William Balch, PhD

Department of Molecular Medicine


Scripps Research Joint Appointments

Professor, Department of Molecular Medicine
Faculty, Graduate Program

Research Focus

Modeling the evolution of genetic variation in the human population to describe the role of proteostasis in managing the function of the protein fold in health and disease in the individual.

The Balch laboratory works to link the evolution of genetic variation in the human population to experimental and computational approaches to describe and manage the function of the protein fold in health and disease.  

Defining the role of genetic variation in shaping biological diversity is critical to understanding the global forces at play in health, disease, and aging. We generate an integrated view of genetic variation in the genome and the corresponding changes in the proteome in response to the environment and natural selection using novel machine learning tools that allow us to rigorously assess protein fold function and structure on a residue-by-residue basis at atomic resolution. 

Current efforts utilize cell biological, molecular, biochemical and structural approaches in the context of state-of-the-art machine learning Gaussian process (GP) and in silico computational platforms to link the sequence information found in the genome to the proteome managed by the  proteostasis machinery (Hsp70 and Hsp90 co-chaperone systems). Our approach provides a standard model to begin to describe the evolution of protein fold design for any gene dictating health that is compromised in disease - and for development of novel therapeutic approaches to correct the folding problem in the individual.


Ph.D. (Microbiology), University of Illinois at Urbana-Champaign, 1979

Professional Experience

2013-2017 Professor, Cell and Molecular Biology (CMB), Scripps Research
1995-2012 Professor, Cell Biology, Scripps Research
-2012 Professor (Joint Appointment), Molecular Biology, Scripps Research

Selected References

All Publications

Link to complete list of William E. Balch publications here

Sun S., Wang C., Zhao P., Kline G.M., Grandjean J.M.D., Jiang X., Labaudiniere R., Wiseman R.L., Kelly J.W., Balch W.E. 2023. Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis. Cell Chem Biol. 20(1):22-42. (Link).

Stoeger, T., Grant, R.A., McQuattie-Pimentel, A.C. et al.  2022. Aging is associated with a systemic length-associated transcriptome imbalance. Nat Aging 2, 1191–1206. (Link).

Loguercio, S., Hutt, D.M., Campos, A.R., Stoeger, T., Grant, R.A., McQuattie-Pimentel, A.C., Abdala-Valencia, H., Lu, Z., Joshi, N., Ridge, K., Chandel, N.S., Sznajder, J.I., Morimoto, R.I., Misharin, A.V., Budinger, G.R.S., Balch, W.E. 2019. Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease. BioRxiv. (Link).

Wang C., Angles F., Balch W.E. 2022. Triangulating variation in the population to define mechanisms for precision management of genetic disease. Structure. 30(8):1190-1207. (Link).

Wang, C., Elghobashi-Meinhardt, N., Balch, W.E. 2022. Covariant Fitness Clusters Reveal Structural Evolution of SARS-CoV-2 Polymerase Across the Human Population. BioRxiv. January 2022. (Link).

Angles F., Wang C., Balch W.E. 2022. Spatial Covariance analysis reveals the residue-by-residue thermodynamic contribution of variation to the CFTR fold. Commun. Biol. 5(1):356.

McQuattie-Pimentel, A. C., Ren, Z., Joshi, N., Watanabe, S., Stoeger, T., Chi, M., Lu, Z., Sichizya, L., Aillon, R. P., Chen, C. I., Soberanes, S., Chen, Z., Reyfman, P. A., Walter, J. M., Anekalla, K. R., Davis, J. M., Helmin, K. A., Runyan, C. E., Abdala-Valencia, H., Nam, K., Meliton, A. Y., Winter, D. R., Morimoto, R. I., Mutlu, G. M., Bharat, A., Perlman, H., Gottardi, C. J., Ridge, K. M., Chandel, N. S., Sznajder, J. I., Balch, W. E., Singer, B. D., Misharin, A. V., and Budinger, G. R. S. 2021. The Lung Microenvironment Shapes a Dysfunctional Response of Alveolar Macrophages in Aging. J Clin Invest. 131(4). (Link)

Wang, C., Zhao, P., Sun, S., Teckman, J., and Balch, W. E.  2020. Leveraging Population Genomics for Individualized Correction of the Hallmarks of Alpha-1 Antitrypsin Deficiency. Chronic Obstr. Pulm. Dis. 7, 224-246. (Link).

