Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Shear-stress sensing by PIEZO1 regulates tendon stiffness in rodents and influences jumping performance in humans

Abstract

Athletic performance relies on tendons, which enable movement by transferring forces from muscles to the skeleton. Yet, how load-bearing structures in tendons sense and adapt to physical demands is not understood. Here, by performing calcium (Ca2+) imaging in mechanically loaded tendon explants from rats and in primary tendon cells from rats and humans, we show that tenocytes detect mechanical forces through the mechanosensitive ion channel PIEZO1, which senses shear stresses induced by collagen-fibre sliding. Through tenocyte-targeted loss-of-function and gain-of-function experiments in rodents, we show that reduced PIEZO1 activity decreased tendon stiffness and that elevated PIEZO1 mechanosignalling increased tendon stiffness and strength, seemingly through upregulated collagen cross-linking. We also show that humans carrying the PIEZO1 E756del gain-of-function mutation display a 13.2% average increase in normalized jumping height, presumably due to a higher rate of force generation or to the release of a larger amount of stored elastic energy. Further understanding of the PIEZO1-mediated mechanoregulation of tendon stiffness should aid research on musculoskeletal medicine and on sports performance.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Mechanically induced Ca2+ elevations in tissue-resident tenocytes.
Fig. 2: Shear stress as a key stimulus driving Ca2+ signals in isolated tenocytes.
Fig. 3: PIEZO1-mediated shear-stress response in human tenocytes.
Fig. 4: Decreased stretch-induced Ca2+ response and stiffness in fascicles from tenocyte-targeted Piezo1-knockout mice.
Fig. 5: Stiffness and strength regulation of murine tendons by PIEZO1.
Fig. 6: Unchanged collagen fibrils but increased cross-link-associated thermal stability and autofluorescence in load-bearing tendons from Piezo1GOF mice.
Fig. 7: Human jumping performance is influenced by PIEZO1GOF E756 mutation with no effect on Achilles tendon morphology.
Fig. 8: Proposed mechanism of tendon mechanotransduction that adapts the tissue and influences physical performance.

Data availability

The main data supporting the findings of this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, yet they are available from the corresponding author on reasonable request.

Code availability

The software of the stretching device, as well as MATLAB, ImageJ and R codes, are all available from the corresponding author on request. The toolbox CHIPS is freely available65.

References

  1. Magnusson, S. P., Langberg, H. & Kjaer, M. The pathogenesis of tendinopathy: balancing the response to loading. Nat. Rev. Rheumatol. 6, 262–268 (2010).

    PubMed  Article  Google Scholar 

  2. Dickinson, M. H. et al. How animals move: an integrative view. Science 288, 100–106 (2000).

    CAS  PubMed  Article  Google Scholar 

  3. Roberts, T. J., Marsh, R. L., Weyand, P. G. & Taylor, C. R. Muscular force in running turkeys: the economy of minimizing work. Science 275, 1113–1115 (1997).

    CAS  PubMed  Article  Google Scholar 

  4. Wilson, A. M., Watson, J. C. & Lichtwark, G. A. Biomechanics: a catapult action for rapid limb protraction. Nature 421, 35–36 (2003).

    CAS  PubMed  Article  Google Scholar 

  5. Arampatzis, A., Karamanidis, K. & Albracht, K. Adaptational responses of the human Achilles tendon by modulation of the applied cyclic strain magnitude. J. Exp. Biol. 210, 2743–2753 (2007).

    PubMed  Article  Google Scholar 

  6. Heinemeier, K. M. et al. Uphill running improves rat Achilles tendon tissue mechanical properties and alters gene expression without inducing pathological changes. J. Appl Physiol. 113, 827–836 (2012).

    CAS  PubMed  Article  Google Scholar 

  7. Arampatzis, A., Karamanidis, K., Morey-Klapsing, G., De Monte, G. & Stafilidis, S. Mechanical properties of the triceps surae tendon and aponeurosis in relation to intensity of sport activity. J. Biomech. 40, 1946–1952 (2007).

    PubMed  Article  Google Scholar 

  8. Riley, G. Tendinopathy–from basic science to treatment. Nat. Clin. Pract. Rheumatol. 4, 82–89 (2008).

    PubMed  Article  Google Scholar 

  9. Nourissat, G., Berenbaum, F. & Duprez, D. Tendon injury: from biology to tendon repair. Nat. Rev. Rheumatol. 11, 223–233 (2015).

