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.

  • Metabolic Messengers
  • Published:

Metabolic Messengers: fibroblast growth factor 15/19

Nature Metabolism volume 1, pages 588–594 (2019)Cite this article

Subjects

Abstract

Fibroblast growth factor (FGF) 15 in mice and its human orthologue FGF19 (together denoted FGF15/19) are gut hormones that control homeostasis of bile acids and glucose during the transition from the fed to the fasted state. Apart from its central role in the regulation of bile acid homeostasis, FGF15/19 is now recognized as a transversal metabolic coordinator at the crossroads of the gut, liver, brain and white adipose tissue. Dysregulation of FGF15/19 signalling may contribute to the pathogenesis of several diseases affecting the gut–liver axis and to metabolic diseases. Here, we provide an overview of current knowledge of the physiological roles of the enterokine FGF15/19 and highlight commonalities and differences between the two orthologues. We also discuss the putative therapeutic potential in areas of unmet medical need—such has cholestatic liver diseases and non-alcoholic steatohepatitis, for which FGF19 is being tested in ongoing clinical trials—as well as the possibility of using FGF19 for the treatment of obesity and type II diabetes.

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: Timeline of major discoveries in FGF15/19 identification and biological functions.
Fig. 2: FGF15/19 production and hepatic metabolic effects.
Fig. 3: Metabolic control and receptor specificity of the enterokine FGF15/19.

Similar content being viewed by others

References

  1. Beenken, A. & Mohammadi, M. The FGF family: biology, pathophysiology and therapy. Nat. Rev. Drug Discov. 8, 235–253 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Itoh, N. & Ornitz, D. M. Evolution of the Fgf and Fgfr gene families. Trends Genet. 20, 563–569 (2004).

    CAS  PubMed  Google Scholar 

  3. McWhirter, J. R., Goulding, M., Weiner, J. A., Chun, J. & Murre, C. A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1. Development 124, 3221–3232 (1997).

    CAS  PubMed  Google Scholar 

  4. Nishimura, T., Utsunomiya, Y., Hoshikawa, M., Ohuchi, H. & Itoh, N. Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain. Biochim. Biophys. Acta 1444, 148–151 (1999).

    CAS  PubMed  Google Scholar 

  5. Katoh, M. & Katoh, M. Evolutionary conservation of CCND1-ORAOV1-FGF19-FGF4 locus from zebrafish to human. Int. J. Mol. Med. 12, 45–50 (2003).

    CAS  PubMed  Google Scholar 

  6. Fon Tacer, K. et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol. Endocrinol. 24, 2050–2064 (2010).

    PubMed  PubMed Central  Google Scholar 

  7. Choi, M. et al. Identification of a hormonal basis for gallbladder filling. Nat. Med. 12, 1253–1255 (2006).

    CAS  PubMed  Google Scholar 

  8. Holt, J. A. et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 17, 1581–1591 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Inagaki, T. et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2, 217–225 (2005).

    CAS  PubMed  Google Scholar 

  10. Song, K. H., Li, T., Owsley, E., Strom, S. & Chiang, J. Y. Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression. Hepatology 49, 297–305 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kir, S. et al. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science 331, 1621–1624 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Potthoff, M. J. et al. FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway. Cell Metab. 13, 729–738 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu, X. et al. Co-receptor requirements for fibroblast growth factor-19 signaling. J. Biol. Chem. 282, 29069–29072 (2007).

    CAS  PubMed  Google Scholar 

  14. Kurosu, H. et al. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem. 282, 26687–26695 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Lin, B. C. & Desnoyers, L. R. FGF19 and cancer. Adv. Exp. Med. Biol. 728, 183–194 (2012).

    CAS  PubMed  Google Scholar 

  16. Miyata, M. et al. Involvement of multiple elements in FXR-mediated transcriptional activation of FGF19. J. Steroid Biochem. Mol. Biol. 132, 41–47 (2012).

    CAS  PubMed  Google Scholar 

  17. Lundåsen, T., Gälman, C., Angelin, B. & Rudling, M. Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J. Intern. Med. 260, 530–536 (2006).