Tran, D. T., Pottekat, A., Mir, S. A., Loguercio, S., Jang, I., Campos, A. R., Scully, K. M., Lahmy, R., Liu, M., Arvan, P., Balch, W. E., Kaufman, R. J., and Itkin-Ansari, P.  2020. Unbiased Profiling of the Human Proinsulin Biosynthetic Interaction Network Reveals a Role For Peroxiredoxin 4 in Proinsulin Folding. Diabetes. 2020 May 26;db200245. doi: 10.2337/db20-0245. Online ahead of print. (Link).

Singh, J., Hutt, D. M., Tait, B. D., Guy, N. C., Sivils, J. C., Ortiz, N. R., Payan, A. N., Komaragiri, S. K., Owens, J. J., Culbertson, D., Blair, L. J., Dickey, C., Kuo, S. Y., Finley, D., Dyson, H. J., Cox, M. B., Chaudhary, J., Gestwicki, J. E., and Balch, W. E.  2020. Management of Hsp90-Dependent Protein Folding by Small Molecule Targeting the Aha1 Co-Chaperone. Cell Chem. Biol. 27(3):292-305.e6, 412908. (Link).

Subramanian, K., Hutt, D.M., Scott, S.M., Gupta, V., Mao, S., Balch, W.E. 2020. Correction of Niemann-Pick type C1 trafficking and activity with histone deacetylase inhibitor valproic acid.  J. Biol. Chem. 2020, Apr 30. doi: 10.1074/jbc.RA119.010524. (Link).

Wang, C., Scott, S. M., Sun, S., Zhao, P., Hutt, D. M., Shao, H., Gestwicki, J. E., and Balch, W. E. 2019. Individualized Management of Genetic Diversity in Niemann-Pick C1 through Modulation of the Hsp70 Chaperone System. Hum. Mol. Genet. doi: 10.1093/hmg/ddz215. [Epub ahead of print].

Angles, F., Hutt, D. M., and Balch, W. E. 2019. HDAC inhibitors rescue multiple disease-causing CFTR variants. Hum. Mol. Genet. 28, 1982-2000.

Subramanian, K., Hutt, D. M., Gupta, V., Mao, S., and Balch, W. E. 2019. Correction of Niemann-Pick type C1 disease with the histone deacetylase inhibitor valproic acid. bioRxiv, 724187. doi: 10.1093/hmg/ddz215. [Epub ahead of print].

Soberanes, S., Misharin, A. V., Jairaman, A., Morales-Nebreda, L., McQuattie-Pimentel, A. C., Cho, T., Hamanaka, R. B., Meliton, A. Y., Reyfman, P. A., Walter, J. M., Chen, C. I., Chi, M., Chiu, S., Gonzalez-Gonzalez, F. J., Antalek, M., Abdala-Valencia, H., Chiarella, S. E., Sun, K. A., Woods, P. S., Ghio, A. J., Jain, M., Perlman, H., Ridge, K. M., Morimoto, R. I., Sznajder, J. I., Balch, W. E., Bhorade, S. M., Bharat, A., Prakriya, M., Chandel, N. S., Mutlu, G. M., and Budinger, G. R. S. 2019. Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis. Cell Metab 29, 335-347 e335

Wang, C., Balch, W.E. 2018. Bridging Genomics to Phenomics at Atomic Resolution through Variation Spatial Profiling. Cell Rep. 24(8):2013-2028 e2016. DOI: 10.1016/j.celrep.2018.07.059.

Hutt, D.M., Loguercio, S., Roth, D.M., Su, A.I., Balch, W.E. 2018. Correcting the F508del-CFTR variant by modulating eukaryotic translation initiation factor 3-mediated translation initiation. J. Biol. Chem.2018 Jul 13. pii: jbc.RA118.003192. doi: 10.1074/jbc.RA118.003192. [Epub ahead of print].

Hutt, D.M., Mishra, S.K., Roth, D.M., Larsen, M.B., Angles, F., Frizzell, R.A., Balch, W.E. 2018. Silencing of the Hsp70-specific nucleotide-exchange factor BAG3 corrects the F508del-CFTR variant by restoring autophagy. J. Biol. Chem. 2018 Jul 9. pii: jbc.RA118.002607. doi: 10.1074/jbc.RA118.002607. [Epub ahead of print].

