title: Microbe hunting.
abstract: Platforms for pathogen discovery have improved since the days of Koch and Pasteur; nonetheless, the challenges of proving causation are at least as daunting as they were in the late 1800 s. Although we will almost certainly continue to accumulate low-hanging fruit, where simple relationships will be found between the presence of a cultivatable agent and a disease, these successes will be increasingly infrequent. The future of the field rests instead in our ability to follow footprints of infectious agents that cannot be characterized using classical microbiological techniques and to develop the laboratory and computational infrastructure required to dissect complex host-microbe interactions. I have tried to refine the criteria used by Koch and successors to prove linkage to disease. These refinements are working constructs that will continue to evolve in light of new technologies, new models, and new insights. What will endure is the excitement of the chase. Happy hunting!
authors.affiliation: Center for Infection and Immunity, Mailman School of Public Health, Columbia University, 722 West 168th Street, New York, NY 10032, USA. wil2001@columbia.edu
authors.forename: W Ian
authors.initials: WI
authors.lastname: Lipkin
mesh_terms: D001419:Bacteria / Q000302:isolation & purification; D001424:Bacterial Infections / Q000382:microbiology; D001426:Bacterial Proteins / Q000737:chemistry; D003141:Communicable Diseases / Q000188:drug therapy / Q000382:microbiology*; D006801:Humans; D055432:Metabolomics / Q000379:methods; D040901:Proteomics / Q000379:methods
chemical_list: D001426:Bacterial Proteins
references.citation: Proc Natl Acad Sci U S A. 1990 Jun;87(11):4184-8
references.pmid: 1693432
references.citation: Eur J Gastroenterol Hepatol. 2005 Aug;17(8):827-36
references.pmid: 16003132
references.citation: J Clin Virol. 2008 Oct;43(2):219-22
references.pmid: 18674964
references.citation: PLoS One. 2007 Oct 03;2(10):e966
references.pmid: 17912345
references.citation: Nucleic Acids Res. 2000 Jun 15;28(12):E63
references.pmid: 10871386
references.citation: J Infect Dis. 2007 Dec 15;196(12):1754-60
references.pmid: 18190255
references.citation: J Bacteriol. 2001 Jun;183(12):3770-83
references.pmid: 11371542
references.citation: Diagn Mol Pathol. 2006 Sep;15(3):169-73
references.pmid: 16932073
references.citation: Antimicrob Agents Chemother. 1988 Apr;32(4):492-7
references.pmid: 2837139
references.citation: Pediatr Infect Dis J. 2009 Jan;28(1):59-61
references.pmid: 19057460
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15687-92
references.pmid: 12429852
references.citation: Science. 1985 May 10;228(4700):755-6
references.pmid: 3922055
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1316-21
references.pmid: 12552129
references.citation: J Infect Dis. 2007 Sep 15;196(6):817-25
references.pmid: 17703411
references.citation: Am J Gastroenterol. 2000 Sep;95(9):2285-95
references.pmid: 11007230
references.citation: J Gen Virol. 2006 Oct;87(Pt 10):2827-2837
references.pmid: 16963740
references.citation: Lancet. 1998 Feb 28;351(9103):637-41
references.pmid: 9500320
references.citation: Nat Biotechnol. 1996 Mar;14(3):303-8
references.pmid: 9630890
references.citation: Antimicrob Agents Chemother. 1977 Jun;11(6):946-51
references.pmid: 879760
