Category: research methods

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Being open about animal research

Today is Being Open about Animal Research Day, #BOARD21. If I can pretend to speak on behalf of my institution, this is what I would say about us. This is what I’m trying to act in line with.

We do research with animals. We also develop non-animal models for biomedical research. Transparency means talking about both, in a way that is as unbiased and as honest as possible.

I’m not a typical researcher using animal models, and my way of being open about animal research will be particular for my own professional self and context.

I’m an animal welfare scientist in a biomedical research institution, i3s – Instituto de Investigação e Inovação em Saúde. I have worked in this organization for 20 years, I have learned a lot, unlearned some, and hopefully achieved one thing or another in terms of institutional culture, practice and infrastructure.

My greatest passion in the field is the research we develop to improve animal welfare, and in particular our research into survival of laboratory mouse pups. This is the topic I have worked on for the longest time, and it has brought fantastic collaborations with great colleagues and outstanding research institutions. At the point where we are now, I’m also believing our research finding can bring about change.

But changing the world through research is a very slow process. Training is much more impactful – or at least so I hope, since this is the other main part of my work. My institution has hosted a training course in laboratory animal science for researchers working with animals since 2005. It makes a huge difference for the mindset and for the standard that everyone who works with animals has been extensively trained to do so. It helps to create a spiral effect where knowledgeable researchers demand high quality support from the animal facility – and the animal facility can set high standards for how animals are treated in research. For us, adhering to international accreditation schemes – FELASA for our training course, AAALAC-International for the animal care and use program as a whole – has been crucial to keep up the quality and to improve.

Institutional measures to promote quality in research with animals are important. The same is true for quality in animal care. Working with international accreditation schemes (FELASA, AAALAC) help us to keep up the quality and improve.

But there is a lot more we can do.

I would like to know that all researchers when planning their research think carefully about what the right model is to address their research questions. And that they get support in this – that they are challenged to think, that they have experts to “think together” with, and that they get expert support in implementing the models. This should be the case for both animal and non-animal models.

I have a vision for how to achieve this within my own institution. To get the entire research community to think this way is beyond my reach, but of course it’s an important ideal.

In the meantime, I wish for all of us to be honest about what we do and what we can achieve. There are problems in practice with animal model research and problems with non-animal model research. We should work to prevent and overcome these problems, and not deny that they exist, or act as if they only happen in one type of research. There are limitations of animal models and limitations of non-animal models. If we speak about the limitations of one, we should also speak about the limitations of the other. Selective use of facts is not good practice in science communication. But it’s far too common in the discussion of animal experimentation – on both sides of the debate.

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Survey to assess requests for evidence on animals – or research with an agenda?

A Survey to Assess Journal and Reviewer Requests for Evidence in Animals is doing the rounds in the research community around Replacement of animal research. This survey addresses an important question in the discussion of how the research community self-regulates (or not) the use of animals in research. Colleagues who study biological mechanisms such as gene regulation or the role of a given molecule in a certain context have repeatedly commented that trying to publish a paper with only work done in non-animal or at least non-vertebrate systems is often met with requests for experiments in animals. People who are not normally using animals in their research are driven to do so to meet these requests and get their work published in the desired journal. Of course, such anecdotal evidence is only relevant to point out that there is an issue to investigate. We do indeed need systematic research to understand how often it happens, in which contexts and to what extent this phenomenon actually drives the use of animals in research.

But is the present survey a credible systematic research effort? Unfortunately, I find two serious reasons to question that Physicians Committee for Responsible Medicine is a credibly author of research into drivers for the use of laboratory animals.

Before I develop my reasoning further, I need to make a reservation. I know – because I just did so! – that if you google “Physicians Committee for Responsible Medicine Criticism” you will find harsh statements against the NGO. I’m not echoing this criticism here, in particular because it comes from sources which are in themselves just as questionable or perhaps even more so.

But PCRM is an advocacy organisation, with an agenda:

Would you trust a study into the impact of meat consumption run by an entity whose mission was to promote beef or pork? I wouldn’t. I apply the same skepticism when it comes to studies run by entities with the opposite agenda. PCRM lobbies against the use of animals in research. Which is a perfectly valid mission for an advocacy organisation. But research and advocacy are not easy bedfellows. And that’s my first reason not to think PCRM is the right entity to run this survey.

