, right, which is a very different way of looking at the animal research.
Marianna:And what I'm trying to say is that what counts for us is also, of course, the kind of output and the kind of impact our output has.
Marianna:Right, this is the meter by which we as scientists get judged, which we as scientists get judged right, and we as scientists that review our own works right, as peer reviewers, we are the worst in this aspect, because what we do is that we set the bar at a certain level, right, and then we say, okay, you've done this experiment, you've used 25 different kinds of ex vivo models and you've done the, the, the, the, the, the, the. Maybe the zebrafish, which is not really an animal for unknown reasons, but you haven't done the experiment in the mouse, for example, and therefore your impact is, yeah, it's okay, but you know you have to do that in vivo experiment, so, and that's. I think that's, that's. I think this is part of the problem. I mean, we are part of the problem, meaning that we should also be open to see the approach in a different way and to see that, indeed, maybe the replacement of the animal model with the organ and chip model can be or could be something there, but I don't think we have the data for that yet.
Cathy:Kathy, go right, yeah mariana, just commenting on that. I think that's absolutely true, because a researcher is pursuing a deeper understanding of their area of research and they will use whatever you know not being so often the models that will provide them with that information, whether that be an in vitro and silico, an, an animal model, a lower organism, et cetera, et cetera. But I did want to add, and I think that is true, and also you get that interaction sometimes with publishers. That looks great, but have you done it in an animal model? When you give us that data, you can publish it. That's another part of the struggle as well, but I think I would say so.
Cathy:I I have been nc3rs for nearly 13 years now and I think it's changed even in that time. You know you will always have animal researchers who are wedded to their animal models for, for whatever reasons, and may be hard to entice to sort of collaborate and explore. But I think you you know some of these, especially as, again going back to this, the huge acceleration in knowledge and technology that's been sort of unleashed through microfluidics, organoids, ips, cells. You know the appetite's there already now for researchers no longer thinking in vitro is second best, but actually considering some of these alternatives as being what they've been looking for to enable that study.
Marianna:Oh, don't get me wrong, I, I would love that. That would actually be the, the new quality. One of the things that we do here at the university of vernon is that we run co-clinical trials with organoids. Right, yeah, fantastic, exactly. So what we are trying to do, so is to run phase two trials or even phase three trials that don't require, you know, that can use actually the predicting skill of the organoid and the AI that we are developing to bring this to another level, so that we're going to bypass the whole concept of maybe, you know, having to do repetitive biopsies on humans even, you know, and not use the animal work and have a. You know, we have one of the Europeans largest repository of live organoids, so, and we share these models with people.
Marianna:But what I'm trying to say is that I realize that we, as scientists, are almost the worst in judging ourselves. That's the kind of and I do agree that it is changing, but we have been faced with, so my research has been faced in terms of you can't get into that journal until you do that animal experiment, and the answer to me was well, we're not going to publish there because I don't want to do the animal experiment. So that's the, the, that's the answer that you should give, right yeah, you could.
Armand:You could probably only afford to do so the certain level already of of recognition. So yeah, I, I hear that it's it's unfortunate and and you know some some effort probably it's unfortunate and some effort probably should be made everywhere to just align these incentives right. So align the incentives to do really really good work. That's three R's principle backed.
Miles:We lost your sound a little bit there, Armand.
Cathy:I can just sort of add to that, while our mom's getting back online and I think some of what marianne was saying was alluding to some of that training you know, if you've been trained throughout your career in in vivo skills, it's quite a big step to refurbish your lab with tissue incubators, cell incubators, learn all the skills and so I think support for to help facilitate some of that transition, not only in design but also in the skills and training, sorry, I'm on. I don't know if you're back online now I don't know oh yes well done.
Armand:No, no, it was. It was really, I think the the the end there that that was um already said by you which which was just making sure that we have those incentives and hopefully things like the funding programs Crack it already make something like that incentivized. We have some parallel funding schemes within the 3RCC that try to incentivize that, but I'm not sure where the NC3Rs or the kind of incentives that you are able to give align with the national incentives um. But you know, certainly for the 3rcc we're a drop in the in the funding bucket um for scientists, unfortunately, um, and yet our demand is is still pretty high. But but certainly some thought and planning um needs to needs to go along in that direction for incentivizing the right ways to do things.
Marianna:But what about if you know you, three authorities that are here in the three-hour world, would get together and think about a way that we could work together as scientists, like find a funding scheme that, for example, would allow Steve and myself to put a grant together? You know, we come from backgrounds that are completely different and but you know, working together could be something that we could bring. And you know what I'm saying is that the funding schemes that we have are nationwide, so they're focused on what we do, and I'm not saying that we don't have the innovation and the technology and the scientists and the brains in the individual countries. But you know, doing science together across borders is much more fun and could open doors that are not only within our own country. And I'm saying this because the grand challenges are due tomorrow, so that's why very topical for you but okay, so that's.
Marianna:I think that's the idea. I mean the fun I have had in the last few weeks and in brainstorming with all these people across the globe on how we can work together, how we can make the new organ on chip, how we can reduce the animal work. That's just what we do. That's fun and stimulates our intellectual I would say capacities to new challenges. I think I agree.
