Biological feedback control-Respect the loops
Open accessAbstract
We, and all organisms, are an evolutionary masterpiece of multiscale feedback control. Feedback loops enable our cells to grow and then stop at the right size, to divide and self-repair, and to respond with agility to their changing environment. Individual cells engage in long range extracellular feedback with other cells, ensuring continued homeostasis of our tissues and organs. Many long ranging feedback loops regulate vital physiological variables. Here, I will argue that focused efforts to understand the properties and constraints of biological feedback control networks should be central to the quest of understanding life. I will also propose many pressing challenges in this field and review conceptual frameworks that might be consequential for addressing them.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Feedback and feedforward are key network motifs that underpin dynamic behaviors including signal amplification, multistability, adaptation, homeostasis, oscillation, fold-change detection, signaling delay and acceleration, threshold and nonmonotonic effect.
“Feedback and feedforward are key network motifs that underpin a variety of dynamic behaviors, including signal amplification, multistability, adaptation, homeostasis, oscillation, fold-change detection, signaling delay and acceleration, threshold and nonmonotonic effect etc. (48, 49).”
From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [49]
A better understanding of complex pathways requires formulation of mathematical models to simulate the network as nonlinear dynamical systems.
“A better understanding of complex pathways as such requires formulation of mathematical models to simulate the network as nonlinear dynamical systems (49).”
From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [49]
Cites
Hodgkin, A. L., & Huxley, A. F. (1952) · The Journal of Physiology · doi:10.1113/jphysiol.1952.sp004764 · Cited by 23,191 · see citing works
Genetic regulatory mechanisms in the synthesis of proteins
Jacob, F., & Monod, J. (1961) · Journal of Molecular Biology · doi:10.1016/s0022-2836(61)80072-7 · Cited by 6,605 · see citing works
Thompson, D. W. (2019) · Princeton University Press eBooks · doi:10.1515/9780691183978-018 · Cited by 4,179 · see citing works
Hematopoiesis: An Evolving Paradigm for Stem Cell Biology
Orkin, S. H., & Zon, L. I. (2008) · Cell · doi:10.1016/j.cell.2008.01.025 · Cited by 2,570 · see citing works
Waddington, C. H. (2014) · doi:10.4324/9781315765471 · Cited by 2,153 · see citing works
Feedback systems: an introduction for scientists and engineers
Åström, K. J., & Murray, R. M. (2008) · Choice Reviews Online · doi:10.5860/choice.46-2107 · Cited by 1,968 · see citing works
Organization for physiological homeostasis
Cannon, W. B. (1929) · Physiological Reviews · doi:10.1152/physrev.1929.9.3.399 · Cited by 1,844 · see citing works
Lecture notes in control and information sciences
Aplevich, J. D. (1991) · Springer eBooks · Cited by 1,832 · see citing works
Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell
Tyson, J. J., Chen, K. C., & Novak, B. (2003) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(03)00017-6 · Cited by 1,583 · see citing works
The adult Drosophila posterior midgut is maintained by pluripotent stem cells
Ohlstein, B., & Spradling, A. C. (2005) · Nature · doi:10.1038/nature04333 · Cited by 1,089 · see citing works
Multistability in the lactose utilization network of Escherichia coli
Ozbudak, E. M., Thattai, M., Lim, H. N., Shraiman, B. I., & van Oudenaarden, A. (2004) · Nature · doi:10.1038/nature02298 · Cited by 1,030 · see citing works
Vertebrate neural cell-fate determination: Lessons from the retina
Livesey, F. J., & Cepko, C. L. (2001) · Nature reviews. Neuroscience · doi:10.1038/35053522 · Cited by 948 · see citing works
Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2
Pomerening, J. R., Sontag, E., & Ferrell, J. E. J. (2003) · Nature Cell Biology · doi:10.1038/ncb954 · Cited by 784 · see citing works
A positive-feedback-based bistable ‘memory module’ that governs a cell fate decision.
