Dr. Safar is Professor in the Departments of Pathology and Neurology at Case Western Reserve University (CWRU). He is an internationally recognized leader in research on neurodegenerative diseases caused by protein misfolding, such as Creutzfeldt-Jakob Disease, mad cow disease (BSE), and Alzheimer’s disease with extensive research experience in molecular biology, biochemistry, and conformation of prions and amyloids. He discovered previously unknown forms of prions, which led to the findings of new prion diseases, better understanding of the conformation of prion proteins, and unraveling molecular mechanisms of prion strains. Dr. Safar invented the Conformation-Dependent Immunoassay (CDI) for detection, Conformational Stability Assay (CSA) for differentiation of prions and prion-like proteins, including those causing Alzheimer’s disease, and synthesized the first artificial human prion. The new concept for detecting prions and other misfolded proteins was patented internationally, and the CDI was validated for diagnosis of Creutzfeldt-Jakob Disease, and animal diseases (BSE, scrapie) in European Union.
After completing his residency, chief residency, and PhD training in Biochemistry, Dr. Safar received Research Fellowship in the Laboratory of Central Nervous System Studies at the National Institutes of Health (NIH), directed by D.C. Gajdusek (Nobel Prize for Medicine 1976). Here he demonstrated that the difference between the normal and pathogenic prion protein lies in the conformational transition, and he introduced a novel concept of the folding intermediate as a crucial stage in the prion formation. For this groundbreaking research, he received the National Institutes of Health Merit Award. In 1996, he took a position of a Senior Scientist at the Institute for Neurodegenerative Diseases, directed by Stanley B. Prusiner (Nobel Prize for Medicine 1997), and Associate Professor at the University of California at San Francisco (UCSF). During his 12 years at UCSF he expanded his prion research, discovered new oligomeric forms of prions, and led a research team that developed a new concept for the detection and differentiation of prions exploiting differences in their structural organization.
In 2008, Dr. Safar was recruited to continue his research on neurodegenerative diseases caused by prions and protein misfolding at CWRU where he established a new research laboratory at the Department of Pathology, and developed a strong long-term collaboration with the Department of Physiology and Biophysics, and Department of Neurology.
Dr. Safar holds 27 US and Europeans patents, including one for a method for detecting misfolded proteins (Prusiner, S.B., Safar, J. (1999) US Patent # 5,891,641) and another for a device that removes prions from blood, plasma and other liquids (Prusiner, S.B., Safar, J. (2001) US Patent # 6,221,614 B1).
The Replication Mechanism of Human Prions and Molecular Basis of Prion Diseases
To deepen knowledge of the structure of the prion protein in both its normal and pathogenic forms and mechanism of human prion replication, so that efficient diagnostic tools and therapies can be developed.
The Role of Small Oligomers of Misfolded Proteins in the Pathogenesis of Neurodegeneration
To improve our understanding of the molecular mechanisms governing the phenotypic heterogeneity and progression rates of Alzheimer’s diseases and prion diseases, specifically on different conformers of small oligomers of Amyloid beta, tau, and pathogenic prion protein.
Molecular Diagnostics and Prion Strain Differentiation
To develop a preclinical test that can diagnose and differentiate distinct subtypes of human prion as well as other protein misfolding diseases at the earliest possible time.
Awards and Honors
- Prion Expert External Review Panel, Canada
- British Spongiform Encephalopathy Advisory Committee, UK
- European Union's Prion Expert Group, UK
- Medical Research Council, UK
- Ministry of Agriculture, Food, and Fisheries, UK
- Swiss National Science Foundation, Switzerland
- World Health Organization's Advisory Board for Prion Diseases, Switzerland
- Editorial boards of Prion (UK), and Frontiers in Aging Neuroscience Journal (Switzerland)
Dr. Safar is the author of 114 peer-reviewed papers and book chapters, encompassing a broad range of research in conformational protein chemistry, molecular biology, immunology, and proteomics of neurodegenerative diseases, particularly prion diseases and Alzheimer’s disease. His 1998 Nature Medicine paper is the most quoted original work published on prions in the past 20 years (Cited 887-times, Institute for Scientific Information, 1998-2018).
