30/06/2022
WASHINGTON, D.C.—A hand-size monkey called Callithrix jacchus—the common marmoset—is in great demand in labs and yet almost nowhere to be found. Marmosets' small size, fast growth, and sophisticated social life were already enough to catch the eye of neuroscientists. They've now been genetically engineered to make their brains easier to image and to serve as models for neurological disorders such as autism and Parkinson's. The problem: "There are just no monkeys," says Cory Miller, a neuroscientist at the University of California, San Diego.
At a meeting here this week, convened by the National Academies of Sciences, Engineering, and Medicine's (NASEM's) Institute for Laboratory Animal Research, neuroscientist Jon Levine, who directs the Wisconsin National Primate Research Center at the University of Wisconsin in Madison, likened the surge in demand to "a 10-alarm fire that's about to be set." In response, the National Institutes of Health (NIH) plans to launch funding to expand marmoset research. And established marmoset researchers, including Miller, are working together to help new labs get animals.
When Miller's lab started to work with marmosets in 2009, many colleagues who studied macaques—the most popular genus of research monkey—didn't even know that marmosets were monkeys, he remembers. "They were like, ‘Is it those chipmunks that were in the Rocky Mountains?'" (They were thinking of marmots.)
Now, he says, "All of those people want marmosets." In a survey, Miller and colleagues found that the number of U.S. marmoset research colonies jumped from eight in 2009 to 27 today, totaling 1900 marmosets across about 40 principal investigators.
Among monkeys, marmosets are known for cooperative social behavior: They call to each other in back-and-forth conversations, and mated pairs share responsibility for rearing young. They're smaller and easier to house than rhesus macaques, and they give birth twice a year versus once every year or two, aiding multigeneration genetic experiments. Because marmosets mature and age more quickly than bigger monkeys, they speed up studies of diseases that affect development and aging. And a marmoset's brain is less furrowed than a macaque's, which makes it easier to image or record activity from its surface.
Enthusiasm for marmosets surged in 2009, when they became the first primates shown to pass a genetic modification to offspring in their s***m and eggs. A team at the Central Institute for Experimental Animals (CIEA) in Kawasaki, Japan, injected embryos with the gene for a fluorescent protein. The skin and hair of the resulting animals shone green under ultraviolet light.
A series of transgenic marmosets followed—many from CIEA geneticist Erika Sasaki and neuroscientist Hideyuki Okano of Keio University in Tokyo. On 5 November at the Society for Neuroscience meeting in San Diego, their teams will present updates on two transgenic efforts: marmosets with genetic mutations that in humans are linked to Parkinson's disease and the neurodevelopmental disorder Rett syndrome. Researchers hope that by watching disease progress in a marmoset while analyzing its brain, they can lay bare mechanisms that cause illness in people—and maybe find and test new therapies.
Japanese research got a leg up in 2014 with a 40 billion yen ($350 million) government initiative to map the marmoset brain. But several U.S. labs now have transgenic primates under development. In 2016, a team at NIH's National Institute of Neurological Disorders and Stroke, with Sasaki, created marmosets with brain cells that fluoresce when excited—a potential tool for monitoring neural activity. And in April, the first marmoset with a mutation in the gene SHANK3—implicated in some cases of autism—was born at the Massachusetts Institute of Technology (MIT) in Cambridge.
Making transgenic monkeys requires a large colony, in part because females implanted with manipulated embryos don't always get pregnant. Guoping Feng, who leads the MIT project, estimates the ideal size is at least 300 animals, far more than a single U.S. facility can breed. (Feng's group has gradually built up a colony of about 200.) When the new transgenic models become widely available—likely in the next few years—labs hoping to use them may also need their own animals for breeding. Attendees at this week's meeting also discussed ways to maintain genetic diversity within the U.S. marmoset population.
But the supply of new marmosets is limited. An international agreement restricts the export of wild animals from their native Brazil. And importing animals from breeding facilities in Asia is "really, really difficult," Feng says. Most airlines, facing pressure from animal rights groups, have stopped carrying research animals.
Already, public resistance to nonhuman primate research is prompting researchers to tread carefully. Increasing interest in marmoset research is "concerning to us," says Kathleen Conlee, vice president of animal research issues at the Humane Society of the United States here. It's especially problematic, she says, to genetically design animals that will become ill.
But scientists see no substitute for primates in some studies. "When it comes to [studying] cognitive processes and other complex behaviors, some things you just need to do in a primate model," Joshua Gordon, director of NIH's National Institute of Mental Health in Bethesda, Maryland, said at a 4 October NASEM meeting on genetically engineered nonhuman primates. The study of mental illness requires an understanding of brain structures that don't exist in rodents, he added. But such research must consider "the degree to which primate experiments are acceptable to the general public," he said.
Next year, Gordon's agency plans to announce funding opportunities to support centralized infrastructure for marmoset research. Although details are hazy, the funding might bring in new marmosets, expand or establish breeding colonies, or advance transgenic projects, he said. Its money could come from the federal Brain Research through Advancing Innovative Neurotechnologies Initiative or NIH's Blueprint for Neuroscience Research.
In the meantime, labs are improvising. Last month, several investigators launched a virtual pool, to which existing marmoset colonies will contribute 10% of their animals per year for new investigators to buy or inherit. It's a stopgap to keep up momentum in the field, Miller says, "because it's kind of a once-in-a-career opportunity."