references.citation: Pediatr Rev. 1998 Sep;19(9):291-302
references.pmid: 9745311
references.citation: Nat Methods. 2009 Sep;6(9):647-9
references.pmid: 19668204
references.citation: BMJ. 1996 Feb 10;312(7027):335-8
references.pmid: 8611829
references.citation: Nature. 2001 Feb 22;409(6823):1092-101
references.pmid: 11234023
references.citation: Emerg Infect Dis. 2008 Jun;14(6):944-7
references.pmid: 18507910
references.citation: J Clin Microbiol. 2007 Feb;45(2):443-52
references.pmid: 17135438
references.citation: Lancet. 1997 Jan 18;349(9046):178-9
references.pmid: 9111548
references.citation: Science. 1990 Nov 30;250(4985):1278-81
references.pmid: 2244211
references.citation: Lancet. 1999 Oct 9;354(9186):1261-2
references.pmid: 10520637
references.citation: Microbiol Mol Biol Rev. 2000 Sep;64(3):548-72
references.pmid: 10974126
references.citation: J Bacteriol. 1937 Jan;33(1):1-12
references.pmid: 16559982
references.citation: J Clin Microbiol. 2007 Jul;45(7):2105-9
references.pmid: 17507510
references.citation: Science. 2006 Oct 13;314(5797):308-12
references.pmid: 16973841
references.citation: Appl Environ Microbiol. 2008 Aug;74(15):4898-909
references.pmid: 18487399
references.citation: J Clin Immunol. 2004 Nov;24(6):664-73
references.pmid: 15622451
references.citation: Mol Pathol. 2002 Apr;55(2):84-90
references.pmid: 11950955
references.citation: Dig Dis Sci. 2000 Apr;45(4):723-9
references.pmid: 10759242
references.citation: Ann N Y Acad Sci. 2007 Apr;1102:109-20
references.pmid: 17470915
references.citation: Emerg Infect Dis. 2008 Oct;14(10):1665-7
references.pmid: 18826844
references.citation: Virus Res. 2007 Jan;123(1):19-29
references.pmid: 16965832
references.citation: Biotechniques. 2004 Oct;37(4):642-4, 646, 648 passim
references.pmid: 15517976
references.citation: FEBS Lett. 1996 Jan 8;378(2):145-9
references.pmid: 8549821
references.citation: Emerg Infect Dis. 2008 Dec;14(12):1883-6
references.pmid: 19046511
references.citation: Microbiol Mol Biol Rev. 2004 Dec;68(4):669-85
references.pmid: 15590779
references.citation: Genome Biol. 2001;2(6):REVIEWS1017
references.pmid: 11423012
references.citation: Clin Cornerstone. 2003;Suppl 3:S12-20
references.pmid: 14992416
references.citation: Science. 1999 Dec 17;286(5448):2333-7
references.pmid: 10600742
references.citation: J Med Virol. 2007 May;79(5):605-15
references.pmid: 17385684
references.citation: Lancet. 2000 Aug 26;356(9231):772
references.pmid: 11085720
references.citation: N Engl J Med. 1992 Jul 30;327(5):293-301
references.pmid: 1377787
references.citation: J Pediatr. 2001 Mar;138(3):366-72
references.pmid: 11241044
references.citation: Virus Res. 2007 Jun;126(1-2):9-18
references.pmid: 17313986
references.citation: Microbiol Immunol. 1999;43(7):679-89
references.pmid: 10529109
references.citation: J Clin Microbiol. 2005 Nov;43(11):5721-32
references.pmid: 16272510
references.citation: FASEB J. 2009 Apr;23(4):1064-71
references.pmid: 19036857
references.citation: Emerg Infect Dis. 2007 Mar;13(3):396-403
references.pmid: 17552092
references.citation: Science. 1993 Nov 5;262(5135):914-7
references.pmid: 8235615
references.citation: PLoS One. 2008 Apr 02;3(4):e1847
references.pmid: 18382652
references.citation: Cell. 1990 Oct 19;63(2):353-62
references.pmid: 2170026
references.citation: Clin Infect Dis. 2006 Oct 15;43(8):e71-6
references.pmid: 16983602
