After decades of effort, scientists have finally managed to derive embryonic stem (ES) cells from cows and keep them in their primitive state in a dish. Access to these versatile cells, which can become all kinds of tissues, from skin to muscle to bone, could make it easier to tweak and preserve useful genetic traits of beef and dairy breeds. That in turn could lead to animals that produce more milk or more tender meat, face fewer complications in giving birth, or have greater resistance to diseases. The discovery might also open up new ways to study the cow’s basic development and to model human diseases.
“I thought I would never see this happen in my lifetime,” says Jose Cibelli, a developmental biologist at Michigan State University in East Lansing, who was part of a team that attempted to harvest bovine ES cells in the late 1990s. In those efforts and many others since, stem cells from cow embryos would develop into other cell types when grown in a lab dish, meaning that they would quickly lose their “stemmy-ness,” or pluripotency.
Researchers turned their eyes to cattle soon after the mouse gave up its ES cells in 1981, allowing researchers to study early embryonic development and test the effects of genetic defects. But other species have been more difficult. It would take researchers until 1998 to find the right broth of nutrients to culture human ES cells.
Jun Wu, part of the team that has now isolated bovine ES cells, has spent very little of his career contemplating the cow. The stem cell biologist at the University of Texas Southwestern Medical Center in Dallas has been more interested in capturing new types of stem cells from the mouse and human, and in developing chimeras that blend cells from two species, such as pigs with human cells that might someday grow into organs for transplant. In 2015, he and his collaborators reported that they had found the right culture conditions to derive a new type of human pluripotent stem cell that was easy to grow in the lab and inside of mice.
But one collaborator on that project had his eyes on another prize. Reproductive biologist Pablo Juan Ross of the University of California, Davis, who had previously worked in Cibelli’s lab, hoped that these same culture conditions might finally sustain ES cells from livestock, which could make it easier to improve the animals’ genetics. So the group, which also included developmental biologist Juan Carlos Izpisúa Belmonte and his team at the Salk Institute in San Diego, California, exposed stem cells isolated from cow embryos to the new culture medium. The mixture had two key ingredients: a protein that encourages cells to grow and proliferate, and another molecule that inhibits them from differentiating into more mature cell types.
“They used an accelerator and a brake at the same time,” says George Seidel, a cattle rancher and a reproductive physiologist at Colorado State University in Fort Collins. The result: cells that retained their pluripotent state while growing for more than a year in the lab. “I’ve had many colleagues and students invest many years in trying to accomplish this,” Seidel says. When injected mice with weak immune systems, the cells grew into tumors made up of lots of cell types, known as teratomas—a key sign that they were truly pluripotent stem cells, the researchers report online this week in the Proceedings of the National Academy of Sciences.
Interest in bovine ES cells has waned somewhat with the development of cloning, Seidel notes. Using the same technique that produced Dolly the sheep, in which DNA from an adult cell is place in an egg stripped of its DNA, livestock breeders can duplicate the genetics of an animal with desirable traits such as speedy growth or copious milk production. Valuable bulls bearing these traits turn profits for livestock breeders, who sell semen to cattle and dairy producers to inseminate their cows and bring better traits into each new generation.
But the cells usually used to make these clones—connective tissue cells called fibroblasts—are short-lived, Cibelli notes, and can only divide 20 or 30 times. With these long-lasting ES cells, breeders could more easily hang onto a winning cell line, and make multiple rounds of edits to the cow genome through technologies such as CRISPR.
Even without any genetic engineering—a technology that consumers might be reluctant to see applied to their steaks and milkshakes—ES cells could make it easier for cattle breeders to select for superior animals. They could test ES cells from different embryos for the presence of genetic advantages, like genes associated with more milk production. Once they identified a set of traits they like, Cibelli says, they could create unlimited clones from those cells.
For Ross, the most exciting application depends on his team now figuring out how to develop these ES cells into cattle sperm and egg cells. If they succeed, livestock genetics companies could combine these sperm and eggs to create embryos with new genetic combinations and then isolate even more stem cells from the best ones. They could use this cycle—stem cell, sperm and egg, embryo, stem cell—to speed their way through ever-improving generations without any animal being born. That means less time spent waiting through a cow’s 9-month pregnancy, and fewer wasted animals. “It could accelerate genetic progress by orders of magnitude,” Ross says.
For biomedical researchers, access to ES cells from a new species might also open new avenues of research. The authors note that scientists could tweak the genes of these cells to create large-animal models that might mimic human diseases more closely than mice do. (Few labs can accommodate a herd of these massive beasts, of course.)
Despite the success in cows, ES cells from most species remain elusive. So far, the new culture medium appears to work for sheep cells, Ross says, but it has failed with pigs. Cibelli now has his eye on the technique for dogs, because access to these pluripotent cells could lead to new veterinary treatments or new models of human disease. “I’m dying to try it,” he says.