A general hypothesis of multistable systems in pathophysiology.
Open accessAbstract
Despite intensive investigations numerous diseases remain etiologically puzzling and recalcitrant to treatments. A hypothesis is proposed here assuming that these difficulties are due to an unsuitable approach to the mechanisms of life, which is subjugated by an apparent complexity and fails to grasp the uniformity that lays behind. The stability of metabolism, despite the enormous complex of chemical reactions, suggests that reciprocal control is a prerequisite of life. Negative feedback loops have been known for a long time to maintain homeostasis, while more recently, different life processes involved in transitions or changes have been modeled by positive loops giving rise to bistable switches, also including various diseases. The present hypothesis makes a generalization, by assuming that any functional element of a biological system is involved in a positive or a negative feedback loop. Consequently, the hypothesis holds that the starting mechanism of any disease that affects a healthy human can be conceptually reduced to a bistable or multistationary loop system, thus providing a unifying model leading to the discovery of critical therapeutic targets.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Similarly to the thalamocortical loop, the endocrine loop can behave as a switch driving pathogenesis.
“Hence, similarly to the thalamocortical loop, this endocrine loop can behave as a switch driving pathogenesis [27].”
From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [27]
The Introduction proposes that positive functional loops can act as multistable switches, moving a system from a physiological to a pathological state. That supports the proposed mechanism, but our copy does not identify this endocrine loop or compare it with a thalamocortical loop. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Early-warning signals for critical transitions
Scheffer, M., Bascompte, J., Brock, W. A., Brovkin, V., Carpenter, S. R., Dakos, V., Held, H., van Nes, E. H., Rietkerk, M., & Sugihara, G. (2009) · Nature · doi:10.1038/nature08227 · Cited by 4,854 · see citing works
Evolution of the Cancer Stem Cell Model
Kreso, A., & Dick, J. E. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.02.006 · Cited by 2,212 · see citing works
An estimation of the number of cells in the human body
Bianconi, E., Piovesan, A., Facchin, F., Beraudi, A., Casadei, R., Frabetti, F., Vitale, L., Pelleri, M. C., Tassani, S., Piva, F., et al. (2013) · Annals of Human Biology · doi:10.3109/03014460.2013.807878 · Cited by 1,012 · see citing works
Angeli, D., Ferrell, J. E., & Sontag, E. D. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308265100 · Cited by 1,007 · see citing works
Multistability: a major means of differentiation and evolution in biological systems
Laurent, M., & Kellershohn, N. (1999) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(99)01473-5 · Cited by 285 · see citing works
Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases
Beutler, B. (2008) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00733.x · Cited by 261 · see citing works
A Canonical Model of Multistability and Scale-Invariance in Biological Systems
Freyer, F., Roberts, J. A., Ritter, P., & Breakspear, M. J. (2012) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002634 · Cited by 186 · see citing works
A hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK pathways
Kim, D., Rath, O., Kolch, W., & Cho, K.-H. (2007) · Oncogene · doi:10.1038/sj.onc.1210230 · Cited by 166 · see citing works
Bistable switches control memory and plasticity in cellular differentiation
Wang, L., Walker, B. L., Iannaccone, S., Bhatt, D., Kennedy, P. J., & Tse, W. T. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806137106 · Cited by 120 · see citing works
Cyclin A-cdk1-Dependent Phosphorylation of Bora Is the Triggering Factor Promoting Mitotic Entry
Vigneron, S., Sundermann, L., Labbé, J., Pintard, L., Radulescu, O., Castro, A., & Lorca, T. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.05.005 · Cited by 118 · see citing works
Rac1 and RhoA: Networks, loops and bistability
Nguyen, L. K., Kholodenko, B. Ν., & von Kriegsheim, A. (2016) · Small GTPases · doi:10.1080/21541248.2016.1224399 · Cited by 107 · see citing works
Feedback dynamics and cell function: why systems biology is called systems biology
Wolkenhauer, O., & Mesarović, M. (2005) · Molecular BioSystems · doi:10.1039/b502088n · Cited by 106 · see citing works
Liu, X., Liu, R., Zhao, X.-M., & Chen, L. (2013) · BMC Medical Genomics · doi:10.1186/1755-8794-6-s2-s8 · Cited by 101 · see citing works
Huang, B., Lu, M., Jolly, M. K., Tsarfaty, I., Onuchic, J., & Ben-Jacob, E. (2014) · Scientific Reports · doi:10.1038/srep06449 · Cited by 91 · see citing works
Biological feedback control-Respect the loops
El-Samad, H. (2021) · Cell Systems · doi:10.1016/j.cels.2021.05.004 · Cited by 90 · see citing works
Two Bistable Switches Govern M Phase Entry
Mochida, S., Rata, S., Hino, H., Nagai, T., & Novák, B. (2016) · Current Biology · doi:10.1016/j.cub.2016.10.022 · Cited by 86 · see citing works
Feed-forward inhibition as a buffer of the neuronal input-output relation
Ferrante, M., Migliore, M., & Ascoli, G. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904784106 · Cited by 80 · see citing works
Large-Scale Analysis of Network Bistability for Human Cancers
Shiraishi, T., Matsuyama, S., & Kitano, H. (2010) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000851 · Cited by 75 · see citing works
Caluwé, J. D., & Dupont, G. (2013) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2013.04.015 · Cited by 65 · see citing works
