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When Adriano Aguzzi, a neuropathologist at the University of Zurich, learned that the application to renew his lab’s license for mouse experiments was rejected in December, he was stunned. Aguzzi uses rodents to investigate prions—misfolded proteins that cause fatal neurodegenerative disorders such as Creutzfeldt-Jakob Disease—and for the last two decades, he has successfully received authorization to conduct studies that involve inoculating animals with prions and monitoring their vital signs as they develop disease. The latest license request was “the same application that has been renewed every three years,” he tells The Scientist.

Aguzzi is one of several scientists who say it has become increasingly difficult to get licenses for animal experiments in recent years. Switzerland has some of the strictest animal protection laws in the world, and as a result, the quantity of animals used in research has steadily declined over the years. Between 2008 and 2017, for example, the number dropped by more than 100,000 per year.

“What I’ve seen over the past 20 years is that regulations have tightened quite a lot. It requires much more work to write a license application and to get it approved,” says Isabelle Mansuy, a neuroepigeneticist at the University of Zurich and ETH Zurich. “Most of the additional requirements are good, because they have optimized the research in terms of animal numbers and forced us to better plan and document our experiments—but some changes are not necessary and have complicated our work.”

Before conducting experiments with animals, researchers must obtain a permit from the veterinary office in their state (also known as a canton), which makes decisions based on the recommendation of a regional animal experimentation commission—a group that includes representatives from both research institutions and animal protection organizations. This process requires scientists to submit detailed descriptions of their proposed protocols and to demonstrate that the societal benefits gained from their research outweigh the suffering of their subjects.

New knowledge of animal suffering, animal physiology, and the current best practices have to [be considered]. —Kaspar Jörger, FSVO

This “balancing of the goods,” is a good thing, Aguzzi says, but accurately measuring the increase in knowledge is not always possible. While scientists testing a new drug may be able to clearly illustrate how the potential benefit of their research weighs against the harm done to animals, this calculation is much more difficult for scientists conducting basic research, he adds. “We never know what we are going to find out. If we don’t go into uncharted territory, then we’re not doing our job.”

Mona Neidhart, the communications officer at the Zurich Veterinary Office, tells The Scientist in an email that the emphasis on this harm-benefit analysis stems from the results of the 1992 referendum in Switzerland, in which the public voted to include the protection of animal dignity into the country’s constitution, and the subsequent implementation of several changes to animal protection legislation over the last decade. “We can understand that this is perceived as more restrictive by the research community, but it is ultimately a consequence of the requirements of federal law,” she writes.

Assessing harm to animals

Richard Hahnloser, a neuroscientist at the ETH Zurich, has been unable to conduct in vivo experiments with zebra finches since his licenses expired in 2017. For more than a decade, he had been approved to place electrodes into the animals’ brains and record neural activity while they conduct behavioral tasks, a common technique in neuroscience labs that use these model organisms. After applying to renew the licenses for this research in 2016, his lab waited for more than a year as Zurich’s animal experimentation commission sent several rounds of questions about the potential stress these procedures may impose on the birds, then ultimately decided neither to reject nor approve his request, Hahnloser tells The Scientist. “There was no conclusive decision, just an invitation to apply again [with] several smaller and clearer license applications.”

One of the biggest issues with the vetting process, Hahnloser says, was the way that the commission determined the level of animal suffering caused by an experiment. “They’re calling something a burden to animals without any measurable data,” he explains. In an attempt to gather such measures, Hahnloser subsequently submitted requests to quantify the stress levels zebra finches experience due to head-fixing and temporary immobilization—two techniques required for the in vivo experiments his lab hoped to conduct. Those were rejected on the grounds that the information gained from these investigations would be limited, and that studies solely to improve the design of future experiments were unwarranted. “I was very disappointed by the outcome,” Hahnloser says.

Hahnloser still has valid licenses to conduct behavioral and anatomical research with the birds, but the inability to perform in vivo experiments is a big problem for students and postdocs wanting to complete their experiments, he says. “It’s challenging to get a valid conclusion about anything if their projects are interrupted in the middle.”

