As an early embryo, every mammal, bird, and reptile contains a clump of cells with a remarkable power. Called “the organizer,” it prompts neighboring cells to develop into what will later become the animal’s brain and spinal cord. Biologists have not been able to show that such an organizer exists in human embryos because of ethical constraints on such research. But now, for the first time, these organizer cells have emerged in a dish of human stem cells—and researchers have proved their developmental powers by using them to seed the beginnings of a second nervous system in the embryo of a chicken.
“It is mind-blowing” that cells from such evolutionarily distant species can share these developmental instructions, says Ali Brivanlou, a stem cell biologist at The Rockefeller University in New York City and a senior author on the new study. The organizer “has been conserved evolutionarily over hundreds of millions of years, so not seeing it would have been a surprise,” he says. But, “There is something really emotional about looking that far back at human origin.”
The study of the organizer has bizarre and legendary beginnings. In the early 1920s, German embryologist Hans Spemann and his graduate student Hilde Mangold were exploring how the embryos of vertebrate animals transform from a hollow ball of cells to a multilayered structure organized along an axis from future head to future tail. In that transition, the embryo forms a furrow called the primitive streak and folds inward on itself while cells mature into different lineages that will later give rise to all the organs and tissues of the body.
In salamander embryos, Spemann and Mangold found a unique cluster of cells at one end of the streak. When grafted into the embryo of a different salamander species, it prompted nearby cells to form the beginnings of a brain and spinal cord—a nascent second salamander, belly to belly with the first. The study, considered one of the most important in developmental biology, earned Spemann the Nobel Prize in Physiology or Medicine in 1935. “It was the dawn of manipulating different parts of the embryo to ask, ‘Where does the information come from … to make a brain or discrete organs?’” Brivanlou says.
Since then, scientists have found similar organizers—sometimes called Spemann organizers—in the embryos of frogs, birds, and mice. But to see a human organizer, they would have to culture embryos a day or two longer than the 14-day threshold that international guidelines and U.K. law have set. That’s the point when an embryo is no longer able to divide into twins, and could thus be considered an individual.
So Brivanlou and his team, in collaboration with the lab of Rockefeller University physicist Eric Siggia, found a workaround. They cultured stem cells derived from human embryos—which have the potential to develop into any type of cell in the body—on specially patterned lab dishes where they take on embryolike structures. In the new experiment, the team exposed the cells to two proteins that are key to embryonic development. Those growth factors prompted some of the cells to express the genetic hallmarks of an organizer.
Then came the Spemann and Mangold-inspired graft. When the researchers put some of these human cells into a chicken embryo, an organized line of neural tissue appeared alongside the chicken’s own emerging nervous system, the team reports online today in Nature. The human organizer cells—themselves destined to become other (nonneural) types of tissue—could apparently direct the chicken cells to change their fate and start to orient themselves around a second body axis.
Developmental biologist Claudio Stern of University College London calls the work “a nice technical advance,” albeit one with major limitations. This new ability to make organizerlike cells outside of the developing human embryo could help researchers understand what gives these cells their unique signaling abilities. But the method is no substitute for the study of the organizer in a real embryo, which could consist of a more diverse mixture of cells than what emerged from the stem cell colonies. To find out, researchers would have to go beyond the 14-day culture limit, something not considered technically feasible until recently. “If we could work on it for a day or two more,” Stern says, “we could actually study the real organizer.”
Still, the new method could be used to study how the signaling between cells during early development varies between humans and other species, says Ben Steventon, a developmental biologist at the University of Cambridge in the United Kindgom, who was not involved in the study.
Meanwhile, Brivanlou plans to use his embryolike cell colonies to explore key steps in early development—and tease out various ways that the process can go wrong. He plans to use the CRISPR gene-editing tool to introduce disease-causing mutations and observe their effects on some of the earliest stages of development. Even the 4-day window during which his group can keep these embryolike colonies growing is “plenty of time” to explore, he says. “That’s going to keep us busy for a couple of generations.”