19.1 Why Do Identical Cells Behave Differently?

19.1 Why Do Identical Cells Behave Differently?

Imagine two genetically identical bacterial cells growing side by side in the same nutrient medium.

Both cells possess the same genome.

Both experience nearly identical environmental conditions.

Both contain the same regulatory networks.

From the perspective of a deterministic model, we would therefore expect both cells to behave almost identically.

Surprisingly, experiments often show something quite different.

One cell may begin expressing a particular gene immediately, while the other remains inactive for an extended period.

One cell may divide earlier than its neighbor.

Another may survive an environmental stress that kills genetically identical cells growing only a few micrometers away.

These observations raise a fundamental question.

Where does this variability come from?

Phenotypic plasticity and cellular heterogeneity

The observable characteristics of a cell—its morphology, physiology, metabolism, and gene expression profile—constitute its phenotype.

Importantly, phenotype is not determined by the genome alone.

Instead, it emerges from the interaction between genetic information, environmental influences, and the molecular processes occurring within the cell.

As a result, genetically identical cells can exhibit different phenotypes even when growing under apparently identical conditions.

This phenomenon is known as phenotypic heterogeneity.

In many cases, such variability represents a form of phenotypic plasticity, allowing populations to respond flexibly to changing environments.

Rather than behaving as perfectly synchronized individuals, cells explore a range of possible physiological states.

Is variability merely experimental error?

When biological variability was first observed, it was often attributed to technical limitations.

Perhaps the measurements were simply too noisy.

Perhaps small environmental differences had been overlooked.

Modern single-cell technologies have fundamentally changed this view.

By measuring thousands of individual cells simultaneously, researchers have demonstrated that much of the observed variability is genuine.

Cells with identical genomes and nearly identical environments still exhibit substantial differences in gene expression, protein abundance, and cellular behavior.

The variability therefore reflects an intrinsic property of biological systems rather than imperfections in experimental measurements.

A new modelling challenge

These observations expose an important limitation of deterministic models.

A deterministic model predicts a single trajectory for a given initial condition.

If two cells begin in exactly the same state, the model predicts that they will remain identical forever.

Real biological systems often violate this expectation.

Instead of producing one reproducible trajectory, they generate a population of similar—but not identical—behaviors.

The question is therefore no longer

Which trajectory will the system follow?

Instead, we must ask

What range of possible trajectories can the system generate, and how likely is each one?

Answering this question requires a fundamentally different modelling framework.

Before introducing this new framework, however, we must first understand where biological variability originates.

Key concepts

• Genetically identical cells often display different phenotypes.
• Cellular heterogeneity is a genuine biological phenomenon.
• Phenotypic plasticity allows populations to occupy multiple physiological states.
• Single-cell experiments demonstrate that much biological variability is intrinsic.
• Deterministic models predict one trajectory, whereas real biological systems often exhibit many possible trajectories.

Summary

Modern single-cell biology has revealed that genetically identical cells frequently behave differently, even under nearly identical environmental conditions. This phenotypic heterogeneity cannot be explained solely by deterministic models that predict a single trajectory. Instead, understanding biological variability requires a framework capable of describing multiple possible outcomes and their probabilities.

Self-check questions

1. Why might one expect genetically identical cells to behave identically?
2. What is meant by phenotypic heterogeneity?
3. How does phenotypic plasticity differ from genetic variation?
4. Why can biological variability not simply be dismissed as measurement error?
5. Why do observations from single-cell experiments challenge deterministic modelling?
6. What new modelling question emerges from these observations?