Xiong, W., & Ferrell, J. E. (2003) · Nature · doi:10.1038/nature02089 · Cited by 741 · see citing works
Dubnau, D. A., & Losick, R. M. (2006) · Molecular Microbiology · doi:10.1111/j.1365-2958.2006.05249.x · Cited by 729 · see citing works
Negative Autoregulation Speeds the Response Times of Transcription Networks
Rosenfeld, N., Elowitz, M. B., & Alon, U. S. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)00994-4 · Cited by 714 · see citing works
ISOLATION OF THE LAC REPRESSOR
Gilbert, W., & Müller‐Hill, B. (1966) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.56.6.1891 · Cited by 657 · see citing works
Complexity in Biological Signaling Systems
Weng, G., Bhalla, U. S., & Iyengar, R. (1999) · Science · doi:10.1126/science.284.5411.92 · Cited by 609 · see citing works
Feedback control of intercellular signalling in development
Freeman, M. (2000) · Nature · doi:10.1038/35042500 · Cited by 534 · see citing works
Phenotypic variation in bacteria: the role of feedback regulation
Smits, W. K., Kuipers, O. P., & Veening, J. (2006) · Nature Reviews Microbiology · doi:10.1038/nrmicro1381 · Cited by 497 · see citing works
Frenette, P. S., Pinho, S., Lucas, D., & Scheiermann, C. (2013) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032712-095919 · Cited by 462 · see citing works
The energy–speed–accuracy trade-off in sensory adaptation
Lan, G., Sartori, P., Neumann, S., Sourjik, V., & Tu, Y. (2012) · Nature Physics · doi:10.1038/nphys2276 · Cited by 452 · see citing works
CONTROL OF PYRIMIDINE BIOSYNTHESIS IN ESCHERICHIA COLI BY A FEED-BACK MECHANISM
Yates, R. A., & Pardee, A. B. (1956) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)65188-9 · Cited by 447 · see citing works
Fambrough, D., McClure, K. D., Kazlauskas, A., & Lander, E. S. (1999) · Cell · doi:10.1016/s0092-8674(00)80785-0 · Cited by 439 · see citing works
Evidence for a Negative-Feedback Mechanism in the Biosynthesis of Isoleucine
Umbarger, H. E. (1956) · Science · doi:10.1126/science.123.3202.848 · Cited by 419 · see citing works
Mathematics of cellular control processes II. Positive feedback to one gene
Griffith, J. S. (1968) · Journal of Theoretical Biology · doi:10.1016/0022-5193(68)90190-2 · Cited by 358 · see citing works
Pomerening, J. R., Kim, S. Y., & Ferrell, J. E. (2005) · Cell · doi:10.1016/j.cell.2005.06.016 · Cited by 345 · see citing works
Mathematics of cellular control processes I. Negative feedback to one gene
Griffith, J. S. (1968) · Journal of Theoretical Biology · doi:10.1016/0022-5193(68)90189-6 · Cited by 343 · see citing works
The Application of Control Theory to Physiological Systems.
(1966) · Annals of Internal Medicine · doi:10.7326/0003-4819-65-6-1350_2 · Cited by 335 · see citing works
Biological control systems analysis
Milsum, J. H. (1966) · Medical Entomology and Zoology · Cited by 308 · see citing works
Bistability in the Bacillus subtilis K‐state (competence) system requires a positive feedback loop
Maamar, H., & Dubnau, D. A. (2005) · Molecular Microbiology · doi:10.1111/j.1365-2958.2005.04592.x · Cited by 295 · see citing works
MAPK-mediated bimodal gene expression and adaptive gradient sensing in yeast
Paliwal, S., Iglesias, P. A., Campbell, K., Hilioti, Z., Groisman, A., & Levchenko, A. (2007) · Nature · doi:10.1038/nature05561 · Cited by 291 · see citing works
Cell Lineages and the Logic of Proliferative Control
Lander, A. D., Gokoffski, K. K., Wan, F. Y. M., Nie, Q. H., & Calof, A. L. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000015 · Cited by 289 · see citing works
Specific Binding of the λ Phage Repressor to λ DNA
Ptashne, M. (1967) · Nature · doi:10.1038/214232a0 · Cited by 259 · see citing works
Marciniak-Czochra, A. K., Stiehl, T., Ho, A. D., Jäger, W., & Wagner, W. (2008) · Stem Cells and Development · doi:10.1089/scd.2008.0143 · Cited by 255 · see citing works
A brief history of automatic control
Bennett, S. (1996) · IEEE Control Systems · doi:10.1109/37.506394 · Cited by 244 · see citing works
Bistability in the JNK cascade
Bagowski, C. P., & Ferrell, J. E. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00330-x · Cited by 239 · see citing works
Design of gene circuits: lessons from bacteria
Wall, M. E., Hlavacek, W. S., & Savageau, M. A. (2004) · Nature Reviews Genetics · doi:10.1038/nrg1244 · Cited by 228 · see citing works
Control theory and biological systems
