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.

  • Review Article
  • Published:

Unconventional insulins from predators and pathogens

Nature Chemical Biology volume 18, pages 688–697 (2022)Cite this article

Subjects

Abstract

Insulin and its related peptides are found throughout the animal kingdom, in which they serve diverse functions. This includes regulation of glucose homeostasis, neuronal development and cognition. The surprising recent discovery that venomous snails evolved specialized insulins to capture fish demonstrated the nefarious use of this hormone in nature. Because of their streamlined role in predation, these repurposed insulins exhibit unique characteristics that have unraveled new aspects of the chemical ecology and structural biology of this important hormone. Recently, insulins were also reported in other venomous predators and pathogenic viruses, demonstrating the broader use of insulin by one organism to manipulate the physiology of another. In this Review, we provide an overview of the discovery and biomedical application of repurposed insulins and other hormones found in nature and highlight several unique insights gained from these unusual compounds.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The fish-hunting cone snail C. geographus uses insulin for prey capture.
Fig. 2: Insights gained from cone snail insulins and their analogs based on structural studies.
Fig. 3: Diversity of insulin sequences identified in the venom glands of cone snails and other members of the superfamily Conoidea.
Fig. 4: Viral insulin-like sequences (VILPs) share high sequence and structural similarity with members of the human insulin superfamily.

Similar content being viewed by others

References

  1. Zheng, S. et al. A functional study of all 40 Caenorhabditis elegans insulin-like peptides. J. Biol. Chem. 293, 16912–16922 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wu, Q. & Brown, M. R. Signaling and function of insulin-like peptides in insects. Annu. Rev. Entomol. 51, 1–24 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Avruch, J. Insulin signal transduction through protein kinase cascades. Mol. Cell. Biochem. 182, 31–48 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critical nodes in signalling pathways: insights into insulin action. Nat. Rev. Mol. Cell Biol. 7, 85–96 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Menting, J. G. et al. Protective hinge in insulin opens to enable its receptor engagement. Proc. Natl Acad. Sci. USA 111, E3395–E3404 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Menting, J. G. et al. How insulin engages its primary binding site on the insulin receptor. Nature 493, 241–245 (2013). Seminal study that revealed the structural interactions of insulin with the μIR, a domain-minimized version of the IR comprising the two-domain L1–CR receptor fragment and the αCT segment that form the receptor’s primary hormone-binding site.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Scapin, G. et al. Structure of the insulin receptor–insulin complex by single-particle cryo-EM analysis. Nature 556, 122–125 (2018). A cryo-EM structure of the IR–insulin complex.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gutmann, T. et al. Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain. J. Cell Biol. 219, e201907210 (2020).

    Article  PubMed  Google Scholar 

  9. Uchikawa, E., Choi, E., Shang, G., Yu, H. & Bai, X. C. Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor–ligand complex. eLife 8, e48630 (2019).

  10. Weis, F. et al. The signalling conformation of the insulin receptor ectodomain. Nat. Commun. 9, 4420 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Xiong, X. et al. Symmetric and asymmetric receptor conformation continuum induced by a new insulin. Nat. Chem. Biol.18, 511–519 (2022).

  12. Nielsen, J. et al. Structural investigations of full-length insulin receptor dynamics and signalling. J. Mol. Biol. 434, 167458 (2022).

    Article  CAS  PubMed  Google Scholar 

  13. Lawrence, M. C. Understanding insulin and its receptor from their three-dimensional structures. Mol. Metab. 52, 101255 (2021). Insightful review on the current understanding of how insulin engages with the IR. It also discusses important remaining questions in the field.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Blumenthal, S. From insulin and insulin-like activity to the insulin superfamily of growth-promoting peptides: a 20th-century odyssey. Perspect. Biol. Med. 53, 491–508 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Cherif-Feildel, M. et al. Molecular evolution and functional characterisation of insulin related peptides in molluscs: contributions of Crassostrea gigas genomic and transcriptomic-wide screening. Gen. Comp. Endocrinol. 271, 15–29 (2019).

