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C.H. Waddington’s powerful image of embryonic stem cells specializing on a rolling landscape has captivated biologists since the 1950s. As Philip Ball reports, experimental data is finally confirming– and complicating– his visionary ideas…

By the middle of the 20th century, it had begun to seem that biology was almost solved. Charles Darwin’s theory of evolution by natural selection explained how organisms change and adapt. The modern science of genetics showed how it works at the molecular scale. Genes governing the traits of organisms get passed down from parent to offspring, and random mutations create the variations from which natural selection picks the “fittest.” Natural selection and genetics fitted together in what the biologist Julian Huxley christened “the modern synthesis” in his 1942 book). Once it was shown in 1953 that the genes are encoded by DNA, the rest of biology looked like little more than piecing together details.

But not everyone was satisfied. The British biologist Conrad Hal Waddington), known to his friends and colleagues as Wad, thought this focus on genes was all very well. But it wasn’t clear to him, or anyone else, exactly how genes shape the forms and features of organisms — how they reliably generate all the different tissues of the body, in all the right places, during embryonic development. Around the same time that Huxley unveiled the modern synthesis, Waddington presented a novel picture of how this might unfold.

He visualized the developmental process as a landscape with hills and valleys that split every so often like those in a river network. At the very top of the highest hill he imagined a ball, which represented a population of cells in their earliest embryonic form — what we now call stem or pluripotent cells, which have the potential to become any cell type. The progression of the cells towards their fates — to become, say, skin cells, muscle cells, or nerve cells — is like the ball rolling downhill through the landscape.

When the ball reaches a branching point (bifurcation), the model’s “gravity” pulls it to one track or the other: In scientific terms, it must differentiate. Through a particular sequence of such branching decisions, Waddington argued, cells specialize into their mature types, or fates, each expressing a particular set of genes. The cells are restricted to a small number of well-defined states because they are “canalized,” in Waddington’s lexicon: trapped and channeled by the sides of the valley. In this way, a limited number of cell types reliably arise from the activity of an army of genes.

Waddington’s landscape has been “remarkably useful as a conceptual scaffold,” said James Briscoe, a developmental biologist at the Francis Crick Institute in London. “The core ideas — that development is progressive, that cell states are distinct, that bifurcations represent [cell] fate decisions, that canalization implies robustness — all survive.”

“There’s so much richness to some of the concepts Waddington was trying to share,” said Susanne Rafelski, a biochemist at the Institute for Stem Cell and Regenerative Medicine in Seattle.

But the concept was more of a visual metaphor than a representation of an actual biological process. Or so it seemed. In the past several years, researchers have mapped out the real topography of cell-state spaces — in effect, Waddington’s landscapes — from experimental data collected from many thousands of cells over the course of embryonic development. Those analyses are revealing that development is not a mere readout of a genetic program, but rather a dynamic process in which communities of cells build themselves, and the very landscape they navigate, by mutual negotiation and interaction, into an organism.

This cartography of development is now helping researchers understand how identical cells in the early embryo develop into the distinct tissues and cell types of a complex organism. This matters enormously for regenerative medicine and stem-cell engineering, Briscoe said: “If you understand the landscape topology and know where the bifurcations lie, you can in principle design methods that steer cell populations to desired states with precision, rather than by trial and error.”

Waddington’s metaphor, then, could be the key to understanding and reshaping possibilities for what cells, tissues, and embryos can be…

Read on: “How Does Life Unfold? A Landscape Metaphor Comes Into Its Own.” from @philipcball.bsky.social in @quantamagazine.org.

* Stewart Sell

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As we appreciate adaptability, we might send healing birthday greetings to Robert Peter Gale; he was born on this date in 1945. A physician and medical researcher, he conducted important research into leukemia and other bone marrow disorders (e.g., aplastic anemia). Gale was a a pioneer in bone marrow transplantation and co-founded the International Bone Marrow Registry. But he is perhaps most widely known for his assistance to foreign governments in treating radiation victims – to the Soviet Union (1986) after the Chernobyl disaster and to Brazil (1987) following an accident in Goiania. As a specialist in bone marrow transplants, he volunteered to treat Chernobyl victims and was invited by Mikhail Gorbachev to travel with a group to Moscow immediately after the April 1986 accident. He performed bone marrow transplants on 13 Chernobyl victims (though many of the highly exposed Chernobyl survivors have since died from latent radiation effects).

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