To wild depths for new models
29 Jul 2019
There are animals out there with unique phenotypes that could yield insight into human health and disease. Meet three such fishes from waters around the world: Antarctic icefish, Mexican cavefish, and Atlantic killfish.
In the course of developing an animal model for osteoporosis, William Detrich shattered his left hip. In 2018, the professor of biochemistry and marine biology at Northeastern University was far from a lab. He was aboard a research vessel in the Drake Passage, a frigid body of water that stretches between the southern tip of South America and the northern tip of Antarctica, when a violent wave rocked the ship and threw him off his top bunk. Instead of spending the field season at Palmer Station in Antarctica, he had to be Medevac’ed to Argentina and then back to Boston, where surgery and months of recovery awaited.
Why make this dangerous journey? For icefish. Icefish are unique animals, with porous bones that allow them to float in the water column to feed. That attribute, one of several unique features, makes them a unique kind of animal model. They display a phenotype without ill effect that, in humans, would be pathological. The remodeling that has occurred in icefish bones over millions of years, possibly including changes to regulatory elements that determine bone density and mineralization, may be similar to the mechanisms underlying osteopenia and osteoporosis over a human lifetime, says Detrich.
Icefish aren’t alone; as researchers look outside the lab, it’s not hard to find other examples of animals with unique phenotypes. For example, Mexican river fish, cousins to the common aquarium Tetra, that moved into darkened, barren caverns have since evolved mechanisms to maximize nutrient use that evoke both human diabetes and risk factors for colon cancer; minnows living in waters off the northeastern US have managed to shrug off industrial toxins that could otherwise kill the developing embryo—a talent that could shed light on how smoking leads to lung cancer.
Such fishes are being examined as alternatives to the mice, rats, and other ‘model’ species that tend to dominate animal research. These familiar workhorses are popular, but results can disappoint. Deliberate genetic alterations to model a disease in a mouse or rat don’t always account for the array of other changes that may accompany that disease in patients. They are artificial constructs that only imperfectly mimic human disease. As a result, positive results in these models often disappear when tested in humans.
Detrich and other researchers argue a need to take a fresh view. The ability to analyze the identity and expression of massive numbers of genes, proteins, metabolites, and other factors in model systems has granted scientists a much clearer understanding of genes and their networks. These days, genes can also be edited in almost any species. This is leading biology into a new era, according to Misty Riddle, a postdoctoral fellow in genetics at Harvard Medical School who works with Mexican cavefish.
Detrich certainly agrees. “The fact is, we have model systems for reasons, because they’re usually manipulable in a genetic sense, with all of the molecular tools that you can bring to bear. But maybe they don’t display the phenotype that you’re really interested in. That’s why you have to look beyond conventional models to what I sometimes call non-model model systems.”