Scientists have been puzzled by the size of cells ever since they were discovered way back in 1676. Now, over three centuries later, Stanford biologists have zeroed in on a previously-unknown mechanism within the cell growth cycle that determines how large they get to become before splitting apart.
Findings of the study were published in the science journal Nature.
Jan Skotheim, an Associate Professor of Biology at Stanford, had been trying to figure out what causes cells to start dividing as they reach a certain size for nearly a decade. Cell size was known to affect the first part of the cell division pathway when cells begin to replicate their DNA, known as the G1/S transition.
The research was carried out on yeast, as it’s easy to manipulate, and contains the same pathways as most other organisms. If the trigger could be found in yeast, researchers would likely be able to extrapolate it to other species.
The first suspect was Cln3 – the protein which “headlines” the chain of molecular events leading up to the G1/S. Surprisingly, though, the research team found its concentration to remain relatively stable throughout the whole cycle, making it a weak contender for the first “mover” that sets off the reaction.
Frustrated with the result, study lead author Kurt Schmoller, a post-doctoral candidate at the university, went on to examine the other proteins involved in the same process. This had led the team to Whi5, a protein that’s smack-dab in the middle of the pathway.
All of the proteins involved in G1/S were found to remain in steady supply at all times, whereas Whi5 started out high and then became increasingly diluted as the cell grew larger.
“This finding was extremely exciting because it immediately lead to a new idea of how size control could work,” said Schmoller. “The inhibitor-dilution mechanism, where the cells dilute out an inhibitor of cell division, is very elegant and, in retrospect, seems almost obvious.”
To make sure Whi5 was affecting cell size from the middle of the pathway, the research team tried to manipulate its quantity both ways, and found that lower levels of the protein nudge the cell to divide at a smaller size, while larger concentrations slightly delay the same process, allowing it to grow larger.
The strange thing about this is that, traditionally, signalling pathways jump into action by switching on the catalyst located at the very beginning of the pathway and then transmitting information down the line in a chain reaction.
“We don’t know of any other pathways that operate like this,” said Skotheim. “This looks like a huge breakthrough for us to solve this really old problem.”
Even though the work was done with outstanding science mysteries in mind, it might have far-reaching implication down the road. If the same mechanism is found to be present in human cells – as it is likely to be – researchers could gain a much better understanding of diseases that overtake the pathway, a prime example being cancerous tumours.
For their next endeavour, Skotheim’s research team is planning to carry out a genome-wide analysis to identify other biological mechanisms that could be affected by cell size and geometry.
“Tons of things have been learned from studying the yeast cell cycle that apply directly to human cells,” explained Skotheim. “Finding something like this that’s so intuitively unlikely, I don’t think we could have done it without the yeast work. But now we can test it, and we plan to apply these models to human cells.”