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):732-7
references.pmid: 16407106
references.citation: Emerg Infect Dis. 2007 Jun;13(6):899-901
references.pmid: 17553231
references.citation: Lancet. 2000 May 6;355(9215):1614-5
references.pmid: 10821368
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2365-70
references.pmid: 19164560
references.citation: J Clin Microbiol. 2006 Nov;44(11):4157-62
references.pmid: 17005760
references.citation: Microbes Infect. 2006 Jun;8(7):1813-25
references.pmid: 16730210
references.citation: Proc Natl Acad Sci U S A. 2004 May 4;101(18):6888-93
references.pmid: 15107500
references.citation: Emerg Infect Dis. 2008 Nov;14(11):1793-6
references.pmid: 18976575
references.citation: Science. 2009 Jul 10;325(5937):204-6
references.pmid: 19590002
references.citation: J Neuroimmunol. 2006 Apr;173(1-2):126-34
references.pmid: 16494951
references.citation: MMWR Morb Mortal Wkly Rep. 2004 Apr 9;53(13):281-4
references.pmid: 15071426
references.citation: Rev Infect Dis. 1990 Nov-Dec;12(6):1139-46
references.pmid: 2267489
references.citation: J Pediatr. 1978 Oct;93(4):699-703
references.pmid: 702254
references.citation: J Virol Methods. 1997 Jun;66(1):39-50
references.pmid: 9220389
references.citation: Clin Microbiol Rev. 1998 Jul;11(3):480-96
references.pmid: 9665979
references.citation: J Neurovirol. 1999 Oct;5(5):495-9
references.pmid: 10568886
references.citation: J Virol. 2006 Apr;80(7):3135-46
references.pmid: 16537582
references.citation: Cell. 1995 May 5;81(3):323-30
references.pmid: 7736585
references.citation: Arch Microbiol. 1978 May 30;117(2):189-96
references.pmid: 678024
references.citation: J Med Virol. 2006 Sep;78(9):1232-40
references.pmid: 16847968
references.citation: Emerg Infect Dis. 2005 Feb;11(2):310-3
references.pmid: 15752453
references.citation: Annu Rev Microbiol. 1977;31:107-33
references.pmid: 334036
references.citation: J Infect Dis. 1999 Feb;179(2):295-302
references.pmid: 9878011
references.citation: Genome Res. 2004 Mar;14(3):398-405
references.pmid: 14993206
references.citation: J Clin Microbiol. 2004 Apr;42(4):1564-9
references.pmid: 15071005
references.citation: Clin Microbiol Rev. 1996 Jan;9(1):18-33
references.pmid: 8665474
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11404-9
references.pmid: 15277677
references.citation: Antiviral Res. 1985 Feb;5(1):39-48
references.pmid: 3985607
references.citation: Lancet. 1977 Mar 12;1(8011):571-3
references.pmid: 65662
references.citation: J Clin Virol. 2007 Jun;39(2):67-75
references.pmid: 17482871
references.citation: Nature. 2008 Jul 24;454(7203):436-44
references.pmid: 18650914
references.citation: J Neurovirol. 1999 Dec;5(6):604-12
references.pmid: 10602401
references.citation: Ann Neurol. 2002 Jun;51(6):673-80
references.pmid: 12112071
references.citation: Mass Spectrom Rev. 2005 Mar-Apr;24(2):265-85
references.pmid: 15389854
references.citation: J Clin Immunol. 2003 Nov;23(6):504-17
references.pmid: 15031638
references.citation: Microbiol Immunol. 1995;39(3):161-8
references.pmid: 7603360
references.citation: Emerg Infect Dis. 2006 Apr;12(4):692-5
references.pmid: 16704825
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2927-32
references.pmid: 17293459
references.citation: Science. 1964 May 15;144(3620):862-3
references.pmid: 14151624
references.citation: Clin Infect Dis. 2000 Mar;30(3):413-8
