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¹https://www.nimh.nih.gov/health/statistics/schizophrenia#part_2544.

²https://www.nimh.nih.gov/health/statistics/schizophrenia.

³https://www.nimh.nih.gov/health/statistics/schizophrenia#part_2715.

⁴Simon GE, et al. Psychiatric Services 2017;68(5):456-461. PMID: 28045349.

⁵https://www.nimh.nih.gov/health/topics/schizophrenia/raise.

⁶Sullivan HS. American Journal of Psychiatry 1994;151,6 Sesquicentennial Supplement:135-9. PMID: 8192188.

⁷Craig TK, et al. British Medical Journal 2004;329(7474):1067. PMID: 15485934.

⁸Petersen L, et al. British Medical Journal 2005;331(7517):602. PMID: 16141449.

⁹Kane JM, et al. American Journal of Psychiatry 2016;173(4):362-72. PMID: 26481174.

¹⁰Dixon LB, et al. Psychiatric Services 2015;66(7):691–98. PMID: 25772764.

¹¹Goldman HH. Schizophrenia Bulletin 2010;36(5):893–94. PMID: 20660023.

¹²Public Law 113–76—Jan. 17, 2014, 113th Congress. Available at: https://www.govinfo.gov/content/pkg/PLAW-113publ76/pdf/PLAW-113publ76.pdf.

¹³https://med.stanford.edu/peppnet.

¹⁴Correll CU, et al. JAMA Psychiatry 2014;71(12):1350–63. PMID: 25321337.

¹⁵https://grants.nih.gov/grants/guide/rfa-files/RFA-MH-16-600.html.

¹⁶https://www.hhs.gov/guidance/sites/default/files/hhs-guidance-documents/cib-10-16-2015_26.pdf.

¹⁷Srihari VH, et al. Psychiatric Services 2015;66(7): 705-12. PMID: 25639994.

¹⁸https://www.nimh.nih.gov/health/topics/schizophrenia/raise/state-health-administrators-and-clinics.

¹⁹US Department of Health and Human Services. Agency Priority Goal Action Plan: Serious Mental Illness. 2018. Available at: https://assets.performance.gov/APG/HHS/FY2018_Q4_HHS_Serious_Mental_Illness.pdf.

²⁰Substance Abuse and Mental Health Services Administration. Snapshot of State Plans for Using the Community Mental Health Block Grant (MHBG) Ten Percent Set-Aside for Early Intervention Programs: Fiscal Years 2016 & 2017. 2016. Available at: https://www.nri-inc.org/media/1547/nri_2016_2017_snapshotpdf.pdf.

²¹Addington J, et al. Psychiatric services 2015;66(7):753–756. PMID: 25588418.

²²https://grants.nih.gov/grants/guide/pa-files/PAR-16-264.html

²³https://grants.nih.gov/grants/guide/pa-files/PAR-16-265.html

²⁴https://www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf.

²⁵Nossel N, et al. Psychiatric Services 2018; 69(8):863-70. PMID: 29759055.

²⁶Substance Abuse and Mental Health Services Administration. Snapshot of State Plans for Using the Community Mental Health Block Grant (MHBG) Ten Percent Set-Aside for Early Intervention Programs: Fiscal Year 2018. 2018. Available at: https://www.nasmhpd.org/sites/default/files/Snapshot_of_State_Plans.pdf

²⁷Substance Abuse and Mental Health Services Administration. 2019 Uniform Reporting System (URS) Output Tables. 2020. Available at: https://www.samhsa.gov/data/report/2019-uniform-reporting-system-urs-output-tables.

²⁸Department of Veterans Affairs, Veterans Health Administration, VHA Directive 1163.07, 2020. Available at: https://www.va.gov/vhapublications/publications.cfm?pub=1&order=asc&orderby=pub_Number.

²⁹Substance Abuse and Mental Health Services Administration. 2020 Uniform Reporting System (URS) Output Tables. 2021. Available at https://www.samhsa.gov/data/report/2020-uniform-reporting-system-urs-output-tables.

³⁰Ho B, et al. American Journal of Psychiatry 2000;157:808-15. PMID: 10784476.

³¹Correll CU, et al. JAMA Psychiatry 2018;75(6):555-565. PMID: 29800949.

³²Marino L, et al. Early Intervention in Psychiatry 2020;14(5):544–52. PMID: 31502409.

³³Keepers GA, et al. American Journal of Psychiatry 2020;177(9): 868-72. PMID: 32867516.

³⁴Societal Costs of Schizophrenia and Related Disorders, 2021. Available at https://sczaction.org/wp-content/uploads/2021/11/571-012_WhitePaper_Report_FINAL_updated_11.09.21.pdf.

³⁵Rosenheck R, et al. Schizophrenia Bulletin 2016;42(4):896-906. PMID: 26834024.

• Recovery After an Initial Schizophrenia Episode (RAISE)

¹Centers for Disease Control and Prevention. Leading Causes of Death, 1900-1998. Natl Vital Stat Rep. 1998;48:1-67. http://www.cdc.gov/nchs/data/dvs/lead1900_98.pdf.

²Mahmood SS, Levy D, Vasan RS, Wang TJ. The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet (London, England). 2014;383(9921):999-1008. doi:10.1016/S0140-6736(13)61752-3.

³Tsao CW, Vasan RS. The Framingham Heart Study: past, present and future. Int J Epidemiol. 2015;44(6):1763-1766. doi:10.1093/ije/dyv336.

⁴Gordon T, Kannel W, Cole C, et al. The Framingham Study: An Epidemiological Investigation of Cardiovascular Disease, Sections 1 and 2. 1968.

⁵Framingham Heart Study (FHS) | National Heart, Lung, and Blood Institute (NHLBI). https://www.nhlbi.nih.gov/science/framingham-heart-study-fhs. Accessed September 22, 2017.

⁶Tsao CW, Vasan RS. Cohort Profile: The Framingham Heart Study (FHS): overview of milestones in cardiovascular epidemiology. doi:10.1093/ije/dyv337.

⁷Levy D, Brink S. A Change of Heart. New York, N.Y.: Vintage Books; 2005.

⁸DAWBER TR, KANNEL WB, REVOTSKIE N, STOKES J, KAGAN A, GORDON T. Some factors associated with the development of coronary heart disease: six years’ follow-up experience in the Framingham study. Am J Public Health Nations Health. 1959;49:1349-1356.

⁹Kannel WB, Dawber TR, Kagan a, Revotskie N, Stokes J. Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study. Ann Intern Med. 1961;55:33-50.

¹⁰Marshall TR. The 1964 Surgeon General’s report and Americans’ beliefs about smoking. J Hist Med Allied Sci. 2015;70(2):250-278. doi:10.1093/jhmas/jrt057.

¹¹Kannel WB, LeBauer EJ, Dawber TR, McNamara PM. Relation of body weight to development of coronary heart disease. The Framingham study. Circulation. 1967;35(4):734-744.

¹²Kannel WB. Habitual level of physical activity and risk of coronary heart disease: the Framingham study. Can Med Assoc J. 1967;96(12):811-812.

¹³Sorlie PD, Sholinsky PD, Lauer MS, et al. Reinvestment in government-funded research: a great way to share. Circulation. 2015;131(1):17-18. doi:10.1161/CIRCULATIONAHA.114.014204.

¹⁴Kannel WB, Wolf PA, Verter J, McNamara PM. Epidemiologic assessment of the role of blood pressure in stroke. The Framingham study. JAMA. 1970;214(2):301-310.

¹⁵Feinleib M, Kannel WB, Garrison RJ, Mcnamara PM, Castelli WP. The Framingham Offspring Study. Design and Preliminary Data1. Prev Med (Baltim). 1975;4(5):18-525.

¹⁶Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and risk of cardiovascular disease: the Framingham study. Ann Intern Med. 1976;85(4):447-452.

¹⁷Wolf PA, Kannel WB, McGee DL, Meeks SL, Bharucha NE, McNamara PM. Duration of atrial fibrillation and imminence of stroke: the Framingham study. Stroke. 14(5):664-667.

¹⁸Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22(8):983-988. doi:10.1161/01.STR.22.8.983.

¹⁹Lowering Blood Cholesterol To Prevent Heart Disease. NIH Consens Statement. Arteriosclerosis. 1985;5(4):404-12.

²⁰Hannan MT, Felson DT, Dawson-Hughes B, et al. Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study. J Bone Miner Res. 2000;15(4):710-720. doi:10.1359/jbmr.2000.15.4.710.

²¹Farmer ME, White LR, Abbott RD, et al. Blood pressure and cognitive performance. The Framingham Study. Am J Epidemiol. 1987;126(6):1103-1114.

²²Elias MF, D’Agostino RB, Elias PK, Wolf PA. Neuropsychological test performance, cognitive functioning, blood pressure, and age: the Framingham Heart Study. Exp Aging Res. 1995;21(4):369-391. doi:10.1080/03610739508253991.

²³Elias PK, D’Agostino RB, Elias MF, Wolf PA. Blood pressure, hypertension, and age as risk factors for poor cognitive performance. Exp Aging Res. 1995;21(4):393-417. doi:10.1080/03610739508253992.

²⁴Levy D, Garrison R, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. New Engl J Med. 1990;322(22):1561-6.

²⁵Benjamin EJ, Wolf PA, Agostino RBD, Silbershatz H, Kannel WB, Levy D. Clinical Investigation and Reports Impact of Atrial Fibrillation on the Risk of Death The Framingham Heart Study. Circulation. 1998;98(10):946-953.

