BBy the mid-20th century, it was beginning to appear 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 has shown how it works at the molecular level. The genes governing the characteristics of organisms are passed from parent to offspring, and random mutations create the variations from which natural selection selects the “fittest.” Natural selection and genetics combined in what biologist Julian Huxley called “the modern synthesis” in his 1942 book. Once it was demonstrated in 1953 that genes were encoded by DNA, the rest of biology amounted to little more than piecing together details.
But not everyone was satisfied. British biologist Conrad Hal Waddington, known to his friends and colleagues as Wad, thought this focus on genes was a very good thing. But he didn’t know exactly how genes shape the shapes and features of organisms – how they reliably generate all the body’s different tissues, in the right places, during embryonic development. Around the same time that Huxley was unveiling the modern synthesis, Waddington was presenting a new picture of how it might play out.
He visualized the development process as a landscape with hills and valleys that divide from time to time like those of a river system. At the top of the highest hill, he imagined a ball representing a population of cells in their first embryonic form – what we today call stem or pluripotent cells, which have the potential to become any type of cell. The progression of cells towards their destiny – to become, for example, skin cells, muscle cells or nerve cells – is like a ball rolling down the landscape.
When the ball reaches a bifurcation (bifurcation) point, the “gravity” of the model pulls it towards one track or the other: in scientific terms, it must differentiate. According to Waddington, through a particular sequence of such branching decisions, cells specialize into their mature types, or fates, each expressing a particular set of genes. Cells are limited to a small number of well-defined states because they are “canalized,” according to Waddington’s lexicon: trapped and channeled by the sides of the valley. In this way, a limited number of cell types reliably result from the activity of an army of genes.
The Waddington landscape was “remarkably useful as a conceptual scaffolding,” said James Briscoe, a developmental biologist at the Francis Crick Institute in London. “The fundamental ideas – that development is progressive, that cellular states are distinct, that bifurcations represent decisions about (cell) fate, that canalization implies robustness – all survive. »
“Some of the concepts that Waddington was trying to share are so rich,” said Susanne Rafelski, a biochemist at the Institute for Stem Cells 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. Over the past few years, researchers have mapped the actual topography of cellular state spaces—in effect, Waddington landscapes—from experimental data collected from several thousand cells during embryonic development. These analyzes reveal that development is not a simple reading of a genetic program, but rather a dynamic process in which communities of cells construct themselves and the very landscape in which they evolve, through mutual negotiation and interaction, to become an organism.
This developmental mapping now helps researchers understand how identical cells in the young embryo transform into distinct tissues and cell types in a complex organism. This is extremely important for regenerative medicine and stem cell engineering, Briscoe said: “If you understand the topology of the landscape and know where the bifurcations are, you can in principle design methods that steer cell populations toward desired states precisely, rather than by trial and error. »
Waddington’s metaphor may therefore be the key to understanding and reshaping the possibilities of what cells, tissues and embryos can be.
Mapping a landscape
In the 1940s, genetics and embryology were separate sciences; not everyone even believed that genes played an important role in development. Yet Waddington’s own experiments in embryology, as well as those of others, convinced him that the formation and configuration of an embryo’s tissues were indeed controlled by genes. Cells from different tissues had different groups of genes activated in their chromosomes, he thought. A process of differentiation gradually specialized the cells into skin cells, nerve cells, etc.
Waddington reasoned that developmental pathways—for example, the formation of the neural tube from a layer of embryonic tissue called the ectoderm, which ultimately develops into the central nervous system—are inevitable once the process begins, just as water flowing in a river valley is constrained by its environment. The path can be a little winding, but the valley maintains the course of the river. Differentiation is the branching of a valley, and the final destinations are the mature cell types of the body.
Waddington’s classic drawing of the epigenetic landscape. A ball, representing a pluripotent cell or population, is about to descend into valleys, each representing a specialized cell type, such as a blood cell, liver cell, or brain cell.
From The gene strategy by CH Waddington
Waddington visualized this as a landscape in drawings, but these had “no basis in physical reality,” wrote Scott Gilbert, a developmental biologist at Swarthmore College in Pennsylvania, in a 1991 essay in Biology and philosophy. They were useful frameworks for thinking about the problem of development, and nothing more.
“Without mathematical content,” Briscoe said, the metaphor “could not distinguish between alternative mechanisms, make quantitative predictions, or be falsified.” As a result, he says, Waddington’s landscape “has sometimes become a cliché rather than a meaningful explanation”.
What determines, for example, the topography of hills and valleys? In his 1957 book The gene strategyWaddington depicted the landscape as he thought it might be seen from underneath: as a leaf pulled into shape by a network of ropes attached to stakes. The pegs represented individual genes and the strings their developmental effects. Expressing a particular gene – turning it into the corresponding protein – is like pulling its strings to change the shape of the leaf.
What determines the shape of the landscape? Waddington drew a network of stakes and ropes under the hills; the pegs are genes and the strings are their interconnections. Together, they shape the landscape and represent what we now call genetic regulatory networks.
From The gene strategy by CH Waddington
It’s much more complex than that, Waddington realized, because the strings are connected in a network. Any one of them can influence the landscape at several points, and any given point on the landscape can be attached to several ropes.
These hidden connections correspond to what researchers now call genetic regulatory networks: interactions between genes by which an increase in the expression of one can modify or regulate the activity of others. Therein lies the enigmatic complexity of development. A given process, such as neural tube formation, may be influenced by many interacting genes; there is no simple relationship between genes (genotype) and the developmental landscape that determines fitness (phenotype). Gene regulatory networks mediate between them.
So it makes no sense to look for genes dedicated to creating specific tissues, organs, or structures in an entire organism, which is one of the reasons Waddington’s metaphor proved useful. The landscape image was “valuable because it offered an alternative to a purely gene-centered view of development,” Briscoe said. By emphasizing landscape form, he pointed “to system-level properties that cannot be inferred from a single gene.”
Genetic regulation was not understood when Waddington first designed his landscape network and ropes. A few years later, in the early 1960s, it became clear that one gene could turn another gene on or off. Researchers, such as complexity theorist Stuart Kauffman, have begun to build simple mathematical models of genetic interaction networks. But too little was known about actual genetic networks to connect abstract theory to experiment. “Given that the canals and spheres had no physical reality,” Gilbert wrote, “what was an embryologist supposed to do with them?”
Answers have begun to emerge over the past two decades thanks to new experimental tools for characterizing cellular states. Biologists are finally able to map experimental data into a real mathematical landscape for differentiation purposes and show how prescient Waddington was.
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