“Seek simplicity and distrust it”

Abstract

Science often looks for simplicity in explaining reality. In biology, however, a simple explanation is often not a correct one.

I was sitting my final biochemistry examination at the National University of Ireland in Galway when I first read this pithy quote. I was first confused to see it on a science paper: it was a side‐step from facts and thought‐provoking. That was more than 50 years ago and I have never forgotten the full message: “The aim of science is to seek the simplest explanations of complex facts. We are apt to fall into the error of thinking that the facts are simple because simplicity is the goal of our quest. The guiding motto in the life of every natural philosopher should be, Seek simplicity and distrust it”. It was written in 1919 by Alfred North Whitehead, a British mathematician and philosopher, when the new post‐war reality forced serious reflection on all matters of life (Whitehead, 1919). In a similar vein, the French Philosopher Jean Jaurès, reflecting a path to peace at that time said, “We must seek the ideal and understand reality”. The shared ideal of many life scientists is to understand the human condition. The reality is that there are practical and ethical barriers to the direct route to address human physiology and we have to choose more simple and realistic paths to achieve this goal. As Polonius in Shakespeare’s Hamlet said, “By indirections find directions out”.

However, it seems that there is a collective amnesia among scientists such that we forget to distrust the simplicity that we pursue on our path to insight. The central dogma of molecular biology—that information flows unidirectionally from DNA to RNA to protein—was overturned, at least in part, with the discovery that this linear cascade could be reversed by reverse transcription. The great quote from Jacques Monod “What is true for E. coli is true for the elephant”, held valid only until the discovery of introns in eukaryotes. As I was close to the earliest data that pointed to the existence of split genes, I am well aware of the incredulity of biologists when they realised that genetic material did not have the same simple design irrespective of the organism.

The death of “Junk DNA”—a term, coined in 1972 by Susumu Ohno for the non‐coding parts of the genome—has been more gradual. The perception that exons are the only useful part of the genome has been proven wrong with the discoveries of noncoding RNA, the controlling roles of intra‐genomic areas, the essential interactions between distant genomic regions and peptides encoded by short open frame regions. Nonetheless, there is still a hierarchy in the way how genetic material is seen: genes that encode proteins are being treated as implicitly more important than everything that controls expression of these gene. Genome sequencing to diagnose a rare disease often involves only Whole Exome Sequencing. Genome Wide Association Studies (GWAS) are a powerful tool to identify genomic regions that are linked to a disease or trait. When the results come in, the first step is to look for genes nearby and which proteins these encode to further identify possible metabolic pathways, thereby ignoring many other, equally important, genetic elements.

But then, GWAS is built on another simplification: the often‐stated claim that “cancer is a genetic disease” caused by overactive “oncogenes” or inactive “tumour suppressor genes”, such as the publicly acknowledged “bad gene” brca1. Yet, many people have such genetic misfortunes and do not get the disease. Moreover, we all accumulate nominally deleterious mutations during our lives without any impact in most cases. Being dealt a bad genetic hand is not sufficient for a bad outcome. We now know that epigenetics, a term which Conrad Waddington coined as early as 1942, plays a crucial role for personal health risks, yet we still gloss over the implications. Compared to the more simplistic “binary” logic of genetics, epigenetics is a complex machinery with multiple switches and combinations and a high degree of redundancy. It is not surprising then that many studies search for the simplicity of mutations in the genome rather than getting bogged down in the complexity of epigenetic regulation.

This implies another fact that research has ignored for long: that when a cell is altered by some combination of events, it does not inexorably lead to disaster. The vast majority of deleterious mutations and epigenetic changes either trigger apoptosis or attract the immune system’s attention to kill any deviant cell. Indeed, the Covid pandemic has shown that there is still a lot to discover about our friendly immune security guard. We need to learn more about the nature of individual variation of immune responses, the effect and molecular basis of “immune exhaustion”, the interplay between the different arms of the immune system and much more. Moreover, our knowledge of the immune system comes predominantly from studies using mice. Jacques Monod’s quote could be paraphrased as “mice are like humans only smaller” and it carries the same flaw of simplification as there are real differences between the immune systems of these two species.

That is not to say that we should abandon model systems. As we have shifted over time from Escherichia coli to yeast to Drosophila/Caenorhabditis elegans/zebra fish to mice we have learned a lot about biology. But we have to remain focussed on the final goal which is, for most in the life sciences, Homo sapiens. Sydney Brenner famously suggested that we no longer need model systems as human genetic material can be analysed to the single‐nucleotide level. But we are not capable to extrapolate from genomic data to physiology. In fact, we happily ignore the fact that the single DNA sequence or transcription read‐out is obtained from multiple cells with minor individual local variations or at different stages of the cell cycle. We normally look at the average of cells in a tissue, or in a petri dish because it is practical, but it carries the risk that we miss some key data submerged in the innocuous mass.

At least, we have slowly accepted that we live in synergy with another complex “organism”, the microbiome. Like epigenetic changes, it is a soup of interconnected components that dynamically change and shift and adapt with profound effects on our physiology including the efficacy of immune therapies. But we have not reached the stage where oncologists first try to retune the patients' microbiome before starting a cancer therapy.

We skip the hard part even though we know it is there. We consider data from mouse experiments as reliable, irrespective of the impact of the environment, the diet, or the microbiome. We happily accept the structure of a protein, albeit we know that the publication describes a domain derived from an artificially frozen crystal and not the full three‐dimensional reality. We set up experiments by injecting tumour cells as if cancer were an acute disease rather than a chronic one that outfoxes our suppression systems. We use CRISPR as if it had laser‐like specificity even though studies show otherwise. More generally, we avoid the dark areas and search for insights under the light of a lamppost that we have defined as the core of a problem. The daylight of reality reveals much more though. We ignore Whitehead’s dictum at our own peril: even if we seek simplicity in nature, we must be equally diligent in distrusting it.

Disclosure and competing interests statement

The author declares that he has no conflict of interest.

EMBO reports (2022) 23: e55402.