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(12) United States Patent (10) Patent No.: US 9.458,509 B2 Benenson Et Al

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(12) United States Patent (10) Patent No.: US 9.458,509 B2 Benenson Et Al US0094.58509B2 (12) United States Patent (10) Patent No.: US 9.458,509 B2 Benenson et al. 45) Date of Patent: Oct. 4,9 2016 (54) MULTIPLE INPUT BIOLOGIC CLASSIFIER (52) U.S. Cl. CIRCUITS FOR CELLS CPC ............. CI2O 1/6886 (2013.01): CI2N 15/63 (2013.01); C12O 1/6897 (2013.01); G06F (75) Inventors: Yates'Biseiss. Newton :"A Liliana Ron 19/20 (2013.01); G06F 19/24 (2013.01) Wroblewska,s Arlington,s MAs (US); (58)58) Field ofO ClassificationSSCO SSea h Zhen Xie, Malden, MA (US) See application file for complete search history. (73) Assignees: PRESIDENT AND FELLOWS OF HARVARD COLLEGE, Cambridge, (56) References Cited MA (US); MASSACHUSETTS INSTITUTE OF TECHNOLOGY, FOREIGN PATENT DOCUMENTS Cambridge, MA (US) WO WO 2008134593 A1 * 11/2008 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S.C. 154(b) by 385 days. “Encode” definition; Oxford dictionary; http://www.oxford dictionaries.com/us/definition/american english encode; accessed (21) Appl. No.: 13/811,126 Apr. 27, 2015; pp. 5-6.* (22) PCT Filed: Jul. 22, 2011 * cited by examiner (86). PCT No.: PCT/US2O11AO45038 Primary Examiner — Antonio Galisteo Gonzalez S 371 (c)(1), (74) Attorney, Agent, or Firm — Nath, Goldberg & Meyer; (2), (4) Date: Apr. 5, 2013 Tanya E. Harkins (87) PCT Pub. No.: WO2012/012739 (57) ABSTRACT PCT Pub. Date: Jan. 26, 2012 Provided herein are high-input detector modules and multi input biological classifier circuits and systems that integrate (65) Prior Publication Data Sophisticated sensing, information processing, and actuation in living cells and permit new directions in basic biology, US 2013/02O2532 A1 Aug. 8, 2013 biotechnology and medicine. The multi-input biological Related U.S. Application Data classifier circuits described herein comprise synthetic, scale able transcriptional/post-transcriptional regulatory circuits (60) Provisional application No. 61/366,787, filed on Jul. that are designed to interrogate the status of a cell by 22, 2010. simultaneously sensing expression levels of multiple endog enous inputs, such as microRNAS. The classifier circuits (51) Int. Cl thenh compute whetherheth to trigger a desired output or response CI2O I/68 (2006.01) if the expression levels match a pre-determined profile of CI2N 15/63 (2006.01) interest. GO6F 9/20 (2011.01) GO6F 9/24 (2011.01) 21 Claims, 22 Drawing Sheets U.S. Patent Oct. 4, 2016 Sheet 1 of 22 US 9.458,509 B2 stigi saissii) tag st r is st * 3 issil is iège-gig for ç—---+------ CIL-VJsaun61-I ELL U.S. Patent Oct. 4, 2016 Sheet 2 of 22 US 9.458,509 B2 &:::::::::::::::::::s: gxoeiexo yzseun61-I ? U.S. Patent Oct. 4, 2016 Sheet 3 of 22 US 9.458,509 B2 U.S. Patent US 9.458,509 B2 ?ndino)---- ?unôl-Hy U.S. Patent Oct. 4, 2016 Sheet 5 of 22 US 9.458,509 B2 |11****** saun61-IgG-tyg U.S. Patent Oct. 4, 2016 Sheet 6 of 22 US 9.458,509 B2 e e regree als f S. ii. 335i i *u is is leg & g- “s s: gig 3. sh:sai: , likotLivi.e., Lif : o, c. p. co c. s - g Six is tailiw . l ". s E. g. l s t s t S. * D N N f O l as U.S. Patent Oct. 4, 2016 Sheet 8 of 22 US 9.458,509 B2 3. |} {}} {}{ 18-szºglu| !!!!!!! Zaun61-I U.S. Patent US 9.458,509 B2 G8-V9saun61-I U.S. Patent Oct. 4, 2016 Sheet 10 of 22 US 9.458,509 B2 98-E8saun61-I U.S. Patent 86-v6saun61-I U.S. Patent Oct. 4, 2016 Sheet 12 of 22 US 9.458,509 B2 Asifiest o6aunôl-ff U.S. Patent US 9.458,509 B2 - Op?un61-I U.S. Patent Oct. 4, 2016 Sheet 14 of 22 US 9,458,509 B2 Al-H?WA úG tiC) uC) |#4]+?Ž.L. ppaun61–? l U.S. Patent US 9.458,509 B2 (%) eouepunqeleo 07 OZ Z?aun61-I U.S. Patent Oct. 4, 2016 Sheet 16 of 22 US 9.458,509 B2 U.S. Patent Oct. 4, 2016 Sheet 17 of 22 US 9.458,509 B2 ??eep||30SseuddnS ?Oue?S?Seu?Onpu| ?A?AunS >ON ||30.?u?SI ToN|ON||sau ??nOJIOJ???SSeIO U.S. Patent Oct. 4, 2016 Sheet 19 of 22 US 9.458,509 B2 [×] ¿??? Oypaun61-I U.S. Patent US 9.458,509 B2 egy 10! Gpaun61-1 U.S. Patent US 9.458,509 B2 : 89p-y9psaun61-I U.S. Patent Oct. 4, 2016 Sheet 22 of 22 US 9.458,509 B2 &&&&&&& st e i eAguiyipads) US 9,458,509 B2 1. 