²⁶Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97(18):1837-1847.

²⁷Splansky GL, Corey D, Yang Q, et al. The Third Generation Cohort of the National Heart, Lung, and Blood Institute’s Framingham Heart Study: Design, Recruitment, and Initial Examination. Am J Epidemiol. 2007;165(11):1328-1335. doi:10.1093/aje/kwm021.

²⁸Speliotes EK, Willer CJ, Berndt SI, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet. 2010;42(11):937-948. doi:10.1038/ng.686.

²⁹Psaty BM, O ’donnell CJ, Gudnason V, et al. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from five cohorts. doi:10.1161/CIRCGENETICS.108.829747.

³⁰Benjamin I, Brown N, Burke G, et al. American Heart Association Cardiovascular Genome-Phenome Study: Foundational Basis and Program. Circulation. 2015;131(1):100-112. doi:10.1161/CIRCULATIONAHA.114.014190.

³¹Trans-Omics for Precision Medicine (TOPMed) Program - NHLBI, NIH. https://www.nhlbi.nih.gov/research/resources/nhlbi-precision-medicine-initiative/topmed. Accessed September 22, 2017.

³²Epidemiological Background and Design: The Framingham Study. https://www.framinghamheartstudy.org/about-fhs/background.php. Accessed September 22, 2017.

³³Ma J, Ward EM, Siegel RL, Jemal A. Temporal Trends in Mortality in the United States, 1969-2013. JAMA. 2015;314(16):1731-1739. doi:10.1001/jama.2015.12319.

³⁴Centers for Disease Control and Prevention. Achievements in Public Health, 1900-1999: Decline in Deaths from Heart Disease and Stroke — United States, 1900–1999. Morb Mortal Wkly Rep. 1999;48(30):649-656.

³⁵St. Sauver JL, Warner DO, Yawn BP, et al. Why Patients Visit Their Doctors: Assessing the Most Prevalent Conditions in a Defined American Population. Mayo Clin Proc. 2013;88(1):56-67. doi:10.1016/j.mayocp.2012.08.020.

³⁶Saklayen MG, Deshpande N V. Timeline of History of Hypertension Treatment. Front Cardiovasc Med. 2016;3:3. doi:10.3389/fcvm.2016.00003.

³⁷Remington PL, Brownson RC, Centers for Disease Control and Prevention (CDC). Fifty years of progress in chronic disease epidemiology and control. MMWR Suppl. 2011;60(4):70-77.

³⁸Ford ES, Ajani U a, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med. 2007;356(23):2388-2398. doi:10.1097/sa.0b013e31815c1098.

³⁹Levy D. 60 years studying heart-disease risk. Nat Rev Drug Discov. 2008;7(9):715-715. doi:10.1038/nrd2667.

⁴⁰Framingham Risk Functions. https://www.framinghamheartstudy.org/risk-functions/. Accessed September 22, 2017.

⁴¹Manton KG, Woodbury MA. Analysis of the Components of CHD Risk in the Framingham Study: New Multivariate Procedures for the Analysis of Chronic Disease Development. Comput Biomed Res. 1979;12:109-123.

⁴²Murphy KM, Topel RH. The Value of Health and Longevity. J Polit Econ. 2006;114(5):871-904. doi:10.1086/508033.

⁴³Cutler DM, Rosen AB, Vijan S. The Value of Medical Spending in the United States, 1960–2000. N Engl J Med. 2006;355(9):920-927. doi:doi:10.1056/NEJMsa054744.

⁴⁴Bibliography | Framingham Heart Study. https://www.framinghamheartstudy.org/fhs-bibliography/index.php. Accessed September 22, 2017.

⁴⁵dbGaP | phs000007.v29.p10 | Framingham Cohort. https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000007.v29.p10. Accessed September 22, 2017.

⁴⁶For Researchers | Framingham Heart Study. https://www.framinghamheartstudy.org/researchers/index.php. Accessed September 22, 2017.

⁴⁷Writing Group Members, Mozaffarian D, Benjamin EJ, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016;133(4):e38-60. doi:10.1161/CIR.0000000000000350.

• The Framingham Heart Study Website
• NHLBI — About the Framingham Heart Study
• CDC — Heart Disease Information
• CDC — Stroke Information

¹Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Wilks AF, Harpur AG, Kurban RR, Ralph SJ, Zürcher G, Ziemiecki A. Mol Cell Biol. 1991 Apr;11(4):2057-65. PMID: 1848670

²Examples include:

A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Velazquez L, Fellous M, Stark GR, Pellegrini S. Cell. 1992 Jul 24;70(2):313-22. PMID: 1386289

Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Stahl N, Boulton TG, Farruggella T, Ip NY, Davis S, Witthuhn BA, Quelle FW, Silvennoinen O, Barbieri G, Pellegrini S, et al. Science. 1994 Jan 7;263(5143):92-5. PMID: 8272873

Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Shuai K, Ziemiecki A, Wilks AF, Harpur AG, Sadowski HB, Gilman MZ, Darnell JE. Nature. 1993 Dec 9;366(6455):580-3. PMID: 7504784

³Molecular cloning of rat JAK3, a novel member of the JAK family of protein tyrosine kinases. Takahashi T, Shirasawa T. FEBS Lett. 1994 Apr 4;342(2):124-8. PMID: 8143863

Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Kawamura M, McVicar DW, Johnston JA, Blake TB, Chen YQ, Lal BK, Lloyd AR, Kelvin DJ, Staples JE, Ortaldo JR, et al. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6374-8. PMID: 8022790

JAK3: a novel JAK kinase associated with terminal differentiation of hematopoietic cells. Rane SG, Reddy EP. Oncogene. 1994 Aug;9(8):2415-23. PMID: 7518579

Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Johnston JA, Kawamura M, Kirken RA, Chen YQ, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O'Shea JJ. Nature. 1994 Jul 14;370(6485):151-3. PMID: 8022485

⁴Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman MJ, Migone TS, Noguchi M, Markert ML, Buckley RH, O'Shea JJ, Leonard WJ. Science. 1995 Nov 3;270(5237):797-800. PMID: 7481768

Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, Ugazio AG, Johnston JA, Candotti F, O'Shea JJ, et al. Nature. 1995 Sep 7;377(6544):65-8. PMID: 7659163

⁵Regulation of JAK3 expression and activation in human B cells and B cell malignancies. Tortolani PJ, Lal BK, Riva A, Johnston JA, Chen YQ, Reaman GH, Beckwith M, Longo D, Ortaldo JR, Bhatia K, McGrath I, Kehrl J, Tuscano J, McVicar DW, O'Shea JJ. J Immunol. 1995 Dec 1;155(11):5220-6. PMID: 7594533

⁶The amino terminus of JAK3 is necessary and sufficient for binding to the common gamma chain and confers the ability to transmit interleukin 2-mediated signals. Chen M, Cheng A, Chen YQ, Hymel A, Hanson EP, Kimmel L, Minami Y, Taniguchi T, Changelian PS, O'Shea JJ. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6910-5. PMID: 9192665

Distinct tyrosine phosphorylation sites in JAK3 kinase domain positively and negatively regulate its enzymatic activity. Zhou YJ, Hanson EP, Chen YQ, Magnuson K, Chen M, Swann PG, Wange RL, Changelian PS, O'Shea JJ. Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13850-5. PMID: 9391116

Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases. Zhou YJ, Chen M, Cusack NA, Kimmel LH, Magnuson KS, Boyd JG, Lin W, Roberts JL, Lengi A, Buckley RH, Geahlen RL, Candotti F, Gadina M, Changelian PS, O'Shea JJ. Mol Cell. 2001 Nov;8(5):959-69. PMID: 11741532

Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). Ghoreschi K, Jesson MI, Li X, Lee JL, Ghosh S, Alsup JW, Warner JD, Tanaka M, Steward-Tharp SM, Gadina M, Thomas CJ, Minnerly JC, Storer CE, LaBranche TP, Radi ZA, Dowty ME, Head RD, Meyer DM, Kishore N, O'Shea JJ. J Immunol. 2011 Apr 1;186(7):4234-43. doi: 10.4049/jimmunol.1003668. Epub 2011 Mar 7. PMID: 21383241

⁷Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin WH, Rizzuti BJ, Sawyer PS, Perry BD, Brissette WH, McCurdy SP, Kudlacz EM, Conklyn MJ, Elliott EA, Koslov ER, Fisher MB, Strelevitz TJ, Yoon K, Whipple DA, Sun J, Munchhof MJ, Doty JL, Casavant JM, Blumenkopf TA, Hines M, Brown MF, Lillie BM, Subramanyam C, Shang-Poa C, Milici AJ, Beckius GE, Moyer JD, Su C, Woodworth TG, Gaweco AS, Beals CR, Littman BH, Fisher DA, Smith JF, Zagouras P, Magna HA, Saltarelli MJ, Johnson KS, Nelms LF, Des Etages SG, Hayes LS, Kawabata TT, Finco-Kent D, Baker DL, Larson M, Si MS, Paniagua R, Higgins J, Holm B, Reitz B, Zhou YJ, Morris RE, O'Shea JJ, Borie DC. Science. 2003 Oct 31;302(5646):875-8. PMID: 14593182