Steven:also, I think that when we team up and as I think that at least in natural sciences, we're good at making teams and big and international teams can make such an impact and we can see this both in clinical research, can be in improving analytical technologies and so forth and I think that that also seeing how European 3R centers and persons like yourself collaborating will be a very important part of that puzzle. So that's really cool.
Armand:Yeah, I think there's some great collaborations already. I know Adrian and the RACOBA and the 3RCC directly collaborated on some data analysis things and we're within the RACOBA network as well by having sufficient stakeholders we're in a part of. I think the challenge comes in when it's about sharing money, and not only for the obvious reasons, but I think about how we are funded and then the mandates that were put under by those funders as well, kind of hurdles that we have. You know, if already a whole bunch of research groups are within the project, then clearly they will already be comfortable with the implementation and the more widespread those things are, then that's a sort of multiple seeds approach that can actually grow from rather than the single laboratory approach, and we know that generally collaborations do produce better science. No-transcript.
Steven:I'd like also just to ask, also related to collaborations, and, adrian, you were touching upon reaching out to other research areas and other resources. I'm just curious because I've seen that in humanities in Norway there's been some it's starting to be some more focus on alternatives to animal research. I saw that the Norwegian research funding gave some researchers in humanities a grant on this recently. I was curious Adrian, are there? Do you think that the involvement of also psychology and humanities would be very relevant for natural scientists, or do you think that that is still a bit of a parallel run, so to speak?
Adrian:Adrian De La Feuille. Yeah, I think I prefer to see priority given to more dialogue between the sciences as I mentioned, neuroscience not least, who have these enormous congresses where many, many animal models are presented, physiologists, etc. And another thing I wanted to mention in that connection is which I think is probably on your notepad of things to talk about is these is collaboration between the, the European three, our centers and what they can do. We we have a cost action called improve that has worked to establish a network of European three hour centres. We have about 30 of them now. We have something called EU three hour net, which has had several meetings to, where we've spent most of the time so far just getting to know each other but certainly planning the way ahead to collaborate so we can be better at spreading information. And then to scientists, who maybe don't understand the full ramifications of the three R's. So I personally would like to concentrate on dialogue with those who are using animals in products, like in the neurosciences I see.
Armand:I think there's because of the low-hanging fruit that I mentioned before, like there is a lot that can just be done when you think about the basics. Like a lot of it isn't, oh, we're having to fine-tune some of the ideas and concepts and reach out. So there's a lot of it, isn't? Oh, we're having to fine tune some of the ideas and concepts and reach out, so there's a lot of groundwork to be had. So you know, I agree with Adrian there.
Armand:I think there is and there's a few projects going on in Switzerland that maybe I can provide a link to later, but which are humanities based projects and they're really looking, it's a bit of change psychology. So how do you motivate people to change their minds and and that sort of area of the humanities I think? I think is quite relevant here. You know, again, with this implementation problem, um, and and just figuring out what it takes for, let's, an older, established research group to go, you know what. It's time for us to move to a different path, and I think there there's lessons that we can learn in the humanities.
Steven:Do you think, Armin, as in your background in psychology, do you find that you can see things in a somewhat different angle than one who's been working his or her whole life strictly in, for example, cell biology?
Armand:I don't know if the background discipline gives you that. I think there's just sort of and for very good reasons just different sort of personality types and different priorities that people within the, within the research groups, have. Um, and perhaps again it might be an incentive question where the sort of people that don't mind doing kind of the low level grunt work and planning work, they're not necessarily the type of people that then become leaders of the group and uh and and determine the research strategy. So I think there may just be more low level things going on there than than, let's say, academic background or career ambitions and things like that interesting.
Miles:Well, thank you everybody. We've been here for about an hour and the conversations, I think could keep going for several hours, which is fun. That's what it's all about, and the communication is key, and that's what we're trying to do at workcommunity is to make information accessible to everybody. You can't have everything, but I think what's always important is to have a relevant examples and success stories for people to hear. Um, in this modern world of tick, tocking, social metering and all the rest of it, how do you disseminate the noise? Um, it's trying to reach people quickly and effectively before going into the detail, and that's also part of the events, like word put together.
Miles:Um, which reminds me, actually a long way off yet, but on the 4th of december we're having an organoid and chip christmas party with queen mary university, london at the center for predictive in vitro Models, with Martin Knight and Hazel Screen and Stefan Verbruggen. There We've got speakers from Pharma, astrazeneca, gsk, cosign and lots of academia as well, and the chance to have some proper conversations as well for several hours, and there might be some fizz, lots of mince pies for that sort of thing as well. So lots of events coming up, but I'd just like to say I think we're gonna have to wrap it up now, but just thank you so much to our our special guests today. Thank you, my regular hosts as well, to steve and to mariana. Thank everybody for joining for another episode of organoids and a large portion of chips, and we hope to see you all again soon. Take care, bye-bye.
Armand:Thank you everyone, Bye. Thanks for having us.