2 MULTIPLE INPUT BIOLOGIC CLASSIFIER molecular information in mammalian cells. These classifier CIRCUITS FOR CELLS circuits use transcriptional and posttranscriptional regulation in order to classify the status of a cell, i.e., determine CROSS-REFERENCE TO RELATED whether a cell is in a specific state of interest. The biological APPLICATIONS classifier circuits described herein implement this task by interrogating the state of the cell through simultaneous This is a National Phase Application filed under 35 U.S.C. assessment of multiple inputs, such as the expression levels 371 as a national stage of PCT/US2011/045038, filed on 22 of a Subset of predefined markers, for example, endogenous, Jul. 2011, an application claiming the benefit under 35 mature microRNAs. The classifier circuits described herein U.S.C. S 119(e) from U.S. Provisional Patent Application 1 No. 61/366,787, filed on Jul 22, 2010, the entire content of O are designed to compute whether the expression profile of each of which is hereby incorporated by reference in its the markers matches a pre-determined reference profile that entirety. characterizes the specific cell state that the classifier circuits are intended to detect. If so, the classifier circuits produce a GOVERNMENT SUPPORT biological response, Such as expression of a reporter mol 15 ecule. These biological circuits are termed herein as clas This invention was made with Government support under sifiers because they classify individual cells into a number NIGMS Grant GMO68763 from the National Institutes of of categories based on processing a multitude of inputs Health and grant W81XWH-09-1-0240 BC085163 from the indicative of the cells internal states, in a manner similar to Department of Defense Congressionally Directed Medical current practices for characterizing bulk tissue (e.g., biopsy Research Program (CDMRP). The Government has certain samples) using gene array analysis and computer algorithms rights in the invention. (31). The biological classifier circuits described herein can be FIELD OF THE INVENTION used in a variety of applications, such as those requiring precise classification and identification of cell types. In some The present invention relates to multi-input engineered 25 aspects, described herein are biological classifier circuits for genetic circuits for classifying cells. use as therapeutic agents, for example, in highly precise and The Sequence Listing submitted in text format (..txt) filed selective cancer therapy. Many mainstream and experimen on Jan. 18, 2013, named “50295PCT.txt', (created on Jan. 8, tal drugs exhibit a degree of selectivity toward cancer cells 2013, 222 KB), is incorporated herein by reference. by relying on individual cancer markers (32). However, 30 cancer cells exhibit a complex set of conditions deviating BACKGROUND from the normal state of their progenitor tissue (33, 34), and using a single marker to distinguish them from healthy cells An important feature of biological pathways is their is rarely sufficient and often results in harmful side-effects two-way interaction with the cellular environment in which (35). Therefore, sensing and integration of information from they operate. Such interaction usually involves (1) sensing 35 multiple markers by a therapeutic agent is crucial for cre of relevant input conditions in the cell, (2) processing those ating next-generation treatments, and for use in a variety of inputs to determine whether and which action to take; and applications, which can include, but are not limited to, (3) producing a biologically-active output to actuate a physi identification, sorting, or targeting of stem cells from het ological effect in the cell. Some engineered analogues of erogenous populations of differentiated cells; identification, natural pathways with sensing, computational and actuation 40 sorting, or targeting of specific cell types for the treatments functionalities (1, 2) have been developed that can augment of various diseases, such as cancer, identification, Sorting, endogenous processes and enable rational manipulation and targeting, or detection of cell types at various developmental control of biological systems. While reporter constructs (3) stages; drug screening assays; and identification, Sorting, that transduce cellular inputs into a detectable output, and targeting, or detection of cell types in experimental models tissue-specific transgenes controlled transcriptionally and/or 45 to be used in tracking therapuetic treatment responses to a posttranscriptionally (4-6) lack complexity, they represent drug or other molecule. Such as during a tumor treatment. useful components for the development of synthetic circuits. For example, described herein is an exemplary biological Some synthetic circuits have demonstrated programmed classifier circuit tested in human cell culture that acts as a dynamic behavior in cells (oscillators (7-10), memory (11 programmed therapeutic agent that, via identification and 14), spatial patterns (15), cascades (16) and pulse generators 50 processing of a combination of input markers, selectively (17)), digital and analog computations (18-20), and complex identifies and triggers apoptosis in a cancer cell line, but not biosynthetic pathways (21), but the interaction of these in healthy cells. circuits with the cellular context has been limited (22, 23).
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