To develop my second reason, I will put my peer reviewer hat on. As a senior researcher, I serve or have served on panels which assess applications for research funding for publicly funded research councils in several European countries. Any given call that opens will get many more applications than its budget allows it to fund, and it is important that the proposals are assessed by experts to make sure that the public money is spent on research projects which can be expected to deliver reliable research results. One of the critical questions any reviewer of a project proposal will ask is: Does this team have the relevant expertise and experience to carry out the proposed research? Previous publications by the research team presents the most important proof that they have enough experience and expertise in the field to be trusted with money for a research project.

Assessed on basis of the publications they present, PCRM wouldn’t score high in a funding review. This is what we find under “Our research”: one paper on diabetic neuropathy, six papers on diabetes, seven papers on diet interventions, and 30 “reviews, editorials and additional research”, all on nutrition. Not a single paper on research models, and as far as I can see not a single paper using survey methodology. Would a research council entrust this team public money to use survey methodology to investigate issues affecting model choice? I don’t think so.

Having said all the above, one thing would make me reassess my skepticism: preregistration of the study. No researcher is completely neutral and any researcher is prone to wishful interpretation and even to analysis methods that supports such interpretations. That’s why the concept of preregistration was born. By declaring up front what a study aims to do and which methods it will use, researchers are prevented from ‘sliding’ interpretations of the kind that worry me here. If PCRM had preregistered their study, with a clear declaration of the research aim, the method for data collection and the planned analysis, I would be much less worried. Both because I would know that the authors would be committed to their registered approach, and if the registration was public I could also assess the quality myself.

Unfortunately, I don’t think they have (but I would be happy to stand corrected!) and therefore I’m not taking the survey. But we need the research.

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Painting mice

Why are we recording a video of my colleague Rita Santos painting the back of a white IKEA mouse with a black marker pen?

The background story is that nearly 50 years ago, in 1974, a US researcher painted real laboratory mice as part of what has become a well known story of scientific misconduct in biomedical research. The story isn’t as well-known among biologists and animal scientists as it is among immunologists (or at least so I assume, based on anecdotal evidence = whom among my contacts and colleagues who were or were not aware of it when I asked), despite being both striking and somewhat sad.

Striking, because once you’ve heard the story, you are likely to remember it. Dr William T Summerlin was doing research into transplantation immunology. He believed that by keeping the tissue in laboratory culture for some time before transplanting it into the recipient animal, it could be transplanted without rejection. His proof-of-concept experiment was to graft skin from black mice to (genetically unrelated) white mice. Did he actually ever transplant skin? I don’t know – this amount of detail is not given in the easily accessible internet sources. But what is very clear is that his demonstration of success was a fraud. An attentive technician discovered that the black patch on the back of the white mouse could be rubbed off with ethanol. As reported in this NY Times account of the case, published only a month later, Summerlin admitted to having painted the mice.

Sad, for a number of reasons, going beyond the actual misconduct itself, which is of course in itself highly lamentable. The painted mice seems not to be a one-off event – when Summerlin was investigated the committee also discovered a seemingly very dubious case of cornea transplant experiments in rabbits. Whereas having their backs painted would hardly have harmed the mice, the failed cornea transplants must have caused the rabbits pain. And none of this was justified. Scientific experimentation is not about simply trying something to see if it works: there has to be a reasonably developed idea of what mechanisms are involved. I don’t find any reference to a theory about mechanisms involved in the purported transformation of a xenograft (from a genetically different individual) into tissue that is not recognised as foreign when transplanted into a recipient. All that is to be found is that Summerlin had claimed for some years that he had a method for laboratory culture of tissues that removed the problem with transplant rejection, and that other researchers were unable to make the procedure work when they tried to repeat it in their own labs (a classic way through which fraudulent or poorly conducted research is discovered). The requirement that an experiment is based on a reasonably developed theoretical framework and previous, related studies is even stronger when the health and well-being of living beings are involved.

Why, then, are we painting mice? As part of the INTEGRITY project, we are developing teaching material into ethics and research integrity issues in animal experimentation, for high school students, ready for road testing in about a month. And please note, we’re not painting mice, we’re painting toy mice. The first R, Replacement, of the 3Rs principle of course. Knowing what mice are like, I actually believe that using real mice for this purpose would not only have been stressful for them but a pain for us!

