How evolution can make cells smaller without slowing down their growth

A new study led by Marco Fumasoni, Principal Investigator at Fundação GIMM, shows that evolution can substantially reduce cell size without significantly compromising cells’ ability to grow. The work, carried out in yeast in collaboration with researchers at Cornell University, USA, was published in Proceedings of the National Academy of Sciences.

“Why are cells the size they are?” The question may seem simple, but cell size influences fundamental processes, including metabolism, growth and cell division. Despite the enormous diversity of shapes and sizes found in nature, each cell type tends to remain within a relatively narrow size range. When a cell becomes too large or too small, its function can be compromised.

“Previous studies have shown that each cell type tends to have a characteristic size, and that this size is important for its function” explains Marco Fumasoni. “When we make cells larger or smaller, they start to perform worse”.

The question driving this study was how, over the course of evolution, cells of such different sizes could arise if even small changes to a cell’s normal size can come with biological costs.

To address this question, the researchers used experimental evolution. Over approximately 1,500 generations, they selected the smallest yeast cells in each population every day. But these cells also had to compete for nutrients and multiply quickly before the next round of selection.

“In the morning, we selected the smallest cells, and for the rest of the day they competed with one another in terms of growth,” says Fumasoni. “In practice, evolution was selecting simultaneously for smaller cells and for cells able to grow fast”.

This process allowed the team to observe evolution in real time and identify genetic solutions that would have been difficult to predict using classical genetic engineering approaches. By sequencing yeast populations at different stages of the experiment, the researchers were able to track the emergence and spread of mutations associated with reduced cell size.

“The great advantage of experimental evolution is that it allows us to preserve a kind of living fossil record, which we can revive to understand how evolution took place”, says the researcher.

The study identified genetic changes in conserved cellular pathways associated with growth and the cell cycle. These changes enabled the emergence of substantially smaller cells that were still able to grow rapidly. Direct manipulation of these genes confirmed their causal relationship with cell size.

The results suggest that evolution can gradually fine-tune fundamental cellular mechanisms to alter cell size, partially uncoupling two traits that appeared to be inevitably linked: miniaturisation and growth capacity.

Though this is a fundamental biology study, the findings may have implications for areas such as ageing, cancer and synthetic biology. Many of the pathways that control cell size are shared across eukaryotic organisms, including humans.

“Human cells control their size in a very similar way. The proteins involved may be different, but the general principles seem to be the same”, says Fumasoni.

In ageing, for example, increased cell size has been associated with senescence, a state in which cells stop dividing and which contributes to the progressive decline of tissues. In tumours, cells with irregular sizes and shapes are also frequently observed, reflecting alterations in the normal mechanisms that control cell growth.

The results may also be relevant for synthetic biology, where controlling cell size could help researchers design cells with specific functions.

“If we want to engineer cells with specific functions, we need to be able to control their size”, adds Fumasoni.

For now, the study’s main contribution is to show how evolution can reshape one of life’s most fundamental features — cell size — while preserving cells’ ability to grow.