    PubMed  Article  Google Scholar 

  10. Pan, B. et al. TMC1 forms the pore of mechanosensory transduction channels in vertebrate inner ear hair cells. Neuron 99, 736–753 e736 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Ranade, S. S. et al. Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 516, 121–125 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Li, J. et al. Piezo1 integration of vascular architecture with physiological force. Nature 515, 279–282 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Wang, S. et al. Endothelial cation channel PIEZO1 controls blood pressure by mediating flow-induced ATP release. J. Clin. Invest. 126, 4527–4536 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  14. Woo, S. H. et al. Piezo2 is the principal mechanotransduction channel for proprioception. Nat. Neurosci. 18, 1756–1762 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Nonomura, K. et al. Piezo2 senses airway stretch and mediates lung inflation-induced apnoea. Nature 541, 176–181 (2017).

    CAS  PubMed  Article  Google Scholar 

  16. Coste, B. et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330, 55–60 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Kang, L., Gao, J., Schafer, W. R., Xie, Z. & Xu, X. S. C. elegans TRP family protein TRP-4 is a pore-forming subunit of a native mechanotransduction channel. Neuron 67, 381–391 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Servin-Vences, M. R., Moroni, M., Lewin, G. R. & Poole, K. Direct measurement of TRPV4 and PIEZO1 activity reveals multiple mechanotransduction pathways in chondrocytes. eLife 6, e21074 (2017).

    PubMed  Article  Google Scholar 

  19. Patel, A. J. et al. A mammalian two pore domain mechano-gated S-like K+ channel. EMBO J. 17, 4283–4290 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Maingret, F., Fosset, M., Lesage, F., Lazdunski, M. & Honoré, E. TRAAK is a mammalian neuronal mechano-gated K+ channel. J. Biol. Chem. 274, 1381–1387 (1999).

    CAS  PubMed  Article  Google Scholar 

  21. Xu, J. et al. GPR68 senses flow and is essential for vascular physiology. Cell 173, 762–775 e716 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. O’Hagan, R., Chalfie, M. & Goodman, M. B. The MEC-4 DEG/ENaC channel of Caenorhabditis elegans touch receptor neurons transduces mechanical signals. Nat. Neurosci. 8, 43–50 (2005).

    PubMed  Article  CAS  Google Scholar 

  23. Zhang, M. et al. Structure of the mechanosensitive OSCA channels. Nat. Struct. Mol. Biol. 25, 850–858 (2018).

    CAS  PubMed  Article  Google Scholar 

  24. Murthy, S. E. et al. OSCA/TMEM63 are an evolutionarily conserved family of mechanically activated ion channels. eLife 7, e41844 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  25. Lukacs, V. et al. Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia. Nat. Commun. 6, 8329 (2015).

    CAS  PubMed  Article  Google Scholar 

  26. Fotiou, E. et al. Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis. Nat. Commun. 6, 8085 (2015).

    PubMed  Article  Google Scholar 

  27. Retailleau, K. et al. Piezo1 in smooth muscle cells is involved in hypertension-dependent arterial remodeling. Cell Rep. 13, 1161–1171 (2015).

    CAS  PubMed  Article  Google Scholar 

  28. Peyronnet, R. et al. Piezo1-dependent stretch-activated channels are inhibited by polycystin-2 in renal tubular epithelial cells. EMBO Rep. 14, 1143–1148 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Cahalan, S. M. et al. Piezo1 links mechanical forces to red blood cell volume. eLife 4, e07370 (2015).

    PubMed Central  Article  Google Scholar 

  30. Sun, W. et al. The mechanosensitive Piezo1 channel is required for bone formation. eLife 8, e47454 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Ma, S. et al. Common PIEZO1 allele in African populations causes RBC dehydration and attenuates Plasmodium infection. Cell 173, 443–455 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Stauber, T., Blache, U. & Snedeker, J. G. Tendon tissue microdamage and the limits of intrinsic repair. Matrix Biol. 85-86, 68–79 (2020).

    CAS  PubMed  Article  Google Scholar 

  33. Snedeker, J. G., Ben Arav, A., Zilberman, Y., Pelled, G. & Gazit, D. Functional fibered confocal microscopy: a promising tool for assessing tendon regeneration. Tissue Eng. C 15, 485–491 (2009).