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Reading to update my teaching

Opening a Twitter account has consequences. I’m carefully keeping to scholarly activities, and so the main side effect for me has been an ever expanding list of interesting papers I really need to read. This is mainly a good thing: as a senior researcher and group leader I certainly don’t read enough new papers simply because they are interesting and relevant (as opposed to: because I need to do something with them as I’m either a co-author of, editor for or reviewer of them).

It’s nearly August and I teach in September. My reading list for now is about what I would like to read and think about to update my teaching:

The challenge for me is to find the right balance in helping students to do what they can where they are as researchers using animals, and challenging them to find ways of doing better. Unless I challenge myself, I easily settle too much on the status-quo side!

There’s also Heather Browning’s very recent PhD thesis If I could talk to animals: Measuring subjective welfare, of which I’m very interested in the second part which addresses measuring welfare from a philosophy-of-science perspective. And I want to take Daniel Lakens’ Coursera courses Improving your statistical questions / Improving your statistical interferences.

And then there are a couple of books on my desk…

 

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Of hens, mites and teabags: Interview with Francesca Nunn

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Congratulations Francesca Nunn to the NC3Rs Prize! You were awarded this prize for your work on a new approach to testing treatments against red poultry mites. Tell us more about the project!

Poultry red mites are parasites that live in hen houses and emerge at night to bite hens and consume blood. There are a number of studies ongoing worldwide to develop new ways of controlling the mites but this is a really tricky host:parasite model to work with because the mites spend most of their time off of the host. To help with this, we needed a technology which kept small numbers of mites on the host and allowed feeding and recovery of the parasites. The NC3Rs funded project was to optimise and further develop a prototype “on-hen feeding device” that had achieved ~50% mite feeding in a pilot study. This device allows accurate assessment of mite control methods on small numbers of hens before conducting field studies, for example. This addresses “Reduction” by greatly reducing the number of hens used, as it would accurately identify poorly performing mite control methods before they were progressed to field trials. This system can also be used to test the effectiveness of mite control methods across prolonged periods on small numbers of hens (4 per treatment group, as opposed to 400 per treatment group in field trials) without continually exposing birds to the parasites. This therefore addresses “Refinement” as it allows the birds to remain free from the parasites, with parasites only accessing the birds for short (3 hour) periods every 3 weeks instead of the continual exposure encountered in field trials. The project involved developing the device for all the blood feeding mite stages as well as studies to optimising feeding rates, minimising background mite mortality and using the device in trials to test its performance.

Your approach allows a huge reduction in animal numbers. What about animal welfare? What would a traditional test approach be like for a hen, and what will she experience with your refined method?

Novel systemic acarines or vaccines are tested on hens using an experimental infestation model. This involves releasing a set number of mites into a cage of hens, and then monitoring the mite population growth over time. And of course, you’d compare the treatment group to a control group. This means that the experimental hens are exposed to thousands (often tens of thousands) of mites over a number of weeks. As we know, mites cause discomfort and stress to the hens which is why we need the treatment in the first place! Using our feeding device, the hens are only exposed to 50-100 mites per time point – the rest of the time they are free to just be hens in enriched floor pens and parasite free.

Can you tell us something about where the idea came from and how you went from idea to device?

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Similar rigid devices, which were glued onto the hen had been used previously but weren’t widely adopted. This is probably due to the mites not being able to attach to the hen when the hen’s movement caused the device to move. The team at Moredun, led by Dr. Kath Bartley and Dr. Al Nisbet, came up with a tea bag type prototype which solved this problem while also managing to contain the mites. The next issue was to find a material that the mites could feed through-originally we used phytoplankton mesh but had to find an alternative that allowed the much smaller nymph stages to feed also without escaping.

 

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Is a positive attitude to animal research desirable?

The question is motivated by a recently published research paper in JALAAS: Attitudes Toward Animal Research Among Medical Students in the United States by David Q Beversdorf and Nellie R Adams.

The authors recruited student members of the American Academy of Neurology to fill in a questionnaire. 168 students completed the questionnaire, expressing their agreement or disagreement with a set of 14 positively- or negatively-biased statements regarding animal research. After that, they were given the opportunity to watch a video about animal research, and asked to fill in the same questionnaire again, which 108 students did. In the text box to the right, you can see examples of the statements the students were presented with.

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After having watched the video, the students were slightly more positive towards research with animals: the score went from an average of 4.0 to an average of 4.1. (A score near 5 shows a positive attitude to animal research, a score near 1 a negative attitude).

