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NIH supports research in a wide variety of biomedical research areas, advancing our knowledge of health and disease. NIH is an integral part of a biomedical research ecosystem that includes universities, researchers, private companies, and other government agencies. The knowledge produced by NIH-supported research can take many years and pass through many organizations on its pathway toward improving health. Explore this page to look at a few stories of how NIH has contributed to important biomedical advances, and how these advances have made a difference in our knowledge, our health, and our society.
Rare Autoinflammatory Diseases Research: Saving Lives, Giving Hope to Families
Autoinflammatory diseases are a relatively new category of conditions that differ from autoimmune diseases. Although both kinds of illnesses happen when the immune system attacks the body’s own tissues, they occur by different processes. Read the story of how NIH researchers played a vital role in differentiating between the two groups of diseases, discovering the molecular causes for different autoinflammatory diseases, and identifying life-saving treatments
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References
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
Related Resources on Rare Autoinflammatory Diseases Research
Neurostimulation Technologies: Harnessing Electricity To Treat Lost Neural Function
The human nervous system is so complex and fundamental, that until recently, it was believed that any damage to it was irreversible. NIH support and years of scientific effort, however, have begun to make it possible to compensate for lost function using electrical stimulation to enhance nervous system activity. Read the story of how NIH-supported research helped harness the electrical nature of the nervous system to develop cutting-edge therapies
Additional materials
References
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
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.
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
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.
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
Appendix
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
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. |
Related Resources on Neurostimulation Technologies
Fighting Cancer: Ushering in a New Era of Molecular Medicine
Huge advances in our understanding of disease at a molecular level are paving the way for more effective, personalized treatments. Gleevec®, a drug used to treat chronic myelogenous leukemia (CML), was among the first successful molecular medicines developed. Read the story of how NIH-supported research helped create a revolutionary cancer drug that changed the way we think about designing new medicines
Additional materials
References
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.
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.
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
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
Appendix
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. |
Related Resources on Gleevec
Childhood Hib Vaccines: Nearly Eliminating the Threat of Bacterial Meningitis
NIH has contributed to the development of many important vaccines, including the vaccine against Haemophilus influenzae type b (Hib) infection. Once the leading cause of bacterial meningitis in children, Hib infection can result in serious, long-term disability and death. Today, Hib has been nearly eliminated. Read the story of how NIH-supported research helped create a vaccine that has nearly eliminated childhood meningitis
Additional materials
References
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.
Appendix
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 |
Related Resources on Hib and Other Vaccines
This page last reviewed on September 6, 2016