    Article  Google Scholar 

  34. Zheng, K. et al. Time-resolved imaging reveals heterogeneous landscapes of nanomolar Ca2+ in neurons and astroglia. Neuron 88, 277–288 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Screen, H. R., Lee, D. A., Bader, D. L. & Shelton, J. C. An investigation into the effects of the hierarchical structure of tendon fascicles on micromechanical properties. Proc. Inst. Mech. Eng. H 218, 109–119 (2004).

    CAS  PubMed  Article  Google Scholar 

  36. Murthy, S. E., Dubin, A. E. & Patapoutian, A. Piezos thrive under pressure: mechanically activated ion channels in health and disease. Nat. Rev. Mol. Cell Biol. 18, 771–783 (2017).

    CAS  PubMed  Article  Google Scholar 

  37. Wunderli, S. L. et al. Tendon response to matrix unloading is determined by the patho-physiological niche. Matrix Biol. 89, 11–26 (2020).

    CAS  PubMed  Article  Google Scholar 

  38. Peffers, M. J. et al. Transcriptome analysis of ageing in uninjured human Achilles tendon. Arthritis Res. Ther. 17, 33 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. Ranade, S. S. et al. Piezo1, a mechanically activated ion channel, is required for vascular development in mice. Proc. Natl Acad. Sci. USA 111, 10347–10352 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Howell, K. et al. Novel model of tendon regeneration reveals distinct cell mechanisms underlying regenerative and fibrotic tendon healing. Sci. Rep. 7, 45238 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Syeda, R. et al. Chemical activation of the mechanotransduction channel Piezo1. eLife 4, e07369 (2015).

    PubMed Central  Article  Google Scholar 

  42. Wunderli, S. L. et al. Minimal mechanical load and tissue culture conditions preserve native cell phenotype and morphology in tendon-a novel ex vivo mouse explant model. J. Orthop. Res. 36, 1383–1390 (2018).

    CAS  PubMed  Article  Google Scholar 

  43. Couppé, C. et al. Life-long endurance running is associated with reduced glycation and mechanical stress in connective tissue. Age 36, 9665 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. Thorpe, C. T., Stark, R. J., Goodship, A. E. & Birch, H. L. Mechanical properties of the equine superficial digital flexor tendon relate to specific collagen cross-link levels. Equine Vet. J. Suppl. 42, 538–543 (2010).

    Article  Google Scholar 

  45. Zeeman, R. et al. Successive epoxy and carbodiimide cross-linking of dermal sheep collagen. Biomaterials 20, 921–931 (1999).

    CAS  PubMed  Article  Google Scholar 

  46. Marturano, J. E., Xylas, J. F., Sridharan, G. V., Georgakoudi, I. & Kuo, C. K. Lysyl oxidase-mediated collagen crosslinks may be assessed as markers of functional properties of tendon tissue formation. Acta Biomater. 10, 1370–1379 (2014).

    CAS  PubMed  Article  Google Scholar 

  47. Mersha, T. B. & Abebe, T. Self-reported race/ethnicity in the age of genomic research: its potential impact on understanding health disparities. Hum. Genomics 9, 1 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  48. Yancy, C. W. & McNally E. Reporting genetic markers and the social determinants of health in clinical cardiovascular research—it is time to recalibrate the use of race. JAMA Cardiol. https://doi.org/10.1001/jamacardio.2020.6576 (2020).

  49. Athletics—100m men. Olympic Games www.olympic.org/athletics/100m-men (accessed May 2020).

  50. 100 meters men. World Athletics www.worldathletics.org/records/all-time-toplists/sprints/100-metres/outdoor/men/senior (accessed May 2020).

  51. Long jump men. World Athletics www.worldathletics.org/records/all-time-toplists/jumps/long-jump/outdoor/men/senior (accessed May 2020).

  52. Ishikawa, M., Niemela, E. & Komi, P. V. Interaction between fascicle and tendinous tissues in short-contact stretch-shortening cycle exercise with varying eccentric intensities. J. Appl Physiol. 99, 217–223 (2005).

    CAS  PubMed  Article  Google Scholar 

  53. Earp, J. E. et al. Influence of muscle-tendon unit structure on rate of force development during the squat, countermovement, and drop jumps. J. Strength Cond. Res. 25, 340–347 (2011).

    PubMed  Article  Google Scholar 

  54. Lavagnino, M. et al. Tendon mechanobiology: current knowledge and future research opportunities. J. Orthop. Res. 33, 813–822 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  55. Arnoczky, S. P., Lavagnino, M. & Egerbacher, M. The response of tendon cells to changing loads: implications in the etiopathogenesis of tendinopathy. Tendinopathy Athl. 1, 46–59 (2007).