    Article  CAS  PubMed  Google Scholar 

  16. Elphick, M. R., Mirabeau, O. & Larhammar, D. Evolution of neuropeptide signalling systems. J. Exp. Biol. 221, jeb151092 (2018).

  17. Mack, L. R. & Tomich, P. G. Gestational diabetes: diagnosis, classification, and clinical care. Obstet. Gynecol. Clin. North Am. 44, 207–217 (2017).

    Article  PubMed  Google Scholar 

  18. Nkonge, K. M., Nkonge, D. K. & Nkonge, T. N. The epidemiology, molecular pathogenesis, diagnosis, and treatment of maturity-onset diabetes of the young (MODY). Clin. Diabetes Endocrinol. 6, 20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zaykov, A. N., Mayer, J. P. & DiMarchi, R. D. Pursuit of a perfect insulin. Nat. Rev. Drug Discov. 15, 425–439 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. Beardwood, J. T. A case of attempted suicide with insulin. J. Am. Med. Assoc. 102, 765–766 (1943).

    Article  Google Scholar 

  21. Marks, V. Murder by insulin: suspected, purported and proven—a review. Drug Test. Anal. 1, 162–176 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Marks, V. & Richmond, C. Insulin Murders: True Life Cases 1st edn (RSM, 2007).

  23. Nelson, J., Ibrahim, J., Bugeja, L. & Ranson, D. Killing of elderly patients by health care professionals: insights from coroners’ inquests and inquiries in three cases. J. Law Med. 28, 620–631 (2021).

    PubMed  Google Scholar 

  24. Geppert, C. The angel of death in Clarksburg. Fed. Practitioner 38, 564–565 (2021).

    Google Scholar 

  25. Safavi-Hemami, H. et al. Specialized insulin is used for chemical warfare by fish-hunting cone snails. Proc. Natl Acad. Sci. USA 112, 1743–1748 (2015). Discovery of the use of insulin as a weapon for prey capture by venomous marine cone snails.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Johnson, C. R. & Stablum, W. Observations on the feeding behavior of Conus geographus (Gastropoda: Toxoglossa). Pac. Sci. 25, 109–111 (1971).

    Google Scholar 

  27. Aman, J. W. et al. Insights into the origins of fish hunting in venomous cone snails from studies of Conus tessulatus. Proc. Natl Acad. Sci. USA 112, 5087–5092 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bingham, J. P., Baker, M. R. & Chun, J. B. Analysis of a cone snail’s killer cocktail—the milked venom of Conus geographus. Toxicon 60, 1166–1170 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Menting, J. G. et al. A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin. Nat. Struct. Mol. Biol. 23, 916–920 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Gradel, A. K. J. et al. Factors affecting the absorption of subcutaneously administered insulin: effect on variability. J. Diabetes Res. 2018, 1205121 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Heinemann, L. Variability of insulin absorption and insulin action. Diabetes Technol. Ther. 4, 673–682 (2004).

    Article  Google Scholar 

  32. Carpenter, F. H. Relationship of structure to biological activity of insulin as revealed by degradative studies. Am. J. Med. 40, 750–758 (1966).

    Article  CAS  PubMed  Google Scholar 

  33. Xiong, X. et al. A structurally minimized yet fully active insulin based on cone-snail venom insulin principles. Nat. Struct. Mol. Biol. 27, 615–624 (2020). This study demonstrates that an insulin from cone snail venom could inform on the design of a monomeric insulin analog as a potential therapeutic for diabetes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. De Meyts, P. Structural basis for the poisonous activity of a predator’s venom insulin. Nat. Struct. Mol. Biol. 23, 872–874 (2016).

    Article  PubMed  Google Scholar 

  35. Lu, A. et al. Transcriptomic profiling reveals extraordinary diversity of venom peptides in unexplored predatory gastropods of the genus Clavus. Genome Biol. Evol. 12, 684–700 (2020).

  36. Fassio, G. et al. Venom diversity and evolution in the most divergent cone snail genus Profundiconus. Toxins 11, 623 (2019).

  37. Pardos-Blas, J. R. et al. The genome of the venomous snail Lautoconus ventricosus sheds light on the origin of conotoxin diversity. GigaScience 10, giab037 (2021).