Rosén, R. (1964) · Bulletin of Mathematical Biology · doi:10.1007/bf02484237 · Cited by 218 · see citing works
Glycolytic Oscillations and Limits on Robust Efficiency
Chandra, F. A., Buzi, G., & Doyle, J. C. (2011) · Science · doi:10.1126/science.1200705 · Cited by 217 · see citing works
Comparison of classical and autogenous systems of regulation in inducible operons
Savageau, M. A. (1974) · Nature · doi:10.1038/252546a0 · Cited by 215 · see citing works
Autogenous Regulation of Gene Expression
Goldberger, R. F. (1974) · Science · doi:10.1126/science.183.4127.810 · Cited by 205 · see citing works
Noise Propagation and Signaling Sensitivity in Biological Networks: A Role for Positive Feedback
Hornung, G., & Barkai, N. (2008) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0040008 · Cited by 200 · see citing works
Ribes, V., Balaskas, N., Sasai, N., Cruz, C., Dessaud, É., Cayuso, J., Tozer, S., Yang, L., Novitch, B. G., Martı́, E., et al. (2010) · Genes & Development · doi:10.1101/gad.559910 · Cited by 193 · see citing works
Control Theory and Biological Systems
Grodins, F. S. (1963) · Cited by 188 · see citing works
Phosphatases modulate the bistable sporulation gene expression pattern in Bacillus subtilis
Veening, J., Hamoen, L. W., & Kuipers, O. P. (2005) · Molecular Microbiology · doi:10.1111/j.1365-2958.2005.04659.x · Cited by 185 · see citing works
Control theory and physiological feedback mechanisms
Riggs, D. S. (1970) · Medical Entomology and Zoology · Cited by 168 · see citing works
The Behavior of Intact Biochemical Control Systems
(1972) · Current topics in cellular regulation · doi:10.1016/b978-0-12-152806-5.50010-2 · Cited by 156 · see citing works
The JNK Cascade as a Biochemical Switch in Mammalian Cells
Bagowski, C. P., Besser, J., Frey, C. R., & Ferrell, J. E. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00083-6 · Cited by 139 · see citing works
Dynamic interaction networks in a hierarchically organized tissue
Kirouac, D. C., Ito, C. Y., Csaszar, E., Roch, A., Yu, M., Sykes, E. A., Bader, G. D., & Zandstra, P. W. (2010) · Molecular Systems Biology · doi:10.1038/msb.2010.71 · Cited by 135 · see citing works
Englesberg, E., Squires, C. L., & Meronk, F. (1969) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.62.4.1100 · Cited by 129 · see citing works
Detection and Isolation of the Repressor Protein for the Tryptophan Operon of Escherichia coli
Zubay, G., Morse, D. E., Schrenk, W., & Miller, J. H. (1972) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.69.5.1100 · Cited by 124 · see citing works
Positive Feedback Regulates Switching of Phosphate Transporters in S. cerevisiae
Wykoff, D. D., Rizvi, A. H., Raser, J. M., Margolin, B., & O’Shea, E. K. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.07.022 · Cited by 119 · see citing works
Evidence for a Negative-Feedback Mechanism in the Biosynthesis of Isoleucine
Umbarger, H. E. (1956) · Science · doi:10.1126/science.123.3202.848.a · Cited by 116 · see citing works
Regulatory Dynamics of Synthetic Gene Networks with Positive Feedback
Maeda, Y. T., & Sano, M. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.03.064 · Cited by 110 · see citing works
Oscillatory stress stimulation uncovers an Achilles’ heel of the yeast MAPK signaling network
Mitchell, A., Wei, P., & Lim, W. A. (2015) · Science · doi:10.1126/science.aab0892 · Cited by 107 · see citing works
Gokoffski, K. K., Wu, H., Beites, C. L., Kim, J., Kim, E. J., Matzuk, M. M., Johnson, J. E. B., Lander, A. D., & Calof, A. L. (2011) · Development · doi:10.1242/dev.065870 · Cited by 104 · see citing works
THE l-RHAMNOSE GENETIC SYSTEM IN ESCHERICHIA COLI K-12
Power, J. (1967) · Genetics · doi:10.1093/genetics/55.3.557 · Cited by 97 · see citing works
ENZYME VARIATION IN MICRO‐ORGANISMS
Yudkin, J. S. (1938) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/j.1469-185x.1938.tb00508.x · Cited by 92 · see citing works
Cardiovascular and Respiratory Systems: Modeling, Analysis, and Control
Batzel, J. J., Kappel, F., Schneditz, D., & Tran, H. T. (2007) · Cited by 78 · see citing works
Specificity and Degeneracy in Antigen Recognition: Yin and Yang in the Immune System
Eisen, H. N. (2001) · Annual Review of Immunology · doi:10.1146/annurev.immunol.19.1.1 · Cited by 76 · see citing works
Complementation studies in the maltose-A region of the Escherichia coli K12 genetic map
