Josh Tycko

Systematic discovery of protein functions in human cells to understand gene regulation and enable genetic medicine


Department of Neurobiology

Harvard Medical School


I develop high-throughput synthetic biology technologies to manipulate and measure human gene regulation. 

I am a postdoctoral fellow at Harvard Medical School and BIDMC. I completed my Ph.D. in the labs of Michael Bassik and Lacra Bintu with support from the NIH F99/K00 Fellowship and NSF GRFP.  At Stanford, I was a teaching assistant for a course on the science and bioethics of CRISPR, was an instructor for a hands-on cell engineering lab, and mentor to our amazing iGEM team. As a BioFutures Fellow and co-leader of The Genetics Advocacy Committee, I collaborated with fellow trainees to critically analyze and improve graduate STEM training.

Research




Gene and chromatin regulation


We discovered transcriptional effector domains in 600 human proteins and shed new light on the evolution of major transcription factor families, like KRAB and Hox, while also engineering improved activator and repressor domains for synthetic biology.




Gene delivery


We identified novel recombinases from bacteriophages that can integrate large DNA sequences into the human genome. Previously, we used AAV vectors to deliver antibody genes as a way to prevent RSV infection.




Genetic and epigenetic editing


We built and used CRISPR tools to functionally investigate the non-coding genome. We also developed new biochemical, cellular, and computational approaches to measure, model, and mitigate CRISPR off-target effects to make safer therapies.

Selected Research Articles


Multicenter integrated analysis of noncoding CRISPRi screens


David Yao*, Josh Tycko*#, Jin Woo Oh*, Lexi R. Bounds*, Sager J. Gosai*, Lazaros Lataniotis*, Ava Mackay-Smith, Benjamin R. Doughty, I. Gabdank, Henri Schmidt, Tania Guerrero-Altamirano, Keith Siklenka, Katherine Guo, Alexander D White, Ingrid Youngworth, Kalina Andreeva, Xingjie Ren, Alejandro Barrera, Yunhai Luo, G. Yardımcı, R. Tewhey, A. Kundaje, William J. Greenleaf, P. Sabeti, Christina S. Leslie, Y. Pritykin, Jill E. Moore, Michael A Beer, C. Gersbach, Timothy E. Reddy, Yin Shen, Jesse M Engreitz, M. Bassik, Steven K. Reilly#

Nature Methods, 2024


Development of compact transcriptional effectors using high-throughput measurements in diverse contexts


Josh Tycko, Mike V. Van, Aradhana, Nicole DelRosso, David Yao, Xiaoshu Xu, Connor Ludwig, Kaitlyn K. Spees, Kathy Liu, Gaelen T. Hess, Mingxin Gu, Aditya Mukund, Peter H. Suzuki, Roarke A. Kamber, Lei S. Qi, Lacramioara Bintu, M. Bassik

bioRxiv, 2023


Large-scale mapping and mutagenesis of human transcriptional effector domains


Nicole DelRosso, Josh Tycko, Peter H. Suzuki, Cecelia Andrews, Aradhana, Aditya Mukund, Ivan Liongson, Connor Ludwig, Kaitlyn K. Spees, P. Fordyce, M. Bassik, Lacramioara Bintu

Nature, 2023


Systematic discovery of recombinases for efficient integration of large DNA sequences into the human genome.


Matthew Durrant*, Alison Fanton*, Josh Tycko*, Michaela Hinks, Sita Chandrasekaran, Nicholas T Perry, Julia M. Schaepe, Peter P. Du, Peter Lotfy, Michael Bassik, Lacramioara Bintu, Ami Bhatt, Patrick Hsu

Nature Biotechnology, 2022


High-Throughput Discovery and Characterization of Human Transcriptional Effectors


Josh Tycko, Nicole DelRosso, Gaelen T. Hess, Aradhana, A. Banerjee, Aditya Mukund, Mike V. Van, Braeden K. Ego, David Yao, Kaitlyn K. Spees, Peter H. Suzuki, G. Marinov, A. Kundaje, M. Bassik#, Lacramioara Bintu#

Cell, 2020


Mitigation of off-target toxicity in CRISPR-Cas9 screens for essential non-coding elements


Josh Tycko*, M. Wainberg*, G. Marinov*, Oana Ursu, Gaelen T. Hess, Braeden K. Ego, Aradhana, Amy Li, Alisa N Truong, Alexandro E. Trevino, Kaitlyn K. Spees, David Yao, Irene M. Kaplow, P. Greenside, D. Morgens, D. Phanstiel, M. Snyder, Lacramioara Bintu, W. Greenleaf, A. Kundaje, M. Bassik

Nature Communications, 2019


Pairwise library screen systematically interrogates Staphylococcus aureus Cas9 specificity in human cells


Josh Tycko, Luis A. Barrera, Nicholas C. Huston, Ari E. Friedland, Xuebing Wu, J. Gootenberg, O. Abudayyeh, V. Myer, Christopher J. Wilson, P. Hsu

Nature Communications, 2018


Reviews


The sound of silence: Transgene silencing in mammalian cell engineering.