  38. Safavi-Hemami, H. et al. Venom insulins of cone snails diversify rapidly and track prey taxa. Mol. Biol. Evol. 33, 2924–2934 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ahorukomeye, P. et al. Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor. eLife 8, e41574 (2019).

  40. Conlon, M. Molecular evolution of insulin in non-mammalian vertebrates. Am. Zool. 40, 200–212 (2000).

    CAS  Google Scholar 

  41. Jiracek, J. & Zakova, L. From venom peptides to a potential diabetes treatment. eLife 8, e44829 (2019).

  42. Vonk, F. J. et al. The king cobra genome reveals dynamic gene evolution and adaptation in the snake venom system. Proc. Natl Acad. Sci. USA 110, 20651–20656 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sparkman, A. M. et al. Rates of molecular evolution vary in vertebrates for insulin-like growth factor-1 (IGF-1), a pleiotropic locus that regulates life history traits. Gen. Comp. Endocrinol. 178, 164–173 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Kunalan, S., Othman, I., Syed Hassan, S. & Hodgson, W. C. Proteomic characterization of two medically important Malaysian snake venoms, Calloselasma rhodostoma (Malayan pit viper) and Ophiophagus hannah (king cobra). Toxins 10, 434 (2018).

  45. Tan, C. H., Tan, K. Y., Fung, S. Y. & Tan, N. H. Venom-gland transcriptome and venom proteome of the Malaysian king cobra (Ophiophagus hannah). BMC Genomics 16, 687 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Danpaiboon, W. et al. Ophiophagus hannah venom: proteome, components bound by Naja kaouthia antivenin and neutralization by N. kaouthia neurotoxin-specific human ScFv. Toxins 6, 1526–1558 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hu, H., Bandyopadhyay, P. K., Olivera, B. M. & Yandell, M. Elucidation of the molecular envenomation strategy of the cone snail Conus geographus through transcriptome sequencing of its venom duct. BMC Genomics 13, 284 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. McCullough, D., Atofanei, C., Knight, E., Trim, S. A. & Trim, C. M. Kinome scale profiling of venom effects on cancer cells reveals potential new venom activities. Toxicon 185, 129–146 (2020).

    Article  CAS  PubMed  Google Scholar 

  49. Altindis, E. et al. Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: a paradigm shift for host–microbe interactions. Proc. Natl Acad. Sci. USA 115, 2461–2466 (2018). Discovery that viruses encode insulin-like peptides that can activate human insulin and IGF-1 receptor signaling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chrudinová, M. et al. Characterization of viral insulins reveals white adipose tissue-specific effects in mice. Mol. Metab. 44, 101121 (2021).

    Article  PubMed  Google Scholar 

  51. Zhang, F., Altindis, E., Kahn, C. R., DiMarchi, R. D. & Gelfanov, V. A viral insulin-like peptide is a natural competitive antagonist of the human IGF-1 receptor. Mol. Metab. 53, 101316 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Huang, Q., Kahn, C. R. & Altindis, E. Viral hormones: expanding dimensions in endocrinology. Endocrinology 160, 2165–2179 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Girdhar, K. et al. Viruses and metabolism: the effects of viral infections and viral insulins on host metabolism. Annu. Rev. Virol. 8, 373–391 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Nadkarni, P., Chepurny, O. G. & Holz, G. G. Regulation of glucose homeostasis by GLP-1. Prog. Mol. Biol. Transl. Sci. 121, 23–65 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mentlein, R., Gallwitz, B. & Schmidt, W. E. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur. J. Biochem. 214, 829–835 (1993).

    Article  CAS  PubMed  Google Scholar 

  56. Tsend-Ayush, E. et al. Monotreme glucagon-like peptide-1 in venom and gut: one gene—two very different functions. Sci. Rep. 6, 37744 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wong, E. S., Nicol, S., Warren, W. C. & Belov, K. Echidna venom gland transcriptome provides insights into the evolution of monotreme venom. PLoS ONE 8, e79092 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Xu, X. & Lai, R. The chemistry and biological activities of peptides from amphibian skin secretions. Chem. Rev. 115, 1760–1846 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Montecucchi, P. C., de Castiglione, R., Piani, S., Gozzini, L. & Erspamer, V. Amino acid composition and sequence of dermorphin, a novel opiate-like peptide from the skin of Phyllomedusa sauvagei. Int. J. Pept. Protein Res. 17, 275–283 (1981).

