More than 80 years ago, the German scientist Hans Spemann conducted a famous experiment that laid the foundations for the field of embryonic development – research that would later earn him a Nobel Prize. After dividing a salamander embryo in half, Spemann noticed that one half – the ventral half that gives rise to the salamander’s “belly” – starts to wither away. However, the “back” (dorsal) half, from which the head, brain and spinal cord arise, continues to grow, regenerating the missing belly and developing into a complete – though small – embryo. Spemann then conducted another experiment. This time, he removed a few cells from the back half of one embryo and transplanted them into the belly half of a different embryo. To his surprise, the result was a Siamese twin embryo with an extra head generated from the transplanted cells. Although the resulting embryo was smaller than normal, all its tissues and organs developed in the right proportions, and they functioned properly.
How does this happen? How exactly is half an embryo able to maintain its tissues and organs in the correct proportions even though it’s smaller than normal? Despite the attention this question has received in the ensuing years, it has remained unanswered – until now. Four scientists – Prof. Naama Barkai and research student Danny Ben-Zvi of the Molecular Genetics Department, and Prof. Ben-Zion Shilo, Dean of the Faculty of Biochemistry, together with Prof. Abraham Fainsod of the Hebrew University-Hadassah School of Medicine, Jerusalem – have finally discovered the mechanisms involved.
The scientists knew that the growth and development of cells and organs within the embryo are linked to a unique group of substances called morphogens. Morphogens are produced in one particular area of the embryo, and from there they spread throughout the entire embryo in varying concentrations. Scientists have begun to realize that the different morphogen levels themselves contain information, and that the fate of embryo cells – the specific type of tissue and organ they are eventually going to develop into – is determined by the amount of the morphogen they come into contact with. But how those concentrations are determined in a way that maintains organ proportions is a question that remained unanswered.
The idea for the present research came about when Barkai and her colleagues developed a mathematical model to describe the interactions that occur within an embryo’s gene networks. In this model, the dorsal side contains all the morphogens needed for organ development, while the ventral side has none.
The data suggest that morphogens become unevenly distributed in the embryo in a different way than previously thought. The team predicted that an inhibitor molecule secreted from a localized source on one side of the embryo binds the morphogen and acts as a type of ferry for “shuttling” it over to the other side. According to the model, the interactions between the two substances determine the morphogen concentration in any location, enabling the embryo to preserve the relative proportion of its organs. Barkai and her team then tested and validated their predictions in experiments conducted on frog embryos.
The importance of the role of these morphogenic substances, as well as their mechanism of action, is evidenced by the fact that they have been conserved throughout evolution: Variants can be found in species ranging from worms to fruit flies to higher species, including humans. Understanding the processes that govern embryonic cell development, therefore, could have many implications. For example, it could lead, in the future, to the development of new ways to repair injured tissue.
A Piece of Work
When Hamlet said “What a piece of work is man,” he had no idea how right he was: The human body has trillions of living cells that make up several hundred tissues and organs. Each one of these cells is more sophisticated than the most powerful computer; the transportation and communications systems in a single cell are more complex than those of a mid-sized city. And all of this is run by 30,000 genes that manage everything from embryonic development to aging and death.
How is this colossal undertaking coordinated? What are the basic rules governing life? Life scientists have struggled with these questions for decades, but they have recently been joined by physicists who, until a few years ago, were mainly investigating phenomena in non-living materials. Physicists such as Prof. Naama Barkai bring to this effort a new set of research tools and new approaches, many of them particularly well adapted to sorting out complex systems. No less importantly, they come with new ways of thinking that lead them to ask novel questions and follow fresh paths of inquiry.
Much of this work involves mapping such large, tangled, multi-scale gene networks as those that manage embryonic development, intercellular communication or the processes within cells that are involved in diseases such as cancer. As the models of these networks become ever more precise, they provide scientists with ever better methods for approaching those basic questions about the nature of life, as well as practical tools for biomedical applications.
Prof. Naama Barkai’s research is supported by the Kahn Family Foundation for Humanitarian Support; the Helen and Martin Kimmel Award for Innovative Investigation; the Carolito Stiftung; the Minna James Heineman Stiftung; the PW-Iris Foundation; and the PW-Jani. M Research Fund.
Prof. Ben-Zion Shilo’s research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine; the J&R Center for Scientific Research; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; and the Mary Ralph Designated Philanthropic Fund. Prof. Shilo is the incumbent of the Hilda and Cecil Lewis Professorial Chair of Molecular Genetics.