⁸Super-enhancers delineate disease-associated regulatory nodes in T cells. Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos MR, Davis SR, Roychoudhuri R, Restifo NP, Gadina M, Tang Z, Ruan Y, Collins FS, Sartorelli V, O'Shea JJ. Nature. 2015 Apr 23;520(7548):558-62. doi: 10.1038/nature14154. Epub 2015 Feb 16. PMID: 25686607

⁹ClinicalTrials.gov Identifier: NCT02535689

¹⁰Reviewed in The JAK-STAT pathway: impact on human disease and therapeutic intervention. O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. Annu Rev Med. 2015;66:311-28. doi: 10.1146/annurev-med-051113-024537. Review. PMID: 25587654

¹¹Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Schwartz DM, Bonelli M, Gadina M, O'Shea JJ. Nat Rev Rheumatol. 2016 Jan;12(1):25-36. doi: 10.1038/nrrheum.2015.167. Epub 2015 Dec 3. Review. PMID: 26633291

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¹Examples include: Siegal S. Benign paroxysmal peritonitis. Ann Intern Med. 1945;23(1):1-21, as cited in Centola M, Aksentijevich I, Kastner DL. The hereditary periodic fever syndromes: molecular analysis of a new family of inflammatory diseases. Hum Mol Genet. 1998;7(10):1581-1588. PMID: 9735379 Reimann HA. Periodic disease; a probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclic neutropenia and intermittent arthralgia. J Am Med Assoc. 1948;136(4):239-244. PMID: 18920089/p>

²One of many examples: Wright DG, Wolff SM, Fauci AS, Alling DW. Efficacy of intermittent colchicine therapy in familial Mediterranean fever. Ann Intern Med. 1977;86(2):162-165.

³Williamson LM, Hull D, Mehta R, Reeves WG, Robinson BH, Toghill PJ. Familial Hibernian fever. Q J Med. 1982;51(204):469-480. PMID: 7156325

⁴Pras E, Aksentijevich I, Gruberg L, et al. Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med. 1992 Jun 4;326(23):1509-1513. PMID: 1579134
International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997;90(4):797-807. PMID: 9288758
French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17(1):25-31. PMID: 9288094

⁵McDermott MF, Aksentijevich I, Galon J, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97(1):133-144. PMID: 10199409

⁶Aksentijevich I, Nowak M, Mallah M, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 2002;46(12):3340-3348. PMID: 12483741
Feldmann J, Prieur A-M, Quartier P, et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet. 2002;71(1):198-203. PMID: 12032915

⁷Goldbach-Mansky R, Dailey NJ, Canna SW, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition. N Engl J Med. 2006;355(6):581-592. PMID: 16899778

⁸Booty MG, Chae JJ, Masters SL, et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum. 2009;60(6):1851-1861. PMID: 19479870

⁹Aksentijevich I, Masters SL, Ferguson PJ, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360(23):2426-2437. PMID: 19494218

¹⁰Liu Y, Ramot Y, Torrelo A, et al. Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum. 2012;64(3):895-907. PMID: 21953331

¹¹Sibley CH, Plass N, Snow J, et al. Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes. Arthritis Rheum. 2012;64(7):2375-86. PMID: 22294344

¹²Jesus AA, Goldbach-Mansky R. IL-1 blockade in autoinflammatory syndromes. Annu Rev Med. 2014;65:223-244. PMID: 24422572

¹³Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371(6):507-518. PMID: 25029335

¹⁴De Jesus AA, Canna SW, Liu Y, Goldbach-Mansky R. Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling. Annu Rev Immunol. 2015;33:823-874. PMID: 25706096

¹⁵De Jesus AA, Canna SW, Liu Y, Goldbach-Mansky R. Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling. Annu Rev Immunol. 2015;33:823-874. PMID: 25706096

¹⁶National Institutes of Health. NIH scientists identify gene linked to fatal inflammatory disease in children. NIAMS Press Releases. Published July 17, 2014. Accessed August 1, 2016.

¹⁷National Institute of Arthritis and Musculoskeletal and Skin Diseases. NIH study contributes to approval of promising treatment for genetic inflammatory disorder. Spotlight on Research. Published March 2013. Accessed August 1, 2016.

¹⁸National Institute of Arthritis and Musculoskeletal and Skin Diseases. Deficiency of the Interleukin-1 Receptor Antagonist (DIRA). Autoinflammatory Diseases. Published March 2016. Accessed August 1, 2016.

¹⁹National Institutes of Health. NIH scientists discover link among spectrum of childhood diseases. NIAMS Press Releases. Published October 31, 2011. Accessed August 1, 2016.

²⁰U.S. National Library of Medicine. Familial Mediterranean fever: frequency. Genetics Home Reference. Updated July 26, 2016. Accessed August 1, 2016.

²¹Jesus AA, Goldbach-Mansky R. IL-1 blockade in autoinflammatory syndromes. Annu Rev Med. 2014;65:223-244. PMID: 24422572

²²U.S. National Library of Medicine. Tumor necrosis factor receptor-associated periodic syndrome: Frequency. Genetics Home Reference. Updated July 26, 2016. Accessed August 1, 2016.

²³Bulua AC, Simon A, Maddipati R, et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med. 2011;208(3):519-533. PMID: 21282379

²⁴U.S. National Library of Medicine. Neonatal onset multisystem inflammatory disease: Frequency. Genetics Home Reference. Updated July 26, 2016. Accessed August 1, 2016.
Collins F. Meet Alex—Before and after NIH clinical trial. NIH Director’s blog. Published April 9, 2013. Accessed May 23, 2016

• Understanding Autoinflammatory Diseases
• NIH Director’s Blog: Meet Alex—Before and After NIH Clinical Trial
• Autoinflammatory Diseases Studies at the NIH Clinical Center
• Autoinflammatory Diseases Research at NIAMS

¹Donald R. McNeal, “2000 years of electrical stimulation” in F. Terry Hambrecht and James B. Reswick, eds., Functional Electrical StimulationApplications in Neural Prosthesis (New York and BaselMacel Dekker, Inc., 1977) pp. 3-35.

²Thompson DM, Koppes AN, Hardy JG, Schmidt CE. Electrical stimuli in the central nervous system microenvironment. Annual review of biomedical engineering. 2014;16:397-430.

³Aquilina O. A brief history of cardiac pacing. Images in paediatric cardiology. 2006;8(2):17-81.

⁴FDA Premarket Approval P8300693M: Brand Cochlear Implant System/House Design

⁵FDA Premarket Approval P960009: Medtronic Activa Tremor Control System and Supplement S007: Medtronic Activa Parkinson’s Control System

⁶http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm343162.htm

⁷House WF, Urban J. Long term results of electrode implantation and electronic stimulation of the cochlea in man. The Annals of otology, rhinology, and laryngology. 1973;82(4):504-517.

⁸http://www.nidcd.nih.gov/health/hearing/pages/coch.aspx

⁹Sekhon LH, Fehlings MG. Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine. 2001;26(24 Suppl):S2-12.

¹⁰http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm343162.htm

¹¹Gerasimenko YP, Lu DC, Modaber M, et al. Noninvasive Reactivation of Motor Descending Control after Paralysis. Journal of neurotrauma. 2015;32(24):1968-1980.

¹²Donald R. McNeal, “2000 years of electrical stimulation” in F. Terry Hambrecht and James B. Reswick, eds., Functional Electrical StimulationApplications in Neural Prosthesis (New York and BaselMacel Dekker, Inc., 1977) pp. 3-35.

¹³Penfield W. Epilepsy and surgical therapy. Archives of Neurology & Psychiatry. 1936;36(3):449-484.

¹⁴Aquilina O. A brief history of cardiac pacing. Images in paediatric cardiology. 2006;8(2):17-81.

¹⁵Djourno A, Eyries C. Auditory prosthesis by means of a distant electrical stimulation of the sensory nerve with the use of an indwelt coiling. La Presse medicale. 1957;65(63):1417.

¹⁶Chatrian GE, Petersen MC, Uihlein A. Electrical stimulation of the human brain through implanted electrodespreliminary observations. Diseases of the nervous system. 1960;21:321-326.

¹⁷House WF, Urban J. Long term results of electrode implantation and electronic stimulation of the cochlea in man. The Annals of otology, rhinology, and laryngology. 1973;82(4):504-517.

¹⁸Simmons FB, Mongeon CJ, Lewis WR, Huntington DA. Electrical Stimulation of Acoustical Nerve and Inferior Colliculus. Archives of otolaryngology. 1964;79:559-568.

¹⁹Kumar K, Rizvi S. Historical and present state of neuromodulation in chronic pain. Current pain and headache reports. 2014;18(1):387.

²⁰DeLong MR. Activity of pallidal neurons during movement. Journal of neurophysiology. 1971;34(3):414-427.

²¹DeLong MR. Activity of basal ganglia neurons during movement. Brain research. 1972;40(1):127-135.

²²DeLong MR. Putamen: activity of single units during slow and rapid arm movements. Science. 1973;179(4079):1240-1242.

²³House WF, Urban J. Long term results of electrode implantation and electronic stimulation of the cochlea in man. The Annals of otology, rhinology, and laryngology. 1973;82(4):504-517.

²⁴Hosobuchi Y, Adams JE, Rutkin B. Chronic thalamic stimulation for the control of facial anesthesia dolorosa. Archives of neurology. 1973;29(3):158-161., NIH training grant NS5593

²⁵Mudry A, Mills M. The early history of the cochlear implant: a retrospective. JAMA otolaryngology-- head & neck surgery. 2013;139(5):446-453.