Hutt, D.M., Loguercio, S., Campos, A.R., Balch, W.E. 2018. A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited and Somatic Disease.  J. Mol. Biol. 2018 Jun 18. pii: S0022-2836(18)30613-2. doi: 10.1016/j.jmb.2018.06.017. [Epub ahead of print].

Subramanian, K., Rauniyar, N., Lavallee-Adam, M., Yates III, J.R., Balch, W.E. 2017. Quantitative Analysis of the Proteome Response to the Histone Deacetylase Inhibitor (HDACi) Vorinostat in Niemann-Pick Type C1 disease. J. Mol. Proteomics. 16(11):1938-1957. doi: 10.1074/mcp.M116.064949.

Wang, C., Bouchecareilh, M., Balch, W.E. 2017. Measuring the Effect of Histone Deacetylase Inhibitors (HDACi) on the Secretion and Activity of Alpha-1 Antitrypsin. Methods Mol. Biol.  1639:185-193.

Misharin, A.V., Morales-Nebreda, L., Reyfman, P.A., Cuda, C.M., Walter, J.M., McQuattie-Pimentel, A.C., Chen, C.I., Anekalla, K.R., Joshi, N., Williams, K.J.N., Abdala-Valencia, H., Yacoub, T.J., Chi, M., Chiu, S., Gonzalez-Gonzalez, F.J., Gates, K., Lam, A.P., Nicholson, T.T., Homan, P.J., Soberanes, S., Dominguez, S., Morgan, V.K., Saber, R., Shaffer, A., Hinchcliff, M., Marshall, S.A., Bharat, A., Berdnikovs, S., Bhorade, S.M., Bartom, E.T., Morimoto, R.I., Balch, W.E., Sznajder, J.I., Chandel, N.S., Mutlu, G.M., Jain, M., Gottardi, C.J., Singer, B.D., Ridge, K.M., Bagheri, N., Shilatifard, A., Budinger, G.R.S., Perlman, H. 2017. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J. Exp. Med. J Exp Med. 2017 Aug 7;214(8):2387-2404. doi: 10.1084/jem.20162152. Epub 2017 Jul 10.

Budinger, G.S., Kohanski, R.A., Gan, W., Kobor, M.S., Amaral, L.A., Armanios, M., Kelsey, K.T., Pardo, A., Tuder, R., Macian, F., Chandel, N., Vaughan, D., Rojas, M., Mora, A.L., Kovacs, E., Duncan, S.R., Finkel, T., Choi, A., Eickelberg, O., Chen, D., Agusti, A., Selman, M., Balch, W.E., Busse, P., Lin, A., Morimoto, R., Sznajder, J.I., Thannickal, V.J. 2017. The Intersection Of Aging Biology and The Pathobiology of Lung Diseases: A Joint NHLBI/NIA Workshop. J. Gerontol. A. Biol. Sci. Med. Sci. doi: 10.1093/gerona/glx090. [Epub ahead of print].

Pipalia, N.H., Subramanian, K., Mao, S., Ralph, H., Hutt, D.M., Scott, S.M., Balch, W.E., Maxfield, F.R. 2017. Histone deacetylase inhibitors correct the cholesterol storage defect in most NPC1 mutant cells. J. Lipid Res.. doi: 10.1194/jlr.M072140. [Epub ahead of print].

Wang, C., Balch, W.E. 2016. Managing the adaptive proteostatic landscape: restoring resilience in Alpha-1 antitrypsin deficiency. In: Adam Wanner, M.a.R.A.S., MD, Ph.D editor. Respir. Med.: Humana Press - Springer International Publishing AG Switzerland; p. 53-83.

Veit, G., Avramescu, R.G., Chiang, A.N., Houck, S.A., Cai, Z., Peters, K.W., Hong, J.S., Pollard, H.B., Guggino, W.B., Balch, W.E., Skach, W.R., Cutting, G.R., Frizzell, R.A., Sheppard, D.N., Cyr, D.M., Sorscher, E.J., Brodsky, J.L., Lukacs, G.L. 2016. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol. Biol. Cell. 27(3):424-433.