The authors do not make much out of that change (not surprisingly, it’s so small that it doesn’t really matter) but instead discuss the observation that “a substantial number of
medical students express disagreement with statements that
describe essential components of the drug and procedure
development pipeline. As described above, 13.2% disagreed
with the statement ‘New surgical procedures should be tested
on animals before they are used on people,’ and 7.2% disagreed
with ‘New drugs should be tested on animals before
they are used on people.’” They continue to conclude that “The changes in attitudes after observing the video suggests that negative attitudes can be changed, and that medical education may have a role in this setting.” If you want to read the full paper, you can request a copy from the authors at ResearchGate.

Numerous studies with bigger samples and more comprehensive approaches have measured the attitude of different publics to animal research, but the present study is novel in the choice of a very specific public: medical students. My main issue with how the study was conducted is the quite one-sided study design. The video in question is produced by Americans for Medical Progress, an advocacy organisation for biomedical research and in particular the use of animals in such research. While I think the video is quite reasonable, it definitely represents a selective use of information. That’s not surprising, as the organisation behind it is working in favour of public support for biomedical researh with animals.

Should a goal for medical education be to make students more positive to the use of animals in research? I’m really not convinced that this should be a priority. I think it’s crucial that medical students get a reasonable understanding of the role of animals in biomedical research and drug development. But that also includes an understanding of critical challenges to how useful such research is. And an understanding of why the issue is contentious.

There is no equivalent video advocating in a comparable way for the replacement of animals in biomedical research. People such as the authors behind the book Animal Experimentation: Working Towards a Paradigm Change would probably be able to produce one, and it would be as credible (reasonably so) and balanced (not very) as the AMP video.

And sadly, both of them would miss out on the most critical issue in animal-based biomedical research today: how to design studies so that the results are reliable and translate to humans.

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Are you going to a conference in 2020?

The beginning of a new calendar year is usually the time to think about conferences. Calls for abstracts are about to open – or in some cases even to close. I haven’t made up my mind yet about which conferences to attend, except for two for which I have an invitation (Scand-LAS and World Congress on Alternatives and Animals in the Life Sciences) which I will honour and one I know I won’t attend (ISAE – I usually attend when it’s in Europe and this year it’s in India).

Here are the ones I’m considering:

Canine Science Forum – Lisbon, Portugal 7-10 July

It would be a first time for me and it would be well justified by my increasing engagement in research with dogs. I would be an attendee only, not a presenter, but I expect that somebody else from our research team will be presenting work. Besides, it’s in Lisbon, a 3-h train ride away, and a place where I always enjoy spending some time. Other than that, I can’t really say much since I’ve never attended before.

World Congress on Alternatives and Animals in the Life Sciences – Maastricht, Netherlands 23-27 August

This is an interesting (in more than one way) conference that I’ve attended twice before (it’s held every 3 years). In my experience, it is more of a conference on Replacement alternatives to animals than Refinement alternatives, and the focus on Replacement has been heavily biased towards animal testing (toxicology etc). Whereas I obviously think it’s great that animal tests are being replaced, I don’t really have any scholarly interest in toxicology tests. But this year I have a particular reason for wanting to be present in a Replacement context: we have a project just starting on organoids and other advanced 3D models for research. This would also be a great chance for our newly hired junior researcher and project manager to get a peek into the alternatives research community. I really should discuss with my team what to present. Maastricht is a lovely city too.

EAAP – Porto, Portugal 31 August – 4 September

Again, this is a conference I’ve never attended but one which I know farm animal researchers in Europe always have on their conference agenda. Farm animal science is my background, and this would be an excellent opportunity for a much needed update, within walking distance from home! What speaks against participation is that I’m not sure what I would be able to present, and since this is a costly conference (even when not having to pay for travel or accomodation) I need to be able to fit it into a research project budget.

Will we be meeting at any of these conferences?

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Should research ethics protect non-human primates as children?

I’ve played with the idea of writing about why chimpanzees are not more protected than children. But whenever I start to develop the argument it seems absurd – anyone who knows what laboratory animal research regulation looks like knows that chimpanzees are not more protected than children! Except that I regularly come across people who argue that in Europe chimpanzees are more protected than children.