references.pmid: 10722421
references.citation: Nat Med. 2000 Dec;6(12):1375-9
references.pmid: 11100123
references.citation: Mol Psychiatry. 2002;7 Suppl 2:S44-6
references.pmid: 12142948
references.citation: Genome Res. 1996 Oct;6(10):986-94
references.pmid: 8908518
references.citation: Virology. 1995 Jun 20;210(1):1-8
references.pmid: 7793061
references.citation: Arch Gen Psychiatry. 2004 Aug;61(8):774-80
references.pmid: 15289276
references.citation: MMWR Morb Mortal Wkly Rep. 2003 Aug 15;52(32):769-72
references.pmid: 12917583
references.citation: N Engl J Med. 2001 Jun 14;344(24):1807-14
references.pmid: 11407341
references.citation: Emerg Infect Dis. 2007 Jan;13(1):73-81
references.pmid: 17370518
references.citation: PLoS One. 2008 Sep 04;3(9):e3140
references.pmid: 18769550
references.citation: J Clin Microbiol. 2007 Nov;45(11):3655-64
references.pmid: 17804649
references.citation: J Virol. 1995 Dec;69(12):8132-6
references.pmid: 7494336
references.citation: Pediatr Res. 2000 Jan;47(1):64-72
references.pmid: 10625084
references.citation: Proc Natl Acad Sci U S A. 1996 May 28;93(11):5177-84
references.pmid: 8643549
references.citation: Arch Virol. 1997;142(10):2035-42
references.pmid: 9413511
references.citation: Nat Rev Cancer. 2002 May;2(5):342-50
references.pmid: 12044010
references.citation: Vet Pathol. 2000 May;37(3):208-24
references.pmid: 10810985
references.citation: Neurology. 2000 Jan 11;54(1):20-5
references.pmid: 10636120
references.citation: J Allergy Clin Immunol. 2009 Jan;123(1):98-104.e1
references.pmid: 19027147
references.citation: Science. 1970 Jul 10;169(3941):203-4
references.pmid: 5427356
references.citation: J Infect Dis. 2003 Mar 15;187(6):1000-9
references.pmid: 12660947
references.citation: Neurology. 2004 Apr 27;62(8):1372-7
references.pmid: 15111676
references.citation: Cell. 1989 Dec 1;59(5):847-57
references.pmid: 2574076
references.citation: J Gen Virol. 2009 Jun;90(Pt 6):1371-1381
references.pmid: 19264616
references.citation: Nature. 2005 Sep 15;437(7057):356-61
references.pmid: 16163346
references.citation: N Engl J Med. 2008 Mar 6;358(10):991-8
references.pmid: 18256387
references.citation: Lancet. 1999 Oct 9;354(9186):1253-6
references.pmid: 10520634
references.citation: J Clin Microbiol. 2007 Jul;45(7):2340-3
references.pmid: 17494722
references.citation: PLoS One. 2009 Dec 31;4(12):e8540
references.pmid: 20046873
references.citation: J Infect Dis. 1997 Dec;176 Suppl 2:S125-8
references.pmid: 9396695
references.citation: J Virol Methods. 2007 Jan;139(1):78-84
references.pmid: 17052763
references.citation: Yale J Biol Med. 1976 May;49(2):175-95
references.pmid: 782050
references.citation: Nucleic Acids Res. 2006;34(22):6605-11
references.pmid: 17135211
references.citation: J Natl Cancer Inst. 1995 Jun 7;87(11):796-802
references.pmid: 7791229
references.citation: Science. 2005 Jun 10;308(5728):1635-8
references.pmid: 15831718
references.citation: Ann Neurol. 2001 Feb;49(2):249-53
references.pmid: 11221802
references.citation: Virol J. 2008 Jul 31;5:88
references.pmid: 18671869
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4250-5
references.pmid: 15016918
references.citation: Science. 2005 Oct 7;310(5745):77-80
references.pmid: 16210530
references.citation: J Infect Dis. 2006 Nov 15;194(10):1398-402
references.pmid: 17054069