Pankow, S., Bamberger, C., Calzolari, D., Martinez-Bartolome, S., Lavallee-Adam, M., Balch, W.E., Yates, J.R., 3rd. 2015. F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature.  528(7583):510-516.

Amaral, M.D., Balch, W.E. 2015. Hallmarks of therapeutic management of the cystic fibrosis functional landscape. J. Cyst Fibrosis.14(6):687-99.

Rauniyar, N., Subramanian, K., Lavallee-Adam, M., Martinez-Bartolome, S., Balch, W.E., Yates, J.R., 3rd. 2015. Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann-Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis. Mol. Cell Proteomics. 14(7):1734-1749.

Singh, J.K., Balch, W.E. 2015. Proteostatic hotspots in amyloid fibrils protect us from neurodegeneration. Dev. Cell. 32(6):659-660.

Roth, D.M., Hutt, D.M., Tong, J., Bouchecareilh, M., Wang, N., Seeley, T., Dekkers, J.F., Beekman, J.M., Garza, D., Drew, L., Masliah, E., Morimoto, R.I., Balch, W.E. 2014. Modulation of the maladaptive stress response to manage diseases of protein folding. PLoS Biol. 12(11):e1001998.

Rauniyar, N., Gupta, V., Balch, W.E., Yates, J.R. 2014. Quantitative proteomic profiling reveals differentially regulated proteins in cystic fibrosis cells. J. Proteome Res. 13(11):4668-75.

Balch, W. E., Sznajder, J. I., Budinger, S., Finley, D., Laposky, A. D., Cuervo, A. M., Benjamin, I. J., Barreiro, E., Morimoto, R. I., Postow, L., Weissman, A. M., Gail, D., Banks-Schlegel, S., Croxton, T., and Gan, W. 2014. Malfolded protein structure and proteostasis in lung diseases. Am. J. Respir. Crit. Care Med. 189, 96-103

Hamvas, A., Deterding, R., Balch, W. E., Schwartz, D. A., Albertine, K. H., Whitsett, J. A., Cardoso, W. V., Kotton, D. N., Kourembanas, S., and Hagood, J. S. 2014. Diffuse lung disease in children: Summary of a scientific conference. Pediatr. Pulmonol. 49, 400-409

Pottekat, A., Becker, S., Spencer, K. R., Yates, J. R., 3rd, Manning, G., Itkin-Ansari, P., and Balch, W. E. 2013. Insulin biosynthetic interaction network component, TMEM24, facilitates insulin reserve pool release. Cell Rep 4, 921-930

Roth, D. M., and Balch, W. E. 2013. Q-bodies monitor the quinary state of the protein fold. Nat Cell Biol 15, 1137-1139

Powers, E.T., Balch, W.E. 2013. Diversity in the origins of proteostasis networks - a driver for protein function in evolution. Nat. Rev. Mo. Cell Biol. 14(4):237-248.

Calamini, B., Silva, M. C., Madoux, F., Hutt, D. M., Khanna, S., Chalfant, M. A., Allais, C., Ouizem, S., Saldanha, S. A., Ferguson, J., Mercer, B. A., Michael, C., Tait, B. D., Garza, D., Balch, W. E., Roush, W. R., Morimoto, R. I., and Hodder, P. 2013. ML346: A Novel Modulator of Proteostasis for Protein Conformational Diseases. Probe Reports from the NIH Molecular Libraries Program.

Bannykh, S. I., Balch, W. E., Kelly, J. W., Page, L. J., and Shelton, G. D. 2013. Formation of gelsolin amyloid fibrils in the rough endoplasmic reticulum of skeletal muscle in the gelsolin mouse model of inclusion body myositis: comparative analysis to human sporadic inclusion body myositis. Ultrastruct. Pathol. 37, 304-311

Hutt, D.M., Balch, W.E. 2013. Expanding Proteostasis by Membrane Trafficking Networks. Cold Spring Harb Perspect Biol. 10.1101/cshperspect.a013383. [Epub ahead of print].

Gupta, V., and Balch, W.E. 2013. Protein folding: Salty sea regulators of cystic fibrosis. Nat. Chem. Biol. 9:12-14.

