When Scientific “Failures” Lead to Breakthroughs: The Hidden Power of Unexpected Results

Science is often depicted as a meticulous, step-by-step process, where experiments neatly confirm or refute hypotheses. In reality, however, discovery is far more complicated - full of unexpected twists, surprises, and so-called “failures” that ultimately reshape our understanding of the world. Some of the most groundbreaking discoveries haven’t come from flawless experiments but from those that seem to have gone wrong - especially when control experiments did not behave as expected.

Think of a control in an experiment as the “unseasoned” version of a dish you are trying to perfect. If you are testing a new spice, you need a version without that spice to see its true effect. In science, controls serve as a baseline, a predictable standard against which new results are measured. They are supposed to be reliable and uneventful - the solid foundation of rigorous research. But what happens when a control, something assumed to behave predictably, suddenly doesn’t?

As André Schneider explores in his EMBO Reports essay, “The Controls That Got Out of Control”, these “oops” moments - when controls don’t work as expected - have sometimes led to revolutionary discoveries. He shares five compelling examples where failed controls weren’t signs of failure but rather windows into entirely new areas of scientific understanding.

Take the discovery of catalytic RNA. Scientists studying RNA processing in cells designed a control experiment to confirm that the process couldn’t occur without certain cellular components. But the unexpected happened - the process still took place. This “failed” control led to the groundbreaking discovery that RNA, once thought to serve only as a genetic messenger, could also act as a catalyst. Initially met with skepticism, this discovery later earned the 1989 Nobel Prize in Chemistry for Sidney Altman and Thomas Cech, who independently demonstrated that RNA could catalyze chemical reactions, and it gave rise to the 'RNA world' hypothesis, the major theory about the origins of life.

Schneider also highlights the discovery of RNA interference (RNAi), a powerful gene-silencing mechanism. In what initially appeared to be a flawed control experiment, both the “antisense” RNA strand and the “sense” RNA strand (intended as a negative control) unexpectedly silenced a gene. This puzzling result was later explained by the presence of small amounts of double-stranded RNA - contaminants from in vitro transcription - which turned out to be the true trigger for gene silencing. This finding revolutionized the field of gene regulation and earned the 2006 Nobel Prize in Physiology or Medicine for Andrew Fire and Craig Mello, who discovered RNA interference (RNAi) as a fundamental mechanism for gene silencing.

These examples underscore the reality in research: scientific progress is rarely a straight path. While most unexpected results in controls stem from experimental flaws, occasionally, a persistently “failing” control signals something profound. Such moments can challenge established knowledge and pave the way for transformative discoveries.

Schneider’s message is clear: while rigor and careful experimental design are essential to good science, so too is an openness to the unexpected. Sometimes, the greatest breakthroughs come from embracing the surprises - the “oops” moments that force us to see the world in a new way.

Source

• Link to the original article: https://www.embopress.org/doi/full/10.1038/s44319-025-00369-w
• More about the author: schneider.dcbp.unibe.ch