Advertisement

Molecular Medicine

, Volume 19, Issue 1, pp 305–313 | Cite as

A Journey in Science: Promise, Purpose, Privilege

  • Carl Nathan
Anthony Cerami Award in Translational Medicine

Abstract

Real innovations in medicine and science are historic and singular; the stories behind each occurrence are precious. At Molecular Medicine we have established the Anthony Cerami Award in Translational Medicine to document and preserve these histories. The monographs recount the seminal events as told in the voice of the original investigators who provided the crucial early insight. These essays capture the essence of discovery, chronicling the birth of ideas that created new fields of research; and launched trajectories that persisted and ultimately influenced how disease is prevented, diagnosed, and treated. In this volume, the first Cerami Award Monograph, by Carl Nathan, MD, chairman of the Department of Microbiology and Immunology at Weill Cornell Medical College, reflects towering genius and soaring inspiration.

References

  1. 1.
    Boyden S. (1962) The chemotactic effect of mixtures of antibody and antigen on polymorphonuclear leucocytes. J. Exp. Med. 115:453–66.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Nathan C. (2002) Points of control in inflammation. Nature. 420:846–52.CrossRefGoogle Scholar
  3. 3.
    Nathan C, Shiloh MU. (2000) Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc. Natl. Acad. Sci. U. S. A. 97:8841–8.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Nathan C. (1992) Nitric oxide as a secretory product of mammalian cells. FASEB J. 6:3051–64.CrossRefPubMedGoogle Scholar
  5. 5.
    Nathan C. (2003) Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling. J. Clin. Invest. 111:769–78.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Nathan C, Cunningham-Bussel A. (2013) Beyond oxidative stress: an immunologist’s guide to reactive oxygen species. Nat. Rev. Immunol. 13:349–61.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mackaness GB. (1962) Cellular resistance to infection. J. Exp. Med. 116:381–406.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Mackaness GB. (1964) The immunological basis of acquired cellular resistance. J. Exp. Med. 120:105–120.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Mackaness GB, Blanden RV. (1967) Cellular immunity. Prog. Allergy. 11:89–140.PubMedGoogle Scholar
  10. 10.
    David JR. (1966) Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc. Natl. Acad. Sci. U. S. A. 56:72–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bloom BR, Bennett B. (1966) Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science. 153:80–2.CrossRefPubMedGoogle Scholar
  12. 12.
    Ward PA, Remold HG, David JR. (1969) Leukotactic factor produced by sensitized lymphocytes. Science. 163:1079–81.CrossRefPubMedGoogle Scholar
  13. 13.
    Granger GA, Shacks SJ, Williams TW, Kolb WP. (1969) Lymphocyte in vitro cytotoxicity: specific release of lymphotoxin-like materials from tuberculin-sensitive lymphoid cells. Nature. 221:1155–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Baehner RL, Gilman N, Karnovsky ML. (1970) Respiration and glucose oxidation in human and guinea pig leukocytes: comparative studies. J. Clin. Invest. 49:692–700.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Noseworthy J Jr, Karnovsky ML. (1972) Role of peroxide in the stimulation of the hexose monophosphate shunt during phagocytosis by polymorphonuclear leukocytes. Enzyme. 13:110–31.CrossRefPubMedGoogle Scholar
  16. 16.
    Nathan CF, Rosenberg SA, Karnovsky ML, David JR. (1970) Effects of MIF-rich supernatants on macrophages. In: Harris JE, editor, Proceedings [of the Fifth Leukocyte Culture Conference]; 1970 Jun 25–27; Ottawa, Ontario, Canada. New York: Academic Press. pp. 629–638.Google Scholar
  17. 17.
    Nathan CF, Karnovsky ML, David JR. (1971) Alterations of macrophage functions by mediators from lymphocytes. J. Exp. Med. 133:1356–76.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Nathan CF, Remold HG, David JR. (1973) Characterization of a lymphocyte factor which alters macrophage functions. J. Exp. Med. 137:275–90.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Fowles RE, Fajardo IM, Leibowitch JL, David JR. (1973) The enhancement of macrophage bacteriostasis by products of activated lymphocytes. J. Exp. Med. 138:952–64.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Nathan CF, Root RK. (1977) Hydrogen peroxide release from mouse peritoneal macrophages: dependence on sequential activation and triggering. J. Exp. Med. 146:1646–62.CrossRefGoogle Scholar