Hofnung, M. J., Schwartz, M., & Hatfield, D. L. (1971) · Journal of Molecular Biology · doi:10.1016/0022-2836(71)90072-6 · Cited by 71 · see citing works
Biological control systems analysis
D., P. E. K. (1967) · Medical & Biological Engineering & Computing · doi:10.1007/bf02474511 · Cited by 68 · see citing works
An engineering viewpoint on biological robustness
Khammash, M. (2016) · BMC Biology · doi:10.1186/s12915-016-0241-x · Cited by 60 · see citing works
Tuning the Activation Threshold of a Kinase Network by Nested Feedback Loops
Justman, Q. A., Serber, Z., Ferrell, J. E., El‐Samad, H., & Shokat, K. M. (2009) · Science · doi:10.1126/science.1169498 · Cited by 49 · see citing works
Self-citationPrinciples of Biological Regulation: An Introduction to Feedback Systems
Jones, R. W., & Hemami, H. (1974) · IEEE Transactions on Systems Man and Cybernetics · doi:10.1109/tsmc.1974.4309382 · Cited by 41 · see citing works
Avendaño, M. S., Leidy, C., & Pedraza, J. M. (2013) · Nature Communications · doi:10.1038/ncomms3605 · Cited by 39 · see citing works
Cell lineage branching as a strategy for proliferative control
Buzi, G., Lander, A. D., & Khammash, M. (2015) · BMC Biology · doi:10.1186/s12915-015-0122-8 · Cited by 38 · see citing works
Robust and tunable bursting requires slow positive feedback
Franci, A., Drion, G., & Sepulchre, R. J. (2018) · Journal of Neurophysiology · doi:10.1152/jn.00804.2017 · Cited by 36 · see citing works
Savageau, M. A. (1975) · Nature · doi:10.1038/258208a0 · Cited by 35 · see citing works
Isolation of the gal Repressor
Parks, J. S., Gottesman, M. M., Shimada, K., Weisberg, R. A., Perlman, R. L., & Pastan, I. H. (1971) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.68.8.1891 · Cited by 34 · see citing works
Doubt and certainty in science : a biologist's reflections on the brain
Young, J. Z. (1968) · CERN Document Server (European Organization for Nuclear Research) · Cited by 30 · see citing works
Different effects of redundant feedback loops on a bistable switch
Domingo-Sananes, M. R., & Novák, B. (2010) · Chaos An Interdisciplinary Journal of Nonlinear Science · doi:10.1063/1.3526967 · Cited by 19 · see citing works
Cybernetics Or Control and Communication in the Animal and the Machine, Second Edition
Wiener, N. (1965) · Cumulative Index of Computer Aided Architectural Design · Cited by 15 · see citing works
Antagonistic autoregulation speeds up a homogeneous response in Escherichia coli
Rodrigo, G., Bajić, D., Elola, I., & Poyatos, J. F. (2016) · Scientific Reports · doi:10.1038/srep36196 · Cited by 10 · see citing works
CoRa—A general approach for quantifying biological feedback control
Gómez-Schiavon, M., & El‐Samad, H. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2206825119 · Cited by 6 · see citing works
Self-citationMathematical modeling of the apo and holo transcriptional regulation in Escherichia coli
Alvarez‐Vasquez, F., Freyre-González, J. A., Balderas-Martínez, Y. I., Delgado-Carrillo, M. I., & Collado‐Vides, J. (2015) · Molecular BioSystems · doi:10.1039/c4mb00561a · Cited by 1 · see citing works
Flagged first, then by citations
2 of the 79 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Alternative splicing and related RNA binding proteins in human health and disease
Tao, Y., Zhang, Q., Wang, H., Yang, X., & Mu, H. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01734-2 · Cited by 342 · see citing works
Navigating Environmental Transitions: the Role of Phenotypic Variation in Bacterial Responses
Spratt, M. R., & Lane, K. M. (2022) · mBio · doi:10.1128/mbio.02212-22 · Cited by 65 · see citing works
Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion
Jing, L., & Zhang, Q. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.992883 · Cited by 61 · see citing works
Tanaka, M., Szabó, Á., & Vécsei, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312767 · Cited by 62 · see citing works
Dynamics and Functional Roles of Splicing Factor Autoregulation
Ding, F., Su, C. J., Edmonds, K. K., Liang, G., & Elowitz, M. B. (2021) · Cell Reports · doi:10.1016/j.celrep.2022.110985 · Cited by 35 · see citing works
Jafari, M., Marquez, G., Dechiraju, H., Gomez, M. M., & Rolandi, M. (2023) · Cell Reports Physical Science · doi:10.1016/j.xcrp.2023.101535 · Cited by 34 · see citing works
Stefanov, B., & Fussenegger, M. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.986210 · Cited by 31 · see citing works
Are physiological oscillations physiological ?
