How gene editing is changing what a lab animal looks like

Anyone who reads news about science (at Science News or otherwise) will recognize that, like the X-Men or any other superhero franchise, there’s a recurring cast of experimental characters. Instead of Magneto, Professor X, Mystique and the Phoenix, scientists have mice, fruit flies, zebrafish and monkeys. Different types of studies use different stand-ins: Flies for genetics; zebrafish for early development; rats and mice and monkeys for cancer, neuroscience and more. Many of these species have been carefully bred so they are genetically identical, giving scientists maximum control as they study changes in genetics or environment. These animal models have added huge volumes to our understanding of human and animal biology, and will continue to add to our knowledge for many years to come.

Now, new techniques such as gene editing mean that scientists can probe and alter the genes of any animal. The methods open the door for new organisms — such as squid and octopuses — to join scientists’ basic toolkits. With these new arrivals come new questions. What is needed for a good animal model, and how are gene-snipping tools changing the game?

In the early days of biology, the main emphasis was on description of organisms. But description did not allow for experimentation. “One of the major reasons for doing experiments is [that] you can control a system and make predictions from it,” says Garland Allen, a science historian at Washington University in St. Louis. To conduct good experiments, scientists needed models — stand-ins that had some characteristic they needed to know about, whether that was, say, genetics, heart function or behavior. Those stand-ins had to be well-controlled, well-characterized animals that could be kept the same in every way. Once experiments were conducted in those models, the findings could be applied to other species.

The first animal models, then, came about from efforts to control experiments. Animals such as mice and flies are relatively easy to genetically manipulate.  Pick out characteristics that are reliably passed down and easy to identify, such as fly eye color and wing shape. To ensure as much purity as possible, inbreed mice to each other, brother to sister, so they are all genetically identical. “For the past 100 years the tendency and the trend has been to develop as consistent a model as possible, so every individual will respond the same way to the same challenges,” says Nadia Rosenthal, the scientific director at Jackson Laboratory in Bar Harbor, Maine. “If you have five mice that are identical genetically you can modulate their environment with impunity, secure in the knowledge when you get the result, it’s going to be about the environment.”

Animals such as flies, rats and mice have other advantages. First, they breed like — well, mice. “Mice … have a very short reproduction cycle. That’s a critical thing in genetics,” Rosenthal explains. “You need multiple generations, and unless you are very patient, elephants are not a good model for this.”

Other models, such as zebrafish, have the advantage of clear embryos. Transparent eggs and fry are “ideal for getting light in and getting light out,” notes Eric Edsinger, who develops model organisms at the Marine Biological Laboratory in Woods Hole, Mass. This can be useful for everything from using a simple light microscope to watch cells divide to using light-based techniques to drive genetic and cellular actions.

Once these model organisms grow up, another advantage becomes clear — they grow up small. When looking for model organisms, Edsinger explains, it’s a real boon to be able to keep many in the lab at once. An octopus model can be useful for studying motion, nervous systems and camouflage — but you’d need a lot of space. “A standard aquarium might only be able to hold one octopus, but you could have 10 pygmy squid,” he notes. A lab the size of a closet can easily hold thousands of fruit flies — a real advantage when scientific space and funding are tight.

It also helps if their food is cheap, Allen notes. Grain pellets for mice and rats or a single banana for fruit flies means less money spent.

But perhaps the biggest advantage a model organism can have is being able to rough it. “Some octopuses, if the pH just get off by a little bit, they’ll deteriorate and die,” says Edsinger. But pygmy squid — an animal model he has been developing — are a lot more resilient. “I’ve had pygmy squid where I threw them in a bucket and left them on my porch and they were fine. They didn’t mind,” he says.

CRISPR cuts in

Having a genetically identical, reliable animal model meant the most when an animal’s genetic blueprints, or genomes, were hard to come by. In flies and mice, “their robustness comes in their genetics, and in particular the ability to rapidly develop systems where we can alter genes,” explains Jonathan Gitlin, a developmental biologist and director of research at MBL.

That is changing with the advent of CRISPR/Cas9. This gene editing system allows scientists to target specific spots in a genome, where the Cas9 enzyme can then slice, dice and even add in new genes. CRISPR/Cas9 doesn’t require knowing the entire genetic blueprint of the organism you’re tweaking, or developing a specialized system for editing each new area. All the scientist needs is a guide sequence to the right spot.  The ability to edit a single, carefully targeted gene in each organism means that individual members don’t need to be the perfect genetic clones currently filling mouse and fly labs. Scientists may be able to tweak the genes of a single animal to see an effect, and juggle the same gene in another and observe the same impact, even though the two animals aren’t otherwise genetically similar.

And if scientists don’t need known DNA sequences, the animal world is their oyster. “I can now take virtually any organism and manipulate the genome and create model systems where I can track cells, manipulate genes,” says Gitlin. Before, he says, if you thought the answers to your scientific question could be found in a cephalopod, “you’d be limited because you [couldn’t] manipulate the genome. Now, you can.”

With the help of CRISPR/Cas9, Edsinger is hoping to establish one or more cephalopod organisms that can be used to study motion, camouflage and neural systems. The new models could benefit robotics, computing, prosthetics and much more.  “Genome editing is democratizing the ability of a single person to spend a year focused on something and do powerful functional studies,” Edsinger says.

But plenty of care — and plenty of octopuses — will still be required. “I’m not sure there’s any attribute that doesn’t vary at some level,” Rosenthal notes. “You have to assume you’re going to see variability and build that into your experimental design.”

Cephalopods and culture shifts

CRISPR/Cas9 bursts the world of animal models wide open. But it also runs up against established science and scientific culture.  Right now, the biggest question for new animal models is who will buy. “It’s a marvelous cultural conundrum,” Rosenthal says. “People want to use what others have used, so you can build on people’s observations.” If a scientist writes a grant to study mice, he or she can cite large amounts of literature in that model. For a grant to study cephalopods, the history is a lot thinner. And scientists are human, she notes; they feel most comfortable with what they’ve seen before.

So the cycle begins. A grant review committee might reject a grant to work on a new squid or squirrel, citing a lack of research in the area. In rejecting the grant, research doesn’t get done, and so there’s no new literature in the field. Wash, rinse, repeat.

Edsinger wonders how the world of animal models will look in five or 10 years. Will it be 10 labs trying to establish a single species, or will each lab be working on their favorite? A single species might make for better controlled experiments. But a single scientific laboratory working on a charismatic species might catch the public eye. Young scientists trying to establish new animal models are also trying to establish their careers. In a world filled with mice, fish and flies, Edsinger says, “there’s no template for that.” While CRISPR/Cas9 may provide the tools, it is up to the culture of science itself to determine how many new animals will join the model zoo.