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This is the first “Data Brief” in a new series quantifying biology. Please send feedback and corrections to editors@asimov.com. All the datasets created for this article are freely available on GitHub.

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A human body is built from 30 trillion cells — excluding microbes — that each arise from a lone, fertilized egg. These cells come in a multiplicity of shapes and sizes, with internal volumes spanning five orders of magnitude. The smallest human cell, a sperm, fills a volume of just 30 µm³, whereas an oocyte boasts a volume of 4,000,000 µm³, making it the largest cell in the human body.¹

What accounts for this huge range? A simplistic answer would be that evolution has simply made each cell whatever size best suits its function. Under this explanation, sperm are small because the body produces many of them, and tinier cells cost less energy to make. Sperm are also ultra-minimal, stripped down to little more than DNA and the few mitochondria necessary for providing energy to spin their whip-like tails. By contrast, an oocyte needs massive reserves of mitochondria and nutrients to support early embryonic growth. In short, every cell is as large or small as it needs to be — within reason.

But we can derive far more satisfying answers from physics.

One major limitation on a cell’s size is surface area-to-volume ratio. Assuming that a cell is roughly spherical in shape, its internal volume grows proportionally to the cube of the sphere’s radius, and its surface area grows proportionally to the square of that radius. In other words, a cell’s volume grows much more swiftly than its surface area.

This ratio has serious consequences for cellular survival. The cell’s membrane funnels nutrients into the cell and secretes waste. It’s also where the energy in a prokaryotic cell — like E. coli — gets made. If the interior grows too large relative to the membrane, the cell’s metabolic processes slow to a crawl.

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A second constraint is diffusion, or the tendency for molecules to migrate from areas of high concentration to areas of lower concentration. This migration dictates how quickly enzymes find substrates, how effectively signaling molecules reach receptors, and how often ribosomes collide with mRNAs. Inside a cell, nearly everything happens by chance encounters among these molecules. As a cell’s volume grows, the chance for any given encounter diminishes (assuming the numbers of molecules stay constant).

A molecule’s diffusion rate hinges on several factors. For instance, the cytoplasm is extremely crowded, and so molecules spend lots of time ricocheting off obstacles, delaying their arrival at a distant location. Every protein in a cell collides with about 10 billion water molecules per second, on average. These frequent collisions mean that the vast majority of proteins in a bacterium only diffuse between 5 and 10 µm² per second. Some molecules also aggregate, or stick to charged surfaces, further slowing their movement. (Molecules move very slowly near the densely-packed nucleoid, for example.) In general, larger molecules diffuse more sluggishly than smaller ones.

Metabolites in E. coli can diffuse from one side to the other in milliseconds, which means collisions — and cellular outcomes — occur quickly. A typical protein takes just 0.01 seconds to traverse a bacterium’s diameter (about 1 micrometer), but the same protein would take around four minutes to move one millimeter and more than six hours to move one centimeter. This is, in part, why cells are so tiny.

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With these constraints in mind, we can begin to speculate as to why various cells are shaped the way they are. Red blood cells are tiny and shaped like biconcave discs to aid with diffusion; by abandoning a spherical shape and evolving more toward a “donut,” they increase their surface area without compromising their compact volume. This, in turn, enhances their ability to exchange oxygen with cells in the body. Their small size (just 8 micrometers across) also helps them move through narrow capillaries.

In contrast, oocytes can grow so large (around 100 micrometers in diameter), in part, because they are less metabolically active than other types of human cells — and thus don’t depend so much on “random” collisions. They stockpile nutrients during oogenesis to “wait out” fertilization. Eukaryotic cells also grow large, in general, because they’ve evolved compartmentalization; by modularizing specific functions into organelles, they bring molecules closer together to help get the job done.

Cell sizes are not fixed, however, even within a single species. Cells often swell as they increase their production of proteins and metabolites in preparation for division. This is in line with biology’s only rule: namely, there are exceptions to every rule!

Case in point: a giant bacterium called Thiomargarita magnifica can exceed one centimeter in diameter, so large that it can be seen by the naked eye. It does so by breaking the surface area-to-volume rule, filling between 65-80 percent of its internal volume with an empty vacuole. In other words, it pushes most of its “working” molecules to the cell periphery, thus shortening diffusion distances.

Despite their variety, these architectures hinge on molecules bumping into each other, guided by the immutable laws of physics. Or, as D’Arcy Wentworth Thompson mused in On Growth and Form (1917), “The form of an object is a ‘diagram of forces.’” Cells bear witness to internal and external forces. They are constrained by diffusion and indelibly shaped by the delicate trade-off between volume and surface area.

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Niko McCarty is a founding editor of Asimov Press.

Thanks to Ben Andrew and Ashish Uppala for reviewing drafts and contributing data.

Cite: McCarty, N. “What Limits a Cell’s Size?” Asimov Press (2025). DOI: 10.62211/97to-41re

Lead image by Ella Watkins-Dulaney.

Footnote

1. I find it difficult to wrap my head around large numbers and have found it helpful to rethink them as real-world analogies. To understand the difference between a million and a billion, for example, one could think about time. If a worker earned $100 per hour, it would take them 416 days of non-stop work to make $1 million and more than 1,100 non-stop years of work to make $1 billion. That’s a big difference! Similarly, when thinking about biological numbers, it’s helpful to scale things up and recontextualize them. Imagine a sperm “blown up” to the size of a glass marble, about two cubic centimeters in volume. A single oocyte, scaled in the same way, would then occupy roughly the size of a refrigerator — more than 100,000-times larger.

This article was published on March 26, 2025.