    PubMed  Google Scholar 

  18. Wang, C. et al. Hepatocyte FRS2α is essential for the endocrine fibroblast growth factor to limit the amplitude of bile acid production induced by prandial activity. Curr. Mol. Med. 14, 703–711 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Li, S. et al. Cytoplasmic tyrosine phosphatase Shp2 coordinates hepatic regulation of bile acid and FGF15/19 signaling to repress bile acid synthesis. Cell Metab. 20, 320–332 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Ito, S. et al. Impaired negative feedback suppression of bile acid synthesis in mice lacking βKlotho. J. Clin. Invest. 115, 2202–2208 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Tomiyama, K. et al. Relevant use of Klotho in FGF19 subfamily signaling system in vivo. Proc. Natl Acad. Sci. USA 107, 1666–1671 (2010).

    CAS  PubMed  Google Scholar 

  22. Yu, C. et al. Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. J. Biol. Chem. 275, 15482–15489 (2000).

    CAS  PubMed  Google Scholar 

  23. Yu, C., Wang, F., Jin, C., Huang, X. & McKeehan, W. L. Independent repression of bile acid synthesis and activation of c-Jun N-terminal kinase (JNK) by activated hepatocyte fibroblast growth factor receptor 4 (FGFR4) and bile acids. J. Biol. Chem. 280, 17707–17714 (2005).

    CAS  PubMed  Google Scholar 

  24. Byun, S. et al. Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis. Nat. Commun. 9, 2590 (2018).

    PubMed  PubMed Central  Google Scholar 

  25. Kim, I. et al. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J. Lipid Res. 48, 2664–2672 (2007).

    CAS  PubMed  Google Scholar 

  26. Kir, S., Zhang, Y., Gerard, R. D., Kliewer, S. A. & Mangelsdorf, D. J. Nuclear receptors HNF4α and LRH-1 cooperate in regulating Cyp7a1 in vivo. J. Biol. Chem. 287, 41334–41341 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Nitta, M., Ku, S., Brown, C., Okamoto, A. Y. & Shan, B. CPF: an orphan nuclear receptor that regulates liver-specific expression of the human cholesterol 7alpha-hydroxylase gene. Proc. Natl Acad. Sci. USA 96, 6660–6665 (1999).

    CAS  PubMed  Google Scholar 

  28. Stroup, D. & Chiang, J. Y. HNF4 and COUP-TFII interact to modulate transcription of the cholesterol 7alpha-hydroxylase gene (CYP7A1). J. Lipid Res. 41, 1–11 (2000).

    CAS  PubMed  Google Scholar 

  29. Kong, B. et al. Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice. Hepatology 56, 1034–1043 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Lee, Y. K. et al. Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis. Mol. Endocrinol. 22, 1345–1356 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Fu, T. et al. FXR primes the liver for intestinal FGF15 signaling by transient induction of β-klotho. Mol. Endocrinol. 30, 92–103 (2016).

    CAS  PubMed  Google Scholar 

  32. Wunsch, E. et al. Expression of hepatic fibroblast growth factor 19 is enhanced in primary biliary cirrhosis and correlates with severity of the disease. Sci. Rep. 5, 13462 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Schaap, F. G., van der Gaag, N. A., Gouma, D. J. & Jansen, P. L. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology 49, 1228–1235 (2009).

    CAS  PubMed  Google Scholar 

  34. Zweers, S. J. et al. The human gallbladder secretes fibroblast growth factor 19 into bile: towards defining the role of fibroblast growth factor 19 in the enterobiliary tract. Hepatology 55, 575–583 (2012).

    CAS  PubMed  Google Scholar 

  35. Tomlinson, E. et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 143, 1741–1747 (2002).

    CAS  PubMed  Google Scholar 

  36. Fu, L. et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 145, 2594–2603 (2004).

    CAS  PubMed  Google Scholar 

  37. Shin, D. J. & Osborne, T. F. FGF15/FGFR4 integrates growth factor signaling with hepatic bile acid metabolism and insulin action. J. Biol. Chem. 284, 11110–11120 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Ge, H. et al. Fibroblast growth factor receptor 4 (FGFR4) deficiency improves insulin resistance and glucose metabolism under diet-induced obesity conditions. J. Biol. Chem. 289, 30470–30480 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Yu, X. X. et al. Peripheral reduction of FGFR4 with antisense oligonucleotides increases metabolic rate and lowers adiposity in diet-induced obese mice. PLoS One 8, e66923 (2013).

