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Take a blood sample from someone in the dead of winter. Take another in midsummer. Same person, same laboratory. And yet, at the level of gene activity, the molecular picture can look surprisingly different. This is not an anomaly. This, the new nature communications study argues, is simply how human biology works and it has significant implications for the way biomarkers have traditionally been studied.
Researchers from Kiel University's Excellence Cluster PMI, KU Leuven, and the German Center for Neurodegenerative Diseases (DZNE) in Bonn tracked 333 volunteers in Flanders over six months, drawing blood three times and measuring the activity of roughly 14,000 genes on each occasion. What they found suggests that an important source of biological variation has been underappreciated in many clinical studies: in 85 percent of all genes, the variation within a single person over time is larger than the variation between different people. In other words, for most genes the largest differences are observed between two time points in the same individual rather than between different individuals.
The findings held up in two independent datasets – a British twin study that helped untangle genetic from environmental effects, and a cross-sectional study of 3,480 participants from the DZNE in Bonn.
Time as a Biological Factor
"When we compare blood samples, we usually think in categories: sick versus healthy, this person versus that one," says Prof. Philip Rosenstiel of the Institute for Clinical Molecular Biology (IKMB) at CAU and UKSH, Kiel Campus, one of the study's senior authors. "What we see here is that the greatest biological distance often lies not between two people, but between the same person at different points in time."
That temporal noise has multiple drivers. Season matters: the study identified more than 4,000 genes that shift their activity systematically between winter and summer. In the colder months, immune signaling dominates; come summer, genes tied to the biological clock, governing sleep, metabolism, hormone balance, move to the fore. Time of day matters too, as do minor infections that may not even register as illness. And then there is something subtler: alternative splicing, a process by which the same gene can produce functionally different proteins depending on when you look. This layer of variation has so far been largely overlooked in biomedical research.
"The scale of the seasonal shifts genuinely surprised us," says Franziska Kimmig, one of the study's first authors. "More than 4,000 genes change their activity pattern between winter and summer. A January blood draw and a July blood draw capture different biological states of the same individual."
But some things hold
Yet not all genes behave this way. Roughly 15 percent of genes – concentrated in the immune system, particularly those linked to T and B cells – turn out to be strikingly stable within individuals over time. These are the genes that vary most between people, not within them. They function like a molecular fingerprint: persistent, individual, resistant to seasonal noise.
"Every person appears to carry a kind of immunological signature – stable over months, unmistakably their own," says Prof. Stefan Schreiber, PMI spokesperson and director of internal medicine at UKSH Kiel. "That is precisely what precision medicine needs to build on: not the average patient, but the individual immune profile."
Sex matters
One of the study's more striking findings concerns sex differences – not just in which genes are active, but in how stable that activity is over time. Women show consistently higher temporal variability in gene expression than men. Menopause reduces it somewhat, but not by as much as you might expect: for the majority of genes, elevated variability persists even after the menstrual cycle is no longer a factor.
"We had expected the menstrual cycle to explain the difference," says Dr. Neha Mishra, the study's other first author. "What surprised us was that much of this elevated variability persists after menopause. That tells us we don't actually understand the causes yet."
Men, meanwhile, are more stable within themselves over time – but show greater differences from one another. These findings have implications for biomarker development. Clinical research has historically over-relied on male participants, then applied those findings to women without adjustment. This study now offers systematic evidence that gene expression profiles in men and women behave fundamentally differently across time. A biomarker that performs reliably in men may need to be interpreted differently in women because temporal variability is higher.
Time to rethink
The implications are substantial. A substantial share of what clinical studies have interpreted as disease-associated variation in gene activity may, in fact, be ordinary physiological fluctuation. Biomarker research into cardiovascular disease, neurodegeneration, and chronic inflammatory conditions like IBD is likely to be particularly affected.
"This doesn't mean previous research is wrong," says Prof. Jeroen Raes of KU Leuven and VIB, study lead of the Flemish gut flora project, the cohort that donated samples for this study. "But it does mean we need to take the temporal dimension far more seriously – and treat sex, season, and time of day as biological variables, not footnotes."
The practical implications are straightforward: repeated measurements instead of single snapshots; study designs that account for when blood is drawn; a willingness to revisit genes previously flagged as disease markers. None of this requires new technology. It requires a different habit of mind – one that treats time not as a nuisance variable to be controlled away, but as a biological dimension in its own right.
Photos and graphics are available for download:
The two first authors Dr. Neha Mishra and Franziska Kimmig © Sascha Klahn and private
https://www.niadu-live.uv.uni-kiel.de/fileadmin/user_upload/cluster/pmi/pressebi...
Prof. Philip Rosenstiel © Tebke Böschen, PMI
https://www.niadu-live.uv.uni-kiel.de/fileadmin/user_upload/cluster/pmi/pressebi...
Prof. Stefan Schreiber © UKSH
https://www.niadu-live.uv.uni-kiel.de/fileadmin/user_upload/cluster/pmi/pressebi...
Grafical abstract © Susanne Landis
https://www.niadu-live.uv.uni-kiel.de/fileadmin/user_upload/cluster/pmi/pressebi...
The Cluster of Excellence “Precision Medicine in Chronic Inflammation” (PMI) is entering its second funding phase (2026–2032) in 2026, receiving its fourth consecutive grant for inflammation research. The Joint Science Conference (GWK) of the federal and state governments, together with the German Research Foundation (DFG), has approved the funding as part of the Excellence Strategy.
The cluster builds on its successful predecessor, “Inflammation at Interfaces” (2007–2018), and the first PMI funding period (2019–2025). Around 400 scientists from eight supporting institutions are involved in the interdisciplinary network: Christian Albrecht University of Kiel, the University of Lübeck, the University Medical Center Schleswig-Holstein, the Research Center Borstel – Leibniz Lung Center, the Muthesius Academy of Fine Arts and Design, Kiel Institute for the World Economy, the Leibniz Institute for Science and Mathematics Education, and the Max Planck Institute for Evolutionary Biology.
Exzellenzcluster Präzisionsmedizin für chronische Entzündungserkrankungen
Wissenschaftliche Geschäftsstelle
Postanschrift: Christian-Albrechts-Platz 4, D-24118 Kiel
Telefon: (0431) 880-4850, Telefax: (0431) 880-4894
Press contact
Dr. Susanne Landis
Telefon: (0431) 880 4682
E-Mail: slandis@uv.uni-kiel.de
LinkedIn: https://www.linkedin.com/showcase/pmi-precision-medicine
https://precisionmedicine.de
Prof. Philip Rosenstiel
Christian-Albrechts-Universität zu Kiel
Institut für Klinische Molekularbiologie
Systems Immunology
p.rosenstiel@mucosa.de
https://www.nature.com/articles/s41467-026-73218-6
https://www.precisionmedicine.de/en/new-study-blood-genes-fluctuate-more-than-ex...
Graphical abstract
Copyright: Susanne Landis, PMI
First shared authors: Dr. Mishra and Kimming
Copyright: Sasha Klahn / Kimming: private
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