  21. 21.
    Nathan CF. (2011) Ralph Steinman, 1943–2011. Nat. Immunol. 12:1129–34.CrossRefGoogle Scholar
  22. 22.
    Griffin FM Jr, Griffin JA, Leider JE, Silverstein SC. (1975) Studies on the mechanism of phagocytosis. I. Requirements for circumferential attachment of particle-bound ligands to specific receptors on the macrophage plasma membrane. J. Exp. Med. 142:1263–82.CrossRefPubMedGoogle Scholar
  23. 23.
    Luster AD, Unkeless JC, Ravetch JV. (1985) Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature. 315:672–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Nathan CF, Murray HW, Wiebe ME, Rubin BY. (1983) Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J. Exp. Med. 158:670–89.CrossRefPubMedGoogle Scholar
  25. 25.
    Murray HW, Rubin BY, Rothermel CD. (1983) Killing of intracellular Leishmania donovani by lymphokine-stimulated human mononuclear phagocytes: evidence that interferon-gamma is the activating lymphokine. J. Clin. Invest. 72:1506–10.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Van Voorhis WC, et al. (1982) The cutaneous infiltrates of leprosy: cellular characteristics and the predominant T-cell phenotypes. N. Engl. J. Med. 307:1593–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Nathan CF, et al. (1986) Local and systemic effects of intradermal recombinant interferon-gamma in patients with lepromatous leprosy. N. Engl. J. Med. 315:6–15.CrossRefPubMedGoogle Scholar
  28. 28.
    Nathan C, et al. (1990) Widespread intradermal accumulation of mononuclear leukocytes in lepromatous leprosy patients treated systemically with recombinant interferon gamma. J. Exp. Med. 172:1509–12.CrossRefPubMedGoogle Scholar
  29. 29.
    Nathan CF, et al. (1985) Administration of recombinant interferon gamma to cancer patients enhances monocyte secretion of hydrogen peroxide. Proc. Natl. Acad. Sci. U. S. A. 82:8686–90.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Badaro R, et al. (1990) Treatment of visceral leishmaniasis with pentavalent antimony and interferon gamma. N. Engl. J. Med. 322:16–21.CrossRefPubMedGoogle Scholar
  31. 31.
    Ezekowitz RA, Dinauer MC, Jaffe HS, Orkin SH, Newburger PE. (1988) Partial correction of the phagocyte defect in patients with X-linked chronic granulomatous disease by subcutaneous interferon gamma. N. Engl. J. Med. 319:146–51.CrossRefPubMedGoogle Scholar
  32. 32.
    Murray HW, Spitalny GL, Nathan CF. (1985) Activation of mouse peritoneal macrophages in vitro and in vivo by interferon-gamma. J. Immunol. 134:1619–22.PubMedGoogle Scholar
  33. 33.
    Kamijo R, et al. (1993) Mice that lack the interferon-gamma receptor have profoundly altered responses to infection with Bacillus Calmette-Guerin and subsequent challenge with lipopolysaccharide. J. Exp. Med. 178:1435–40.CrossRefPubMedGoogle Scholar
  34. 34.
    Jouanguy E, et al. (1996) Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection. N. Engl. J. Med. 335:1956–61.CrossRefPubMedGoogle Scholar
  35. 35.
    Szuro-Sudol A, Nathan CF. (1982) Suppression of macrophage oxidative metabolism by products of malignant and nonmalignant cells. J. Exp. Med. 156:945–61.CrossRefPubMedGoogle Scholar
  36. 36.
    Srimal S, Nathan C. (1990) Purification of macrophage deactivating factor. J. Exp. Med. 171:1347–61.CrossRefPubMedGoogle Scholar
  37. 37.
    Tsunawaki S, Sporn M, Ding A, Nathan C. (1988) Deactivation of macrophages by transforming growth factor-beta. Nature. 334:260–2.CrossRefPubMedGoogle Scholar
  38. 38.
    Bogdan C, Vodovotz Y, Nathan C. (1991) Macrophage deactivation by interleukin 10. J. Exp. Med. 174:1549–55.CrossRefPubMedGoogle Scholar
  39. 39.
    Arrick BA, Nathan CF, Cohn ZA. (1983) Inhibition of glutathione synthesis augments lysis of murine tumor cells by sulfhydryl-reactive antineoplastics. J. Clin. Invest. 71:256–67.CrossRefGoogle Scholar
  40. 40.
    Nathan C, Brukner L, Kaplan G, Unkeless J, Cohn Z. (1980) Role of activated macrophages in antibody-dependent lysis of tumor cells. J. Exp. Med. 152:183–97.CrossRefPubMedGoogle Scholar
  41. 41.
    Nathan C, Cohn Z. (1980) Role of oxygen-dependent mechanisms in antibody-induced lysis of tumor cells by activated macrophages. J. Exp. Med. 152:196–208.Google Scholar
  42. 42.