²⁶Clark G. Cochlear Implants: Fundamentals and Applications. Springer; 2003.

²⁷Clark G, Cowan RSC, Dowell RC. Cochlear Implantation for Infants and Children: Advances. Singular Publishing Group; 1997.

²⁸Davis GC, Williams AC, Markey SP, et al. Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry research. 1979;1(3):249-254.

²⁹Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219(4587):979-980.

³⁰Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proceedings of the National Academy of Sciences of the United States of America. 1983;80(14):4546-4550.

³¹FDA Premarket Approvals P830069: 3M Brand Cochlear Implant System/House Design and P840024: Nucleus Multichannel Implantable Hearing Prosthesis

³²FDA Premarket Approval P890027: Nucleus 22 Channel Cochlear Implant Sys /Children

³³Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J. Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Applied neurophysiology. 1987;50(1-6):344-346.

³⁴Benabid AL, Pollak P, Gervason C, et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet. 1991;337(8738):403-406.

³⁵Limousin P, Pollak P, Benazzouz A, et al. Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet. 1995;345(8942):91-95.

³⁶Limousin P, Krack P, Pollak P, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. The New England journal of medicine. 1998;339(16):1105-1111.

³⁷Medtronic DBS Therapy for Parkinson's Disease and Essential Tremor Clinical Summary, 2013

³⁸Rise MT, W. KG, Inventors; Medtronic, Inc., assignee. Method of treating movement disorders by brain stimulation. US patent 5716377. February 10, 1998.

³⁹FDA Premarket Approval P960009, Supplement S007: Medtronic Activa Parkinson’s Control

⁴⁰http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm125520.htm

⁴¹Harkema S, Gerasimenko Y, Hodes J, et al. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet. 2011;377(9781):1938-1947.

⁴²Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain: a journal of neurology. 2014;137(Pt 5):1394-1409.

⁴³Gerasimenko YP, Lu DC, Modaber M, et al. Noninvasive Reactivation of Motor Descending Control after Paralysis. Journal of neurotrauma. 2015;32(24):1968-1980.

⁴⁴http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm343162.htm

⁴⁵https://consensus.nih.gov/1995/1995CochlearImplants100html.htm

⁴⁶http://www.nidcd.nih.gov/health/hearing/pages/coch.aspx

⁴⁷Semenov YR, Yeh ST, Seshamani M, et al. Age-dependent cost-utility of pediatric cochlear implantation. Ear and hearing. 2013;34(4):402-412.

⁴⁸Contrera KJ, Choi JS, Blake CR, Betz JF, Niparko JK, Lin FR. Rates of long-term cochlear implant use in children. Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 2014;35(3):426-430.

⁴⁹Cheng AK, Rubin HR, Powe NR, Mellon NK, Francis HW, Niparko JK. Cost-utility analysis of the cochlear implant in children. Jama. 2000;284(7):850-856.

⁵⁰Semenov YR, Yeh ST, Seshamani M, et al. Age-dependent cost-utility of pediatric cochlear implantation. Ear and hearing. 2013;34(4):402-412.

⁵¹http://www.laskerfoundation.org/awards/2014_c_description.htm

⁵²Weaver FM, Follett K, Stern M, et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. Jama. 2009;301(1):63-73.

⁵³ibid.

⁵⁴Rizzone MG, Fasano A, Daniele A, et al. Long-term outcome of subthalamic nucleus DBS in Parkinson's disease: from the advanced phase towards the late stage of the disease? Parkinsonism & related disorders. 2014;20(4):376-381.

^55:http://professional.medtronic.com/pt/neuro/dbs-md/eff/data-and-clinical-outcomes

⁵⁶http://www.laskerfoundation.org/awards/2014_c_description.htm

⁵⁷Hariz M, Blomstedt P, Zrinzo L. Future of brain stimulation: new targets, new indications, new technology. Movement disorders: official journal of the Movement Disorder Society. 2013;28(13):1784-1792.

⁵⁸http://braininitiative.nih.gov/about.htm

⁵⁹https://commonfund.nih.gov/sparc/index

⁶⁰NIH Grant UH2NS095495, BRAIN initiative

⁶¹NIH Grant U18EB021793, SPARC program

⁶²http://news.berkeley.edu/2014/05/27/cnep-targets-brain-circuitry-to-treat-mental-disorders/

⁶³NIH Grant UH3NS095554, BRAIN initiative

The table below provides a more detailed list of selected milestones underlying this story’s “Research-to-Practice Milestones” (page 2 of the pdf), including the lead scientists, research institutions, funding sources, and scientific publications involved in each one.

1950s–60s: Stimulating Nerves with Electricity

Year	Description of Milestone	Primary Investigator(s)	Research Institution	Funding source (including NIH grant numbers where available)	Citation 1	Citation 2	Citation 3	Citation 4
1957	>Attempting to repair a facial nerve injury, scientists electrically stimulated the auditory nerve, causing the patient to perceive sounds and providing evidence that electrical stimulation might restore lost hearing.	Andre Djourno, Charles Eyries	Faculté de Médecine, Paris, France	Unknown, Not likely to be NIH	Djourno A, Eyries C. [Auditory prosthesis by means of a distant electrical stimulation of the sensory nerve with the use of an indwelt coiling]. La Presse medicale. 1957;65(63):1417.
1960	Researchers first tested the long-term safety and effectiveness of implanting electrodes in the human brain.	Alfred Uihlein	Mayo Clinic	Unknown, Not likely to be NIH	Chatrian GE, Petersen MC, Uihlein A. Electrical stimulation of the human brain through implanted electrodes: preliminary observations. Diseases of the nervous system. 1960;21:321-326.
1961	The first prototype single-channel cochlear implant is developed, and inserted into two subjects	William F. House and James Doyle	Private Practice, Los Angeles	Private	House WF, Urban J. Long term results of electrode implantation and electronic stimulation of the cochlea in man. The Annals of otology, rhinology, and laryngology. 1973;82(4):504-517.	U.S. Patent 3449786 to James Doyle
1964	First NIH grant for cochlear implants funds a report on the effects of auditory nerve stimulation in a patient with normal hearing.	F. Blair Simmons	Stanford University	Funded by NIH grant NB 02167 from the National Institute of Neurological Diseases and Blindness (NINDB).	Simmons FB, Mongeon CJ, Lewis WR, Huntington DA. Electrical Stimulation of Acoustical Nerve and Inferior Colliculus. Archives of otolaryngology. 1964;79:559-568.
1968	Medtronic became the first company to introduce a spinal cord stimulation system as a treatment for chronic pain.	Unknown	Medtronic Corp	Private	Kumar K, Rizvi S. Historical and present state of neuromodulation in chronic pain. Current pain and headache reports. 2014;18(1):387.

1970s–80s: Unlocking the Potential of Neurotechnology

Year	Description of Milestone	Primary Investigator(s)	Research Institution	Funding source (including NIH grant numbers where available)	Citation 1	Citation 2	Citation 3	Citation 4
1971-3	NIH researchers characterized the normal electrical function of deep brain areas involved in movement, which are affected in Parkinson’s	Mahlon DeLong	NIMH Laboratory of Neurophysiology	NIMH Intramural	DeLong MR. Activity of pallidal neurons during movement. Journal of neurophysiology. 1971;34(3):414-427.	DeLong MR. Activity of basal ganglia neurons during movement. Brain research. 1972;40(1):127-135.	DeLong MR. Putamen: activity of single units during slow and rapid arm movements. Science. 1973;179(4079):1240-1242.
1972	Early cochlear implants developed with a single electrode, and the first functional prototype implanted in a patient	William F. House	Private practice, Los Angeles	Private, included support from 3M	House WF, Urban J. Long term results of electrode implantation and electronic stimulation of the cochlea in man. The Annals of otology, rhinology, and laryngology. 1973;82(4):504-517.
1973	Improving upon the pain relief provided by spinal cord stimulation, NIH-supported investigators developed the first long-term, implanted device to stimulate the brain	Yoshio Hosobuchi	UCSF	NIH training grant NS5593	Hosobuchi Y, Adams JE, Rutkin B. Chronic thalamic stimulation for the control of facial anesthesia dolorosa. Archives of neurology. 1973;29(3):158-161.
1976	The 1976 Bilger report suggests that cochlear implants could be a substantially more useful device for patients with hearing loss than traditional devices and methods.	Robert C. Bilger	Univ. of Pittsburgh	NIH Contract N01 NS-5-2331.	Bilger RC, Black FO, Hopkinson NT. Research plan for evaluating subjects presently fitted with implanted auditory prostheses. The Annals of otology, rhinology & laryngology. Supplement. 1977;86(3 Pt 2 Suppl 38):21-24.	Bilger RC, Black FO, Hopkinson NT, Myers EN. Implanted auditory prosthesis: an evaluation of subjects presently fitted with cochlear implants. Transactions. Section on Otolaryngology. American Academy of Ophthalmology and Otolaryngology. 1977;84(4 Pt 1):ORL-677-682.
1970s-80s	Several groups of academic researchers begin to partner with technology firms to form corporations in Australia, the U.S., and Europe focused on devices to restore hearing.Both industry and academic researchers focused on upgrading cochlear implants with even better resolution, using multiple electrodes (multi-channel).	Graeme Clark; Claude Chouard; F. Blair Simmons and Robert L. White; Michael Merzenich and Robin P. Michelson	Academia: Univ. of Melbourne, Australia; INSERM, France; Stanford; UCSF Industry: Nucleus Ltd. , MedEl	NIH Grants NS 10532, NS10414, NIH grant NS 11804, NIH Contracts N01-NS-5-2388,-2395,and -2396	Mudry A, Mills M. The early history of the cochlear implant: a retrospective. JAMA otolaryngology-- head & neck surgery. 2013;139(5):446-453.	Clark GM. Cochlear implants. New York: Springer Verlag; 2003	Clark GM, Cowan RSC, Dowell DC. Cochlear implantation for infants and children. Advances. San Diego: Singular Publishing Group; 1997.
1979-83	NIH-supported researchers used a new animal model for Parkinson’s disease, called the MPTP model, to identify the brain regions responsible for motor symptoms.	Irwin Kopin	NINDS and NIMH Intramural, Stanford	NIMH and NINDS Intramural, Santa Clara County Medical Services, NIMH Intramural	Davis GC, Williams AC, Markey SP, et al. Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry research. 1979;1(3):249-254.	Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219(4587):979-980.	Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proceedings of the National Academy of Sciences of the United States of America. 1983;80(14):4546-4550.
1984, 1985	FDA Approval of first two cochlear implant devices	William F. House, Graeme Clark	3M/House Research Institute, Univ. of Melbourne/Cochlear Corp	Private--3M and Nucleus Ltd	FDA Premarket Approval P830069: 3M Brand Cochlear Implant System/House Design in citation 1	FDA Premarket Approval P840024: Nucleus Multichannel Implantable Hearing Prosthesis

