Cambridge researchers, led by Markus Ralser, recently published a paper in the journal Nature Microbiology on the importance of metabolic pathways in shaping the behaviour of genes. Before one can tackle the meat of this complex article, there is essential background information you should know.

The ‘Central Dogma’ of molecular biology describes how genes shape every living organism. It goes as follows: the information stored in the form of DNA gets transcribed into RNA, a shorter-lived molecule that carries this information to the ribosome. This is where the information is used to produce proteins, the molecules that do most of the actual work within a cell. DNA, however, is not just a static store of information. Different genes are converted to RNA and then protein at different times and at different rates depending on the needs of the cell and in response to external signals. This ‘differential expression’ of genes is why a white blood cell and a brain cell can have the exact same DNA and yet have completely different forms and functions.

The study centres on differential gene expression in the context of nutrients and metabolism. Metabolism is a broad term encapsulating all of the chemical transformations by which cells break down matter into essential nutrients and build them back up into all the things a cell needs to survive. Scientists have known for a long time that genes play a central role in metabolism. For instance, an individual lacking or producing too little of the enzyme, lactase, cannot break down the sugar, lactose, resulting in lactose intolerance. Thus, genetic factors can dictate if and how nutrients are broken down within the cell.

This latest paper shows that the interaction between genes, nutrients, and metabolic pathways is far more dynamic than previously believed. Much of this study, conducted in yeast cells, explores a commonly exploited trait in cell biology called auxotrophy. Auxotrophs are organisms mutated so that they can no longer synthesize a biological compound that they need to survive. Researchers worked on yeast that cannot synthesize uracil, a molecule necessary for RNA. As a result, these yeast cells will die unless grown in conditions wherein uracil is provided for them. Biologists typically assume that an auxotroph, when provided with the missing nutrient, functions and behaves the same as a normal, non-auxotroph yeast. This turns out to be very wrong.
When investigating only four commonly used laboratory auxotroph mutations, they found that a whopping three quarters of the genome behaved differently than in the regular yeast. The paper therefore had two important findings. Firstly, the nutrients available to a cell can exert tremendous influence on the function of the genes within the cell, not just the other way around. Secondly, auxotrophic mutations may not be as consequence-free of a technique as traditionally assumed; the outcomes of numerous studies may have been shaped by overlooked metabolic influences on cellular behaviour. This study therefore serves as both a guide for structuring more robust experiments and as a caveat for scientists about the risk of assumptions in the dynamic world of the cell.