    Nathan CF, Arrick BA, Murray HW, DeSantis NM, Cohn ZA. (1981) Tumor cell anti-oxidant defenses: inhibition of the glutathione redox cycle enhances macrophage-mediated cytolysis. J. Exp. Med. 153:766–82.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Nathan CF, Brukner LH, Silverstein SC, Cohn ZA. (1979) Extracellular cytolysis by activated macrophages and granulocytes. I. Pharmacologic triggering of effector cells and the release of hydrogen peroxide. J. Exp. Med. 149:84–99.CrossRefPubMedGoogle Scholar
  44. 44.
    Nathan CF, Cohn ZA. (1981) Antitumor effects of hydrogen peroxide in vivo. J. Exp. Med. 154:1539–53.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Nathan CF, Klebanoff SJ. (1982) Augmentation of spontaneous macrophage-mediated cytolysis by eosinophil peroxidase. J. Exp. Med. 155:1291–308.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Nathan CF, Silverstein SC, Brukner LH, Cohn ZA. (1979) Extracellular cytolysis by activated macrophages and granulocytes. II. Hydrogen peroxide as a mediator of cytotoxicity. J. Exp. Med. 149:100–13.CrossRefPubMedGoogle Scholar
  47. 47.
    Nathan CF, Terry WD. (1975) Differential stimulation of murine lymphoma growth in vitro by normal and BCG-activated macrophages. J. Exp. Med. 142:887–902.CrossRefPubMedGoogle Scholar
  48. 48.
    O’Donnell-Tormey J, DeBoer CJ, Nathan CF. (1985) Resistance of human tumor cells in vitro to oxidative cytolysis. J. Clin. Invest. 76:80–6. 49. Szatrowski TP, Nathan CF. (1991) Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 51:794–8.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 50.
    Shen C, Nathan C. (2002) Nonredundant antioxidant defense by multiple two-cysteine peroxire-doxins in human prostate cancer cells. Mol. Med. 8:95–102.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 51.
    Hibbs JB Jr, Taintor RR, Vavrin Z. (1987) Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science. 235:473–6.CrossRefPubMedGoogle Scholar
  51. 52.
    Kwon NS, Nathan CF, Stuehr DJ. (1989) Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages. J. Biol. Chem. 264:20496–501.PubMedGoogle Scholar
  52. 53.
    Kwon NS, Stuehr DJ, Nathan CF. (1991) Inhibition of tumor cell ribonucleotide reductase by macrophage-derived nitric oxide. J. Exp. Med. 174:761–7.CrossRefPubMedGoogle Scholar
  53. 54.
    Stuehr DJ, Cho HJ, Kwon NS, Weise MF, Nathan CF. (1991) Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein. Proc. Natl. Acad. Sci. U. S. A. 88:7773–7.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 55.
    Stuehr DJ, et al. (1991) Inhibition of macrophage and endothelial cell nitric oxide synthase by diphenyleneiodonium and its analogs. FASEB J. 5:96–103.CrossRefGoogle Scholar
  55. 56.
    Stuehr DJ, Gross SS, Sakuma I, Levi R, Nathan CF. (1989) Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide. J. Exp. Med. 169:1011–20.CrossRefPubMedGoogle Scholar
  56. 57.
    Stuehr DJ, et al. (1989) Synthesis of nitrogen oxides from L-arginine by macrophage cytosol: requirement for inducible and constitutive components. Biochem. Biophys. Res. Commun. 161:420–6.CrossRefPubMedGoogle Scholar
  57. 58.
    Stuehr DJ, Kwon NS, Nathan CF. (1990) FAD and GSH participate in macrophage synthesis of nitric oxide. Biochem. Biophys. Res. Commun. 168:556–65.CrossRefGoogle Scholar
  58. 59.
    Stuehr DJ, et al. (1991) N omega-hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine. J. Biol. Chem. 266:6259–63.PubMedGoogle Scholar
  59. 60.
    Stuehr DJ, Nathan CF. (1989) Nitric oxide: a macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J. Exp. Med. 169:1543–55.CrossRefPubMedGoogle Scholar
  60. 61.
    Tayeh MA, Marletta MA. (1989) Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate: tetrahydrobiopterin is required as a cofactor. J. Biol. Chem. 264:19654–8.PubMedGoogle Scholar
  61. 62.
    Xie QW, et al. (1992) Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science. 256:225–8.CrossRefPubMedGoogle Scholar
  62. 63.
    Xie QW, Kashiwabara Y, Nathan C. (1994) Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J. Biol. Chem. 269:4705–8.PubMedGoogle Scholar
  63. 64.
    Xie QW, Nathan C. (1993) Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon-gamma and bacterial lipopolysaccharide. Trans Assoc. Am. Physicians. 106:1–12.PubMedGoogle Scholar
  64. 65.
    Nathan C, Xie QW. (1994) Nitric oxide synthases: roles, tolls, and controls. Cell 78:915–8.CrossRefPubMedGoogle Scholar
  65. 66.
    Bredt DS, et al. (1991) Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature. 351:714–8.CrossRefPubMedGoogle Scholar
  66. 67.