Late 1980s/1990s: Next Generation Devices and Applications

Year	Description of Milestone	Primary Investigator(s)	Research Institution	Funding source (including NIH grant numbers where available)	Citation 1	Citation 2	Citation 3	Citation 4
1986	Publication of  first model for parallel organization of circuits involved in both normal movement and Parkinson's	Garrett Alexander, Mahlon DeLong, and Peter Strick	Johns Hopkins University	NIH Grants NS00632 (G.A.), NS17678 (G.A.), NS16375 (Mahlon DeLong), NS02957 (P.S.), VA, private donations	Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual review of neuroscience. 1986;9:357-381.
1986-1990	Studies in the MPTP primate model implcate dysfunction in two regions for movement symptoms in PD and related  disorders	Mahlon DeLong; John Penney, Anne Young; David Sibley	Johns Hopkins University; University of Michigan, Ann Arbor; NINDS/NIMH Intramural	NIH Grants NS15655, NS19613, NS01300,NS015417 private donations	Penney JB, Jr., Young AB. Striatal inhomogeneities and basal ganglia function. Movement disorders : official journal of the Movement Disorder Society. 1986;1(1):3-15.	Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia disorders. Trends in neurosciences. 1989;12(10):366-375.	DeLong MR. Primate models of movement disorders of basal ganglia origin. Trends in neurosciences. 1990;13(7):281-285.	Gerfen CR, Engber TM, Mahan LC, et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science. 1990;250(4986):1429-1432.
1990	The FDA approved cochlear implant use in children, providing an opportunity to restore hearing to children during their developmental years	Graeme Clark	Cochlear Corp	Private-Cochlear Corp	FDA Premarket Approval P890027: Nucleus 22 Channel Cochlear Implant Sys /Children
1990-91	Studies demonstrated that inactivation of one deep brain region in a primate model reduces tremor symptoms using the MPTP  model for Parkinson's disease	Mahlon DeLong; Alan Crossman	Johns Hopkins University; University of Manchester Medical School, U.K.	NS15417, private funds from the E.K. Dunn family, UK Govt.	Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science. 1990;249(4975):1436-1438.	Aziz TZ, Peggs D, Sambrook MA, Crossman AR. Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Movement disorders : official journal of the Movement Disorder Society. 1991;6(4):288-292.
1987-98	Studies in humans revealed that electrical stimulation of deep brain regions could quickly and reversibly reduce the tremors associated with Parkinson’s disease.	Alim-Louis Benabid	Joseph Fourier University of Grenoble, France	INSERM/French Govt	Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J. Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Applied neurophysiology. 1987;50(1-6):344-346.	Benabid AL, Pollak P, Gervason C, et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet. 1991;337(8738):403-406.	Limousin P, Pollak P, Benazzouz A, et al. Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet. 1995;345(8942):91-95.	Limousin P, Krack P, Pollak P, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. The New England journal of medicine. 1998;339(16):1105-1111.
1990s	Building on earlier research, Medtronic scientists performed clinical trials of deep brain stimulation for tremor and Parkinson’s disease.	N/A	Medtronic	Private-Medtronic	Rise MT, W. KG, Inventors; Medtronic, Inc., assignee. Method of treating movement disorders by brain stimulation. US patent 5716377. February 10, 1998.	Medtronic DBS Therapy for Parkinson's Disease and Essential Tremor Data and Clinical Outcomes
1997	Medtronic received the first FDA approval for deep brain stimulation to treat essential tremor, a common disorder with symptoms similar to Parkinson’s disease.	N/A	Medtronic	Private-Medtronic	FDA Premarket Approval P960009: Medtronic Activa Tremor Control System

2000s-2010s: A Rapidly Growing Field Seeking New Targets

Year	Description of Milestone	Primary Investigator(s)	Research Institution	Funding source (including NIH grant numbers where available)	Citation 1	Citation 2	Citation 3	Citation 4
2002-03	The Medtronic deep brain stimulation device was approved by the FDA to treat symptoms of Parkinson’s disease	N/A	Medtronic	Private-Medtronic	FDA Premarket Approval P960009: Medtronic Activa Tremor Control System, Supplement S007: Medtronic Activa Parkinson’s Control System
2009	A large clinical trial demonstrated that deep brain stimulation is superior to best medical therapy	Frances Weaver	Hines VA Hospital (and many others via the CSP 468 Study Group)	VA, NIH-NINDS, Medtronic	Weaver FM, Follett K, Stern M, et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. Jama. 2009;301(1):63-73.
2009	FDA approves a humanitarian exemption for deep brain stimulation as a treatment for Obsessive-Compulsive Disorder	N/A	Medtronic	Private-Medtronic	FDA: Reclaim™ DBS™ Therapy for OCD - H050003
2011-14	NIH-funded researchers used electrical stimulation strategies to restore lost function in patients with spinal cord injury, who regained bladder control, blood pressure control, sexual function, and the ability to make small voluntary lower body movements and stand unaided for up to 20 minutes	V. Reggie Edgerton; Susan Harkema	University of California, Los Angeles; University of Louisville	NIH Grants EB007615 and GM103507, Reeve Foundation, Leona M. and Harry B. Helmsley Charitable Trust, Kessler Foundation, University of Louisville Foundation, and Jewish Hospital and St. Mary’s Foundation, Frazier Rehab Institute and University of Louisville Hospital	Harkema S, Gerasimenko Y, Hodes J, et al. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet. 2011;377(9781):1938-1947.	Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain : a journal of neurology. 2014;137(Pt 5):1394-1409.
2014	The FDA approved a humanitarian exemption for the use of the first visual prosthesis,the Argus II, which allows patients with certain types of vision loss to perceive a small, low-resolution visual field.	Mark Humayan, Robert Jay Greenberg	Johns Hopkins University, Second Sight Medical Products, Inc.	NIH Grants: EY011888 and EY012893	FDA: Argus II Retinal Prosthesis System - H110002
2015	NIH-funded researchers stimulate the spinal cord through the skin, generating intentional step-like movements in patients with spinal cord injury	V. Reggie Edgerton	University of California, Los Angeles	NIH Grants EB15521, EB007615, TR000124, Reeve Foundation, Walkabout Foundation, F.M. Kirby Foundation	Gerasimenko YP, Lu DC, Modaber M, et al. Noninvasive Reactivation of Motor Descending Control after Paralysis. Journal of neurotrauma. 2015;32(24):1968-1980.

• More on Cochlear Implants
• More on Deep Brain Stimulation
• More on Brain Stimulation Therapies
• Science Education: Bionic Man

¹A Story of Discovery: Gleevec Transforms Cancer Treatment for Chronic Myelogenous Leukemia. National Cancer Institute. Retrieved October 29, 2015, from http://www.cancer.gov/research/progress/discovery/gleevec

²Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. The New England journal of medicine. 2006;355(23):2408-2417.

³http://www.cancer.org/cancer/cancerbasics/thehistoryofcancer/the-history-of-cancer-cancer-treatment-targeted-therapy

⁴https://www.jstage.jst.go.jp/article/kjm/59/1/59_1_1/_pdf

⁵Huang X, Cortes J, Kantarjian H. http://www.ncbi.nlm.nih.gov/pubmed/22294282 Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Cancer. 2012;118(12):3123-3127.

⁶http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf

⁷A Decade of Innovation in Rare Diseases. PhRMA 2015. http://www.phrma.org/sites/default/files/pdf/PhRMA-Decade-of-Innovation-Rare-Diseases.pdf

⁸Boveri T. Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris. Journal of cell science. 2008;121 Suppl 1:1-84.

⁹https://www.genome.gov/Pages/Education/GeneticTimeline.pdf

¹⁰Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. Journal of the National Cancer Institute. 1960;25:85-109.

¹¹Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243(5405):290-293.

¹²Heisterkamp N, Stephenson JR, Groffen J, et al. Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature. 1983;306(5940):239-242.

