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, Michael 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


Additional Research Articles


Cytotoxicity of Activator Expression in CRISPR-based Transcriptional Activation Systems


Aakaanksha Maddineni, Ziyan Liang, Shreya Jambardi, Subrata Roy, Josh Tycko, Ajinkya Patil, Mark Manzano, Eva Gottwein

bioRxiv, 2024


Tunable, self-contained gene dosage control via proteolytic cleavage of CRISPR-Cas systems


Noa Katz, Connie An, Yu-Ju Lee, Josh Tycko, Meng Zhang, Jeewoo Kang, Lacramiora Bintu, Mike C Bassik, Wei-Hsiang Huang, Xiaojing J. Gao

bioRxiv, 2024


Prediction and design of transcriptional repressor domains with large-scale mutational scans and deep learning


Raeline Valbuena*, AkshatKumar Nigam*, Josh Tycko, Peter Suzuki, Kaitlyn Spees, Aradhana, Sophia Arana, Peter Du, Roshni A. Patel, Lacramiora Bintu, Anshul Kundaje, Michael Bassik

bioRxiv, 2024


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 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 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


Reviews


Deciphering the impact of genomic variation on function.


J. Engreitz, Heather A. Lawson, Harinder Singh, Lea M. Starita, Gary C. Hon, Hannah Carter, Nidhi Sahni, Timothy E. Reddy, Xihong Lin, Yun Li, Nikhil V. Munshi, Maria H. Chahrour, Alan P. Boyle, B. Hitz, Ali Mortazavi, Mark Craven, K. Mohlke, Luca Pinello, Ting Wang, A. Kundaje, Feng Yue, Sarah Cody, Nina P. Farrell, Michael I. Love, Lara A Muffley, M. Pazin, Fairlie Reese, Eric Van Buren, Kushal K. Dey, Martin Kircher, Jian Ma, P. Radivojac, Brunilda Balliu, Brian A. Williams, Danwei Huangfu, Chong Y. Park, Thomas Quertermous, Jishnu Das, M. Calderwood, Douglas M. Fowler, Marc Vidal, Lucas Ferreira, Sean D. Mooney, V. Pejaver, Jingjing Zhao, Steven Gazal, Evan Koch, Steven K. Reilly, S. Sunyaev, Anne E. Carpenter, Jason D. Buenrostro, Christina S. Leslie, Rachel E. Savage, Stefanija Giric, Chongyuan Luo, Kathrin Plath, Alejandro Barrera, Max Schubach, A. Gschwind, Jill E. Moore, N. Ahituv, S. Yi, Ingileif B. Hallgrímsdóttir, K. Gaulton, S. Sakaue, Sina Booeshaghi, Eugenio Mattei, Surag Nair, L. Pachter, Austin T. Wang, J. Shendure, Vikram Agarwal, Andrew Blair, Theofilos Chalkiadakis, Florence M. Chardon, P. Dash, Chengyu Deng, Nobuhiko Hamazaki, Pia Keukeleire, Connor A Kubo, Jean-Benoît Lalanne, Thorben Maass, Beth Martin, Troy A. McDiarmid, Mai Nobuhara, Nicholas F. Page, Sam Regalado, Jasmine Sims, A. Ushiki, Sabrina M. Best, Gabe Boyle, Nathan Camp, Silvia Casadei, Estelle Y. Da, Moez Dawood, Samantha C. Dawson, Shawn Fayer, Audrey Hamm, Richard G. James, Gail P. Jarvik, Abbye E. McEwen, Nick Moore, Sriram Pendyala, Nicholas A Popp, Mason Post, Alan F. Rubin, Nahum T. Smith, J. Stone, Malvika Tejura, Ziyu R. Wang, Melinda K. Wheelock, Ivan Woo, Brendan D. Zapp, Dulguun Amgalan, Aradhana Aradhana, Sophia M. Arana, M. Bassik, Julia R. Bauman, Asmita Bhattacharya, Xiangmeng S. Cai, Ziwei