Optical imaging and a Virtual Education Community are doing their part to contribute to the 3Rs.  

The North American 3Rs Collaborative was created recently to advance the education and science of the 3Rs – refining, reducing and replacing the use of animals in research. Members come from academia, industry, and government (including Charles River Laboratories which helped launch the Collaborative.) Eureka spoke to the Norman Peterson, Director of Veterinary Sciences/Translation Sciences at MedImmune and the secretary of the NA3RsC to learn more about the Collaborative’s effort to advance science, innovation and animal welfare through sharing. He also spoke about how MedImmune’s use of imaging in drug development is also advancing the 3Rs. 

What are some of the innovative ways MedImmune is using imaging tools, such as optical imaging, in drug development?

NP: As the biologics arm of AstraZeneca, we mainly develop large molecules (antibodies, proteins, viruses, nanoparticles, etc.) into therapeutics. The chemical structure of these large molecules allows us to put fluorescent or radiolabeled tags on these proteins. We can then inject these labeled biotherapeutics into live animals and using an optical imager or PETCT visualize if the compound reaches the diseased tissue or gets stuck elsewhere in the body (off-target).  We can also use other fluorescent and radiolabeled biomarkers such as FDG or inflammatory markers to evaluate if our biotherapeutics have activity at the targeted site.

How is this contributing to the 3Rs?

NP: We typically follow our labelled biotherapeutics in each animal with five imaging sessions over a weeklong period.  If this were done in a traditional “take-down at every time point” study, it would require five times the number of animals, not to mention the increased inconsistency caused by inter-animal variability. 

But, I think a bigger picture perspective on the 3Rs impact can be gained by addressing how the technology improves the science. By incorporating imaging in our drug development process, we can build confidence in the therapeutics that we are developing. The more confidence we have in our models, methodology, and science the more likely it will be that fewer experiments or trials will be needed to answer our questions, and this results in fewer resources being needed (especially animals). 

You recently became involved in the North American 3Rs Collaborative. Why was it formed and what is its function?

NP: The NA3RsC was conceived and developed over a period of about 2 years with its official kick-off at the World Congress on Alternatives in Seattle in the summer of 2017. One of the main objectives is to bring together 3Rs organizations and individuals (that are supportive of biomedical research) to foster innovation, collaboration, and awareness. We accomplish this through a variety of tools including regular teleconferences and face to face meetings, co-sponsoring 3Rs meeting, webinars, and podcasts (3-minute 3Rs), and our Virtual Education Community The latter offers a web-based community for like- minded organizations to host their own booth, chat, find resources, and attend virtual events.  We have a vision to also attract various scientific groups that are tangentially connected to the 3Rs (e.g. microphysiologic systems labs, toxicology groups, environmental enrichment suppliers, etc.) and provide them with the opportunity to form micro-communities within the VEC.  Virtual visitors will then be able to find 3Rs resources, ask questions/chat, and innovate across a variety of sectors.

How does it differ from the UK-based NC3Rs.

NP: In deciding on a name for our organization, the Board felt strongly that it should include “collaborative”. We felt that there are several groups that do a great job in advancing the 3Rs and we didn’t want to duplicate or compete with their efforts. Rather we focus on providing opportunities for groups like the NC3Rs to come together and work synergistically toward common goals. In a sense, we are kind of like the World Congress on Alternatives but active and accessible every day throughout the year. The NC3Rs staff has been great in providing guidance and we are continually working and communicating with them and other 3Rs organizations on a variety of projects. Although nationally-based, and similar to the NC3Rs, NA3RsC has a global outreach with over 25% of our membership from outside the US and Canada. The NA3RsC has not received any government funding and we rely heavily on volunteers to drive our mission forward.

What sort of 3R innovations do you hope to see in the next 50 years?

NP: In terms of Refinement, I think technologies to digitalize the vivarium are making great inroads at both the animal and people levels. By that I mean, at the animal level, automated cage-side monitoring systems will play a key role in tracking animal behavior and physiology. This information will be used by both the animal care and research staff to monitor well-being and collect research data.  It will also be used to better monitor and adjust the (cage-level) environment. At the people level, robotics and technologies such as RFIDs and similar tracking devices will become more commonplace.  The latter is already being used at some institutions to track and record individual operations (via RFID bracelets), animals, and sample collection vials, etc. With this automation and recording, deviations can be rapidly detected and corrected; fewer deviations results in better care and fewer animal losses.

In terms of replacement/reduction, I believe advances being made in developing more complex tissue culture systems (organoids, microphysiologic systems, tissue-on-a chip) and the utilization of human-tissue hybrid animals (mainly mice) are going to have a major impact on how we do research. Digital technology will also be integrated in these systems to provide more rapid endpoint analyses. We’re gradually progressing in this direction, but still are a long way from this endpoint; 50+ years would be a good estimate. 

Are the 3Rs still an important guideline for animal research today? Why?

Yes, because they are simple basic principles that have been time tested. However, we need to continually adapt our strategies to fit new technologies and re-focus on addressing current challenges. For example, the scientific community has recently received heightened criticism on the reproducibility and predictability of animal models. These challenges offer an opportunity for 3Rs advocates to work with, and within, the scientific community to make models, methods, and technology more efficient, thus ultimately reducing animal use.How do you think the 3Rs has changed animal research in the last 50 years?

One of the most rewarding things about working in this field is in observing the realization (mainly via IACUC review or consultation) that animal welfare considerations are an important aspect in experimental planning and that it may even result in improving experimental outcomes. Over the years, IACUC protocol review has undoubtedly resulted in hundreds of thousands of modifications that have led to better conditions for the animals and improved the science. Greater involvement from veterinary staff or qualified surgical technicians in experimental surgery procedures has been invaluable in reducing pain and distress, increasing survival, and producing better scientific outcomes. Although it may not directly result in fewer animals being used in any given study (reduction), the more recent attention drawn to statistical analyses in study design provides greater assurance for justification and likelihood of meaningful results. 

In addition to these examples, adaption of a 3Rs culture over the last 50 years, has ensured that we take a few moments to stop and consider better (more ethical) ways of achieving our goals. It encourages us to take a different perspective, and science advances faster when multiple perspectives are applied to a problem.