¹³Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984;36(1):93-99.

¹⁴Konopka JB, Watanabe SM, Singer JW, Collins SJ, Witte ON. Cell lines and clinical isolates derived from Ph1-positive chronic myelogenous leukemia patients express c-abl proteins with a common structural alteration. Proceedings of the National Academy of Sciences of the United States of America. 1985;82(6):1810-1814.

¹⁵Druker BJ. Perspectives on the development of imatinib and the future of cancer research. Nature medicine. 2009;15(10):1149-1152.

¹⁶Ibid.

¹⁷Hunter T. Treatment for chronic myelogenous leukemia: the long road to imatinib. The Journal of clinical investigation. 2007;117(8):2036-2043.

¹⁸Pray L. Gleevec: the breakthrough in cancer treatment. Nat Education. 2008;1(1):37.

¹⁹Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature medicine. 1996;2(5):561-566.

²⁰Food and Drug Administration Modernization Act. S. 830. 105th Congress. (1997).

²¹Fast Track. Food and Drug Administration. Updated 2014, September 15. Retrieved October 29, 2015, from http://www.fda.gov/ForPatients/Approvals/Fast/ucm405399.htm

²²Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. The New England journal of medicine. 2001;344(14):1031-1037.

²³Waalen J. Gleevec’s Glory Days. Howard Hughes Medical Institute Bulletin. 2001 Dec;14(5):10-15.

²⁴Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. The New England journal of medicine. 2006;355(23):2408-2417.

²⁵http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm110505.htm

²⁶Cumulative number of publications containing the search term “imatinib” from 1996-2014 in the PubMed database.

²⁷A Decade of Innovation in Rare Diseases. PhRMA 2015. http://www.phrma.org/sites/default/files/pdf/PhRMA-Decade-of-Innovation-Rare-Diseases.pdf

²⁸Ibid.

²⁹https://www.jstage.jst.go.jp/article/kjm/59/1/59_1_1/_pdf

³⁰Determined by searching clinicaltrials.gov for registered clinical trials using the term “imatinib,” “Gleevec,” or “Glivec.”

³¹http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021588s042lbl.pdf

³²http://seer.cancer.gov/csr/1975_2012/browse_csr.php?sectionSEL=13&pageSEL=sect_13_table.16.html#table4

³³https://www.jstage.jst.go.jp/article/kjm/59/1/59_1_1/_pdf

³⁴Determined using data provided by FDA’s Center for Drug Evaluation and Research on mechanism of action of approved FDA drugs, 1999-2015.

³⁵Determined using data provided by FDA’s Center for Drug Evaluation and Research on the companies associated with approved FDA drugs.

³⁶DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. Journal of health economics. 2003;22(2):151-185.

³⁷http://csdd.tufts.edu/files/uploads/Tufts_CSDD_briefing_on_RD_cost_study_-_Nov_18,_2014..pdf

The table below provides a more detailed list of selected milestones underlying this story’s “Research-to-Practice Milestones” (page 2 of the pdf), including the lead scientists, research institutions, funding sources, and scientific publications involved in each one.

Identifying the Molecular Trigger of CML (1914–1990)

Year	Description of Milestone	Primary Investigator(s)	Research Institution	Funding source (including NIH grant numbers where available)	Citation 1	Citation 2
1914	Biologist Theodor Boveri first hypothesized that chromosomal abnormalities may play a role in tumor development, but no tools existed at that time to test his theory.	Boveri	N/A	Unknown (Germany)	Boveri T. Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris. Journal of cell science. 2008;121 Suppl 1:1-84.
1950s	Using newly developed techniques to study cells and chromosomes, researchers began to link chromosomal abnormalities to specific human diseases.	None specific	N/A	N/A	Genome.gov Timeline: From Darwin and Mendel to the Human Genome Project
1960	Drs. Nowell and Hungerford studied cells from CML patients and discovered an atypical small chromosome in the cancer cells, called the Philadelphia chromosome.	Nowell and Hungerford	University of Pennsylvania	NIH (C-3562), American Cancer Society, US Public Health Service	Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. Journal of the National Cancer Institute. 1960;25:85-109.
1973	Dr. Rowley discovered that the Philadelphia chromosome results from a chromosomal translocation between chromosomes 9 and 22.	Rowley	University of Chicago	Unknown	Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243(5405):290-293.
1983	Researchers identified the genes involved in the Philadelphia chromosome, showing that the human oncogene c-abl is part of the translocation.	Heisterkamp	NIH (NCI intramural); Erasmus University	NIH (contract COI-CP-75380), Netherlands Cancer Society	Heisterkamp N, Stephenson JR, Groffen J, et al. Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature. 1983;306(5940):239-242.
1984	Scientists identified the breakpoint cluster region (bcr) on chromosome 22.	Groffen	NIH (NCI intramural); Erasmus University	NIH (contract COI-CP-75380), Netherlands Cancer Society	Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984;36(1):93-99.
1990	Researchers identified the function of the bcr-abl fusion gene, which prompts production of an improperly regulated abnormal tyrosine kinase protein.	Lugo	University of California, Los Angeles	NIH/NCI (T32GM08243 and T32GM07185), Howard Hughes Medical Institute, Leukemia Society of America	Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990;247(4946):1079-1082.

Developing a targeted Bcr-abl kinase inhibitor (1990–1996)

Year	Description of Milestone	Primary Investigator(s)	Research Institution	Funding source (including NIH grant numbers where available)	Citation 1	Citation 2
1990	Scientists at pharmaceutical company Ciba-Geigy (later became Novartis) began to refine a compound that blocks the enzyme that triggers CML without harming other kinases.	Nick Lydon	Ciba-Geigy (now Novartis)	Ciba-Geigy	Druker BJ. Perspectives on the development of imatinib and the future of cancer research. Nature medicine. 2009;15(10):1149-1152.
1990	Dr. Druker began developing model systems to study BCR-ABL signaling and outlined how to characterize BCR-ABL kinase inhibitors.	Brian Druker	Dana-Farber Cancer Institute	NIH/NCI (K08CA001422)	Druker BJ. Perspectives on the development of imatinib and the future of cancer research. Nature medicine. 2009;15(10):1149-1152.
1992	The compound that would become Gleevec was first synthesized, although many years of testing would be needed before its effectiveness was known.	N/A	Ciba-Geigy	Ciba-Geigy	Hunter T. Treatment for chronic myelogenous leukemia: the long road to imatinib. The Journal of clinical investigation. 2007;117(8):2036-2043.
1993	Dr. Druker started his own lab with the goal of finding a drug company that had a BCR-ABL kinase inhibitor that he could help move to the clinic. He partnered with Ciba-Geigy to screen their collection of synthesized compounds for signs of anticancer activity.	Brian Druker	Oregon Health & Sciences University; Ciba-Geigy	NIH/NCI (K08CA001422); Ciba-Geigy	Druker BJ. Perspectives on the development of imatinib and the future of cancer research. Nature medicine. 2009;15(10):1149-1152.	Pray L. Gleevec: the breakthrough in cancer treatment. Nat Education. 2008;1(1):37.
1996	One of the compounds showed promising results in cultured cells. The compound (ST1571) caused a 92-98% decrease in the number of bcr-abl colonies formed and did not appear to harm healthy cells.	Brian Druker	Oregon Health & Sciences University; Ciba-Geigy	NIH/NCI (K08CA001422); Ciba-Geigy	Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature medicine. 1996;2(5):561-566.

Testing and Approving a Life-changing Drug (1997–2015)

Year	Description of Milestone	Primary Investigator(s)	Research Institution	Funding source (including NIH grant numbers where available)	Citation 1	Citation 2
1998	Ciba-Geigy helped develop the drug for patient use, and the first Phase I clinical trial of ST1571 (later renamed Gleevec) began. All 31 patients in the initial trial experienced complete remission with limited side effects.	Brian Druker	Ciba-Geigy; Oregon Health & Sciences University	NIH (R01CA65823 and P01CA032737); Novartis	Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. The New England journal of medicine. 2001;344(14):1031-1037.
2001	Successful clinical trial results led the FDA to grant “fast track” designation for Gleevec, and it was approved only ten weeks after the New Drug Application was submitted.	N/A	Novartis	NIH, Novartis	Waalen J. Gleevec’s Glory Days. Howard Hughes Medical Institute Bulletin. 2001 Dec;14(5):10-15.
2006	After five years of continuous follow-up treatment, patients receiving Gleevec continued to have a high response rate to the drug, and most remained cancer-free.	Druker	Novartis; Oregon Health & Sciences University	Novartis	Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. The New England journal of medicine. 2006;355(23):2408-2417.

• A Story of Discovery: Gleevec Transforms Cancer Treatment for Chronic Myelogenous Leukemia
• More on Gleevec (Imatinib Mesylate)
• More on CML Treatment

¹NIAID Health and Research Topics: Vaccines , CDC Vaccines and Immunizations: List of Vaccines Used in United States

²NIAID Health and Research Topics: Vaccine Benefits , NICHD Mission and Scientific Accomplishments: Hib Vaccine, and WHO Position Paper on Haemophilus infl uenzae type b conjugate vaccines Weekly Epidemiological Record. 2006;81(47):445.

³Whitney CG, Zhou F, Singleton J, Schuchat A, Centers for Disease C, Prevention. Benefits from immunization during the vaccines for children program era - United States, 1994-2013. MMWR. Morbidity and mortality weekly report. 2014;63(16):352-355.

