Joseph Parker has wanted to know what makes rove beetles tick since he was seven years old. The entomologist has spent decades collecting and observing the insects, some of which live among ants and feed on their larvae. But without tools for studying the genetic and brain mechanisms behind the beetles’ behaviour, Parker focused his PhD research on Drosophila fruit flies — an established model organism.
Now, more than a decade later, the rise of the CRISPR gene-editing technique has put Parker’s childhood dream within reach. He is using CRISPR to study symbiosis in rove beetles (Staphylinidae) in his lab at the California Institute of Technology in Pasadena. By knocking out genes in beetles that live with ants and in those that do not, Parker hopes to identify how the insects’ DNA changed as their lifestyles diverged. “We’re designing a model system from scratch,” he says.
Biologists have embraced CRISPR’s ability to quickly and cheaply modify the genomes of popular model organisms, such as mice, fruit flies and monkeys. Now they are trying the tool on more-exotic species, many of which have never been reared in a lab or had their genomes analysed. “We finally are ready to start expanding what we call a model organism,” says Tessa Montague, a molecular biologist at Columbia University in New York City.
Montague works on the Hawaiian bobtail squid (Euprymna scolopes) and the dwarf cuttlefish (Sepia bandensis), species whose unusual camouflage acts as an outward display of their brain activity. The cephalopods project patterns onto their skin to match what they see around them. But probing how their brains process stimuli has been difficult. Researchers would normally do this by embedding electrodes or other sensors into the skull — but squid and cuttlefish are boneless.
Last year, Montague and her colleagues successfully injected CRISPR components into cuttlefish and bobtail-squid embryos for the first time. Now, they are trying to genetically modify the cephalopods’ neurons to light up when they fire.
Technical knock out
Other researchers are using CRISPR to study species’ distinctive social behaviours. Daniel Kronauer, a biologist at the Rockefeller University in New York City, has created raider ants (Ooceraea biroi) that cannot smell pheromones. In experiments, the genetically modified ants were not able to sustain the complex hierarchy seen in a normal raider-ant colony1. The scientists are now using CRISPR to alter genes thought to influence raider ants′ behaviour.
Then there are species that threaten human or environmental health — such as the pea aphid (Acyrthosphion pisum), an insect that attacks legume crops worldwide. To edit the aphid’s genome with CRISPR, a team led by Shuji Shigenobu, an evolutionary geneticist at the National Institute for Basic Biology in Okazaki, Japan, had to manipulate the insect’s complex life cycle. Female aphids born in summer reproduce asexually, by cloning themselves, whereas those born in autumn lay eggs.
Shigenobu’s team set up an incubator that simulated the cool temperatures and short days of autumn so their aphids would lay eggs that the scientists could inject with CRISPR components.
After four years, the team succeeded in editing a pigment gene as a proof of concept, Shigenobu announced last month during a conference at the Howard Hughes Medical Institute’s Janelia Research Campus in Ashburn, Virginia. He hopes that by modifying other parts of the aphid’s genome, researchers can learn more about how the insects interact with plants. That information could lead to the production of better pesticides.
Developing animal models requires immense amounts of time and money, and until recently there was little support for such work. In 2016, the US National Science Foundation launched a US$24-million programme to create model organisms — and in doing so, reveal the genetic and molecular mechanisms behind complex traits and behaviours.
The programme supports research to create tools for probing species’ genomes, study organisms’ life cycles and develop protocols to raise these species in the lab. This support has begun to pay off: in March, for instance, researchers at the University of Georgia in Athens said2 that they had used CRISPR to create the first genetically modified reptile, the brown anole (Anolis sagrei).
Despite such promising early results, the push to create model organisms with CRISPR has revealed how little is known about many species’ genomes, life cycles and habits. Researchers face practical challenges such as determining how to inject CRISPR components into embryos and coaxing finicky, fragile species to breed in the lab.
“The reason classic model systems were chosen was they’re basically pests. Nothing can stop them growing,” Montague says. “But if we take on this challenge of working on new organisms because they have an amazing feature, they’re often not happy to grow under [just] any conditions.”
This has forced scientists to weigh the effort required to study a particular trait against the potential rewards. Modifying a genome requires a deep understanding of a species’ behaviour and lifecycle — a tall order when that organism is studied by only a handful of people worldwide. “People are not choosing these model systems lightly,” says David Stern, a biologist at Janelia.
Stern knows this first hand: he and his colleagues succeeded in breeding one fruit-fly species only after discovering that the insects need an olfactory cue to lay eggs — the smell of a particular chemical made by plants.
Still, researchers’ interest in developing atypical animal models continues to grow. Montague and her colleagues have created a tool called CHOPCHOP, which allows them to design a CRISPR system for editing specific genes in any DNA snippet. So far, scientists have sent her genetic sequences from more than 200 different species, including plants, fungi, viruses and farm animals.
“I had this weekly reminder that these molecular tools do work in pretty much every organism on the planet,” Montague says. “It’s such an exciting time to work on any model organism — especially these new and weird creatures.”
Nature 568, 441-442 (2019)