A Cabera*, HI Edelstein*, F Glykofrydis*, KS Love*, S Palacios*, J Tycko*, M Zhang*, S Lensch, CE Shields, M Livingston, R Weiss, H Zhao, K Haynes, L Morsut, YY Chen, AS Khalil, W Wong, J Collins, S Rosser, K Polizzi, M Elowitz, M Fussenegger, IB Hilton, JN Leonard, L Bintu, KE Galloway, TL Deans

Cell Systems, 2022


Gene drives for schistosomiasis transmission control


T. Maier, Nicolas J. Wheeler, E. Namigai, Josh Tycko, R. Grewelle, Y. Woldeamanuel, Katharina Klohe, J. Perez-Saez, S. Sokolow, G. D. De Leo, T. Yoshino, M. Zamanian, J. Reinhard-Rupp

PLoS Neglected Tropical Diseases, 2019


Methods and Applications of CRISPR-Mediated Base Editing in Eukaryotic Genomes.


Gaelen T. Hess*, Josh Tycko*, David Yao*, M. Bassik

Molecular Cell, 2017


Advancing towards a global mammalian gene regulation model through single-cell analysis and synthetic biology


Josh Tycko*, Mike V. Van*, Michael B. Elowitz, Lacramioara Bintu

Current Opinion in Biomedical Engineering, vol. 4, 2017 Oct 30, pp. 174-193


Methods for Optimizing CRISPR-Cas9 Genome Editing Specificity.


Josh Tycko, Vic Myer, Patrick Hsu

Molecular Cell, 2016


Lessons Learned from the Clinical Development and Market Authorization of Glybera


Laura M. Bryant*, Devin M. Christopher*, April R. Giles*, Christian Hinderer*, Jesse L. Rodriguez*, Jenessa B. Smith*, Elizabeth A. Traxler*, Josh Tycko*, Adam P. Wojno*, James M. Wilson

Human gene therapy. Clinical development, vol. 24(2), 2013 Apr 12, pp. 55-64


Additional Research Articles


High-throughput functional characterization of combinations of transcriptional activators and repressors


Aditya Mukund, Josh Tycko, S. J. Allen, S. A. Robinson, Cecelia Andrews, Joydeb Sinha, Connor H. Ludwig, Kaitlyn K. Spees, M. Bassik, Lacramioara Bintu

Cell Systems, 2023


High-Throughput Discovery and Characterization of Viral Transcriptional Effectors in Human Cells


Connor H. Ludwig, A. Thurm, D. Morgens, Kevin Yang, Josh Tycko, M. Bassik, B. Glaunsinger, Lacramioara Bintu

Cell Systems, 2023


CasKAS: direct profiling of genome-wide dCas9 and Cas9 specificity using ssDNA mapping


G. Marinov, Samuel H. Kim, S. Bagdatli, Soon Il Higashino, Alexandro E. Trevino, Josh Tycko, Tong Wu, Lacramioara Bintu, M. Bassik, Chuan He, A. Kundaje, W.J. Greenleaf

Genome Biology, 2023


A genome-wide genetic screen uncovers determinants of human pigmentation


V. Bajpai, T. Swigut, Jaaved Mohammed, S. Naqvi, M. Arreola, Josh Tycko, Tayne C. Kim, J. Pritchard, M. Bassik, Joanna Wysocka

Science, 2023


Modeling the efficacy of CRISPR gene drive for snail immunity on schistosomiasis control


R. Grewelle, J. Perez-Saez, Josh Tycko, E. Namigai, Chloe Rickards, G. D. De Leo

PLoS Neglected Tropical Diseases, 2022


Adeno-Associated Virus Vector-Mediated Expression of Antirespiratory Syncytial Virus Antibody Prevents Infection in Mouse Airways.


Josh Tycko, V. Adam, M. Crosariol, J. Ohlstein, Julio C. Sanmiguel, A. Tretiakova, Soumitra Roy, S. Worgall, James M. Wilson, M. Limberis

Human gene therapy, 2021


Identification of Guide-Intrinsic Determinants of Cas9 Specificity


Nicholas C. Huston, Josh Tycko, Eric L Tillotson, Christopher J. Wilson, V. Myer, H. Jayaram, Barrett E Steinberg

The CRISPR Journal, 2019


Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements


Maxwell R. Mumbach, Ansuman T. Satpathy, E. Boyle, Chao Dai, Benjamin G. Gowen, S. Cho, M. Nguyen, Adam J. Rubin, Jeffrey M Granja, Katelynn R. Kazane, Yuning Wei, Trieu Nguyen, P. Greenside, M. Corces, Josh Tycko, Dimitre R. Simeonov, Nabeela Suliman, Rui Li, Jin Xu, Ryan A. Flynn, A. Kundaje, P. Khavari, A. Marson, J. Corn, T. Quertermous, W. Greenleaf, Howard Y. Chang

Nature Genetics, 2017


Toolbox for Exploring Modular Gene Regulation in Synthetic Biology Training.


Michael S. Magaraci, Jessica G Bermudez, Deeksha Yogish, D. H. Pak, Viktor Mollov, Josh Tycko, D. Issadore, Sevile G. Mannickarottu, B. Chow

ACS synthetic biology, 2016



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