    Article  CAS  PubMed  Google Scholar 

  60. Hesselink, J. M. K. & Schatman, M. E. Rediscovery of old drugs: the forgotten case of dermorphin for postoperative pain and palliation. J. Pain. Res. 11, 2991–2995 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Anastasi, A., Erspamer, V. & Bucci, M. Isolation and structure of bombesin and alytesin, 2 analogous active peptides from the skin of the European amphibians Bombina and Alytes. Experientia 27, 166–167 (1971).

    Article  CAS  PubMed  Google Scholar 

  62. Ladenheim, E. E. in Handbook of Biologically Active Peptides (ed. Kastin, A. J.) Ch. 142, 1064–1070 (Academic, 2013).

  63. Bordon, K. C. F. et al. From animal poisons and venoms to medicines: achievements, challenges and perspectives in drug discovery. Front. Pharmacol. 11, 1132 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Schweitz, H., Vigne, P., Moinier, D., Frelin, C. & Lazdunski, M. A new member of the natriuretic peptide family is present in the venom of the green mamba (Dendroaspis angusticeps). J. Biol. Chem. 267, 13928–13932 (1992).

    Article  CAS  PubMed  Google Scholar 

  65. Sridharan, S., Kini, R. M. & Richards, A. M. Venom natriuretic peptides guide the design of heart failure therapeutics. Pharmacol. Res. 155, 104687 (2020).

    Article  CAS  PubMed  Google Scholar 

  66. Behbehani, M. M. & Pert, A. A mechanism for the analgesic effect of neurotensin as revealed by behavioral and electrophysiological techniques. Brain Res. 324, 35–42 (1984).

    Article  CAS  PubMed  Google Scholar 

  67. Safavi-Hemami, H., Brogan, S. E. & Olivera, B. M. Pain therapeutics from cone snail venoms: from Ziconotide to novel non-opioid pathways. J. Proteomics 190, 12–20 (2019).

    Article  CAS  PubMed  Google Scholar 

  68. Kumar, U. in Peripheral Receptor Targets for Analgesia (ed. Cairns, B. E.) Ch. 16, 397–417 (John Wiley & Sons, 2009).

  69. Ramiro, I. B. L. et al. Somatostatin venom analogs evolved by fish-hunting cone snails: from prey capture behavior to identifying drug leads. Sci. Adv. 8, eabk1410 (2022).

  70. Koch, T. L. et al. Reconstructing the origins of the somatostatin and allatostatin-C signaling systems using the accelerated evolution of biodiverse cone snail venoms. Mol. Biol. Evol. 39, msac075 (2022).

  71. Edgerton, D. S. et al. Targeting insulin to the liver corrects defects in glucose metabolism caused by peripheral insulin delivery. JCI Insight 5, e126974 (2019).

  72. Jensen, M., Hansen, B., De Meyts, P., Schäffer, L. & Ursø, B. Activation of the insulin receptor by insulin and a synthetic peptide leads to divergent metabolic and mitogenic signaling and responses. J. Biol. Chem. 282, 35179–35186 (2007). Important study indicating that ligands with different binding nodes toward IR can lead to biased signaling.

    Article  CAS  PubMed  Google Scholar 

  73. Schäffer, L. et al. A novel high-affinity peptide antagonist to the insulin receptor. Biochem. Biophys. Res. Commun. 376, 380–383 (2008).

    Article  PubMed  Google Scholar 

  74. De Leon, D. D. & Stanley, C. A. Congenital hypoglycemia disorders: new aspects of etiology, diagnosis, treatment and outcomes: highlights of the Proceedings of the Congenital Hypoglycemia Disorders Symposium, Philadelphia April 2016. Pediatr. Diabetes 18, 3–9 (2017).

