This paper defines, for the first time, the molecular signals that are expressed in Spemann’s Organizer and required for its function.

“...which side of the embryo will become the back? Which side will become the head?”

The Organizer experiment was a critical one in the history of developmental biology—Nature Milestones Development lists it as the first milestone. Nevertheless, our understanding of the molecular signals that are required for Organizer function was still uncertain.

One of the candidate signals of the Organizer, BMP antagonism, had not appeared to be a required signal based on mouse, zebrafish, and Xenopus loss-of-function studies. We showed, for the first time, that the loss of three BMP antagonists was required to eliminate Organizer function, thus cementing the importance of BMP antagonists in Organizer function.

The fertilized egg has a simple structure, but develops into a complex animal. During development of the fertilized egg, the dividing cells become specialized in response to cell-cell communication between different parts of the embryo. An early and critical step is the signal that defines the different sides of the embryo. For example, which side of the embryo will become the back? Which side will become the head?

In 1924, the German Embryologists Hans Spemann (1869-1941) and Hilde Mangold (1898-1924) identified a region of the embryo that produced signals that defined where the head and back should form. They called this region "the organizer."

Spemann was a professor of zoology (1919–35) at the University of Freiburg. By transplanting embryonic tissue to a new location or to another embryo, he investigated the agency that governs the growth and differentiation of cells. He received the 1935 Nobel Prize in Physiology or Medicine for "the organizer effect," and three years later described his award-winning research in his classic text, Embryonic Development and Induction (1938).

Previously, we and others had shown that a class of molecules that block a specific cell-to-cell communication pathway could mimic the function of the Organizer. These BMP antagonists were therefore candidates for the Organizer signal.

In our paper, we show that these were indeed the required signal from the Organizer which instructs the cells to become back and head. Without these signals, only belly structures form. Therefore, for the first time, we identified the required signal from the Organizer—something for which developmental biologists have been searching for over 80 years.

I have had an interest in the molecular signals in Spemann’s Organizer for over 20 years. It has captured the attention of a great many developmental biologists and remains a fascinating problem.

Although we had multiple candidate molecules in hand, the loss-of-function experiments had not proven that the BMP antagonists were required in normal development. We therefore needed to block the function of multiple genes simultaneously, in a manner that would still be specific to each gene.

Therefore, for these experiments, we used an emerging model system, Xenopus tropicalis, a close cousin of the widely used Xenopus laevis. X. tropicalis has a much simpler genome than X. laevis, and this allowed us to design function-blocking oligonucleotides to knock down expression of multiple genes.