Xiong, L., & Garfinkel, A. (2023) · The Journal of Physiology · doi:10.1113/jp285015 · Cited by 32 · see citing works
The value of protein allostery in rational anticancer drug design: an update
Nussinov, R., & Jang, H. (2024) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2024.2384467 · Cited by 29 · see citing works
The evolution of DUX4 gene regulation and its implication for facioscapulohumeral muscular dystrophy
Jagannathan, S. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2022.166367 · Cited by 24 · see citing works
Ranganath, V. A., & Maity, I. (2024) · Angewandte Chemie International Edition · doi:10.1002/anie.202318134 · Cited by 21 · see citing works
Levine, H., & Goldman, D. (2023) · Soft Matter · doi:10.1039/d3sm00171g · Cited by 19 · see citing works
Zhong, Z., Lin, W. J., & Qin, B.-W. (2023) · Physical Review Letters · doi:10.1103/physrevlett.131.138401 · Cited by 19 · see citing works
A feedback control principle common to several biological and engineered systems
Suen, J. Y., & Navlakha, S. (2022) · Journal of The Royal Society Interface · doi:10.1098/rsif.2021.0711 · Cited by 19 · see citing works
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
Demori, I., Giordano, G., Mucci, V., Losacco, S., Marinelli, L., Massobrio, P., Blanchini, F., & Burlando, B. (2022) · Journal of Computational Neuroscience · doi:10.1007/s10827-022-00826-8 · Cited by 14 · see citing works
Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates
Choe, M., Einav, T., Phillips, R., & Titov, D. V. (2025) · Biophysical Journal · doi:10.1016/j.bpj.2025.03.037 · Cited by 13 · see citing works
Regulation strategies for two-output biomolecular networks
Alexis, E., Schulte, C. C. M., Cardelli, L., & Papachristodoulou, A. (2023) · Journal of The Royal Society Interface · doi:10.1098/rsif.2023.0174 · Cited by 10 · see citing works
Reyes, J., Priore, I. S. D., Chaikovsky, A. C., Pasnuri, N., Elhossiny, A. M., Park, J., Weiler, P., Krause, T., Moorman, A. R., Snopkowski, C., et al. (2026) · Cell · doi:10.1016/j.cell.2026.03.032 · Cited by 11 · see citing works
How Does Escherichia coli Allocate Proteome?
Liao, C., ., P., Lai, Y.-H., Rao, C. V., & Lu, T. (2024) · ACS Synthetic Biology · doi:10.1021/acssynbio.3c00537 · Cited by 11 · see citing works
Urease-coupled systems and materials: design strategies, scope and applications
Haranal, S., Ranganath, V. A., & Maity, I. (2025) · Journal of Materials Chemistry B · doi:10.1039/d4tb02853h · Cited by 9 · see citing works
Massri, A. J., McDonald, B. D., Wray, G. A., & McClay, D. R. (2023) · EvoDevo · doi:10.1186/s13227-023-00214-y · Cited by 8 · see citing works
Ranganath, V. A., & Maity, I. (2024) · Angewandte Chemie · doi:10.1002/ange.202318134 · Cited by 8 · see citing works
Weinstein, N., Carlsen, J., Schulz, S., Stapleton, T., Henriksen, H., Travnik, E., & Johansson, P. I. (2024) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2024.1341145 · Cited by 8 · see citing works
Wang, Y., Ma, Z., Chen, G., & Cao, J. (2024) · Neurocomputing · doi:10.1016/j.neucom.2024.128141 · Cited by 8 · see citing works
Distribution modeling quantifies collective T H cell decision circuits in chronic inflammation
Burt, P., & Thurley, K. (2023) · Science Advances · doi:10.1126/sciadv.adg7668 · Cited by 7 · see citing works
Human-Based Distributed Intelligence in Computing Continuum Systems
Donta, P. K., Sedlak, B., Murturi, I., Pujol, V. C., & Dustdar, S. (2025) · IEEE Internet Computing · doi:10.1109/mic.2024.3460908 · Cited by 7 · see citing works
Quantifying the phenotypic information in mRNA abundance
Maltz, E., & Wollman, R. (2022) · Molecular Systems Biology · doi:10.15252/msb.202211001 · Cited by 7 · see citing works
Engineering positive feedback in nucleic acid circuit Biosensors: Design and applications
Zhao, S., Wang, X., Gong, M., Xie, Z., Cao, J., Chen, M., & Chang, K. (2025) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2025.118367 · Cited by 6 · see citing works
Androulakis, I. P. (2022) · Frontiers in Systems Biology · doi:10.3389/fsysb.2022.1044281 · Cited by 6 · see citing works
Fundamental Trade-Offs in the Robustness of Biological Systems with Feedback Regulation
Tran, N., Nguyen, A., Rahman, T. W., & Baetica, A.-A. (2025) · ACS Synthetic Biology · doi:10.1021/acssynbio.4c00704 · Cited by 6 · see citing works
Identifying regulation with adversarial surrogates
Teichner, R., Shomar, A., Barak, O., Brenner, N., Marom, S., Meir, R., & Eytan, D. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2216805120 · Cited by 6 · see citing works
Afik, E., Liu, T. J. B., & Meyerowitz, E. M. (2023) · Nature Communications · doi:10.1038/s41467-023-41813-6 · Cited by 6 · see citing works
A general hypothesis of multistable systems in pathophysiology.
