What’s trending in 3Rs, and life as a disease detective. Day One of the Charles River Short Course.

There was a time when veterinarian Donna Clemons felt like the “ethics police,” a reflection of the years she spent pushing the 3Rs principles of refinement, reduction and replacement to scientists who were more apt to roll their eyes than roll up their sleeves.

Today, scientists are voluntarily bringing articles forward for discussion in journal clubs and major animal research organizations are recognizing and funding, albeit in small ways, studies that address the 3Rs. Pharmaceutical companies are integrating alternative research models in the testing of drugs, and vivariums are giving up dirty bedding sentinels in favor of PCR-based systems to monitor pathogens in their facilities.

Clemons, the global director of AbbVie Pharmaceutical, spent close to two decades with a contract research organization. She knows what’s trending. But even she was a bit surprised to discover how many of the leading journals now include studies that relate to the 3Rs. “The 3Rs is going from the sidelines to the center,” says Clemons during her talk at the 2016 Charles River Short, a four-day conference for laboratory animal scientists now in its 60th year. “The culture is changing.”

Some other highlights from the conference’s 3Rs panel.

  • The Science of Animal Enrichment Is Evolving. Who would have thought that displays of affection might not be such a good thing? In fact, studies suggest that hugging actually increases the stress level of certain large animal models. Apparently immobilizing such animals, even for kindhearted purposes, triggers a defense mechanism not to bite but to run away. The point, says Clemons, is that animal enrichment isn’t as simple as throwing a toy in a cage or handing out treats.
  • The tools of the future. More and more facilities are investing in MRIs and high-quality ultrasound, such as the in vivo imaging technique bioluminescence, that is allowing them to get more and better information out of the animals. Meanwhile, the gene-editing technique CRISPR–Cas9 May 2014 is evolving rapidly and changing the world. If it lives up to its promise, it will revolutionize research models, says Clemons.
  • Learning from humans. Pain management is an obvious animal welfare issue in laboratory research settings. Clemons says some animal scientists have taken a cue from humans—where pre-emptive treatment of nausea is now routine—and looking at it as a method of managing the side effects of anesthesia for research animals as well.
  • Alternative models in the wings. Organs-on-chips or tissue- engineered, three-dimensional organ constructs that can serve as in vitro models for all different segments of the human anatomy are one of the most exciting developments in preclinical research. The role of zebrafish is also growing, deer are being looked at to study prion diseases and the shrew (tiny rodent) for neurology, where photon microscopy can be used to record activity from the entire cerebral column.
  • The growth of integrated toxicology. It will take years before in vitro tests replace in vivo tests, but advances in in vitro cell-based models, in chemico models and in silico models are enabling researchers to take a more integrated approach to their drug studies, says Clive Roper, Charles River’s Head of In Vitro Sciences in Edinburgh. Here’s more about in vitro’s growing space in safety science.

Survival of the fittest

With so much attention fixated on what to do about Zika, it seemed appropriate that the Short Course choose viruses as the theme of the keynote. This being a conference about animal science, the focus was on zoonotic viruses.

One person uniquely familiar with these kinds of outbreaks is Darin Carroll. A zoologist by training, Carroll once envisioned career working at a natural history museum studying rats and rodents, but instead found himself drawn to the organisms that they spread. Carroll is currently the Director of the Environmental Safety and Health Compliance that sits within the US Centers for Disease Control and Prevention’s Office of Safety Security and Asset Management. But much of his career at the CDC has been devoted to chasing obscure or emerging viruses, not just in developing countries where one tends to read about these things, but in the US. One of the clear messages from Carroll’s talk is that viruses are natural survivors, exquisitely exploiting their surroundings in order to replicate and spread, but that they also make mistakes. Understanding the ecology of the animals that harbor these viruses is key.

One of the earliest viruses Carroll worked on was Bolivian hemorrhagic fever—an arenavirus similar to Ebola that is spread by a vesper mouse indigenous to northern Bolivia. The virus emerged in the 1960s. Small outbreaks occasionally surface, but one reason we don’t see more cases, says Carroll, is because of expanding populations of other animals. Black rats and cats feed on vesper mice that harbor this virus.

Deforestation probably helped the Bolivian hemorrhagic virus to emerge, but reforestation appears to be the blame for the emergence of a brain disease in Bangladesh caused by the henipavirus Nipah. During a 2004 outbreak affecting mostly young boys, an epidemiology team from the CDC ultimately concluded that the planting of date palms in heavily populated areas were partly to blame, says Carroll. The bat populations that harbor Nipah apparently enjoy date palms, and the boys were catching the virus from bats while climbing up the trees to pick the fruit. Studies have also shown that drinking date palm is a risk factor for Nipah because when the bats feed on the palms they also leave infected saliva behind.

Lastly, the first human outbreak of monkeypox in the US shows what happens when exotic animals circle the globe. The first US case turned up in a Wisconsin child and his pet prairie dog. But investigators eventually traced the multi-state outbreak of nearly 40 cases to rodents imported from Ghana to Texas. Studies eventually found that infected African giant pouched rats, nine dormice, and three rope squirrels had been housed in cages close to the prairie dogs at an Illinois animal vendor. This led the CDC to prohibit the importation of all African rodents into the United States.

McEnery, Regina. Animal Welfare and Animal Viruses. Eureka blog. June 28, 2016. Available: http://eureka.criver.com/animal-welfare-and-animal-viruses/