    PubMed  PubMed Central  Google Scholar 

  40. Wu, A. L. et al. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways. PLoS One 6, e17868 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Fisher, F. M. et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 59, 2781–2789 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Morton, G. J. et al. FGF19 action in the brain induces insulin-independent glucose lowering. J. Clin. Invest. 123, 4799–4808 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Coskun, T. et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 149, 6018–6027 (2008).

    CAS  PubMed  Google Scholar 

  44. Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Xu, J. et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58, 250–259 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. DePaoli, A.M. et al. FGF19 analogue as a surgical factor mimetic that contributes to metabolic effects beyond glucose homeostasis. Diabetesdb181305 (2019).

  47. Marcelin, G. et al. Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism. Mol. Metab. 3, 19–28 (2013).

    PubMed  PubMed Central  Google Scholar 

  48. Ryan, K. K. et al. Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. Endocrinology 154, 9–15 (2013).

    CAS  PubMed  Google Scholar 

  49. Lenicek, M. et al. Bile acid malabsorption in inflammatory bowel disease: assessment by serum markers. Inflamm. Bowel Dis. 17, 1322–1327 (2011).

    PubMed  Google Scholar 

  50. Walters, J. R. et al. A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis. Clin. Gastroenterol. Hepatol. 7, 1189–1194 (2009).

    CAS  PubMed  Google Scholar 

  51. Mráz, M. et al. Serum concentrations of fibroblast growth factor 19 in patients with obesity and type 2 diabetes mellitus: the influence of acute hyperinsulinemia, very-low calorie diet and PPAR-α agonist treatment. Physiol. Res. 60, 627–636 (2011).

    PubMed  Google Scholar 

  52. Schreuder, T. C. et al. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G440–G445 (2010).

    CAS  PubMed  Google Scholar 

  53. Reiche, M. et al. Fibroblast growth factor 19 serum levels: relation to renal function and metabolic parameters. Horm. Metab. Res. 42, 178–181 (2010).

    CAS  PubMed  Google Scholar 

  54. Ahn, S. M. et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 60, 1972–1982 (2014).

    CAS  PubMed  Google Scholar 

  55. Latasa, M. U. et al. Regulation of amphiregulin gene expression by β-catenin signaling in human hepatocellular carcinoma cells: a novel crosstalk between FGF19 and the EGFR system. PLoS One 7, e52711 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Sawey, E. T. et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell 19, 347–358 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Modica, S. et al. Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology 142, 355–65.e1, 4 (2012).

    CAS  PubMed  Google Scholar 

  58. Degirolamo, C. et al. Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation. Hepatology 61, 161–170 (2015).

    CAS  PubMed  Google Scholar 

  59. Mauad, T. H. et al. Mice with homozygous disruption of the mdr2 P-glycoprotein gene: a novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Am. J. Pathol. 145, 1237–1245 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Cariello, M. et al. Long-term administration of nuclear bile acid receptor FXR agonist prevents spontaneous hepatocarcinogenesis in Abcb4-/-mice. Sci. Rep. 7, 11203 (2017).

    PubMed  PubMed Central  Google Scholar 

  61. Kong, B. et al. Fibroblast growth factor 15 deficiency impairs liver regeneration in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G893–G902 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Uriarte, I. et al. Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice. Gut 62, 899–910 (2013).

    CAS  PubMed  Google Scholar 

  63. Nicholes, K. et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am. J. Pathol. 160, 2295–2307 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. French, D. M. et al. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS One 7, e36713 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Avila, M. A. & Moschetta, A. The FXR-FGF19 gut-liver axis as a novel “hepatostat”. Gastroenterology 149, 537–540 (2015).

    PubMed  Google Scholar 

  66. Naugler, W. E. et al. Fibroblast growth factor signaling controls liver size in mice with humanized livers. Gastroenterology 149, 728–40.e15 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Pai, R. et al. Antibody-mediated inhibition of fibroblast growth factor 19 results in increased bile acids synthesis and ileal malabsorption of bile acids in cynomolgus monkeys. Toxicol. Sci. 126, 446–456 (2012).

