September 15th, 2015
(written by lawrence krubner, however indented passages are often quotes). You can contact lawrence at: firstname.lastname@example.org
Not that long ago, as Partch knew, it had become clear that nearly every cell in nearly every tissue in the body keeps time. Every 24 hours, responding to a biochemical bugle call, a handful of proteins assembles in the cell’s nucleus. When they bind to each other on the genome, they become a team of unrivaled impact: Under their influence, thousands of genes are transcribed into proteins. The gears of the cell jolt into motion, the tissue comes alive, and on the level of the organism, you open your eyes and feel a little hungry for breakfast.
These timekeeping protein complexes, which take some of their cues from a part of the brain that responds to light and darkness, are known as circadian clocks. By some estimates, they regulate the expression of 40 percent of the genes in the body. Researchers are accumulating evidence that circadian clocks have deep effects on everything from fetal development to disease. Circadian clocks are so ubiquitous, and so important to the function of individual cells, that biologists whose research doesn’t overtly connect to a clock are becoming aware of how it might impact their work. “More and more they are stumbling into clock components,” said Charles Weitz, a molecular biologist at Harvard Medical School. “It doesn’t surprise me.”
Very few cells lack a clock, but they include biologically compelling examples like embryonic stem cells and cancer. In an effort to discern how the molecular clock works — and why, sometimes, it appears to stop — Partch decided to look closer at PASD1. As she and her colleagues recently revealed in a paper in Molecular Cell, PASD1 may be a switch that explains how cells as different from each other as cancers and sperm precursors escape the daily rhythms that govern the trillions of other cells in the body. It gives researchers a deep look at the secrets of how the cell ticks.
The Clock the Cow Found
The daily cycling of plants and animals has been a source of fascination for millennia, but it wasn’t until about 50 years ago that research into the underlying biochemistry began to take off. Many people trace the field’s founding to a meeting at Cold Spring Harbor in the summer of 1960, where researchers brainstormed ideas about what might cause circadian rhythms and devised experiments to test their theories. Over the ensuing three decades, researchers identified mutant creatures with abnormal daily cycles — fruit flies, hamsters, yeasts and others — and began to uncover the genes required for a normal rhythm. Studying flies whose natural cycle was 19 or 28 hours, or who had no discernible rhythm, led clock pioneers Ronald Konopka and Seymour Benzer to discover the first family of key clock genes, which they named per, in 1971, and whose levels we now know to rise and fall through the day. Just a year later, researchers reported that a tiny patch of cells in the brain called the suprachiasmatic nucleus was necessary for a 24-hour circadian rhythm in mammals.
….“You’ve got to retract this paper,” Schibler recalls Wuarin saying. “It’s all fake. It doesn’t exist.” When Wuarin performed the isolation, the transcription factor had failed to appear. Schibler, taking his concerns seriously, tried the procedure himself. He found the transcription factor easily.
After a number of weeks, Wuarin realized why he couldn’t find it himself: He and the postdoc had been performing the isolation at different times of day. The postdoc, a late riser, usually arrived around 11 a.m., killed the rats, and had the transcription factor in hand by midafternoon. “But [Wuarin] was a farmer’s son,” Schibler explains. “He got up at 5, milked the cows, then came to lab and killed the rats at 7. And at that time, this protein’s just not there.”
It’s now known that every day, this transcription factor’s levels start at almost nothing, making it impossible to detect in the morning, and then rise 300-fold, making it easy for the postdoc to find in the middle of the day. Schibler notes wryly, as an aside, that in all the years since, no one has ever found a protein that oscillates more wildly. It was just their luck.
A funny commentary about our sexuality:
It’s a tidy, self-governing system, and it’s tempting to call it ubiquitous. But these studies have revealed too that not everything has a clock. Embryonic stem cells, which can develop into almost any cell type, don’t keep time. The testes, almost alone among the organs that have been tested, don’t seem to have a clock either. And many cancer cells do not keep a regular rhythm. What could these things have in common? This is where Partch’s discovery comes in.