So far, these mechanisms across systems and scales — in the developing embryo’s segmentation clock, in a single developing neuron, and in more fundamental protein machinery — have all continued to beat in time.

“Pretty much everything we looked at so far is scaling,” Pourquié said, “which means that there is a global command for all these processes.”

The Tick-Tock of Metabolism

What could this upstream control system be? Pourquié and Diaz Cuadros pondered which system could potentially affect a variety of cellular processes — and they landed on metabolism, driven by mitochondria. Mitochondria produce ATP, the energy currency of the cell, as well as a host of metabolites essential for building proteins and DNA, regulating the genome, and performing other critical processes.

To test that idea, they devised genetic and pharmacological methods to speed up and then slow down the metabolic rates of their stem cells. If mitochondria were indeed setting the cellular tempo, they expected to see their experiments alter the rhythm of the segmentation clock.

When they slowed metabolism in human cells, the segmentation clock slowed too: Its period stretched from five to seven hours, and the rate of protein synthesis slowed as well. And when they sped metabolism up, the clock’s oscillations accelerated, too.

It was as if they had discovered the tuning knob of the cell’s internal metronome, which let them accelerate or decelerate the tempo of embryonic development. “It’s not differences in the gene regulatory architecture that explains these differences in timing,” Pourquié said. The findings were published in Nature earlier this year.

This metabolic tuning knob wasn’t limited to the developing embryo. Iwata and Vanderhaeghen, meanwhile, figured out how to use drugs and genetics to toy with the metabolic tempo of maturing neurons — a process that, unlike that of the segmentation clock, which runs for only a couple of days, takes many weeks or months. When mouse neurons were compelled to generate energy more slowly, the neurons matured more slowly, too. Conversely, by pharmacologically shifting human neurons toward a faster pathway, the researchers could accelerate their maturation. The findings were published in Science in January.

To Vanderhaeghen, the conclusion of their experiments is clear: “Metabolic rate is driving developmental timing.”

Yet, even if metabolism is the upstream regulator of all other cellular processes, those differences must come back to genetic regulation. It’s possible that mitochondria influence the timing of the expression of developmental genes or those involved in the machinery for making, maintaining and recycling proteins.

One possibility, Vanderhaeghen speculated, is that metabolites from the mitochondria are essential to the process that condenses or expands folded DNA in genomes so that it can be transcribed to build proteins. Maybe, he suggested, those metabolites limit the rate of transcription and globally set the pace at which gene regulatory networks are turned on and off. That’s just one idea, however, that needs experimental unpacking.

There is also the question of what makes mitochondria tick in the first place. Diaz Cuadros thinks that the answer must lie in DNA: “Somewhere in their genome, there has to be a sequence difference between mouse and human that is encoding that difference in developmental rate.”

“We still have no idea where that difference is,” she said. “We’re unfortunately still very far from that.”

Finding that answer may take time, and like the mitochondrial clock, scientific progress proceeds at a tempo all its own.

Correction: September 18, 2023
In the introduction, a sentence was revised to clarify that it is the rate of gene expression, not overall metabolic rate, that helps to direct the tempo of development. The article was also updated to correct which species in the stem cell zoo have the fastest and slowest segmentation-clock oscillations.