    Article  PubMed  Google Scholar 

  75. Strodel, R. J. & Greene, J. A. Origins of the insulin crisis: how a century of price-fixing controversies affects the cost of care today. Lancet 398, 1793–1795 (2021). Important review on the history of the ‘insulin crisis’.

    Article  CAS  Google Scholar 

  76. Blanchette, J. E. et al. GoFundMe as a medical plan: ecological study of crowdfunding insulin success. JMIR Diabetes 7, e33205 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Beran, D., Ewen, M. & Laing, R. Constraints and challenges in access to insulin: a global perspective. Lancet Diabetes Endocrinol. 4, 275–285 (2016).

    Article  PubMed  Google Scholar 

  78. Herkert, D. et al. Cost-related insulin underuse among patients with diabetes. JAMA Intern. Med. 179, 112–114 (2019).

    Article  PubMed  Google Scholar 

  79. Luo, J., Kesselheim, A. S., Greene, J. & Lipska, K. J. Strategies to improve the affordability of insulin in the USA. Lancet 5, 158–159 (2017).

    Google Scholar 

  80. Sachkova, M. Y. et al. Toxin-like neuropeptides in the sea anemone Nematostella unravel recruitment from the nervous system to venom. Proc. Natl Acad. Sci. USA 117, 27481–27492 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Roelants, K. et al. Origin and functional diversification of an amphibian defense peptide arsenal. PLoS Genet. 9, e1003662 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Undheim, E. A. et al. Weaponization of a hormone: convergent recruitment of hyperglycemic hormone into the venom of arthropod predators. Structure 23, 1283–1292 (2015).

    Article  CAS  PubMed  Google Scholar 

  83. Eagles, D. A. et al. A peptide toxin in ant venom mimics vertebrate EGF-like hormones to cause long-lasting hypersensitivity in mammals. Proc. Natl Acad. Sci. USA 119, e2112630119 (2022).

  84. LeRoith, D., Shiloach, J., Roth, J. & Lesniak, M. A. Insulin or a closely related molecule is native to Escherichia coli. J. Biol. Chem. 256, 6533–6536 (1981).

    Article  CAS  PubMed  Google Scholar 

  85. Irwin, D. M. Viral hormones: do they impact human endocrinology? Endocrinology 160, 2326–2327 (2019).

    Article  CAS  PubMed  Google Scholar 

  86. Floyd, P. D. et al. Insulin prohormone processing, distribution, and relation to metabolism in Aplysia californica. J. Neurosci. 19, 7732–7741 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mirdita, M. et al. ColabFold: making protein folding accessible to all. Nat. Methods 19, 679–682 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank T. Lund Koch for assistance with structural predictions of VILPs and sequence analysis of venom insulins, P. Flórez Salcedo for illustrations used in the graphical abstract and Y.W. Zhang for helpful discussion of viral insulin sequences. H.S.-H. and S.H.L. receive support from the Carlsberg Foundation (CF19-0445). D.H.-C.C. receives support from National Institute of Health (DK120430).

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

    Sophie Heiden Laugesen & Helena Safavi-Hemami

  2. Department of Pediatrics, Division of Endocrinology and Diabetes, Stanford University, Stanford, CA, USA

    Danny Hung-Chieh Chou

  3. Department of Biochemistry, University of Utah, Salt Lake City, UT, USA

    Helena Safavi-Hemami

  4. School of Biological Sciences, University of Utah, Salt Lake City, UT, USA

    Helena Safavi-Hemami

Authors
  1. Sophie Heiden Laugesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Danny Hung-Chieh Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Helena Safavi-Hemami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helena Safavi-Hemami.

Ethics declarations

Competing interests

D.H.-C.C. and H.S.-H. hold patents on the insulin analogs mini-Ins G1 and Vh-Ins-HSLQ.

Peer review

Peer review information

Nature Chemical Biology thanks Emrah Altindis and Alexander Zaykov for their contribution to the peer review of this work.

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Laugesen, S.H., Chou, D.HC. & Safavi-Hemami, H. Unconventional insulins from predators and pathogens. Nat Chem Biol 18, 688–697 (2022). https://doi.org/10.1038/s41589-022-01068-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41589-022-01068-6

Search

Advanced 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