    Cho HJ, et al. (1992) Calmodulin is a subunit of nitric oxide synthase from macrophages. J. Exp. Med. 176:599–604.CrossRefPubMedGoogle Scholar
  67. 68.
    Ruan J, et al. (1996) Inducible nitric oxide synthase requires both the canonical calmodulin-binding domain and additional sequences in order to bind calmodulin and produce nitric oxide in the absence of free Ca2+. J. Biol. Chem. 271:22679–86.CrossRefPubMedGoogle Scholar
  68. 69.
    Shen Y, Zhukovskaya NL, Guo Q, Florian J, Tang WJ. (2005) Calcium-independent calmodulin binding and two-metal-ion catalytic mechanism of anthrax edema factor. EMBO J. 24(5):929–41.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 70.
    MacMicking JD, et al. (1995) Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell. 81:641–50.CrossRefPubMedGoogle Scholar
  70. 71.
    Laubach VE, Shesely EG, Smithies O, Sherman PA. (1995) Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc. Natl. Acad. Sci. U. S. A. 92:10686–92.CrossRefGoogle Scholar
  71. 72.
    MacMicking JD, et al. (1997) Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc. Natl. Acad. Sci. U. S. A. 94:5243–8.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 73.
    Karupiah G, et al. (1993) Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science. 261:1445–8.CrossRefPubMedGoogle Scholar
  73. 74.
    Nathan C, et al. (2005) Protection from Alzheimer’s-like disease in the mouse by genetic ablation of inducible nitric oxide synthase. J. Exp. Med. 202:1163–9.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 75.
    Perreault M, Marette A. (2001) Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat. Med. 7:1136–43.CrossRefGoogle Scholar
  75. 76.
    Nathan C. (2011) Is iNOS beginning to smoke? Cell. 147:257–8.CrossRefPubMedGoogle Scholar
  76. 77.
    Seimetz M, et al. (2011) Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice. Cell. 147:293–305.CrossRefPubMedGoogle Scholar
  77. 78.
    Nathan C, Ding A. (2010) Nonresolving inflammation. Cell. 140:871–82.CrossRefPubMedGoogle Scholar
  78. 79.
    Shiloh MU, et al. (1999) Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible nitric oxide synthase. Immunity. 10:29–38.CrossRefPubMedGoogle Scholar
  79. 80.
    Nathan C. (2004) Antibiotics at the crossroads. Nature. 431:899–902.CrossRefPubMedGoogle Scholar
  80. 81.
    Nathan C. (2007) Aligning pharmaceutical innovation with medical need. Nat. Med. 13:304–8.CrossRefPubMedGoogle Scholar
  81. 82.
    Nathan C. (2009) Taming tuberculosis: a challenge for science and society. Cell Host Microbe. 5:220–4.CrossRefPubMedGoogle Scholar
  82. 83.
    Nathan C. (2011) Making space for anti-infective drug discovery. Cell Host Microbe. 9:343–8.CrossRefPubMedGoogle Scholar
  83. 84.
    Nathan CF. (2012) Bacterial pathogenesis: fresh approaches to anti-infective therapies. Science Translational Medicine. 4:140sr142.CrossRefGoogle Scholar
  84. 85.
    Bryk R, et al. (2008) Selective killing of nonreplicating mycobacteria. Cell Host Microbe. 3:137–45.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 86.
    Bryk R, Griffin P, Nathan C. (2000) Peroxynitrite reductase activity of bacterial peroxiredoxins. Nature. 407:211–5.CrossRefPubMedGoogle Scholar
  86. 87.
    Bryk R, Lima CD, Erdjument-Bromage H, Tempst P, Nathan C. (2002) Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science. 295:1073–7.CrossRefPubMedGoogle Scholar
  87. 88.
    Darwin KH, Ehrt S, Gutierrez-Ramos JC, Weich N, Nathan CF. (2003) The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science 302:1963–6.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 89.
    Lin G, et al. (2009) Inhibitors selective for mycobacterial versus human proteasomes. Nature. 461:621–6.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 90.
    Vandal OH, Pierini LM, Schnappinger D, Nathan CF, Ehrt S. (2008) A membrane protein preserves intrabacterial pH in intraphagosomal Mycobacterium tuberculosis. Nat. Med. 14:849–54.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 91.
    Venugopal A, et al. (2011) Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. Cell Host Microbe. 9:21–31.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 92.
    Wu K, et al. (2012) Improved control of tuberculosis and activation of macrophages in mice lacking protein kinase R. PLoS One. 7:e30512.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Author(s) 2013

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  1. 1.Weill Cornell Medical CollegeNew YorkUSA

Personalised recommendations