Bouchecareilh, M., Hutt, D.M., Szajner, P., Flotte, T.R., and Balch, W.E. 2012. Histone Deacetylase inhibitor (HDACi) Suberoylanilide Hydroxamic Acid (SAHA) Mediated Correction of Alpha-1 Antitrypsin Deficiency. J. Biol. Chem. 287: 38265-38278.

Hulleman, J.D., Balch, W.E., and Kelly, J.W. 2012. Translational attenuation differentially alters the fate of disease-associated fibulin proteins. FASEB J. 261: 4548-60.

Coppinger, J.A., Hutt, D.M., Razvi, A., Koulov, A.V., Pankow, S., Yates, J.R., 3rd, and Balch, W.E. 2012. A chaperone trap contributes to the onset of cystic fibrosis. PLoS One 7:e37682.

Bouchecareilh, M., and Balch, W.E. 2012. Proteostasis, an Emerging Therapeutic Paradigm for Managing Inflammatory Airway Stress Disease. Curr. Mol. Med. 1:815-826.

Hutt, D.M., Roth, D.M., Chalfant, M.A., Youker, R.T., Matteson, J., Brodsky, J.L., and Balch, W.E. 2012. FK506 Binding Protein 8 Peptidylprolyl Isomerase Activity Manages a Late Stage of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Folding and Stability. J. Biol. Chem. 287:21914-21925.

Solomon, J.P., Page, L.J., Balch, W.E., and Kelly, J.W. 2012. Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention. Crit. Rev. Biochem. Mol. Biol. 4: 282-296.

Calamini, B., Silva, M.C., Madoux, F., Hutt, D.M., Khanna, S., Chalfant, M.A., Saldanha, S.A., Hodder, P., Tait, B.D., Garza, D., Balch, W.E., and Morimoto, R.I. 2012. Small-molecule proteostasis regulators for protein conformational diseases. Nat. Chem. Biol. 8:185-196.

Hulleman, J.D., Kaushal, S., Balch, W.E., and Kelly, J.W. 2011. Compromised mutant EFEMP1 secretion associated with macular dystrophy remedied by proteostasis network alteration. Mol. Biol. Cell 22:4765-4775.

Hutt, D.M., Olsen, C.A., Vickers, C.J., Herman, D., Chalfant, M., Montero, A., Leman, L.J., Burkle, R., Maryanoff, B.E., Balch, W.E., and Ghadiri, M.R. 2011. Potential Agents for Treating Cystic Fibrosis: Cyclic Tetrapeptides that Restore Trafficking and Activity of DeltaF508-CFTR. ACS Med. Chem. Lett. 2:703-707.

Peters, K.W., T. Okiyoneda, W.E. Balch, I. Braakman, J.L. Brodsky, W.B. Guggino, C.M. Penland, H.B. Pollard, E.J. Sorscher, W.R. Skach, P.J. Thomas, G.L. Lukacs, and R.A. Frizzell. 2011. CFTR Folding Consortium: Methods Available for Studies of CFTR Folding and Correction. Methods Mol. Biol. 742:335-53.

Balch, W.E., and J.R. Yates, 3rd. 2011. Application of mass spectrometry to study proteomics and interactomics in cystic fibrosis. Methods Mol. Biol. 742:227-47.

Powers, E.T., and W.E. Balch. 2011. Protein folding: Protection from the outside. Nature. 471:42-3.

Balch, W.E. 2011. Introduction to Section II: Omics in the Biology of Cystic Fibrosis. Methods Mol. Biol. 742:189-91.

Zhang, X., C. Dong, Q.J. Wu, W.E. Balch, and G. Wu. 2011. Di-acidic motifs in the membrane-distal C-termini modulate the transport of angiotensin II receptors from the endoplasmic reticulum to the cell surface. J. Biol. Chem. 23:20525-35.

Roth, D.M., and W.E. Balch. 2011. Modeling general proteostasis: proteome balance in health and disease. Curr. Opin. Cell Biol. 2:126-34.

Balch, W.E., D.M. Roth, and D.M. Hutt. 2011. Emergent properties of proteostasis in managing cystic fibrosis. Cold Spring Harb Perspect Biol. 2:pii: a004499.

Bouchecareilh, M., and W.E. Balch. 2011. Proteostasis: a new therapeutic paradigm for pulmonary disease. Proc. Am. Thorac. Soc. 8:189-95.


Complete List of Balch Publications