Can You Responsibly Practice High-Quality Science and 3Rs?

A US nonprofit advocates for evidence-based science that benefits both people and research animals NOTE: This article is available in other languages (FRANÇAIS CANADIEN.)

This is part of Eureka's ongoing series, 4Rs: Looking Ahead Responsibly, which focuses on innovative projects, partnerships and collaborations that are helping to responsibly reduce, refine and replace research animals. 

Since the days of William Russell and Rex Burch, the two scientists who coined the phrase “3Rs”, laboratories have committed to the concept of finding ways of refining, reducing, or replacing research animals. However, alternative methods are not always consistently incorporated into scientific research, even when the data suggests that specific non-animal methods provide appropriate data as good if not better than the animal model.

The reasons for this are many, including lack of familiarity, training, or confidence in new methods, the absence of clear guidance from regulators that they would accept data from non-animal models, and a lack of understanding in the limitations of the data generated by alternative methods. There are also massive challenges in acceptance of data worldwide—what might be accepted practice in one country or continent might not be recognized or considered validated in another. Hanging over all of this is plain old resistance to change. 

But what if you had the power to encourage research and dialogue across the commercial, government and academic sectors, and help accelerate the adoption of 3Rs principles in the process? What if you could encourage labs to share their data more freely, and push regulatory agencies to be more accepting of alternative methods? 

That is basically the idea behind the 3Rs Collaborative (3RsC), an organization started in 2016 to advance science, innovation, and research animal welfare. As its name suggests, collaboration is key even when relationships get tricky. 

Following the 3Rs data

The 3RsC is currently putting its efforts behind seven major initiatives and tries to accelerate the implementation of evidence-based 3Rs techniques and tools. The initiatives are wide-ranging, from organ chips and translational digital biomarkers to environmental health monitoring and compassion fatigue. “Our strategy is to identify key, evidence-based 3Rs approaches, address barriers and promote them in everyday practice,” says the 3RsC Executive Director Megan LaFollette, a PhD scientist from Purdue with a background in animal behavior and animal welfare. The criteria the 3RsC used to select its initiatives is three-fold, says LaFollette. They have to be evidence-based, positively impact animals and be practical in today’s real-world research environment, says LaFollette. 

The 3RsC’s Initiatives drive different 3Rs techniques. For instance, Rodent Health Monitoring helps research professionals adopt PCR-based methods to monitor their research animal facilities for pathogens, a job traditionally held by rodents known as soiled bedding sentinels. The Microphysiological Systems (MPS) Initiative, which includes over 40 companies, 30 of them developers of MPS systems, focuses on 2D and 3D in vitro platforms that recapitulate the human condition, such as organ chips or organoids, to help replace a portion of animal experiments. Translational digital biomarkers engage end-users and technology providers to increase industry adoption of sensors and computational tools to collect behavioral and physical animal data, a refinement of animal use.

Clive Roper, PhD, who has developed models resulting in the direct replacement of animals in dermal absorption, dermal toxicology, and inhalation toxicology, is one of many scientists involved with the Regulatory and MPS Initiatives. The FDA Modernization Act: 2.0 brings legislation into practice and indicates support for in vitro and in silico technologies. In fact, prior to passage of this act, the FDA had already expanded use of one drug based on microphysiological systems alone, and this data had been used in at least four preliminary drug filings. Many companies are investing in these 3D systems, but more confidence is needed. Roper said many companies use organ chips in their studies, but they do not always include this data in their regulatory filings. “So, the companies are using them, and the FDA wants to see it,” says Roper. “Now we have to set standards.”

History of the 3Rs Collaborative

The seed for the 3RsC was planted at Charles River. CEO Jim Foster wanted the company to not only be a leader in the life sciences but also in the 3Rs, and veterinarian Marilyn Brown, Vice President of Charles River’s Animal Welfare Program at the time, had long thought an independent 3Rs non-profit based in the United States would be an excellent way to advocate for change. She worked with Charles River’s Events Manager Deborah Curry to use US$200K from her budget to help get the Collaborative off the ground. 

Initially, membership drew mostly from industry, but several academic scientists signed on, and even some government stakeholders, including the FDA.

In 2017, the 3RsC officially kicked off at the World Congress for Alternatives in Seattle, but growth was slow at first. Dr. Brown, who ended up running the 3RsC until she retired in 2018, said the lack of funding, staff and organization prevented the group from doing big things. “I remember we wanted to form a virtual meeting place to facilitate information sharing,” she said. “But there wasn’t enough money to make it work, and the tech person who was supposed to be in charge of this never really ran with it. I got pretty frustrated.” 

Things started to turn around about four years ago when the 3RsC hired some full-time staff, built out its leadership team and began to take on important 3Rs issues. It also took the unusual step of including a full slate of MPS companies as members. And with its collaborative nature, it included members from outside North America.

Roper, who directed Charles River’s In Vitro Toxicology program for more than 10 years, and now runs his own consulting firm, Roper Toxicology Consulting, and is a board member of 3RsC, was also one of the early members of the Collaborative. He said it was understood from the beginning that it would not duplicate the UK NC3Rs – one of the oldest National 3Rs organizations based in the UK. “The NC3Rs was born out of political issues with animal rights groups in the UK,” said Roper. “The UK House of Lords wanted to know how it could best educate people about why we do (animal research). In the end, it found itself a neutral portal for ideas, sharing best practices and identifying areas where it could fund projects.”

In contrast, the early vision of the 3RsC was to create an environment where researchers would willingly share their data with other scientists, industry, and other stakeholders. “It was all about sharing ideas,” says Roper. “If an academic institution found a new refinement method, that method should be shared across the globe.” 

The NC3Rs was and continues to be much better funded. Its annual budget of approximately £10 million primarily comes from two UK public agencies— the Medical Research Council and Biotechnology and Biological Sciences Research Council. The global charity Wellcome is also a longstanding supporter of the NC3Rs. In contrast, the 3RsC does not receive direct government funding, but does receive financial support from commercial and academic members and sponsors, though its overall budget is much smaller. They also advocate for government funding for a national, balanced 3Rs center.

“There is a clear realization that the use of animals will end over time as we better understand what animals models tell us and what they do not tell us about the human situation and apply this same thinking to alternatives,” says Alan Hoberman, Executive Director of Global Development, and Reproductive and Juvenile Toxicology at Charles River, and a board member of 3RsC.

In 2023, the 3RsC launched its first formal strategic plan that formally clarifies three strategic goals: (1) promote the 3Rs broadly (2) promote specific 3Rs strategies, and (3) promote the 3Rs Collaborative. It also discusses future looking goals like releasing a broadly applicable 3Rs certificate course, creating resources to help institutional culture of care, and even looking to the application of in silico technology as a key replacement.

As they receive increased financial support, they will be able to fund more projects to make even more impact for the 3Rs across the scientific community, says LaFollette. “I am excited to see the future of the collaborative over the next few years. We are continuing to grow rapidly, be recognized for our efforts, and, most importantly, make real world impacts,” says LaFollette. “There is lots of work out there and passionate people. And when we get increased financial support, we can do even more than we do now.”

Stay tuned for our next story about the Dutch-based Virtual Human Platform project.