⁴Robbins JB, Schneerson R, Anderson P, Smith DH. The 1996 Albert Lasker Medical Research Awards. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide-based vaccines. Jama. 1996;276(14):1181-1185.

⁵Decker MD, Edwards KM. Haemophilus influenzae type b vaccines: history, choice and comparisons. The Pediatric infectious disease journal. 1998;17(9 Suppl):S113-116.

⁶CDC Diseases and the Vaccines that Prevent Them: Hib and NICHD Press Release: NICHD Researchers Honored by WHO for Developing Vaccines Against Haemophilus Influenzae, December 10, 1996.

⁷Coverage with Individual Vaccines and Vaccination Series, by State and Local area. In: CDC, ed. National Immunization Survey 2013.

⁸CDC Vaccine Information Statements: Hib

⁹NIAID Health and Research Topics: Vaccine Benefits

¹⁰NICHD Press Release: NICHD Researchers Honored by WHO for Developing Vaccines Against Haemophilus Influenzae, December 10, 1996.

¹¹Zhou F, Shefer A, Wenger J, et al. Economic evaluation of the routine childhood immunization program in the United States, 2009. Pediatrics. 2014;133(4):577-585.

¹²Albert Lasker Clinical Medical Research Award, 1996 Winners

¹³Zhou F, Shefer A, Wenger J, et al. Economic evaluation of the routine childhood immunization program in the United States, 2009. Pediatrics. 2014;133(4):577-585.

¹⁴ Baker JP, Katz SL. Childhood vaccine development: an overview. Pediatric research. 2004;55(2):347-356. and CDC: The Pink Book: Tetanus Vaccine

¹⁵Pittman M. Variation and Type Specificity in the Bacterial Species Hemophilus Influenzae. The Journal of experimental medicine. 1931;53(4):471-492. and Pittman M. The Action of Type-Specific Hemophilus Influenzae Antiserum. The Journal of experimental medicine. 1933;58(6):683-706.

¹⁶Robbins JB, Schneerson R, Anderson P, Smith DH. The 1996 Albert Lasker Medical Research Awards. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide-based vaccines. Jama. 1996;276(14):1181-1185. and Jin Z, Romero-Steiner S, Carlone GM, Robbins JB, Schneerson R. Haemophilus influenzae type a infection and its prevention. Infection and immunity. 2007;75(6):2650-2654.

¹⁷Landsteiner K, van der Scheer J. On Cross Reactions of Immune Sera to Azoproteins. The Journal of experimental medicine. 1936;63(3):325-339. and Avery OT, Goebel WF. Chemo-Immunological Studies on Conjugated Carbohydrate-Proteins : Ii. Immunological Specificity of Synthetic Sugar-Protein Antigens. The Journal of experimental medicine. 1929;50(4):533-550.

¹⁸Alexander DF. Why should there be an NICHD? Pediatrics. 2011;127(2):325-333, also Albert Lasker Clinical Medical Research Award, 1996 Winners, and Rodrigues LP, Schneerson R, Robbins JB. Immunity to Hemophilus influenzae type b. I. The isolation, and some physicochemical, serologic and biologic properties of the capsular polysaccharide of Hemophilus influenzae type b. Journal of immunology. 1971;107(4):1071-1080.

¹⁹Smith DH, Peter G, Ingram DL, Harding AL, Anderson P. Responses of children immunized with the capsular polysaccharide of Hemophilus influenzae, type b. Pediatrics. 1973;52(5):637-644. and Peltola H, Kayhty H, Sivonen A, Makela H. Haemophilus influenzae type b capsular polysaccharide vaccine in children: a double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland. Pediatrics. 1977;60(5):730-737.

²⁰Albert Lasker Clinical Medical Research Award, 1996 Winners and University of Rochester: Childhood Vaccine with Rochester Roots Recognized

²¹Robbins JB, Schneerson R, Anderson P, Smith DH. The 1996 Albert Lasker Medical Research Awards. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide-based vaccines. Jama. 1996;276(14):1181-1185.

²²ibid. and Albert Lasker Clinical Medical Research Award, 1996 Winners

²³Schneerson R, Barrera O, Sutton A, Robbins JB. Preparation, characterization, and immunogenicity of Haemophilus influenzae type b polysaccharide-protein conjugates. The Journal of experimental medicine. 1980;152(2):361-376. and Robbins JB, Schneerson R, Anderson P, Smith DH. The 1996 Albert Lasker Medical Research Awards. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide-based vaccines. Jama. 1996;276(14):1181-1185.

²⁴Schneerson R, Robbins JB, Chu C, et al. Serum antibody responses of juvenile and infant rhesus monkeys injected with Haemophilus influenzae type b and pneumococcus type 6A capsular polysaccharide-protein conjugates. Infection and immunity. 1984;45(3):582-591.

²⁵Claesson BA, Schneerson R, Robbins JB, et al. Protective levels of serum antibodies stimulated in infants by two injections of Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugate. The Journal of pediatrics. 1989;114(1):97-100. also Anderson P, Pichichero M, Edwards K, Porch CR, Insel R. Priming and induction of Haemophilus influenzae type b capsular antibodies in early infancy by Dpo20, an oligosaccharide-protein conjugate vaccine. The Journal of pediatrics. 1987;111(5):644-650. and Anderson P, Pichichero ME, Insel RA. Immunization of 2-month-old infants with protein-coupled oligosaccharides derived from the capsule of Haemophilus influenzae type b. The Journal of pediatrics. 1985;107(3):346-351

²⁶Decker MD, Edwards KM. Haemophilus influenzae type b vaccines: history, choice and comparisons. The Pediatric infectious disease journal. 1998;17(9 Suppl):S113-116.

²⁷ibid.

²⁸CDC Notice to Readers Recommended Childhood Immunization Schedule — United States, January 1995

²⁹Albert Lasker Clinical Medical Research Award, 1996 Winners

³⁰Kelly DF, Moxon ER, Pollard AJ. Haemophilus influenzae type b conjugate vaccines. Immunology. 2004;113(2):163-174.

³¹Coverage with Individual Vaccines and Vaccination Series, by State and Local area. In: CDC, ed. National Immunization Survey 2013.

³²NIAID Health and Research Topics: Vaccine Benefits and CDC: The Pink Book: Course Textbook — 13th Edition (2015) — Hib (graph adapted from “Secular Trends in the United States” section)

³³Briere EC, Rubin L, Moro PL, et al. Prevention and control of haemophilus influenzae type b disease: recommendations of the advisory committee on immunization practices (ACIP). MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 2014;63(RR-01):1-14.

³⁴Whitney CG, Zhou F, Singleton J, Schuchat A, Centers for Disease C, Prevention. Benefits from immunization during the vaccines for children program era — United States, 1994–2013. MMWR. Morbidity and mortality weekly report. 2014;63(16):352-355.

³⁵Zhou F, Shefer A, Wenger J, et al. Economic evaluation of the routine childhood immunization program in the United States, 2009. Pediatrics. 2014;133(4):577-585.

³⁶Whitney CG, Zhou F, Singleton J, Schuchat A, Centers for Disease C, Prevention. Benefits from immunization during the vaccines for children program era — United States, 1994–2013. MMWR. Morbidity and mortality weekly report. 2014;63(16):352-355. (see Appendix Table 2)

³⁷Albert Lasker Clinical Medical Research Award, 1996 Winners

³⁸Robbins JB, Schneerson R, Anderson P, Smith DH. The 1996 Albert Lasker Medical Research Awards. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide-based vaccines. Jama. 1996;276(14):1181-1185, also Albert Lasker Clinical Medical Research Award, 1996 Winners and NICHD Press Release: NICHD Researchers Honored by WHO for Developing Vaccines Against Haemophilus Influenzae, December 10, 1996.

³⁹Zhou F, Shefer A, Wenger J, et al. Economic evaluation of the routine childhood immunization program in the United States, 2009. Pediatrics. 2014;133(4):577-585.

The table below provides a more detailed list of selected milestones underlying this story’s “Research-to-Practice Milestones” (page 2 of the pdf), including the lead scientists, research institutions, funding sources, and scientific publications involved in each one.

Foundational Research

Year	Description of Milestone	Primary Investigator(s)	Research Institution	Funding source (including NIH grant numbers where available)	Citation 1	Citation 2
1892	Bacteria isolated in sputum of patients during an influenza outbreak – later named Haemophilus	Pfeiffer	N/A	N/A	Jin Z, Romero-Steiner S, Carlone GM, Robbins JB, Schneerson R. Haemophilus influenzae type a infection and its prevention. Infection and immunity. 2007;75(6):2650-2654
1923	First diphtheria vaccine developed	Ramon	Pasteur Institute (France)	N/A	Baker JP, Katz SL. Childhood vaccine development: an overview. Pediatric research. 2004;55(2):347-356
1924	First tetanus vaccine developed	Descombey	N/A	N/A	CDC: The Pink Book: Tetanus Vaccine
1929	The ability of the sugar coat surrounding some bacteria, called the capsular polysaccharide, to generate an immune response was enhanced.	Avery and Goebel	Rockefeller Institute	N/A	Avery OT, Goebel WF. Chemo-Immunological Studies on Conjugated Carbohydrate-Proteins : Ii. Immunological Specificity of Synthetic Sugar-Protein Antigens. The Journal of experimental medicine. 1929;50(4):533-550.
1930s	Hib was discovered and found to be the primary cause of bacterial meningitis. A unique feature of the type b strain is the structure of the sugar molecules on the bacterial coat, later known as the capsular polysaccharide.	Pittman	Rockefeller Institute	N/A	Pittman M. Variation and Type Specificity in the Bacterial Species Hemophilus Influenzae. The Journal of experimental medicine. 1931;53(4):471-492.	Pittman M. The Action of Type-Specific Hemophilus Influenzae Antiserum. The Journal of experimental medicine. 1933;58(6):683-706.
1933	Determined that children develop systemic Hib infections when placental antibodies waned	Fothergill and Wright	Harvard University	Philip Ellis Stevens, Jr., Memorial Fund	Fothergill L, Wright J. The Relation of Age Incidence to the Bactericidal Power of Blood Against the Causal Organism. J Immunol. 1933; 24(4): 273-284
1936	A molecule’s ability to generate antibodies in animals is enhanced when bound to a more immune stimulating molecule	Landsteiner	Rockefeller Institute	N/A	Landsteiner K, van der Scheer J. On Cross Reactions of Immune Sera to Azoproteins. The Journal of experimental medicine. 1936;63(3):325-339.

