From Association to Causation: Why Physiology Matters
Dear Colleagues,
Where is Cellular Electrophysiology heading?
At a time when genomics, artificial intelligence and large-scale data science dominate biomedical research, physiology and electrophysiology can sometimes feel like relics of the past, especially when we look at which disciplines attract the largest funding.
I believe the opposite is true, and we should enter funding discussions with confidence. As our understanding of biology becomes increasingly complex, the need to understand how biological systems actually function and to explain causation through the groundwork of experimental research has never been greater.
The genomic revolution has transformed medicine. Genetics has given us an essential toolbox for understanding how proteins are produced, and how certain diseases are inherited. But we should not fall into the trap of believing that genomic association alone can explain pathophysiological functions. If we compare some of the promises made during the genomic revolution with where we are today, the gap is considerable.
Francis Collins famously predicted that by 2010, if you developed cancer, you would take your genome to the doctor and receive a treatment tailored to cure it*. That did not happen.
Even though “causal” appears in the titles of many genomic studies, association alone does not demonstrate causation. Finding that a genetic variant is associated with a disease does not, by itself, establish that the variant causes the disease. Even large numbers of associations cannot simply be added together to explain a pathophysiological phenotypes. Physiological systems are nonlinear, interconnected and remarkably robust. The effect of one component depends on the state of many others, as well as on the cellular and environmental conditions in which the system operates.
To understand causation, therefore, we need to observe function.
A causal physiological mechanism is a process. It changes over time, responds to perturbation and depends on defined boundary conditions. If we want to understand why a cell behaves differently, we need to measure what the cell actually does and not only what its genome contains.
This is where physiology becomes central, and where cellular electrophysiology has a particularly important role.
Consider membrane voltage. It is not simply an electrical measurement recorded by electrophysiologists. It is a fundamental determinant of cellular function, linked to ion distributions, membrane transport, calcium handling, mitochondrial activity and energy metabolism. Alter the electrical state of a cell, and multiple downstream processes can change. These relationships cannot be reconstructed from genetic association alone.
Cellular electrophysiology gives us access to these dynamics. We can perturb a system, measure its response, define its operating conditions and test whether a proposed mechanism actually produces the predicted consequence. This is the difference between identifying a correlation and demonstrating a functional pathway.
The same principle applies to artificial intelligence. AI can process enormous amounts of information and identify patterns beyond human capacity. But it cannot substitute for new high-quality experimental observations. Our experiments generate the primary data, everything else comes afterwards. The quality of future discovery will depend not only on better algorithms, but on better understanding and handling of the systems that generate the data.
Perhaps it is time for cellular electrophysiologists to remind ourselves what our discipline uniquely contributes: the ability to connect molecular information to dynamic physiological function. With exactly that attitude and confidence, we should enter funding conversations, interdisciplinary conferences and communication with the wider public.
For young scientists willing to understand the fundamentals, challenge assumptions and do the difficult experiments, the opportunities in cellular electrophysiology are thereby enormous. You are needed. Today and tomorrow.
It is a great time to be a cellular electrophysiologist.
Cristina E. Molina & Daniel J. Kroll
P.S. This editorial draws inspiration from the works of (and conversations with) the brilliant Denis Noble. I inherited my laboratory from him at the Department of Physiology, Anatomy & Genetics, led by David Paterson, at the University of Oxford[1].
“We can predict that by the year 2010, predictive genetic tests will exist for many common conditions where interventions can alleviate inherited risk; successful gene therapy will be available for a small set of conditions; and primary care providers will be practicing genetic medicine on a daily basis. By the year 2020, gene-based designer drugs are likely to be available for conditions like diabetes, Alzheimer's disease, hypertension and many other disorders; cancer treatment will precisely target the molecular fingerprints of particular tumors; genetic information will be used routinely to give patients appropriate drug therapy; and the diagnosis and treatment of mental illness will be transformed.“ (Testimony of Francis S. Collins, M.D., Ph.D., Director, National Human Genome Research Institute, National Institutes of Health Before the Appropriations Subcommittee on Labor, Health and Human Services and Education
United States Senate, July 11, 2001).
In addition - ESC Congress 2026 highlight sessions
Following hte ESC Congress 2026 in Munich, the ESC WG on CCE would like to share the following highlight sessions from the Congress with you:
1. Electrophysiology, arrhythmias, and cardiac modelling
2. Multicellular crosstalk in the heart: relevance for arrhythmias and heart failure
3. New human tissue approaches transforming cardiovascular research and care