In the United States, domestic cats kill up to 4 billion birds and 22 billion small mammals every year. These deaths dwarf other man-made causes of wildlife mortality like accidental poisoning and habitat destruction and pose an imminent threat to the health and diversity of our wildlife. One solution is to rein in cat fertility.
Now a team led by David Pepin, a reproductive biologist from Harvard, and William Swanson, the director of animal research at the Cincinnati Zoo, has developed a novel and safe method of gene therapy contraception to control the population of cats—including pets, feral cats, and community cats, which are fed by people but do not belong to an owner.
“On some islands, populations of feral cats run amok without predators,” leading to the extinction of native mammals, reptiles, and birds, says Roland Kays, an ecologist and mammal conservationist at North Carolina State University. Kays, who has studied the hunting range of pet cats, notes that neighborhoods that border nature preserves or beaches can be particularly problematic for vulnerable, endangered species.
Trap-neuter-return programs—where people trap, neuter, and then release cats—can help control population growth, but veterinarian availability is a bottleneck, Swanson says. “We needed a way to get the highly-trained surgeon out of the picture and allow a layperson to be able to give an injection that prevents cats from reproducing.”
From humans to cats
Pepin stumbled into the world of cat contraception through his interest in how ovarian cancer develops in people.His postdoctoral advisor had been studying anti-Mullerian hormone—which is important in the development of male sex organs in the fetus—as a possible treatment for ovarian cancer. Pepin, however, discovered the hormone had an important impact on the ovary and its follicles—the structures inside the ovaries that house what eventually become eggs.
The hormone “was much more potent than we realized,” Pepin says. “With it, we could basically take over the ovary and control the rate at which follicles develop.” Pepin immediately saw the hormone’s potential as a contraceptive.
In the 1960s, human family planning was revolutionized when researchers introduced oral contraceptives—containing estrogen and progesterone—for women. The pill acts on the later stages of follicular development—but this medication had drawbacks. It sometimes triggers side effects including high blood pressure and blood clots.
Anti-Mullerian hormone acts earlier—on primordial follicles, the population present at birth and before they become sensitive to follicle-stimulating hormone—which is released from the brain’s pituitary gland and stimulates follicle growth in the ovaries. After puberty, these follicles start to mature in batches of roughly 20 with every ovarian cycle, until one is selected to release its egg for possible fertilization. The process is highly coordinated—a dance of positive and negative hormone feedback loops connecting the hypothalamus, the pituitary gland, and the ovary.
Produced by growing follicles, the hormone is part of the negative feedback that prevents primordial follicles from maturing while also slowing the development of others. And unlike estrogen and progesterone—which have receptors throughout the body including the bone, brain, and immune system—the receptors for this hormone are largely confined to the ovaries, pituitary gland, and uterus.
“That means very few side effects,” Pepin says.
But progress had stalled. “Funding in women’s health was low; and particularly in contraception, people felt there was no need to innovate in that space,” Pepin says. That’s when the Michelson Found Animals Foundation stepped in. While surgical contraception takes several minutes (male cats) to half an hour (female cats), the procedure—which requires that the animal be under general anesthesia—still carries risk, such as pain, post-operative bleeding, and infection. Motivated by overcrowded shelters and animal welfare concerns, the non-profit financed research to develop non-surgical, permanent contraceptives for pets.
Gene therapy contraception
With the foundation’s support, Pepin expanded his work to include cats. To test the hormone’s impact on this new population, he and his collaborators used gene therapy—a strategy in which a gene encoding the hormone is inserted into cells to produce higher-than-normal levels of the molecule in cats.
The researchers injected a virus carrying the feline version of the hormone’s gene into the muscles of six animals. In addition, the researchers injected three cats with viruses that did not contain the gene to serve as the controls for the experiments. The process is permanent—the gene integrates into the DNA of the cats’ muscle cells and continues to pump out the hormone for years—stalling follicle development to such a degree that the follicles never release an egg for fertilization.
When the researchers investigated the level of various hormones present in the blood and feces after treatment, however, they were surprised to discover that many—notably estrogen—were unchanged compared to controls. This implies that some follicles made it out of the primordial stage and were secreting the hormone. So, rather than stopping these follicles in their tracks, the situation is more nuanced.
“A few follicles still activated, but they didn’t mature like they normally would; they were stunted,” Pepin says. Yet, due to strong feedback mechanisms, this small cadre of follicles was still capable of producing near-normal amounts of estrogen—an important detail given the hormone’s importance for bone and cardiovascular health.
During the cycle, however, the follicles did “peter out,” their development arrested before they could ovulate.
Mating trials, in which the cats were housed with a fertile male cat, confirmed that the hormone treatment suspended fertility. Although two of the six treated female cats mated with the male cat, none became pregnant. In contrast, all three control cats had two to four kittens when they were allowed to mate. That the treated cats that mated did not get pregnant suggests that although estrogen levels appear normal, the hormone had an impact that blocked ovulation and led to infertility.
Pepin acknowledges that their work could sound scary. “We’ve made a virus that causes infertility—many science fiction stories start out like this.” But you can put fears of a global infertility plague aside. Adeno-associated viruses can’t replicate, so there’s no risk of spreading this birth control. They also don’t work across species.
Future goals include reducing the cost of gene therapy, finding efficient ways to administer it, and devising a version of the treatment for dogs. Pepin also co-founded a company to explore AMH’s use in people, including injecting just the hormone directly which, unlike gene therapy, would be completely reversible.
For cat-owner Grant Sizemore, a conservation biologist with the American Bird Conservatory in Washington, D.C., the threat that cats pose to wildlife is clear and present. “Cats could very well be the nail in the coffin for many species—they’re just such effective and pervasive predators and their numbers are so vast in the environment,” he says. They’re also a source of diseases like the parasite-caused toxoplasmosis, which can decimate endangered species like the Hawaiian monk seal and the Hawaiian crow.
But Sizemore is not a fan of programs that sterilize cats and then return them to the environment. “These programs purposely maintain cats on the landscape and a sterilized cat will still hunt and kill wildlife. It will still contribute to disease concerns,” Sizemore says. He also questions the efficacy of these strategies, citing research that demonstrated that they failed to curb cat population growth in two counties in Florida and California.
A 2019 analysis of various strategies, however—including removing cats, sterilizing them, and taking no action—indicate that high-intensity sterilization, in which at least 75 percent of the population is treated, could be an effective way to cut cat numbers by 50 percent over a ten-year period.
According to Swanson, who has worked on this project for the past seven years, the comparative ease of a gene therapy solution will boost that effectiveness. “This really could be game changing, if we can get it to work as well as we hope.”