Domínguez‐Hüttinger, E., Christodoulides, P., Miyauchi, K., Irvine, A. D., Okada, M., Kubo, M., & Tanaka, R. J. (2016) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2016.10.026 · Cited by 57 · see citing works
Recovery of free ADP, Pi, and free energy of ATP hydrolysis in human skeletal muscle
Wackerhage, H., Hoffmann, U., Eßfeld, D., Leyk, D., Mueller, K., & Zange, J. (1998) · Journal of Applied Physiology · doi:10.1152/jappl.1998.85.6.2140 · Cited by 55 · see citing works
A structural classification of candidate oscillatory and multistationary biochemical systems
Blanchini, F., Franco, E., & Giordano, G. (2014) · Bulletin of Mathematical Biology · doi:10.1007/s11538-014-0023-y · Cited by 54 · see citing works
A systems- and signal-oriented approach to intracellular dynamics
Olaf Wolkenhauer, A., Sreenath, S. N., Wellstead, P. E., Ullah, M., & Cho, K.-H. (2005) · Biochemical Society Transactions · doi:10.1042/bst0330507 · Cited by 45 · see citing works
Norwitz, N. G., Soto-Mota, A., Norwitz, S. G., & Clarke, K. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00184 · Cited by 43 · see citing works
Prion Diseases: Dynamics of the Infection and Properties of the Bistable Transition
Kellershohn, N., & Laurent, M. (2001) · Biophysical Journal · doi:10.1016/s0006-3495(01)75897-3 · Cited by 38 · see citing works
Ravera, S., Torazza, C., Bonifacino, T., Provenzano, F., Rebosio, C., Milanese, M., Usai, C., Panfoli, I., & Bonanno, G. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14819 · Cited by 33 · see citing works
Bistable switches as integrators and actuators during cell cycle progression
Stallaert, W., Kedziora, K. M., Chao, H. X., & Purvis, J. E. (2019) · FEBS Letters · doi:10.1002/1873-3468.13628 · Cited by 32 · see citing works
Integrative clustering methods for multi‐omics data
Zhang, X., Zhou, Z., Xu, H., & Liu, C. (2021) · Wiley Interdisciplinary Reviews Computational Statistics · doi:10.1002/wics.1553 · Cited by 28 · see citing works
Aggregates of Monotonic Step Response Systems: A Structural Classification
Blanchini, F., Samaniego, C. C., Franco, E., & Giordano, G. (2018) · IEEE Transactions on Control of Network Systems · doi:10.1109/tcns.2017.2746343 · Cited by 26 · see citing works
Interlinked bistable mechanisms generate robust mitotic transitions
Hutter, L. H., Rata, S., Hochegger, H., & Novák, B. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1371885 · Cited by 25 · see citing works
Identifying critical transitions in complex diseases
Deb, S., Bhandary, S., Sinha, S. K., Jolly, M. K., & Dutta, P. S. (2022) · Journal of Biosciences · doi:10.1007/s12038-022-00258-7 · Cited by 25 · see citing works
Axon growth regulation by a bistable molecular switch
Padmanabhan, P., & Goodhill, G. J. (2018) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2017.2618 · Cited by 20 · see citing works
A portable epigenetic switch for bistable gene expression in bacteria
Olivenza, D. R., Nicoloff, H., Sánchez-Romero, M. A., Cota, I., Andersson, D. I., & Casadesús, J. (2019) · Scientific Reports · doi:10.1038/s41598-019-47650-2 · Cited by 20 · see citing works
Mal de Debarquement Syndrome: A Matter of Loops?
Mucci, V., Indovina, I., Browne, C. J., Blanchini, F., Giordano, G., Marinelli, L., & Burlando, B. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.576860 · Cited by 17 · see citing works
Self-citationLoopomics: a new functional approach to life
Burlando, B. (2017) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00173.2017 · Cited by 13 · see citing works
Self-citationBurlando, B., Milanese, M., Giordano, G., Bonifacino, T., Ravera, S., Blanchini, F., & Bonanno, G. (2020) · PLoS ONE · doi:10.1371/journal.pone.0244234 · Cited by 13 · see citing works
Self-citationLoop analysis of blood pressure/volume homeostasis
Burlando, B., Blanchini, F., & Giordano, G. (2019) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1007346 · Cited by 12 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Fibromyalgia pathogenesis explained by a neuroendocrine multistable model
Demori, I., Losacco, S., Giordano, G., Mucci, V., Blanchini, F., & Burlando, B. (2024) · PLOS ONE · doi:10.1371/journal.pone.0303573 · Cited by 14 · see citing works
Self-citationDemori, I., Siriya, S., & Burlando, B. (2025) · Applied Sciences · doi:10.3390/app151910483 · Cited by 2 · see citing works
Self-citationBurlando, B., & Demori, I. (2026) · International Journal of Translational Medicine · doi:10.3390/ijtm6020019 · Cited by 2 · see citing works
Self-citationDemori, I., & Burlando, B. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27146384 · Cited by 1 · see citing works
Self-citationLoopomics: A possible breakthrough in the understanding and control of life
Burlando, B. (2025) · PNEI REVIEW · doi:10.3280/pnei2025oa19417
Self-citation
- Authors
- Burlando, B.
- Affiliations
- University of Genoa (IT)
- Corresponding author
- Burlando, Bruno
- ORCID
- Burlando, Bruno
- Venue
- F1000Research
- Publisher
- F1000 Research Ltd
- Published
- 2022-09-30
- Volume
- 11
- Pages
- 906
- ISSN
- 2046-1402 (ISSN-L)
- OpenAlex
- W4298138441
- Cited by
- 5
- References
- 37
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1
- FWCI
- 0.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- F1000Research (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Università degli Studi di Genova (100006-2020-SA-FRA_001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Physical Sciences › Physics and Astronomy › Statistical and Nonlinear Physics › Complex Systems and Dynamics
- Physical Sciences › Environmental Science › Global and Planetary Change › Ecosystem dynamics and resilience
- Keywords
- multistability, bistability, feedback loops, positive feedback, negative feedback, homeostasis, etiology, metabolic stability, therapeutic target, pathophysiology
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