    CAS  PubMed  Google Scholar 

  68. Zhou, M. et al. Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res. 74, 3306–3316 (2014).

    CAS  PubMed  Google Scholar 

  69. Luo, J. et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci. Transl. Med. 6, 247ra100 (2014).

    PubMed  Google Scholar 

  70. Gadaleta, R. M. et al. Suppression of hepatic bile acid synthesis by a non-tumorigenic FGF19 analogue protects mice from fibrosis and hepatocarcinogenesis. Sci. Rep. 8, 17210 (2018).

    PubMed  PubMed Central  Google Scholar 

  71. Mayo, M. J. et al. NGM282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial. Hepatol. Commun. 2, 1037–1050 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Oduyebo, I. et al. Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation: a randomized phase 2 trial. Am. J. Gastroenterol. 113, 725–734 (2018).

    CAS  PubMed  Google Scholar 

  73. Hirschfield, G. M. et al. Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial. J. Hepatol. 70, 483–493 (2019).

    CAS  PubMed  Google Scholar 

  74. Harrison, S. A. et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 391, 1174–1185 (2018).

    CAS  PubMed  Google Scholar 

  75. Schmidt, D. R. et al. Regulation of bile acid synthesis by fat-soluble vitamins A and D. J. Biol. Chem. 285, 14486–14494 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Wistuba, W., Gnewuch, C., Liebisch, G., Schmitz, G. & Langmann, T. Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR. World J. Gastroenterol. 13, 4230–4235 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Henkel, A. S., Anderson, K. A., Dewey, A. M., Kavesh, M. H. & Green, R. M. A chronic high-cholesterol diet paradoxically suppresses hepatic CYP7A1 expression in FVB/NJ mice. J. Lipid Res. 52, 289–298 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Shimizu, M., Li, J., Maruyama, R., Inoue, J. & Sato, R. FGF19 (fibroblast growth factor 19) as a novel target gene for activating transcription factor 4 in response to endoplasmic reticulum stress. Biochem. J. 450, 221–229 (2013).

    CAS  PubMed  Google Scholar 

  79. Katafuchi, T. et al. Detection of FGF15 in plasma by stable isotope standards and capture by anti-peptide antibodies and targeted mass spectrometry. Cell Metab. 21, 898–904 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Lan, T. et al. FGF19, FGF21, and an FGFR1/β-Klotho-activating antibody act on the nervous system to regulate body weight and glycemia. Cell Metab. 26, 709–718.e3 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Pournaras, D. J. et al. The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology 153, 3613–3619 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Hansen, A. M. K. et al. Differential receptor selectivity of the FGF15/FGF19 orthologues determines distinct metabolic activities in db/db mice. Biochem. J. 475, 2985–2996 (2018).

    CAS  PubMed  Google Scholar 

  83. Zhou, M. et al. Mouse species-specific control of hepatocarcinogenesis and metabolism by FGF19/FGF15. J. Hepatol. 66, 1182–1192 (2017).

    CAS  PubMed  Google Scholar 

  84. Xie, M. H. et al. FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. Cytokine 11, 729–735 (1999).

    CAS  PubMed  Google Scholar 

  85. Zhou, M. et al. Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice. Hepatology 63, 914–929 (2016).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Interdisciplinary Medicine, University of Bari ‘Aldo Moro’, Bari, Italy

    Raffaella Maria Gadaleta & Antonio Moschetta

  2. National Cancer Center, IRCCS IstitutoTumori ‘Giovanni Paolo II’, Bari, Italy

    Antonio Moschetta

Authors
  1. Raffaella Maria Gadaleta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antonio Moschetta
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.M.G. performed bibliographic searching and wrote the manuscript; A.M. wrote the manuscript.

Corresponding author

Correspondence to Antonio Moschetta.

Ethics declarations

Competing interests

A.M. has received scientific grants from NGM Biopharmaceuticals (San Diego, CA, USA), which developed FGF19 analogues for the treatment of hepatic diseases during the years 2014–2016. R.M.G. declares no conflicts of interest.

Additional information

Peer review information: Primary Handling Editor: Christoph Schmitt.

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

Gadaleta, R.M., Moschetta, A. Metabolic Messengers: fibroblast growth factor 15/19. Nat Metab 1, 588–594 (2019). https://doi.org/10.1038/s42255-019-0074-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-019-0074-3

This article is cited by

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