Right now, we’ve put in a small, revised application for the experiments we will do in the immediate future—otherwise, my lab would have to be disbanded. —Adriano Aguzzi, University of Zurich

Other scientists have experienced similar challenges. Mansuy tells The Scientist that a few years ago, the Zurich Veterinary Office increased the “degree of severity,” the measure of how much an animal is suffering, for the forced swim task—a behavioral test used to identify depressive symptoms in rodents—to the highest level. “We argued at the time, saying the change is not justified because although [the task] is stressful, it is very short and not endangering to survival,” Mansuy recalls. “We spent a lot of time providing explanations and experimental evidence to convince them that it was not that bad, but in the end they didn’t consider our arguments and did not change their decision.”

Although her lab has been able to renew their animal research licenses, Mansuy says this change in severity has put additional constraints on future applications, because every experiment conducted with this task now requires additional justification.

Rolf Zeller, a developmental geneticist at the University of Basel, says he had a similar experience when he applied to renew one of his research licenses last year. Zeller explains that he had been working with a line of genetically modified mice with digit deformities for more than 15 years without issues, but the Basal Veterinary Office decided to increase the severity grade in 2018. “These mice now have a higher severity grade, and for me, this is creating extra administrative work,” Zeller says. “I would accept if this was a new line [of mice], but we’ve been working with [these] for a long time.”

Zeller, who is also president of the Basel Declaration Society, a nonprofit scientific organization aimed at raising awareness about responsible animal experimentation, says that several of his colleagues across Switzerland have also reported an increase in the severity grade of experimental techniques they have used routinely for past projects. “At the moment, there seems to be a tendency to go to the higher end [of severity grades],” Zeller says, adding that he is concerned about the future implications of these changes, specifically, the possibly that they will provide fuel for arguments that animals used in experiments are suffering more these days than they were in the past.

The licensing authorities are “constantly in contact with researchers and animal protection organizations about the degree of severity judgements,” says Kaspar Jörger, the head of the animal protection department at the Federal Food Safety and Veterinary Office (FSVO) in Switzerland, the body that oversees the licensing process and the cantonal veterinary offices. “Of course, new knowledge of animal suffering, animal physiology, and the current best practices have to [be considered].”

Quality control for experimental design

According to Jörger, the vetting process for animal research permits has indeed become more rigorous in recent years, due to the results of an FSVO-funded investigation into the quality of applications for animal experiments. The study, which was conducted at the University of Bern and published in 2016 in PLOS Biology, examined 1,277 applications submitted to Swiss authorities and came to the conclusion that various quality-control measures for scientific experiments, such as sample-size calculations, randomization, and blinding, were not adequately reported in license requests. “[When] we saw that a lot of the applications were of poor quality, we insisted that [the cantonal committees] look more closely at the quality of the applications,” Jörger tells The Scientist.

The publication also spurred additional efforts to increase the quality of license requests. For example, the FSVO recently implemented a legal requirement for research institutions and the pharmaceutical industry to employ animal welfare officers to help researchers with their permit applications. The organization also launched the Swiss 3R Competence Centre (3RCC) to help promote the so-called 3R principles (reduce the number of animals, replace animal studies with other research methods, and refine experiments) through various methods, including fostering communication between various groups, such as researchers and animal welfare organizations, and funding research associated with animal welfare.

As a member of the 3RCC strategic board, Zeller welcomes the initiative, noting that he hopes it will encourage productive discussions between scientists and animal rights groups. However, he adds that while it’s true that poor study design is a problem, it does not justify the recent increase in severity grades.

Many scientists remain frustrated with the licensing process. In response to Aguzzi’s case, three Zurich politicians submitted questions at the end of 2018 to the regional veterinary office regarding its licensing procedures. In the meantime, both Aguzzi and Hahnloser have pending applications and are hoping to hear a positive response sometime soon. “Right now, we’ve put in a small, revised application for the experiments we will do in the immediate future—otherwise, my lab would have to be disbanded,” Aguzzi says. “Animal experimentation is a last resort, but it’s absolutely crucial [for our work].”

Clarification (January 8, 2019): The article has been updated to include both of Mansuy’s affiliations.