Selected Journal Articles
- Cohen ML, Kim C, Haldiman T, ElHag M, Mehndiratta P, Pichet T, Lissemore F, Shea M, Cohen Y, Chen W, Blevins J, Appleby BS, Surewicz K, Surewicz WK, Sajatovic M, Tatsuoka C, Zhang S, Mayo P, Butkiewicz M, Haines JL, Lerner AJ, Safar JG. (2015) Rapidly Progressive Alzheimer Disease Features Distinct Structures of β-Amyloid. Brain: Epub 2015/02/18. PMID: 25688081.
- Safar, J., Wille, H., Itri, V., Groth, D., Serban, H., Torchia, M., Cohen F.E., Prusiner, S.B. (1998) Eight prion strains have PrPSc molecules with different conformations. Nature Medicine 4: 1157-1165. PMID: 9771749.
- Haldiman T, Kim C, Cohen Y, Chen W, Blevins J, Qing L, Cohen ML, Langeveld J, Telling GC, Kong Q, Safar JG. (2013) Co-existence of distinct prion types enables conformational evolution of human PrPSc by competitive selection. J Biol Chem. 2013 Oct 11;288(41):29846-61. PMCID: PMC37952833.
- Safar JG, Xiao X, Kabir ME, Chen S, Kim C, Haldiman T, Cohen Y, Chen W, Cohen ML, Surewicz WK. (2015) Structural determinants of phenotypic diversity and replication rate of human prions. PLoS Pathog. 2015 Apr 14;11(4):e1004832. doi: 10.1371/journal.ppat.1004832. eCollection 2015. PMCID: PMC4397081.
- Safar, J.G., Scott, M., Monaghan, J., Deering, C., Didorenko, S., Vergara, J., Ball, H., Legname, G., Leclerc, E., Solforosi, L., Serban, H., Groth, D., Burton, D.R., Prusiner, S.B., Williamson, R.A. (2002) Measuring prions causing bovine spongiform encephalopathy or chronic wasting disease by immunoassays and transgenic mice. Nature Biotech. 11:1147-50. PMID: 12389035.
- Safar, J.G., Geschwind, M.D., Deering, C., Didorenko, S., Sattavat, M., Sanchez, H., Serban, A., Vey, M., Baron, H., Giles, K., Miller, B.L., Dearmond, S.J., Prusiner, S.B. (2005) Diagnosis of human prion disease. Proc. Natl. Acad. Sci. U S A. Mar 1;102(9):3501-6. PMCID: PMC552933.
- Kim, C., Haldiman,T., Surewicz, K., Cohen, Y., Chen, W., Blevins, J., Sy, M-S., Cohen, M., Kong, Q., Telling, G.C., Surewicz, W.K., and Safar, J.G. (2012) Small Protease Sensitive Oligomers of PrP(Sc) in Distinct Human Prions Determine Conversion Rate of PrP(C). PLoS Pathog. 2012 Aug;8(8):e1002835. Epub 2012 Aug 2. PMCID: PMC3410855.
- Safar, J.G., DeArmond, S., Kociuba, K., Deering, D, Didorenko, S., Bouzamondo-Bernstein, E., Prusiner, S.B., Tremblay, P. (2005) Prion clearance in bigenic mice. J. Gen. Virol., 86(Pt 10):2913-23. PMID: 16186247.
- Mays CE, Kim C, Haldiman T, van der Merwe J, Lau A, Yang J, Grams J, Di Bari MA, Nonno R, Telling GC, Kong Q, Langeveld J, McKenzie D, Westaway D, Safar JG. (2014) Prion disease tempo determined by host-dependent substrate reduction. J Clin Invest. 2014; 124(2):847-58. PMCID: PMC3904628.
- Kim C, Xiao X, Chen S, Haldiman T, Smirnovas V, Kofskey D, Warren M, Surewicz K, Maurer NR, Kong Q, Surewicz W, Safar JG. (2018) Artificial strain of human prions created in vitro. Nature Communications 9(1):2166. doi: 10.1038/s41467-018-04584-z. PMCID: PMC5986862.