Chen, Stephanie Conley, Salil Deshpande, Benjamin R. Doughty, Peter P. Du, James A. Galante, Casey Gifford, W.J. Greenleaf, Katherine Guo, Revant Gupta, Sarasa Isobe, Evelyn Jagoda, Nimit Jain, Hank Jones, Helen Kang, Samuel H. Kim, YeEun Kim, Sandy Klemm, Ramen Kundu, Soumya Kundu, Mauro Lago-Docampo, Yannick C. Lee-Yow, Roni Levin-Konigsberg, Daniel Y. Li, Dominik Lindenhofer, X. R. Ma, Georgi K. Marinov, Gabriella E. Martyn, Chloe V. McCreery, Eyal Metzl-Raz, João P. Monteiro, Michael T. Montgomery, Kristy S. Mualim, Chad J. Munger, Glen Munson, Tri C. Nguyen, Tri C. Nguyen, Brian T. Palmisano, Anusri Pampari, Marlene Rabinovitch, Markus Ramste, Judhajeet Ray, Kevin R. Roy, Oriane M. Rubio, Julia M. Schaepe, Gavin Schnitzler, Jacob M Schreiber, Disha Sharma, Maya U. Sheth, Huitong Shi, Vasundhara Singh, Riya Sinha, Lars M Steinmetz, Jason Tan, Anthony Tan, Josh Tycko, Raeline Valbuena, Valeh Valiollah Pour Amiri, Mariëlle J. F. M. van Kooten, Alun Vaughan-Jackson, Anthony Venida, Chad S. Weldy, Matthew D. Worssam, Fan Xia, David Yao, Tony Zeng, Quanyi Zhao, Ronghao Zhou, Zitong Sam Chen, B. Cimini, Georges Coppin, Atina G. Coté, Marzieh Haghighi, Tong Hao, David E. Hill, Jessica Lacoste, Florent Laval, Chloe Reno, Fritz Roth, Shantanu Singh, Kerstin Spirohn-Fitzgerald, Mikko Taipale, Tanisha Teelucksingh, Maxime Tixhon, Anupama Yadav, Zhipeng Yang, W. L. Kraus, Daniel A. Armendariz, Ashley E. Dederich, Ashlesha Gogate, Lauretta El Hayek, S. Goetsch, Kiran Kaur, Hyung Bum Kim, Melissa K. McCoy, Mpathi Z. Nzima, C. Pinzon-Arteaga, Bruce A. Posner, Daniel A. Schmitz, Sushama Sivakumar, Anjana Sundarrajan, Lei Wang, Yihan Wang, Jun Wu, Lin Xu, Jian Xu, Leqian Yu, Yanfeng Zhang, Huan Zhao, Qinbo Zhou, Hyejung Won, Jessica L Bell, K. A. Broadaway, Katherine N. Degner, A. Etheridge, Beverly H. Koller, Won Mah, Wancen Mu, Kimberly D. Ritola, Jonathan D. Rosen, Sarah A. Schoenrock, Rachel A. Sharp, Daniel Bauer, G. Lettre, Richard Sherwood, Basheer Becerra, Logan J. Blaine, Eric Che, M. Francoeur, Ellie N. Gibbs, Nahye Kim, Emily M. King, B. Kleinstiver, Estelle Lecluze, Zhijian Li, Zain M. Patel, Quang Vinh Phan, Jayoung Ryu, Marlena L. Starr, Ting Wu, C. Gersbach, Gregory E. Crawford, Andrew S. Allen, William H. Majoros, Nahid Iglesias, Ruhi Rai, Revathy Venukuttan, Boxun Li, Taylor Anglen, Lexi R. Bounds, Marisa C. Hamilton, Siyan Liu, Sean R. McCutcheon, Christian McRoberts Amador, Samuel J. Reisman, Maria A. ter Weele, Josephine C. Bodle, Helen L Streff, Keith Siklenka, Kari Strouse, Bradley E. Bernstein, Juliana Babu, Guillermo Barreto Corona, Kevin Dong, Fabiana M. Duarte, Neva C. Durand, Charles B. Epstein, K. Fan, Elizabeth A. Gaskell, Amelia W. Hall, Alexandra M. Ham, Mei K. Knudson, N. Shoresh, Siddarth Wekhande, Cassandra M. White, Wang Xi, Ansuman T. Satpathy, M. Corces, Serena H. Chang, Iris M. Chin, James M Gardner, Zachary A. Gardell, Jacob C. Gutierrez, Alia W. Johnson, Lucas Kampman, Maya Kasowski, Caleb A. Lareau, Vincent Liu, Leif