Burlando, B. (2022) · F1000Research · doi:10.12688/f1000research.123183.3 · Cited by 5 · see citing works
Leydon, A. R., Flores, L., Khakhar, A., & Nemhauser, J. L. (2025) · PLoS ONE · doi:10.1371/journal.pone.0337439 · Cited by 5 · see citing works
Lee, A. J. B., Bi, S., Ridgeway, E., Al-Hussaini, I., Deshpande, S., Krueger, A., Khatri, A., Tsui, D., Deng, J., & Mitchell, C. S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26030872 · Cited by 5 · see citing works
Discovering design principles for biological functionalities: Perspectives from systems biology
Bhattacharya, P., Raman, K., & Tangirala, A. K. (2022) · Journal of Biosciences · doi:10.1007/s12038-022-00293-4 · Cited by 5 · see citing works
Beyond the heat shock pathway: Heat stress responses in Drosophila development
Gibbs, J. R., Mei, C., & Wunderlich, Z. (2024) · Developmental Biology · doi:10.1016/j.ydbio.2024.11.003 · Cited by 5 · see citing works
Control of mammalian cell-based devices with genetic programming
Dray, K. E., Edelstein, H. I., Dreyer, K. S., & Leonard, J. N. (2021) · Current Opinion in Systems Biology · doi:10.1016/j.coisb.2021.100372 · Cited by 5 · see citing works
Bhattacharya, P., Raman, K., & Tangirala, A. K. (2023) · Mathematical Biosciences · doi:10.1016/j.mbs.2023.108984 · Cited by 5 · see citing works
Rashid, F., & Wang, N. (2026) · Mechanobiology in medicine · doi:10.1016/j.mbm.2026.100179 · Cited by 4 · see citing works
Nonlinear Growth Dynamics of Neuronal Cells Cultured on Directional Surfaces
Staii, C. (2024) · Biomimetics · doi:10.3390/biomimetics9040203 · Cited by 4 · see citing works
Morphogenetic evolution with physical influences
Huang, T.-Y., Lemke, S., & Wang, Y. (2026) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2026.103671 · Cited by 4 · see citing works
The role of uncertainty and negative feedback loops in the evolution of induced immune defenses
Asgari, D., Stewart, A. J., & Meisel, R. P. (2024) · G3 Genes Genomes Genetics · doi:10.1093/g3journal/jkae182 · Cited by 4 · see citing works
Stochastic Models of Neuronal Growth
Staii, C. (2025) · AppliedMath · doi:10.3390/appliedmath5040170 · Cited by 4 · see citing works
An emerging role for tissue plasticity in developmental precision
Naganathan, S. R. (2024) · Biochemical Society Transactions · doi:10.1042/bst20230173 · Cited by 3 · see citing works
Analysis of the Identifying Regulation With Adversarial Surrogates Algorithm
Teichner, R., Meir, R., & Michael Margaliot, A. (2024) · IEEE Control Systems Letters · doi:10.1109/lcsys.2024.3400697 · Cited by 3 · see citing works
Demori, I., Siriya, S., & Burlando, B. (2025) · Applied Sciences · doi:10.3390/app151910483 · Cited by 2 · see citing works
Bae, S. M., Chung, M., Lee, J. Y., & Yoo, S. M. (2026) · Biotechnology Advances · doi:10.1016/j.biotechadv.2026.108889 · Cited by 2 · see citing works
Molecular integration of seasonal temperature signals in flowering time control
Montez, M., Schulten, A., Menon, G., & Dean, C. (2026) · Nature Reviews Genetics · doi:10.1038/s41576-026-00979-7 · Cited by 2 · see citing works
Feedback-Driven Dynamical Model for Axonal Extension on Parallel Micropatterns
Cheng, K., Kumarasinghe, U., & Staii, C. (2025) · Biomimetics · doi:10.3390/biomimetics10070456 · Cited by 2 · see citing works
Diet induced insulin resistance is due to induction of PTEN expressionPreprint
Mukherjee, R., Pancholi, P., Sharma, M., Solomon, H., Timaul, M. N., Thant, C. N., Mcgriskin, R., Hayatt, O., Markov, V., D’Allara, J., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.25.645201 · Cited by 2 · see citing works
The Physical Basis of FeelingsPreprint
Lane, N. J., & Rodríguez, E. (2025) · doi:10.31234/osf.io/pnqw9_v1 · Cited by 2 · see citing works