I understand where the argument comes from: there is a single regulatory framework for research with animals in Europe (Directive 2010/63/EU) but not for research involving children. Now, this doesn’t mean that there are no rules for children’s participation in research, it only means that the rules differ between countries. And as far as I know, none of these rules allows any researcher to involve a child in invasive and risky research under any condition – except perhaps if that research is likely to help the child. In contrast, a so called safeguard clause allows EU Member States to lift the general ban on the use of great apes (chimpanzees, bonobos, orangutans and gorillas) in invasive research “in relation to an unexpected outbreak of a lifethreatening or debilitating clinical condition in human beings” (Directive 2010/63/EU Article 55:2). Or in other words, facing an outbreak of Ebola in Europe, vaccine trials in chimpanzees would be permissible. (Whether this research could actually be done in practice is a different question. For a long time, the only industrialized country to keep chimpanzees for invasive research was the USA, but in 2015 the NIH announced it would no longer fund such research and lab chimps are now being retired into sanctuaries).

Interestingly, before I got around to writing any of this, I came across this paper which proposes that research regulation should protect chimpanzees and in fact all non-human primates (NHPs) in much the same way as it protects human research subjects. The authors argue that with so many important similarities in cognitive, emotional and social capacities, it doesn’t make sense to have different ethical frameworks depending on whether a primate is human or non-human. Therefore, they argue, we should move non-human primates out of the utilitarian framework that is generally applied to animal research ethics and into the deontological framework that applies to human research subjects. In practice, this means that research with non-human primates should respect the principles of beneficence and non-malevolence, or in other words, research should preferably benefit and definitely not harm the research subjects.

The paper is an interesting contribution to the debate and well worth reading, for the ideas and the examples of research that would be acceptable under a deontological framework. The idea that some animals should be given a rights-based protection is not new (it underlies the entire animal rights movement), but the paper contributes a unique discussion of the potential to do biomedical research with NHPs in a way that is compatible with the principles of benevolence, non-maleficience and even autonomy and justice. Unfortunately, I don’t think that the picture they paint is realistic. What can be achieved by studying naturally occurring situations is strongly limited, and I would have appreciated if the authors had been more thorough in their analysis of  what research would be made impossible if changing the ethical framework. On the other hand, if this were a paper about how to protect children in research, nobody would dream of arguing about the important research benefits to be lost if children couldn’t be harmed in research! This observation in itself clearly marks the difference in thinking about research in utilitarian and consequentialist terms versus in deontological terms.

From a pragmatic perspective, taking into account the diversity of opinion on the matter, I don’t foresee a change of framework any time soon for non-human primates in research at large. A change for the great apes is way more likely to happen in the near future. With the phasing out of invasive research in chimpanzees, the only great ape species which really played a role in biomedical research, a full ban may be accepted without much protest. By then, it may be reasonable to ask if chimpanzees enjoy greater protection than children in biomedical research. .

 

 

 

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Why the abstract shouldn’t be abstract!

A while ago I had a brief exchange with a friend about the accessibility of research results. Not whether they are clear or understandable – simply whether somebody who’s not in an academic research institution can even get their eyes on them. Often, they can’t. because research is published in academic journals owned by publishers who want to earn money from people’s interest in reading scientific information. When this is the case, all that the common mortal can access is the abstract or summary of the paper.

There is much to be said about ways around it through Open Access publishing. But even a researcher who doesn’t consider themselves to be able to publish OA can do something to make the results accessible – and it isn’t that difficult. Use the abstract!

Here’s an illustrative example of how not to use the abstract. Of the all-in-all 10 000 words available to them, the authors used 94 for the publicly visible abstract, and not surprisingly, we don’t get to learn much about the research through these 94 words. In contrast, this example from the same journal demonstrates how 250 words is enough to clearly describe the research question, the methods and the results.

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Open Science in October

Do you think about Open Science? Do you practice Open Science? Do you think Open Science matters? My research group is working on the topic during the month of October, with the aim of formulating an Open Science strategy for the group. We’re doing this because we think it makes sense for us to put Open Science into practice, but we need to work out the best way for us and our research.

We identified the following burning issues:

  • Study preregistration
  • Protocol and methods sharing
  • Data sharing
  • Preprint publication

These are the ones we are interested in but need to know more about in order to be able to practice (or make an informed decision not to practice) them. In addition, we prioritize  open access publishing and social media communication – but we’re already working on this. Although with a permanent backlog, we are uploading papers to the university open repository and we try to keep the group’s Facebook page up to date.

In a month, I hope to be able to report back on this. In the meantime, if you want to learn more about Open Science you may want to look at the FOSTER project.