How do cells respond to changes? New study finds it's not all in the genes

Cells are constantly on the move, whether in a developing embryo or metastatic cancer. But how do cells adapt to the new environments they encounter? Traditionally, scientists have believed that cells adapt to changes and stressors in their environment through genetic mutations or by altering gene expression.

But a new Yale-led study shows that migrating bacterial cells can also respond to changes in their surroundings, quickly and collectively, without any genetic alterations. Specifically, the researchers found that cell populations can adapt "non-genetically" to new environments just by growing and leaving behind slower cells.

This new discovery, which is described in the journal Proceedings of the National Academy of Sciences, has implications across biology, from advancing our understanding of evolution to informing new therapeutic strategies for diseases like cancer.

"Given the prevalence of collective migration in microbes, cancers, and embryonic development, non-genetic adaptation through collective migration may be a universal mechanism for populations to navigate diverse environments," said corresponding author Thierry Emonet, a professor of molecular, cellular, and developmental biology and of physics in Yale's Faculty of Arts and Sciences and a member of Yale's Quantitative Biology Institute.

Past research has shown that bacterial cells can acquire genetic mutations that confer resistance in response to antibiotics. Similarly, cancer cells can develop resistance to chemotherapy through genetic changes. Yet such adaptations typically require tens of generations before the mutated cells become predominant. (In bacterial cells used by Emonet, cell division or generation happens about every hour).

The new adaptive mechanism, however, which was theorized three years ago by Emonet and co-author Henry Mattingly, a scientist at the Flatiron Institute—and which has now been demonstrated experimentally—enables migrating cell populations to respond to environmental changes in just two or three generations and without relying on gene regulation or mutation.

To show how this works, the researchers placed genetically identical Escherichia coli bacteria—which exhibit different swimming behaviors—in both liquid and porous environments and then observed their collective migration.

In the liquid environment, which the researchers compared to a straight highway, bacteria that swam straight for longer took the lead while those that turned frequently lagged behind. Over time, the population of these bacteria became enriched with these smooth swimmers.

On the other hand, in porous environments with more obstructions, the tendency to turn frequently proved advantageous for escaping dead ends. In these environments, the bacteria that turned more often emerged as the leaders while populations of smooth swimmers gradually thinned.

"Smooth swimmers are like Porsche drivers, and the ones that turn more often are like Jeep drivers," said Lam Vo, a graduate student in Yale's Graduate School of Arts and Sciences and an F31 National Research Service Award fellow, who is also a co-lead author of the study.

"A Porsche is built for speed on a highway, whereas a Jeep excels on rougher terrains, like mountain roads. Different environments dictate who performs best."

Crucially, the enrichment of specific swimming behaviors could not be explained by mutations or gene expression. The researchers found no evidence of an increase or decrease in the expression of genes regulating the swimming behaviors of these bacteria during migration.

Since there were no changes in gene expression or mutations, the populations didn't commit to one environment or another—migration alone was enough to temporarily enrich the population with well-adapted individuals.

"Non-genetic adaptation via collective migration not only permits a rapid response to new environments, but also enables cell populations to respond to many biological challenges simultaneously," said Fotios Avgidis, a postdoctoral associate at Yale and co-author of the study.

"While gene regulation typically allows for a quick reaction by modifying one or two traits at a time, the mechanism we discovered facilitates a rapid response by simultaneously altering many traits."

Beyond enabling populations to adapt to changes in the environment within two to three generations of cell division, this mechanism can also modulate chemoreceptor abundances depending on what attractants the bacteria are chasing, highlighting its potential flexibility, the researchers found.

"This process is likely applicable to many cell types, both prokaryotic and eukaryotic, that break down environmental factors and generate their own gradient to chase," Emonet said.

"Our findings demonstrate that when collective behaviors create selection pressures, cell populations can reversibly adapt multiple traits with a level of speed and flexibility that is difficult to achieve via classical mechanisms," added Mattingly, a former postdoctoral associate at Yale who is now an associate research scientist at the Flatiron Institute in New York.

"Migration and other collective behaviors, when combined with growth, may generally provide rapid and flexible ways for diverse populations to adapt to changing conditions."

Mattingly also led the theoretical work predicting this adaptation mechanism.