Author: Jordana Cepelewicz / Source: WIRED
In 1891, when the German biologist Hans Driesch split two-cell sea urchin embryos in half, he found that each of the separated cells then gave rise to its own complete, albeit smaller, larva. Somehow, the halves “knew” to change their entire developmental program: At that stage, the blueprint for what they would become had apparently not yet been drawn out, at least not in ink.
Since then, scientists have been trying to understand what goes into making this blueprint, and how instructive it is. (Driesch himself, frustrated at his inability to come up with a solution, threw up his hands and left the field entirely.) It’s now known that some form of positional information makes genes variously switch on and off throughout the embryo, giving cells distinct identities based on their location. But the signals carrying that information seem to fluctuate wildly and chaotically—the opposite of what you might expect for an important guiding influence.
“The [embryo] is a noisy environment,” said Robert Brewster, a systems biologist at the University of Massachusetts Medical School. “But somehow it comes together to give you a reproducible, crisp body plan.”
The same precision and reproducibility emerge from a sea of noise again and again in a range of cellular processes. That mounting evidence is leading some biologists to a bold hypothesis: that where information is concerned, cells might often find solutions to life’s challenges that are not just good but optimal—that cells extract as much useful information from their complex surroundings as is theoretically possible. Questions about optimal decoding, according to Aleksandra Walczak, a biophysicist at the École Normale Supérieure in Paris, “are everywhere in biology.”
Biologists haven’t traditionally cast analyses of living systems as optimization problems because the complexity of those systems makes them hard to quantify, and because it can be difficult to discern what would be getting optimized. Moreover, while evolutionary theory suggests that evolving systems can improve over time, nothing guarantees that they should be driven to an optimal level.
Yet when researchers have been able to appropriately determine what cells are doing, many have been surprised to see clear indications of optimization. Hints have turned up in how the brain responds to external stimuli and how microbes respond to chemicals in their environments. Now some of the best evidence has emerged from a new study of fly larva development, reported recently in Cell.
Cells That Understand Statistics
For decades, scientists have been studying fruit fly larvae for clues about how development unfolds. Some details became apparent early on: A cascade of genetic signals establishes a pattern along the larva’s head-to-tail axis. Signaling molecules called morphogens then diffuse through the embryonic tissues, eventually defining the formation of body parts.
Particularly important in the fly are four “gap” genes, which are expressed separately in broad, overlapping domains along the axis. The proteins they make in turn help regulate the expression of “pair-rule” genes, which create an extremely precise, periodic striped pattern along the embryo. The stripes establish the groundwork for the later division of the body into segments.
How cells make sense of these diffusion gradients has always been a mystery. The widespread assumption was that after being pointed in roughly the right direction (so to speak) by the protein levels, cells would continuously monitor their changing surroundings and make small corrective adjustments as development proceeded, locking in on their planned identity relatively late. That model harks back to the “developmental landscape” proposed by Conrad Waddington in 1956. He likened the process of a cell homing in on its fate to a ball rolling down a series of ever-steepening valleys and forked paths. Cells had to acquire more and more information to refine their positional knowledge over time—as if zeroing in on where and what they were through “the 20 questions game,” according to Jané Kondev, a physicist at Brandeis University.
Such a system could be accident prone, however: Some cells would inevitably take the wrong paths and be unable to get back on track. In contrast, comparisons of fly embryos revealed that the placement of pair-rule stripes was incredibly precise, to within 1 percent of the embryo’s length—that is, to single-cell accuracy.
That prompted a group at Princeton University, led by the biophysicists Thomas Gregor and William Bialek, to suspect something else: that the cells could instead get all the information they needed to define the positions of pair-rule stripes from the expression levels of the gap genes alone, even though those are not periodic and therefore not an obvious source for such precise instructions.
And that’s just what they found.
Over the course of 12 years, they measured morphogen and gap-gene protein concentrations, cell by cell, from one embryo to the next, to determine how all four gap genes were most likely to be expressed at every position along the head-to-tail axis. From those probability distributions, they built a “dictionary,” or decoder—an explicit map that could spit out a probabilistic estimate of a cell’s position based on its gap-gene protein concentration levels.
Around five years ago, the researchers—including Mariela Petkova, who started the measurement work as an undergraduate…
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