I employ biological, computational, and mathematical approaches to life science problem solving.
I conduct research in my role as a Biophysics PhD candidate at UCSF.
Kim MS, Bhargava HK, Shavey GE, Lim WA, El-Samad H, Ng AH.
We report the development of bioPROTACs, a novel class of genetically encoded protein degraders that target specific proteins for degradation in response to a user-defined signal. We demonstrate the utility of our bioPROTACs by constructing a genetic circuit to degrade key signalling molecules in CAR-T cells, including CAR receptors and the tyrosine kinase ZAP70 in response to recognition of a specific membrane-bound antigen. This circuit is able to disrupt CAR T cell signaling only in the presence of a specific cell population. These results suggest that bioPROTACs are a powerful tool for expanding the cell engineering toolbox for CAR T cells.
PDF Journal Website PubMed SupplementAllen GM*, Frankel NW*, Reddy NR, Bhargava HK, Yoshida MA, Stark SR, Purl M, Lee J, Yee JL, Yu W, Li AW, Garcia KC, El-Samad H, Roybal KT, Spitzer MH, Lim WA.
We built a synthetic circuit that wires tumor antigen detection to cytokine production in T cells. This circuit produces the inflammatory cytokine IL-2 at super-physiological levels, and enables engineered T cells to overcome imunosuppressive “cold” tumor microenvironments, which are a hallmark of the cancers with the most severe prognoses.
Daniels KG, Wang S, Simic MS, Bhargava HK, Capponi S, Tonai Y, Yu W, Bianco S, Lim WA.
To explore if non-natural combinations of signaling motifs could drive novel cell fates of interest, we constructed a library of CARs containing ∼2,300 synthetic costimulatory domains. The library produced CARs driving diverse fate outputs, which were sensitive to motif combinations and configurations. Neural networks trained to decode the combinatorial grammar of CAR signaling motifs allowed extraction of key design rules.
Deo C*, Abdelfattah AS*, Bhargava HK, Berro A, Falco N, Moeyaert B, Chupanova M, Lavis LD, Schreiter ER
We introduce a new platform for ‘chemigenetic’ fluorescent indicators, utilizing the self-labeling HaloTag protein conjugated to environmentally sensitive synthetic fluorophores. This approach affords bright, far-red calcium and voltage sensors with highly tunable photophysical and chemical properties, which can reliably detect single action potentials in neurons.
PDF Journal Website PubMed SupplementBhargava HK, Tabata K, Byck JM, Hamasaki M, Farrell DP, Anishchenko I, DiMaio F, Im YJ, Yoshimori T, Hurley JH
We report the novel atomic structure of autophagy inhibitor Rubicon bound to GTPase Rab7. Our work provides a roadmap to block Rubicon localization and activity in order to upregulate autophagy, a major drug development goal.
PDF Journal Website PubMed PDB Entry SupplementBhargava HK, Leo P, Elliott R, Janowcyzk A, Whitney J, Gupta S, Fu P, Yamoah K, Rebbeck T, Feldman D, Lal P, Madabhushi A
We developed computer vision and machine learning to predict prostate cancer recurrence risk based on quantitative measurements of the intratumoral stroma computed from digitized H&E images.
Arriola A, Farahani S, Bhargava HK, Guzzo T, Brooks J, Lal P.
This study comprehensively reviews programmed death 1 receptor (PD-1)–positive and CD8+ tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression on tumor epithelium (TE).
PDF Journal Website PubMedKockel L, Griffin C, Ahmed Y, Fidelak L, Rajan A, Gould EP, Haigney M, Ralston B, Tercek RJ, Galligani L, Rao S, Huq L, Bhargava HK, Dooner AC, Lemmerman EG, Malusa RF, Nguyen TH, Chung JS, Gregory SM, Kuwana KM, Regenold JT, Wei A, Ashton J, Dickinson P, Martel K, Cai C, Chen C, Price S, Qiao J, Shepley D, Zhang J, Chalasani M, Nguyen K, Aalto A, Kim B, Tazawa-Goodchild E, Sherwood A, Rahman A, Wu SYC, Lotzkar J, Michaels S, Aristotle H, Clark A, Gasper G, Xiang E, Schlör FL, Lu M, Haering K, Friberg J, Kuwana A, Lee J, Liu A, Norton E, Hamad L, Lee C, Okeremi D, diTullio H, Dumoulin K, Chi SYG, Derossi GS, Horowitch RE, Issa EC, Le DT, Morales BC, Noori A, Shao J, Cho S, Hoang MN, Johnson IM, Lee KC, Lee M, Madamidola EA, Schmitt KE, Byan G, Park T, Chen J, Monovoukas A, Kang MJ, McGowan T, Walewski JJ, Simon B, Zu SJ, Miller GP, Fitzpatrick KB, Lantz N, Fox E, Collette J, Kurtz R, Duncan C, Palmer R, Rotondo C, Janicki E, Chisholm T, Rankin A, Park S, Kim SK.
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