Keeping Everything in Proportion: why cell size must be kept under control

Our bodies contain around 37 trillion cells that come in all shapes and sizes, from rotund fat cells to the cells that line our organs and resemble microscopic paving slabs. However, if you focus on one particular cell type, cell size is remarkably consistent across the population. This narrow distribution suggests that it is important to control the size of our cells, just as it is crucial to regulate our internal body temperature. Now, a study published in Cell may provide insights into why size seems to matter so much.

The range of sizes exhibited in a healthy population of one specific cell type is generally narrow. If, like me, you’ve ever wondered why you can’t quite reach the top shelf of the cupboard whilst others can access the biscuit stash with ease, it’s generally because those taller office mates have produced more cells, rather than grown larger ones like some human Michelin man. In fact, changes to cell size are associated with several diseases; cancer cells may be smaller than their peers. Maintaining a consistent cell size therefore seems to be important, although it is unclear why.

In the lab, it is possible to perturb cell size by preventing cells from dividing. Cell division is the process of one cell splitting to produce two daughter cells, thus allowing the population of cells to proliferate. This proliferation is the main reason that co-worker Geoff developed long enough arms to consistently swipe the custard creams. Cells usually increase in size before dividing, to ensure the two new cells inherit the sufficient cellular machinery to survive. It’s rather like lovingly preparing a toolkit for your kids when they leave home, readying them to face their first leaking roof. If you block division, either by applying drugs or by mutating proteins involved in cell cycle progression, cells may grow without being able to split in two.

A recent report published in Cell has taken advantage of this approach to investigate why regulating cell size is important [1]. Researchers prevented yeast cells from dividing by mutating a key cell cycle protein. With the brakes on cell division applied, the cells started to swell, but were unable to divide or to initiate DNA replication. This erroneous growth led to problems; the scientists found that, once the brake was released, the now engorged cells progressed through the cell cycle slower than their smaller counterparts.

To explore why this might be happening, the team measured how the cell volume and the total protein content of these arrested cells changed as they grew. They found that, initially, protein levels increased at the same rate that cell volume did – the two processes were neck-and-neck. However, there came a point where the cells became so large that their volume was increasing faster than their protein levels. Somehow, protein production became unable to keep pace with the ballooning cell size. This could result in the dilution of the cell’s proteins, presumably affecting reaction rates. Imagine you and your friends are placed in a room, blindfolded, and have to walk silently until you find each other. You would locate each other faster in a cupboard than you would in a sports hall. Similarly, diluting proteins out in a larger cell makes them less likely to interact with their reaction partners, perhaps explaining the larger cells’ slower pace of life.

But what caused protein production rates to fall behind cell growth rate in the first place? Primarily, it was somehow due to DNA levels becoming limiting as cell volume increased. When the researchers doubled the yeast cells’ DNA content, the cells managed to grow to a larger size before the onset of protein dilution; in other words, their protein production rate was able to scale with their growth rate for a longer period of time.

This issue of scaling has been considered before. Cells are composed of several subunits called ‘organelles’, all performing different roles, including protein production. Some of these organelles are able to ‘scale’ to the size of the cell; that is, as the cell grows, the organelles also grow at a similar rate. Like the popular children’s toys that expand evenly when immersed in water, multiple parts of the cell may therefore grow proportionately. This type of growth is known as ‘isometric’. One famous example of an organelle that grows isometrically with the cell is the nucleus.

However, an increase in organelle size does not always correspond to an increase in organelle performance. Mitochondria are, of course, the organelle that launched a thousand memes, with most students knowing them as ‘the powerhouse of the cell’. There is a good reason for this accolade; mitochondria produce ATP, a molecule used as an energy source to drive many of the cell’s chemical reactions. It has been shown that the number of mitochondria increases with cell volume. However, their optimum rate of activity is only achieved in cells of an intermediate size. Similarly, this latest study has demonstrated that rate of protein production does not scale with cell size once the DNA to cytoplasm ratio becomes too low. Ultimately, there might be an optimal cell size at which this ratio is appropriate to support adequate protein production.

This optimal size may explain why cells become senescent (a state reached when older cells become unable to continue dividing as normal). These ageing cells are larger than their younger neighbours, due to accumulated errors from past cell divisions. The researchers found that old yeast cells behaved like the large ones they had artificially created. They even showed that enlarging human fibroblast cells made them more likely to become senescent and stop dividing. This raises the possibility that cells enter senescence once their size increases to suboptimal levels.

In beginning to uncover why cell size control is so important, this study raises implications for our health when this regulation goes wrong. But the key take-home? Well, always remember to keep things in proportion.

[1] Neurohr, Gabriel E., et al. “Excessive Cell Growth Causes Cytoplasm Dilution and Contributes to Senescence.” Cell (2019).

About the author: Having completed a BA in Biological Sciences at the University of Oxford, Laura Hankins stayed on in the city to take up a place on the Wellcome Trust’s Chromosome and Developmental Biology DPhil programme. A graduate student at Merton College, she is now in the third year of her PhD in Jordan Raff’s lab, where she is studying the process of centriole biogenesis as a model to understand how organelle growth is regulated.

Comments from our judge, Dr Jennifer Rohn (@JennyRohn) on the winner of the 2019 competition: The topic was a very abstract, hard-to-describe bit of science that was brought to life and made relevant with some beautiful writing.