Identifying dynamic regulation with machine learning using adversarial surrogates
Teichner, R., Brenner, N., & Meir, R. (2025) · PLoS ONE · doi:10.1371/journal.pone.0325443 · Cited by 1 · see citing works
Mclean, I. C., Gross, S. M., Copperman, J., Derrick, D. S., Paul, I., Emili, A., & Heiser, L. M. (2025) · iScience · doi:10.1016/j.isci.2025.113407 · Cited by 1 · see citing works
The Dark(er) Side of Ostracizing Wrongdoers: An Organizing Framework and Review
Meral, E. O., Heerdink, M. W., & Kleef, G. A. V. (2025) · Small Group Research · doi:10.1177/10464964251368765 · Cited by 1 · see citing works
Modeling constrained tumor evolution through hybrid Ornstein–Uhlenbeck and branching dynamics
Kim, S.-H. (2026) · iScience · doi:10.1016/j.isci.2026.116970 · Cited by 1 · see citing works
A general theory of multistable systems in pathophysiology
Burlando, B. (2022) · F1000Research · doi:10.12688/f1000research.123183.1 · Cited by 1 · see citing works
The Conundrum of the Functional Relationship Between Transcription Factors and Chromatin
Salbert, G., Sérandour, A. A., Staels, B., Lefèbvre, P., & Eeckhoute, J. (2022) · Epigenomics · doi:10.2217/epi-2021-0509 · Cited by 1 · see citing works
A general hypothesis of multistable systems in pathophysiology
Burlando, B. (2022) · F1000Research · doi:10.12688/f1000research.123183.2
An Evolutionary Theory of ValuesPreprint
Griffiths, N., Thomas, K., & Dyer, B. T. J. (2023) · doi:10.31234/osf.io/cwuta · Cited by 1 · see citing works
An Evolutionary Theory of ValuesPreprint
Griffiths, N., Thomas, K., & Dyer, B. T. J. (2023) · doi:10.31219/osf.io/awzkm
Stereotyped cell lineage trees support robust developmentPreprint
Zhang, X., Li, Z., Chen, J., Yang, W., Wu, P., Chen, F., He, X., Chen, X., & Yang, J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.23.581522
CA1 ensemble plasticity is coupled to context change and modulated by task familiarityPreprint
Krajčovič, B., Černotová, D., Stuchlı́k, A., Kubík, Š., & Svoboda, J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.19.608588
A lymphoid tissue chemokine checkpoint prevents loss of CD8 + T cell functionalityPreprint
Altenburger, L. M., Carvoeiro, D. C., Dehio, P., Zhou, J., Laura, C., Katoch, M., Krueger, C., de Albuquerque, J. B., Pfenninger, P., Magdaleno, J. M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.19.613830
Self-renewal without niche instruction, feedback or fine-tuningPreprint
MacArthur, B. D., & Greulich, P. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.20.629654
Loopomics: A possible breakthrough in the understanding and control of life
Burlando, B. (2025) · PNEI REVIEW · doi:10.3280/pnei2025oa19417
DNMT1 targets SRD5A2 to induce mitochondrial homeostasis and EMT in urothelial cells of hypospadias
Chen, Y., Hu, J., Peng, L., & Zhao, Y. (2025) · Molecular Biology Reports · doi:10.1007/s11033-025-10453-y
Zhang, X., Li, Z., Chen, J., Yang, W., He, X., Wu, P., Chen, F., Zhou, Z., Ren, C., Shan, Y., et al. (2025) · Advanced Science · doi:10.1002/advs.202406208
Identifying Internal Control in Biological Systems Through Machine Learning
Teichner, R., & Meir, R. (2025) · International Conference on Knowledge and Smart Technology · doi:10.1109/kst65016.2025.11003301
Biological Regulation and Functional Integration
Militello, G. (2025) · History, philosophy and theory of the life sciences · doi:10.1007/978-3-031-94744-5_3
Cell cycle oscillations in a polarity network facilitate state switching by morphogenetic cues
Ng, K., Sebaa, H., Hirani, N., Chizh, A. N., Messi, Z., Bland, T., Sugioka, K., & Goehring, N. W. (2026) · Science Advances · doi:10.1126/sciadv.aec3379
Tangled Hierarchies and Resonant Phase Spaces for Intelligent Systems
Kaleida, J. (2025) · Enacting Cybernetics · doi:10.58695/ec.14
