It was a sad day in the department of anatomy and reproductive biology at the University of Hawaii, Manoa. On May 5, 2000, an elderly mouse named Cumulina, whose birth had captured international headlines, died of natural causes. “She was special,” Ryuzo Yanagimachi, the laboratory’s principal investigator, said at the time.
Born on October 3, 1997, Cumulina was the first successfully cloned mouse and the second mammal ever cloned from an adult cell. She was also the forerunner of a technique that would establish once and for all that the long-awaited possibility of cloning animals could be readily accomplished. Her birth came just 15 months after the birth of Dolly the Sheep, the world’s first mammal cloned from an adult cell, had shocked scientists and the public alike, raising ethical questions in some quarters about the science fiction-like possibility of human cloning while also inspiring worldwide hopes of coming breakthroughs in biomedicine.
Dolly’s success proved complicated, though; of the 277 embryos her stewards at the Roslin Institute in Edinburgh cloned as part of the experiment, Dolly was the only one born. The team’s method involved removing the nucleus from a Scottish Blackface sheep’s egg cell and electroshocking it with a mammary gland cell from a Finn Dorset sheep to enable the two to fuse. They then implanted this unusual egg cell—which contained a full complement of DNA but had never been fertilized—into a ewe, who brought it to term.
The Roslin scientists went on to clone more lambs, and in 1997 they cloned the first transgenic mammals from adult cells. But in the meantime, Teruhiko Wakayama, one of Yanagimachi’s postdoctoral researchers in Hawaii, came up with another idea.
Wakayama had been galvanized by news of Dolly’s birth, and spent free time in the lab to try to create a mouse clone. He removed nuclei from egg cells and replaced them by injecting nuclei taken from adult mouse cumulus cells, which normally play a role in egg maturation. He then implanted these special eggs into surrogate female mice to see whether they would successfully give birth.
After a number of failed attempts in the fall of 1997, Wakayama and Yanagimachi produced a stunning result: a healthy female mouse pup. He named her Cumulina, after the cells he had used to create her. Celebrated internationally for his achievement, Wakayama went on to become a professor at the University of Yamanashi in Japan and Yanagimachi founded the Institute for Biogenesis Research at the University of Hawaii.
In the year after Cumulina’s birth, Wakayama and Yanagimachi made 84 more cloned mice, putting to rest lingering skepticism over whether cloning was practicable. Wakayama’s method proved more efficient than the one the Roslin scientists had used to produce Dolly. “Cumulina truly represented a breakthrough in the cloning technique,” says W. Steven Ward, director of the University of Hawaii’s Institute for Biogenesis Research.
So far scientists have cloned more than 20 types of animals. Mice created through the nuclear transfer method that was used to make Cumulina are now the most abundant cloned animals in the world. Nonetheless, some of the more spectacular scenarios from the 1990s about cloning have not come true. Researchers still have not managed, for example, to replace a dying person’s failing organ with a new one generated from cloned cells. But the early work that produced Dolly, Cumulina and other cloned animals has contributed to advances in stem-cell technologies that are now helping scientists explore regenerative medicine, investigate the underpinnings of diseases ranging from leukemia to diabetes and research new pharmaceuticals.
Laboratory mice typically don’t reach old age, but Yanagimachi’s crew made every effort to ensure Cumulina’s longevity. They even threw birthday parties for her. “She was a pretty pampered mouse,” says Kristen Frederick-Frost, curator of modern science at the Smithsonian's National Museum of American History.
Cumulina lived well past age 2, the equivalent of over 90 in human years. After she died, Yanagimachi preserved her in a freezer until a local high school teacher offered to taxidermy her body. The teacher posed Cumulina holding a block of fake cheese, and the stuffed mouse sat on display in Yanagimachi’s lab for a couple of years before being relegated to a closet. In 2004, she barely escaped being washed away in a flood, and has since spent most of her time in storage.
Yanagimachi retired in 2005, and last year, Ward contacted curators at the National Museum of American History. The decision to accept Cumulina “was a no-brainer,” Frederick-Frost says. The collection also includes OncoMouse, the world’s first patented genetically modified animal, who, along with his successors, was used for cancer research.
Editor’s note, May 25, 2022: This article has been updated with fuller context for the experiments that led to the cloning of Dolly the Sheep, among others.