    Article  Google Scholar 

  56. Wall, M. E. & Banes, A. J. Early responses to mechanical load in tendon: role for calcium signaling, gap junctions and intercellular communication. J. Musculoskelet. Neuronal Interact. 5, 70–84 (2005).

    CAS  PubMed  Google Scholar 

  57. Maeda, E., Hagiwara, Y., Wang, J. H. & Ohashi, T. A new experimental system for simultaneous application of cyclic tensile strain and fluid shear stress to tenocytes in vitro. Biomed. Microdevices 15, 1067–1075 (2013).

    PubMed  Article  Google Scholar 

  58. Kongsgaard, M. et al. Corticosteroid injections, eccentric decline squat training and heavy slow resistance training in patellar tendinopathy. Scand. J. Med. Sci. Sports 19, 790–802 (2009).

    CAS  PubMed  Article  Google Scholar 

  59. Beyer, R. et al. Heavy slow resistance versus eccentric training as treatment for achilles tendinopathy: a randomized controlled trial. Am. J. Sports Med. 43, 1704–1711 (2015).

    PubMed  Article  Google Scholar 

  60. Frost, H. M. Bone “mass” and the “mechanostat”: a proposal. Anat. Rec. 219, 1–9 (1987).

    CAS  PubMed  Article  Google Scholar 

  61. Heinemeier, K. M., Schjerling, P., Heinemeier, J., Magnusson, S. P. & Kjaer, M. Lack of tissue renewal in human adult Achilles tendon is revealed by nuclear bomb 14C. FASEB J. 27, 2074–2079 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Forde, M. S., Punnett, L. & Wegman, D. H. Prevalence of musculoskeletal disorders in union ironworkers. J. Occup. Environ. Hyg. 2, 203–212 (2005).

    PubMed  Article  Google Scholar 

  63. Sebbag, E. et al. The world-wide burden of musculoskeletal diseases: a systematic analysis of the World Health Organization Burden of Diseases Database. Ann. Rheum. Dis. 78, 844–848 (2019).

    PubMed  Article  Google Scholar 

  64. Gautieri, A. et al. Advanced glycation end-products: mechanics of aged collagen from molecule to tissue. Matrix Biol. 59, 95–108 (2017).

    CAS  PubMed  Article  Google Scholar 

  65. Barrett, M. J. P., Ferrari, K. D., Stobart, J. L., Holub, M. & Weber, B. CHIPS: an extensible toolbox for cellular and hemodynamic two-photon image analysis. Neuroinformatics 16, 145–147 (2018).

    PubMed  Article  Google Scholar 

  66. Li, Y., Fessel, G., Georgiadis, M. & Snedeker, J. G. Advanced glycation end-products diminish tendon collagen fiber sliding. Matrix Biol. 32, 169–177 (2013).

    CAS  PubMed  Article  Google Scholar 

  67. Tinevez, J.-Y. et al. TrackMate: an open and extensible platform for single-particle tracking. Methods 115, 80–90 (2017).

    CAS  PubMed  Article  Google Scholar 

  68. McNeilly, C. M., Banes, A. J., Benjamin, M. & Ralphs, J. R. Tendon cells in vivo form a three dimensional network of cell processes linked by gap junctions. J. Anat. 189, 593–600 (1996).

    PubMed  PubMed Central  Google Scholar 

  69. Song, M. J. et al. Mapping the mechanome of live stem cells using a novel method to measure local strain fields in situ at the fluid-cell interface. PLoS ONE 7, e43601 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Razafiarison, T., Silvan, U., Meier, D. & Snedeker, J. G. Surface-driven collagen self-assembly affects early osteogenic stem cell signaling. Adv. Healthc. Mater. 5, 1481–1492 (2016).

    CAS  PubMed  Article  Google Scholar 

  71. Cornish, R. Flow in a pipe of rectangular cross-section. Proc. R. Soc. A 120, 691–700 (1928).

    Google Scholar 

  72. Naito, Y., Hino, K., Bono, H. & Ui-Tei, K. CRISPRdirect: software for designing CRISPR/Cas guide RNA with reduced off-target sites. Bioinformatics 31, 1120–1123 (2015).