The symphony of shape: A feedback loop conducting zebrafish heart formation
Cao, C., Li, Z., & Wang, L. (2025) · Developmental Cell · doi:10.1016/j.devcel.2025.10.003
Li, J., Moyd, S. A., & Zhang, Q. (2026) · Acta Physiologica · doi:10.1111/apha.70202
A quantitative design guideline for biomolecular positive feedback systems
Kumar, V., & Sen, S. (2026) · IFAC Journal of Systems and Control · doi:10.1016/j.ifacsc.2026.100400
Reyes, J. (2026) · Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) · doi:10.5281/zenodo.18892592
Ge, C., & Li, H. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.20.719759
Lymphoid tissue chemokines limit priming duration to preserve CD8 + T cell functionality
Altenburger, L. M., Carvoeiro, D. C., Dehio, P., Zhou, J., Laura, C., Cuadros, À. B. I., Katoch, M., Krüger, C., de Albuquerque, J. B., Pfenninger, P., et al. (2026) · Science · doi:10.1126/science.adq2080 · Cited by 1 · see citing works
Carlucci, M., Oh, E. S., Silverthorne, T., Stinchcombe, A. R., Želnys, M., & Petronis, A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.27.720664
WayFindR: investigating feedback in biological pathways
Bombina, P., McGee, R. L., Reed, J., Abrams, Z. B., Abruzzo, L. V., & Coombes, K. R. (2026) · NAR Genomics and Bioinformatics · doi:10.1093/nargab/lqag051
Proportional Control of Negative Feedback Physiological Systems
Granata, R., Ricciardi, C., Montefusco, F., Donisi, L., Merola, A., Cosentino, C., Romano, M., Amato, F., & Ponsiglione, A. M. (2026) · World Congress on Medical Physics and Biomedical Engineering, September 7 - 12, 2009, Munich, Germany · doi:10.1007/978-3-032-24724-7_37
Runzer, C. D. T., Roumans, N. J. T., Bouwman, F. G., Herrera, B. P., Cillero‐Pastor, B., Roque, M., Amédée, J., Bonvin, E., Groot, F. B., Plank, C., et al. (2026) · Bioactive Materials · doi:10.1016/j.bioactmat.2026.05.046
Closed-loop Proportional-Integral Control of Physiological Systems
Granata, R., Erzingher, L., Russo, M., Cosentino, C., Amato, F., Romano, M., & Ponsiglione, A. M. (2026) · International Conference on Control, Decision and Information Technologies (CoDIT) · doi:10.1109/codit70676.2026.11631127
Temporal spectroscopy of plant development reveals subcircadian response bands
Anonymous, Rolli, E., Ricci, A., & Cademartiri, L. (2026) · Physical review. E · doi:10.1103/8l7d-rzxg
Almazari, R., Abu-El-Rub, E. M., & Alzu’bi, A. (2026) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-026-02171-4
Biological Systems as Physical Data Processors: Evolution as a Case of Embodied Computing
de Lorenzo, V. (2026) · BioEssays · doi:10.1002/bies.70196
Zyl, W. V., & Henning, S. (2026) · Frontiers in Systems Biology · doi:10.3389/fsysb.2026.1980056
- Authors
- El-Samad, H.
- Venue
- Cell Systems
- Publisher
- Elsevier BV
- Published
- 2021-06
- Volume
- 12
- Issue
- 6
- Pages
- 477-487
- ISSN
- 2405-4712 (ISSN-L)
- OpenAlex
- W3173106926
- Cited by
- 90
- References
- 79
- Citations by year
- 2026: 23 · 2025: 22 · 2024: 18 · 2023: 12 · 2022: 14 · 2021: 1
- FWCI
- 1.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Systems (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Defense Advanced Research Projects Agency (HR0011-16-2-0045)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Social Sciences › Arts and Humanities › History and Philosophy of Science › Philosophy and History of Science
- Physical Sciences › Physics and Astronomy › Statistical and Nonlinear Physics › Complex Systems and Dynamics
- Keywords
- feedback loops, homeostasis, cell size control, cell division, self-healing, extracellular signaling, tissue homeostasis, physiological regulation, control network
- MeSH terms
- Feedback, Homeostasis, Models, Biological
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