Early Hib Vaccine Development

Year	Description of Milestone	Primary Investigator(s)	Research Institution	Funding source (including NIH grant numbers where available)	Citation 1	Citation 2
1968	Hib polysaccharides were isolated, purified, and considered for clinical use	Smith and Anderson	Harvard Medical School	N/A	Albert Lasker Clinical Medical Research Award, 1996 Winners
1970s	Hib polysaccharides were recognized as the predominate bacterial substances that elicited immune responses, as opposed to proteins as widely believed.	Robbins and Schneerson	NIH	NICHD Intramural Research Program	Alexander DF. Why should there be an NICHD? Pediatrics. 2011;127(2):325-333
1971	Hib polysaccharides were isolated and purified	Robbins and Schneerson	Albert Einstein College of Medicine	NIAID grant (R01AI8110), NICHD contract (69-2246), and NICHD grant (K03HD22856)	Rodrigues LP, Schneerson R, Robbins JB. Immunity to Hemophilus influenzae type b. I. The isolation, and some physicochemical, serologic and biologic properties of the capsular polysaccharide of Hemophilus influenzae type b. Journal of immunology. 1971;107(4):1071-1080.
1973	First purified Hib polysaccharide vaccine induced antibody responses in 87% of children over the age of two years, but only in a quarter of infants tested.	Smith and Anderson	Harvard Medical School	NIAID contract (71-2196), NIAID grants (AI20376, AI46905)	Smith DH, Peter G, Ingram DL, Harding AL, Anderson P. Responses of children immunized with the capsular polysaccharide of Hemophilus influenzae, type b. Pediatrics. 1973;52(5):637-644.
1977	A clinical trial assessed the effectiveness of the Hib polysaccharide vaccine in 100,000 children between three months to two years of age. The vaccine proved highly efficacious in those children over 18 months of age, as opposed to younger children.	Peltola	University of Helsinki & National Public Health Institute (Finland)	NIAID contract (AI52502)	Peltola H, Kayhty H, Sivonen A, Makela H. Haemophilus influenzae type b capsular polysaccharide vaccine in children: a double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland. Pediatrics. 1977;60(5):730-737.
1983	Praxis Biologics was founded to further develop childhood vaccines, including Hib.	Smith and Anderson	Praxis Biologics	N/A	Albert Lasker Clinical Medical Research Award, 1996 Winners
1984	When half of the children from the 1977 study were re-evaluated, the children who received the vaccine after 18 months of age continued to show good immune responses, while those vaccinated as infants only showed short-lived antibody responses.	Peltola	University of Helsinki & National Public Health Institute of Finland	NIAID contract (AI52502)	Peltola H, Kayhty H, Virtanen M, Makela PH. Prevention of Hemophilus influenzae type b bacteremic infections with the capsular polysaccharide vaccine. The New England journal of medicine. 1984;310(24):1561-1566.	Kayhty H, Karanko V, Peltola H, Makela PH. Serum antibodies after vaccination with Haemophilus influenzae type b capsular polysaccharide and responses to reimmunization: no evidence of immunologic tolerance or memory. Pediatrics. 1984;74(5):857-865.
1985	The FDA approved Hib polysaccharide vaccines from three companies (including Praxis Biologics) for use in children older than two years of age.	N/A	N/A	N/A	Robbins JB, Schneerson R, Anderson P, Smith DH. The 1996 Albert Lasker Medical Research Awards. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide-based vaccines. Jama. 1996;276(14):1181-1185.	Albert Lasker Clinical Medical Research Award, 1996 Winners

Protecting Infants with a Next-Generation Conjugate Vaccine

Year	Description of Milestone	Primary Investigator(s)	Research Institution	Funding source (including NIH grant numbers where available)	Citation 1	Citation 2
1980	By applying the foundational early 20th century research highlighted above, Hib polysaccharides were linked to proteins shown to be effective vaccines against other bacteria (e.g., diphtheria), producing what is now known as a “conjugate vaccine."	Robbins and Schneerson	FDA	FDA	Schneerson R, Barrera O, Sutton A, Robbins JB. Preparation, characterization, and immunogenicity of Haemophilus influenzae type b polysaccharide-protein conjugates. The Journal of experimental medicine. 1980;152(2):361-376.
1984	NIH and FDA scientists found that this conjugate vaccine triggered immune responses in appropriate animal models.	Robbins and Schneerson	NIH and FDA	NIH Intramural research programs at NICHD, National Institiute of Neurological and Commlunicative Disorders and Stroke, and National Instituite of Arthritis, Metabolism, and Digestive Diseases; FDA's Center for Drugs and Biologics	Schneerson R, Robbins JB, Chu C, et al. Serum antibody responses of juvenile and infant rhesus monkeys injected with Haemophilus influenzae type b and pneumococcus type 6A capsular polysaccharide-protein conjugates. Infection and immunity. 1984;45(3):582-591.
1986	Immune responses in infants could be enhanced if fewer sugar molecules were used with the Hib conjugate vaccine.	Smith and Anderson	University of Rochester, Praxis Biologics	NIAID grants (AI17938, AI12673, AI17217, AI02653)	Anderson PW, Pichichero ME, Insel RA, Betts R, Eby R, Smith DH. Vaccines consisting of periodate-cleaved oligosaccharides from the capsule of Haemophilus influenzae type b coupled to a protein carrier: structural and temporal requirements for priming in the human infant. Journal of immunology. 1986;137(4):1181-1186.
1986	The Hib polysaccharide vaccine linked to tetanus proteins elicited strong, protective immune responses in young adults.	Robbins and Schneerson	NIH, FDA, Uniformed Services University of the Health Sciences, Charlotte Memorial Hospital and Medical Center, State University of New York	NIH Intramural research programs at NICHD and National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases	Schneerson R, Robbins JB, Parke JC, Jr., et al. Quantitative and qualitative analyses of serum antibodies elicited in adults by Haemophilus influenzae type b and pneumococcus type 6A capsular polysaccharide-tetanus toxoid conjugates. Infection and immunit
1987	Infants produced protective antibodies against Hib following vaccination with short segments of Hib sugars linked to diphtheria proteins.	Anderson	University of Rochester	NIAID grants (AI17938, AI02645, AI17217)	Anderson P, Pichichero M, Edwards K, Porch CR, Insel R. Priming and induction of Haemophilus influenzae type b capsular antibodies in early infancy by Dpo20, an oligosaccharide-protein conjugate vaccine. The Journal of pediatrics. 1987;111(5):644-650.	Anderson P, Pichichero ME, Insel RA. Immunization of 2-month-old infants with protein-coupled oligosaccharides derived from the capsule of Haemophilus influenzae type b. The Journal of pediatrics. 1985;107(3):346-351
1988	Hib polysaccharides linked to tetanus proteins was safe and effective in 18- to 23-month old healthy children	Robbins and Schneerson	NIH, CDC, University of Gothenburg (Sweden)	NICHD Intramural Research Program	Claesson BA, Trollfors B, Lagergard T, et al. Clinical and immunologic responses to the capsular polysaccharide of Haemophilus influenzae type b alone or conjugated to tetanus toxoid in 18- to 23-month-old children. The Journal of pediatrics. 1988;112(5):695-702.
1989	A clinical study demonstrated infants produced protective antibodies following Hib polysaccharide-tetanus protein conjugate vaccination	Robbins and Schneerson	NIH, University of Gotheburg (Sweden)	NICHD Intramural Research Program	Claesson BA, Schneerson R, Robbins JB, et al. Protective levels of serum antibodies stimulated in infants by two injections of Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugate. The Journal of pediatrics. 1989;114(1):97-100
1987-1993	The FDA approved the first 4 Hib conjugate vaccines for use in infants.	N/A	N/A	N/A	Decker MD, Edwards KM. Haemophilus influenzae type b vaccines: history, choice and comparisons. The Pediatric infectious disease journal. 1998;17(9 Suppl):S113-116.
1995	The CDC includes Hib conjugate vaccines in the first childhood vaccine schedule.	N/A	N/A	N/A	CDC Notice to Readers Recommended Childhood Immunization Schedule -- United States, January 1995

• CDC’s Child, Adolescent, & “Catch-up” Immunization Schedules
• CDC’s Vaccines for Children Program
• NIAID Health and Research Topics: Vaccines