S. Ludwig, Christopher S. McGinnis, Shreya Menon, Anita Qualls, Katalin D. Sandor, Adam W. Turner, C. J. Ye, Yajie Yin, Wenxi Zhang, Barbara J. Wold, Maria Carilli, Dayeon Cheong, Ghassan Filibam, Kim Green, S. Kawauchi, Charlene Kim, Heidi Liang, Rebekah Loving, L. Luebbert, Grant MacGregor, Angel G. Merchan, Elisabeth Rebboah, Narges Rezaie, Jasmine Sakr, Delaney K. Sullivan, Nikki Swarna, Diane Trout, S. Upchurch, Ryan Weber, Christopher P. Castro, Elysia Chou, Fan Feng, Andre Guerra, Yuanhao Huang, Linghua Jiang, Jie Liu, Ryan E. Mills, Weizhou Qian, Tingting Qin, Maureen A. Sartor, Rintsen N. Sherpa, Jinhao Wang, Yiqun Wang, Joshua D. Welch, Zhenhao Zhang, Nanxiang Zhao, Sayan Mukherjee, C. D. Page, Shannon Clarke, Richard W. Doty, Yuncheng Duan, Raluca Gordân, Kuei-Yueh Ko, Shengyu Li, Boyao Li, Alexander Thomson, Soumya Raychaudhuri, Alkes Price, Thahmina A. Ali, Arun Durvasula, M. Kellis, L. Iakoucheva, Tulika Kakati, Yile Chen, Mariam Benazouz, Shantanu Jain, Daniel Zeiberg, M. C. De Paolis Kaluza, Michelle Velyunskiy, Audrey Gasch, Kunling Huang, Yiyang Jin, Qiongshi Lu, Jiacheng Miao, Michael Ohtake, Eduardo Scopel, Robert D. Steiner, Yuriy Sverchkov, Zhiping Weng, Manuel Garber, Yu Fu, Natalie Haas, Xihao Li, Nishigandha Phalke, Shuo C. Shan, Nicole Shedd, Tianxiong Yu, Yi Zhang, Hufeng Zhou, Alexis Battle, Livnat Jerby, Eran Kotler, Andrew R. Marderstein, Stephen B. Montgomery, AkshatKumar Nigam, Evin M. Padhi, Aman Patel, Jonathan K. Pritchard, Ivy Raine, Vivekanandan Ramalingam, Kameron B. Rodrigues, Jacob M Schreiber, Arpita Singhal, Marisa Abundis, Deepa Bisht, Trirupa Chakraborty, Jingyu Fan, David R. Hall, Zarifeh H. Rarani, Abhinav K. Jain, Babita Kaundal, Swapnil Keshari, Daniel McGrail, Nicholas A. Pease, Vivian F. Yi, Hao Wu, Sreeram Kannan, Hongjun Song, Jingli Cai, Ziyue Gao, Ronni Kurzion, Julia I. Leu, Fan Li, Dongming Liang, Guo-Li Ming, K. Musunuru, Qi Qiu, Junwei Shi, Yijing Su, Sarah Tishkoff, Ning Xie, Qian Yang, Wenli Yang, Hongjie Zhang, Zhijian Zhang, Michael A Beer, A. Hadjantonakis, Sharon Adeniyi, Hyein Cho, Ronald Cutler, Rachel A. Glenn, David Godovich, Nan Hu, Svetlana Jovanic, Renhe Luo, Jin Woo Oh, Milad Razavi-Mohseni, Dustin Shigaki, Simone Sidoli, Thomas Vierbuchen, Xianming Wang, Breanna Williams, Jielin Yan, Dapeng Yang, Yunxiao Yang, Maike Sander, Bing Ren, W. Bartosik, Hannah S Indralingam, A. Klie, Hannah M. Mummey, Mei-Lin Okino, Gaowei Wang, Nathan R. Zemke, Kai Zhang, Han Zhu, Noah Zaitlen, Jason Ernst, J. Langerman, Terence Li, Yu Sun, Alexander Y. Rudensky, P. Periyakoil, Vianne R. Gao, Melanie H. Smith, Norman M. Thomas, L. Donlin, Amit Lakhanpal, Kaden M. Southard, Rico C. Ardy, J. M. Cherry, Mark B. Gerstein, Kalina Andreeva, Pedro Assis, Beatrice Borsari, Eric Douglass, Shengcheng Dong, I. Gabdank, Keenan Graham, Otto Jolanki, Jennifer Jou, Meenakshi S. Kagda

Nature, 2024


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



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