    CAS  PubMed  Article  Google Scholar 

  73. Morgens, D. W. et al. Genome-scale measurement of off-target activity using Cas9 toxicity in high-throughput screens. Nat. Commun. 8, 15178 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Sanjana, N. E., Shalem, O. & Zhang, F. Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods 11, 783–784 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Stewart, S. A. et al. Lentivirus-delivered stable gene silencing by RNAi in primary cells. RNA 9, 493–501 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Arganda-Carreras, I. et al. Trainable Weka segmentation: a machine learning tool for microscopy pixel classification. Bioinformatics 33, 2424–2426 (2017).

    CAS  PubMed  Article  Google Scholar 

  77. Robinson, J. M. et al. The VISA-A questionnaire: a valid and reliable index of the clinical severity of Achilles tendinopathy. Br. J. Sports Med. 35, 335–341 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Grimby, G. Physical activity and muscle training in the elderly. Acta Med. Scand. Suppl. 711, 233–237 (1986).

    CAS  PubMed  Google Scholar 

  79. Silbernagel, K. G., Shelley, K., Powell, S. & Varrecchia, S. Extended field of view ultrasound imaging to evaluate Achilles tendon length and thickness: a reliability and validity study. Muscles Ligaments Tendons J. 6, 104–110 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  80. Silbernagel, K. G., Gustavsson, A., Thomee, R. & Karlsson, J. Evaluation of lower leg function in patients with Achilles tendinopathy. Knee Surg. Sports Traumatol. Arthrosc. 14, 1207–1217 (2006).

    PubMed  Article  Google Scholar 

Download references

Acknowledgements

We thank A. Ziegler for software assistance; N. Wili for support in chemistry; B. Rutishauser and E. Bachmann for engineering assistance; L. Gasser (Statistical Consulting Group, ETH Zurich) for statistical support; members of the Snedeker group for constructive discussions; A. Huang and R. Schweitzer for providing Scx-creERT2 mice; A. Patapoutian for providing Piezo1GOF mice and feedback; U. Lüthi and A. Käch from the Center for Microscopy and Image Analysis (University of Zurich) for help with transmission electron microscopy; R. Mezzenga and Y. Yao (ETH Zurich) for access to the differential scanning calorimeter and assistance during the experiments; and P. Aagaard for insights on the human jumping performance data. Funding was provided by the Swiss National Science Foundation (grant numbers 165670 and 185095).

Author information

Authors and Affiliations

Authors

Contributions

F.S.P., P.K.J., A.S.S. and J.G.S. designed experiments and wrote the manuscript. F.S.P. performed the Ca2+-imaging experiments with tendon explants. F.S.P., K.D.F., D.H., S.C., A.N.H., U.S. and B.W. designed and analysed the Ca2+-imaging experiments. P.K.J. and F.S.P. carried out and analysed the shear-stress experiments. M.J.A., F.S.P., M.B. and B.P.-T. generated and analysed the knockout cells. S.F.F., M.B. and U.B. helped with human tendon tissues and isolation of primary cells. F.S.P. and S.M. performed mouse experiments. S.H., K.G.S., F.S.P. and J.G.S. designed and performed the human study. F.S.P. and B.P.-T. carried out human genotyping. F.S.P., S.H. and T.G. analysed the human data. All of the authors provided feedback on the manuscript.

Corresponding author

Correspondence to Jess G. Snedeker.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Biomedical Engineering thanks Michael Lavagnino and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–7 and Tables 1 and 2, and captions for Supplementary Videos 1–5.

Reporting Summary

Peer Review File

Supplementary Video 1

A tendon fascicle at baseline (unstretched condition), showing sparse spontaneous Ca2+ signals in tenocytes.

Supplementary Video 2

A tendon fascicle during tissue stretching from 0–10% strain, showing a tissue-wide Ca2+ response in tenocytes.

Supplementary Video 3

Propagation of Ca2+ signals to neighbouring cells, potentially through cell–cell communication.

Supplementary Video 4

Isolated human tenocytes showing Ca2+ signals on stimulation with 5 Pa shear stress.

Supplementary Video 5

A tendon fascicle stimulated with the PIEZO1-agonist Yoda1, showing a prompt Ca2+ response in tenocytes.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Passini, F.S., Jaeger, P.K., Saab, A.S. et al. Shear-stress sensing by PIEZO1 regulates tendon stiffness in rodents and influences jumping performance in humans. Nat Biomed Eng 5, 1457–1471 (2021). https://doi.org/10.1038/s41551-021-00716-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-021-00716-x

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing