[ { "id": "https://thesis.library.caltech.edu/id/eprint/14552", "eprint_id": 14552, "rev_number": 28, "documents": [ { "id": "/id/document/136220", "doc_id": 136220, "rev_number": 4, "files": [ { "id": "/id/file/390858", "fileid": 390858, "datasetid": "document", "objectid": 136220, "filename": "Andr\u00e9s' PhD Thesis.zip", "mime_type": "application/zip", "hash": "73d04c74432d2c713e94c7971441c1a0", "hash_type": "MD5", "filesize": 8197336, "mtime": "2022-04-19 02:40:48", "url": "/14552/1/Andr\u00e9s' PhD Thesis.zip" } ], "eprint_id": 14552, "pos": 1, "placement": 2, "mime_type": "application/zip", "format": "application/zip", "format_desc": "source files", "language": "en", "security": "internal", "license": "other", "main": "Andr\u00e9s' PhD Thesis.zip", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "archival" }, { "id": "/id/document/136226", "doc_id": 136226, "rev_number": 5, "files": [ { "id": "/id/file/390890", "fileid": 390890, "datasetid": "document", "objectid": 136226, "filename": "Andre\u0301s'_PhD_Thesis.pdf", "mime_type": "application/pdf", "hash": "4a0e8f17617dd7eacd71c0edfe6e1766", "hash_type": "MD5", "filesize": 4762405, "mtime": "2022-04-19 18:21:25", "url": "/14552/2/Andre\u0301s'_PhD_Thesis.pdf" } ], "eprint_id": 14552, "pos": 2, "placement": 1, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": "other", "main": "Andre\u0301s'_PhD_Thesis.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final" }, { "id": "/id/document/136228", "doc_id": 136228, "rev_number": 1, "files": [ { "id": "/id/file/390974", "fileid": 390974, "datasetid": "document", "objectid": 136228, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "5c25e2d6b5d58172f1fade9faf0c97eb", "hash_type": "MD5", "filesize": 31242, "mtime": "2022-04-21 14:05:35", "url": "/14552/3/indexcodes.txt" } ], "eprint_id": 14552, "pos": 3, "placement": 3, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "internal", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/136226" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/136226" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/136226" } ] } } ], "eprint_status": "archive", "userid": 12792, "dir": "disk0/00/01/45/52", "datestamp": "2022-04-20 19:42:11", "lastmod": "2023-11-08 00:23:11", "status_changed": "2022-04-20 19:42:11", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "Andortiz19@gmail.com", "id": "Ortiz-Mu\u00f1oz-Andr\u00e9s", "name": { "family": "Ortiz-Mu\u00f1oz", "given": "Andr\u00e9s" }, "orcid": "0000-0003-1824-3230", "show_email": "NO" } ] }, "title": "Combinatorics and Stochasticity for Chemical Reaction Networks", "ispublished": "unpub", "full_text_status": "public", "keywords": "Generating functions, chemical reaction networks, universality, combinatorics, molecular assembly", "abstract": "Stochastic chemical reaction networks (SCRNs) are a mathematical model which serves as a first approximation to ensembles of interacting molecules. SCRNs approximate such mixtures as always being well-mixed and consisting of a finite number of molecules, and describe their probabilistic evolution according to the law of mass-action. In this thesis, we attempt to develop a mathematical formalism based on formal power series for defining and analyzing SCRNs that was inspired by two different questions. The first question relates to the equilibrium states of systems of polymerization. Formal power series methods in this case allow us to tame the combinatorial complexity of polymer configurations as well as the infinite state space of possible mixture states. Chapter 1 presents an application of these methods to a model of polymerizing scaffolds. The second question relates to the expressive power of SCRNs as generators of stochasticity. In Chapter 2, we show that SCRNs are universal approximators of discrete distributions, even when only allowing for systems with detailed-balance. We further show that SCRNs can exactly simulate Boltzmann machines. In Chapter 3, we develop a formalism for defining the semantics of SCRNs in terms of formal power series which grew as a result of work included in the previous chapters. We use that formulation to derive expressions for the dynamics and stationary states of SCRNs. Finally, we focus on systems that satisfy complex balance and conservation of mass and derive a general expressions for their factorial moments using generating function methods.", "date": "2022", "date_type": "degree", "id_number": "CaltechTHESIS:04182022-222416729", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:04182022-222416729", "related_url": { "items": [ { "description": "Article related to ch. 1", "type": "doi", "url": "https://doi.org/10.1073/pnas.1912745117" }, { "description": "Article related to ch. 2", "type": "doi", "url": "https://doi.org/10.1007/978-3-319-66799-7_14" }, { "description": "Article related to ch. 3", "type": "doi", "url": "https://doi.org/10.1016/j.tcs.2019.08.013" } ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "suggestions": "2022-04-27 file released after 1-week embargo expired.", "deposited_by": "Andr\u00e9s Ortiz-Mu\u00f1oz", "deposited_on": "2022-04-20 19:42:11", "doi": "10.7907/s9mc-3d59", "divisions": { "items": [ "div_bbe" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "Winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "orcid": "0000-0002-5899-7523", "role": "advisor" }, { "email": "Walter_fontana@hms.Harvard.edu", "id": "Fontana-Walter", "name": { "family": "Fontana", "given": "Walter" }, "orcid": "0000-0003-4062-9957", "role": "co-advisor" } ] }, "thesis_committee": { "items": [ { "email": "Niles@caltech.edu", "id": "Pierce-Niles Pierce-Niles", "name": { "family": "Pierce", "given": "Niles Niles" }, "orcid": "0000-0003-2367-4406", "role": "chair" }, { "email": "Bois@caltech.edu", "id": "Bois-Justin-S", "name": { "family": "Bois", "given": "Justin S." }, "orcid": "0000-0001-7137-8746", "role": "member" }, { "email": "Phillips@pboc.Caltech.edu", "id": "Phillips-Rob-B", "name": { "family": "Phillips", "given": "Robert B." }, "orcid": "0000-0003-3082-2809", "role": "member" }, { "email": "Winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "orcid": "0000-0002-5899-7523", "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2021-11-12", "gradofc_approval_date": "2022-04-19", "review_status": "approved", "option_major": { "items": [ "sysbiol" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2022", "author_list": "Ortiz-Mu\u00f1oz, Andr\u00e9s", "advisor_list": "Winfree, Erik and Fontana, Walter", "comittee_list": "Pierce, Niles Niles; Bois, Justin S.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/14424", "eprint_id": 14424, "rev_number": 55, "documents": [ { "id": "/id/document/135427", "doc_id": 135427, "rev_number": 3, "files": [ { "id": "/id/file/386689", "fileid": 386689, "datasetid": "document", "objectid": 135427, "filename": "Poole_PhD_Thesis_v2_Latex_Source.zip", "mime_type": "application/zip", "hash": "1d6d319ca293ce0bf0ef3b2abe786d63", "hash_type": "MD5", "filesize": 6438490, "mtime": "2021-11-19 20:28:35", "url": "/14424/4/Poole_PhD_Thesis_v2_Latex_Source.zip" } ], "eprint_id": 14424, "pos": 4, "placement": 4, "mime_type": "application/zip", "format": "application/zip", "format_desc": "source files", "language": "en", "security": "internal", "license": "other", "main": "Poole_PhD_Thesis_v2_Latex_Source.zip", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "archival" }, { "id": "/id/document/135428", "doc_id": 135428, "rev_number": 6, "files": [ { "id": "/id/file/386692", "fileid": 386692, "datasetid": "document", "objectid": 135428, "filename": "Poole_PhD_Thesis_v2.pdf", "mime_type": "application/pdf", "hash": "7f056768fb5452d8ee2661811cd1cf49", "hash_type": "MD5", "filesize": 6808789, "mtime": "2021-11-19 20:29:55", "url": "/14424/5/Poole_PhD_Thesis_v2.pdf" } ], "eprint_id": 14424, "pos": 5, "placement": 5, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": "other", "main": "Poole_PhD_Thesis_v2.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final" }, { "id": "/id/document/135442", "doc_id": 135442, "rev_number": 1, "files": [ { "id": "/id/file/386754", "fileid": 386754, "datasetid": "document", "objectid": 135442, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "3e02d73cbdcdc9b5ab2535c7a17acb27", "hash_type": "MD5", "filesize": 48022, "mtime": "2021-11-22 23:54:22", "url": "/14424/6/indexcodes.txt" } ], "eprint_id": 14424, "pos": 6, "placement": 6, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "internal", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/135428" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/135428" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/135428" } ] } } ], "eprint_status": "archive", "userid": 11992, "dir": "disk0/00/01/44/24", "datestamp": "2021-11-22 18:27:36", "lastmod": "2021-12-09 20:50:54", "status_changed": "2021-11-22 18:27:36", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "wp_ix@hotmail.com", "id": "Poole-William", "name": { "family": "Poole", "given": "William" }, "orcid": "0000-0002-2958-6776", "show_email": "NO" } ] }, "title": "Compilation and Inference with Chemical Reaction Networks", "ispublished": "unpub", "full_text_status": "public", "keywords": "Chemical Reaction Networks, Machine Learning, Boltzmann Machines, Synthetic Biology, Systems Biology, Cell Extract", "abstract": "
The successful advancement and deployment of technologies in the field of synthetic biology will require sophisticated computational infrastructure coupled with new theoretical ideas in order to more effectively engineer and reverse engineer biochemical networks. This thesis argues that the field of machine learning can inform the development of these underlying principles and techniques. First, software for compiling diverse chemical reaction network models of biological circuits from simple specifications is described. Second, three chemical reaction network implementations of a powerful machine learning model called a Boltzmann machine are analyzed and compared. Third, the class of detailed balanced chemical reaction networks are proven to be capable of probabilistic inference and, when coupled to a driven chemical system, autonomous learning. Finally, the use of machine learning to interpret and understand biological systems is explored in an experimental case study modeling E. coli cell extract metabolism.
", "date": "2022", "date_type": "degree", "id_number": "CaltechTHESIS:11102021-210013472", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:11102021-210013472", "related_url": { "items": [ { "description": "Thesis Defense", "type": "video", "url": "https://www.youtube.com/watch?v=5niVvhPN3U8" }, { "description": "Chapter 2: BioCRNpyler adapted from this BioRxiv manuscript", "type": "doi", "url": "https://doi.org/10.1101/2020.08.02.233478" }, { "description": "Chapter 3: Chemical Boltzmann Machines adapted from these proceedings", "type": "doi", "url": "https://doi.org/10.1007/978-3-319-66799-7_14" } ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF Graduate Research Fellowship", "grant_number": "2017246618" }, { "agency": "NSF", "grant_number": "CBET-1903477" } ] }, "collection": "CaltechTHESIS", "reviewer": "Melissa Ray", "suggestions": "Released on 11/29/2021 //\r\n\r\nThis record includes updated thesis files (PDF and source) sent on 19Nov2021, prior to Grad Office approval / skj 19Nov2021", "deposited_by": "William Poole", "deposited_on": "2021-11-22 18:27:36", "doi": "10.7907/x3qc-je74", "divisions": { "items": [ "div_bbe" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "orcid": "0000-0002-5899-7523", "role": "advisor" }, { "email": "murray@cds.caltech.edu", "id": "Murray-R-M", "name": { "family": "Murray", "given": "Richard M." }, "orcid": "0000-0002-5785-7481", "role": "co-advisor" } ] }, "thesis_committee": { "items": [ { "email": "mthomson@caltech.edu", "id": "Thomson-Matthew", "name": { "family": "Thomson", "given": "Matthew" }, "orcid": "0000-0003-1021-1234", "role": "chair" }, { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "orcid": "0000-0002-5899-7523", "role": "member" }, { "email": "murray@cds.caltech.edu", "id": "Murray-R-M", "name": { "family": "Murray", "given": "Richard M." }, "orcid": "0000-0002-5785-7481", "role": "member" }, { "email": "phillips@pboc.caltech.edu", "id": "Phillips-R-B", "name": { "family": "Phillips", "given": "Robert B." }, "orcid": "0000-0003-3082-2809", "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2021-08-24", "gradofc_approval_date": "2021-11-19", "thesis_awards": "NSF Graduate Research Fellowship (GRFP), NSF Graduate Research Opportunities Worldwide (GROW)", "review_status": "approved", "option_major": { "items": [ "cns" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2022", "author_list": "Poole, William", "advisor_list": "Winfree, Erik and Murray, Richard M.", "comittee_list": "Thomson, Matthew; Winfree, Erik; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/13687", "eprint_id": 13687, "rev_number": 49, "documents": [ { "id": "/id/document/107355", "doc_id": 107355, "rev_number": 5, "files": [ { "id": "/id/file/329164", "fileid": 329164, "datasetid": "document", "objectid": 107355, "filename": "johnson_robert_2020.pdf", "mime_type": "application/pdf", "hash": "2c2854a9c456090c83dffa0249dd56d4", "hash_type": "MD5", "filesize": 2879128, "mtime": "2020-04-29 21:02:46", "url": "/13687/8/johnson_robert_2020.pdf" } ], "eprint_id": 13687, "pos": 8, "placement": 8, "mime_type": "application/pdf", "format": "application/pdf", "format_desc": "Complete Thesis", 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"http://eprints.org/relation/isVersionOf", "uri": "/id/document/107355" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/107355" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/107355" } ] } } ], "eprint_status": "archive", "userid": 12282, "dir": "disk0/00/01/36/87", "datestamp": "2020-05-11 19:13:07", "lastmod": "2021-11-04 21:22:51", "status_changed": "2020-05-11 19:13:07", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "robfjohnson@gmail.com", "id": "Johnson-Robert-Francis", "name": { "family": "Johnson", "given": "Robert Francis" }, "orcid": "0000-0002-5340-8347", "show_email": "NO" } ] }, "title": "Formal Design and Analysis for DNA Implementations of Chemical Reaction Networks", "ispublished": "unpub", "full_text_status": "public", "keywords": "Molecular programming; DNA; Verification; Chemical Reaction Networks; DNA strand displacement", "abstract": "In molecular programming, the Chemical Reaction Network model is often used to describe systems of interacting molecules. This model can describe either real systems, allowing us to analyze and determine their computational function; or describe hypothetical systems, with known computational function but perhaps no known physical example. One significant breakthrough in the field is that any Chemical Reaction Network can be approximated by a system using DNA Strand Displacement mechanisms. This allows the Chemical Reaction Network model to be treated like a programming language, where programs can be written in the abstract and then compiled into physical molecules. Given a programming language and a proof-of-concept compiler, one would want to take the compiler from the proof-of-concept stage into a more reliable, more systematic, and better understood process. This thesis is made up of my contributions to that effort.
\r\n\r\nFirst, given a programming language and a compiler, it would be useful to formally verify that the compiler is correct. My collaborators, Qing Dong and Erik Winfree, and I defined a Chemical Reaction Network-specific form of bisimulation equivalence, which can compare two such networks and verify that one is (or is not) a correct implementation of the other. For example, the compiler-produced DNA circuit can be verified as an implementation of its abstract program, although this is not the only possible use. After defining this concept of equivalence, we show that it can be checked by algorithm; although various parts of the problem are NP-complete or PSPACE-complete, we give algorithms that meet these lower bounds. We also prove a number of interesting properties of Chemical Reaction Network bisimulation equivalence, including transitivity and modularity properties which are particularly useful for stepwise checking of large systems. We further extend this bisimulation method to linear Polymer Reaction Networks, a strictly more powerful abstraction which has been occasionally used in molecular programming. Again we prove complexity hardness results, which in this case are as expected uncomputable in the general case; however, many practical systems can still be verified, and we give one such example. Finally, we use bisimulation to identify a class of single-locus networks that are practical to implement. Thus we show a method of verification which can simplify use of the above-mentioned compiler by proving general statements of correctness about its results.
\r\n\r\nSecond, given a programming language and a concept of compiling it, it would be useful to optimize the result of the compilation. One particular area of optimization is the number of DNA strands per prepared complex; some experiments suggest that systems with no more than 2 strands per complex are more robust. Lulu Qian and I developed some proposed DNA Strand Displacement schemes for general Chemical Reaction Network implementations with no more than 2 strands per complex, and a number of other desirable properties. Meanwhile, having been shown to be useful for many reasons, the mechanisms of DNA Strand Displacement have recently been formalized, abstracted, and analyzed. I show that this formalization, combined with the bisimulation methods above, can prove various statements about the limits of DNA Strand Displacement systems. For example, a set of desirable conditions including the 2-strand limit cannot be achieved by any general Chemical Reaction Network implementation scheme. I also observe that two of the new schemes we discovered, each meeting all but one condition of the impossible set, were found in the process of coming up with this proof. I thus argue that through formalization of DNA Strand Displacement we can have a more systematic method of finding and designing molecular programs, and of knowing when the programs we want do not exist.
", "date": "2020", "date_type": "degree", "id_number": "CaltechTHESIS:04292020-052418975", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:04292020-052418975", "related_url": { "items": [ { "description": "Article adapted for Chapter 2 on Chemical Reaction Network bisimulation.", "type": "doi", "url": "https://doi.org/10.1016/j.tcs.2018.01.002" }, { "description": "Article adapted for Chapter 5 on impossibility in DNA strand displacement.", "type": "doi", "url": "https://doi.org/10.1007/978-3-030-19311-9_12" } ] }, "referencetext": { "items": [ "Dana Angluin, James Aspnes, and David Eisenstat. Stably computable\r\npredicates are semilinear. In Proceedings of the twenty-fifth annual ACM\r\nsymposium on Principles of distributed computing, pages 292\u2013299. ACM,\r\n2006.", "Dana Angluin, James Aspnes, and David Eisenstat. A simple population\r\nprotocol for fast robust approximate majority. 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Nature Chemistry, 3(2):103\u2013113, 2011." ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Melissa Ray", "deposited_by": "Robert Johnson", "deposited_on": "2020-05-11 19:13:07", "doi": "10.7907/a74v-kv80", "divisions": { "items": [ "div_bbe" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "orcid": "0000-0002-5899-7523", "role": "co-advisor" }, { "email": "luluqian@caltech.edu", "id": "Qian-Lulu", "name": { "family": "Qian", "given": "Lulu" }, "orcid": "0000-0003-4115-2409", "role": "co-advisor" } ] }, "thesis_committee": { "items": [ { "email": "murray@cds.caltech.edu", "id": "Murray-R-M", "name": { "family": "Murray", "given": "Richard M." }, "orcid": "0000-0002-5785-7481", "role": "chair" }, { "email": "niles@caltech.edu", "id": "Pierce-N-A", "name": { "family": "Pierce", "given": "Niles A." }, "orcid": "0000-0003-2367-4406", "role": "member" }, { "email": "bruck@caltech.edu", "id": "Bruck-J", "name": { "family": "Bruck", "given": "Jehoshua" }, "orcid": "0000-0001-8474-0812", "role": "member" }, { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "orcid": "0000-0002-5899-7523", "role": "member" }, { "email": "luluqian@caltech.edu", "id": "Qian-Lulu", "name": { "family": "Qian", "given": "Lulu" }, "orcid": "0000-0003-4115-2409", "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2020-01-21", "gradofc_approval_date": "2020-05-11", "review_status": "approved", "option_major": { "items": [ "bioeng" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. 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nanotechnology; Chemical Reaction Networks; DNA strand displacement; Molecular Programming; Chemical Kinetics;", "abstract": "Over the last century, the silicon revolution has enabled us to build faster, smaller and more sophisticated computers. Today, these computers control phones, cars, satellites, assembly lines, and other electromechanical devices. Just as electrical wiring controls electromechanical devices, living organisms employ \"chemical wiring\" to make decisions about their environment and control physical processes. Currently, the big difference between these two substrates is that while we have the abstractions, design principles, verification and fabrication techniques in place for programming with silicon, we have no comparable understanding or expertise for programming chemistry.
\r\n\r\nIn this thesis we take a small step towards the goal of learning how to systematically engineer prescribed non-equilibrium dynamical behaviors in chemical systems. We use the formalism of chemical reaction networks (CRNs), combined with mass-action kinetics, as our programming language for specifying dynamical behaviors. Leveraging the tools of nucleic acid nanotechnology (introduced in Chapter 1), we employ synthetic DNA molecules as our molecular architecture and toehold-mediated DNA strand displacement as our reaction primitive.
\r\n\r\nAbstraction, modular design and systematic fabrication can work only with well-understood and quantitatively characterized tools. Therefore, we embark on a detailed study of the \"device physics\" of DNA strand displacement (Chapter 2). We present a unified view of strand displacement biophysics and kinetics by studying the process at multiple levels of detail, using an intuitive model of a random walk on a 1-dimensional energy landscape, a secondary structure kinetics model with single base-pair steps, and a coarse-grained molecular model that incorporates three-dimensional geometric and steric effects. Further, we experimentally investigate the thermodynamics of three-way branch migration. Our findings are consistent with previously measured or inferred rates for hybridization, fraying, and branch migration, and provide a biophysical explanation of strand displacement kinetics. Our work paves the way for accurate modeling of strand displacement cascades, which would facilitate the simulation and construction of more complex molecular systems.
\r\n\r\nIn Chapters 3 and 4, we identify and overcome the crucial experimental challenges involved in using our general DNA-based technology for engineering dynamical behaviors in the test tube. In this process, we identify important design rules that inform our choice of molecular motifs and our algorithms for designing and verifying DNA sequences for our molecular implementation. We also develop flexible molecular strategies for \"tuning\" our reaction rates and stoichiometries in order to compensate for unavoidable non-idealities in the molecular implementation, such as imperfectly synthesized molecules and spurious \"leak\" pathways that compete with desired pathways.
\r\n\r\nWe successfully implement three distinct autocatalytic reactions, which we then combine into a de novo chemical oscillator. Unlike biological networks, which use sophisticated evolved molecules (like proteins) to realize such behavior, our test tube realization is the first to demonstrate that Watson-Crick base pairing interactions alone suffice for oscillatory dynamics. Since our design pipeline is general and applicable to any CRN, our experimental demonstration of a de novo chemical oscillator could enable the systematic construction of CRNs with other dynamic behaviors.
", "date": "2015", "date_type": "degree", "id_number": "CaltechTHESIS:06012015-171243593", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:06012015-171243593", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Lindsay Cleary", "deposited_by": "Niranjan Srinivas", "deposited_on": "2015-06-05 18:08:55", "doi": "10.7907/Z9KD1VVJ", "divisions": { "items": [ "div_eng" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "murray@cds.caltech.edu", "id": "Murray-R-M", "name": { "family": "Murray", "given": "Richard M." }, "role": "chair" }, { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "member" }, { "email": "niles@caltech.edu", "id": "Pierce-N-A", "name": { "family": "Pierce", "given": "Niles A." }, "role": "member" }, { "email": "pwkr@dna.caltech.edu", "id": "Rothemund-P-W-K", "name": { "family": "Rothemund", "given": "Paul W. K." }, "role": "member" }, { "email": "melowitz@caltech.edu", "id": "Elowitz-M-B", "name": { "family": "Elowitz", "given": "Michael B." }, "role": "member" }, { "email": "gseelig@uw.edu", "id": "Seelig-G", "name": { "family": "Seelig", "given": "Georg" }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2015-05-20", "gradofc_approval_date": "2015-06-05", "thesis_awards": "Demetriades-Tsafka-Kokkalis Prize In Nanotechnology or Related Fields, 2015", "review_status": "approved", "option_major": { "items": [ "cns" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. 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"/id/document/49913" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/49913" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/49913" } ] } } ], "eprint_status": "archive", "userid": 10023, "dir": "disk0/00/00/82/32", "datestamp": "2014-06-03 19:21:56", "lastmod": "2019-10-04 00:04:45", "status_changed": "2014-06-03 19:21:56", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "cevans@evanslabs.org", "id": "Evans-Constantine-Glen", "name": { "family": "Evans", "given": "Constantine Glen" }, "orcid": "0000-0002-7053-1670", "show_email": "NO" } ] }, "title": "Crystals that Count! Physical Principles and Experimental Investigations of DNA Tile Self-Assembly", "ispublished": "unpub", "full_text_status": "public", "keywords": "DNA computing; tile self-assembly; DNA tiles; molecular programming; algorithmic self-assembly; self-assembly; DNA nanotechnology; nanotechnology; biophysics; physics", "abstract": "Algorithmic DNA tiles systems are fascinating. From a theoretical perspective, they can result in simple systems that assemble themselves into beautiful, complex structures through fundamental interactions and logical rules. As an experimental technique, they provide a promising method for programmably assembling complex, precise crystals that can grow to considerable size while retaining nanoscale resolution. In the journey from theoretical abstractions to experimental demonstrations, however, lie numerous challenges and complications.
\r\n\r\nIn this thesis, to examine these challenges, we consider the physical principles behind DNA tile self-assembly. We survey recent progress in experimental algorithmic self-assembly, and explain the simple physical models behind this progress. Using direct observation of individual tile attachments and detachments with an atomic force microscope, we test some of the fundamental assumptions of the widely-used kinetic Tile Assembly Model, obtaining results that fit the model to within error. We then depart from the simplest form of that model, examining the effects of DNA sticky end sequence energetics on tile system behavior. We develop theoretical models, sequence assignment algorithms, and a software package, StickyDesign, for sticky end sequence design.
\r\n\r\nAs a demonstration of a specific tile system, we design a binary counting ribbon that can accurately count from a programmable starting value and stop growing after overflowing, resulting in a single system that can construct ribbons of precise and programmable length. In the process of designing the system, we explain numerous considerations that provide insight into more general tile system design, particularly with regards to tile concentrations, facet nucleation, the construction of finite assemblies, and design beyond the abstract Tile Assembly Model.
\r\n\r\nFinally, we present our crystals that count: experimental results with our binary counting system that represent a significant improvement in the accuracy of experimental algorithmic self-assembly, including crystals that count perfectly with 5 bits from 0 to 31. We show some preliminary experimental results on the construction of our capping system to stop growth after counters overflow, and offer some speculation on potential future directions of the field.
\r\n", "date": "2014", "date_type": "degree", "id_number": "CaltechTHESIS:05132014-142306756", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:05132014-142306756", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "deposited_by": "Constantine Evans", "deposited_on": "2014-06-03 19:21:56", "doi": "10.7907/7FMK-9403", "alt_title": { "items": [ "Physical Principles and Experimental Investigations of DNA Tile Self-Assembly" ] }, "divisions": { "items": [ "div_pma" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "chair" }, { "email": "kgl@caltech.edu", "id": "Libbrecht-K-G", "name": { "family": "Libbrecht", "given": "Kenneth George" }, "role": "member" }, { "email": "pwkr@dna.caltech.edu", "id": "Rothemund-P-W-K", "name": { "family": "Rothemund", "given": "Paul W. K." }, "role": "member" }, { "email": "bruck@caltech.edu", "id": "Bruck-J", "name": { "family": "Bruck", "given": "Jehoshua" }, "role": "member" }, { "email": "niles@caltech.edu", "id": "Pierce-N-A", "name": { "family": "Pierce", "given": "Niles A." }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2014-05-27", "gradofc_approval_date": "2014-06-03", "review_status": "approved", "option_major": { "items": [ "physics" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2014", "author_list": "Evans, Constantine Glen", "advisor_list": "Winfree, Erik", "comittee_list": "Winfree, Erik; Libbrecht, Kenneth George; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/7460", "eprint_id": 7460, "rev_number": 27, "documents": [ { "id": "/id/document/35416", "doc_id": 35416, "rev_number": 2, "files": [ { "id": "/id/file/111884", "fileid": 111884, "datasetid": "document", "objectid": 35416, "filename": "JosephSchaeffer_PhD_Thesis_Complete.pdf", "mime_type": "application/pdf", "hash": "d320f44f98c905b6cf73323dd962cff7", "hash_type": "MD5", "filesize": 4045542, "mtime": "2013-02-13 21:04:49", "url": "/7460/1/JosephSchaeffer_PhD_Thesis_Complete.pdf" } ], "eprint_id": 7460, "pos": 1, "placement": 1, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", 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"media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/35416" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/35416" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/35416" } ] } } ], "eprint_status": "archive", "userid": 2289, "dir": "disk0/00/00/74/60", "datestamp": "2013-02-14 22:07:06", "lastmod": "2019-10-03 23:58:55", "status_changed": "2013-02-14 22:07:06", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "thiryal@gmail.com", "id": "Schaeffer-Joseph-Malcolm", "name": { "family": "Schaeffer", "given": "Joseph Malcolm" }, "show_email": "NO" } ] }, "title": "Stochastic Simulation of the Kinetics of Multiple Interacting Nucleic Acid Strands", "ispublished": "unpub", "full_text_status": "public", "keywords": "DNA nanotechnology; nucleic acid folding; stochastic simulation; continuous time Markov process; energy model; kinetics model; secondary structure;", "abstract": "DNA nanotechnology is an emerging field which utilizes the unique structural properties of nucleic acids in order to build nanoscale devices, such as logic gates, motors, walkers, and algorithmic structures. Predicting the structure and interactions of a DNA device requires good modeling of both the thermodynamics and the kinetics of the DNA strands within the system. The kinetics of a set of DNA strands can be modeled as a continuous time Markov process through the state space of all secondary structures. The primary means of exploring the kinetics of a DNA system is by simulating trajectories through the state space and aggregating data over many such trajectories.
\r\n\r\nWe expand on previous work by extending the thermodynamics and kinetics models to handle multiple strands in a fixed volume, and show that the new models are consistent with previous models. We developed data structures and algorithms that allow us to take advantage of local properties of secondary structure, improving the efficiency of the simulator so that we can handle larger systems. The new kinetic parameters in our model were calibrated by analyzing simulator results on experimental systems that measure basic kinetic rates of various processes. Finally, we apply the new simulator to explore a case study on toehold-mediated four-way branch migration.
", "date": "2013", "date_type": "degree", "id_number": "CaltechTHESIS:02042013-110332492", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:02042013-110332492", "referencetext": { "items": [ "[1] Jonathan Bath, Simon J. Green, and Andrew J. Turberfield. A free-running DNA motor powered by a nicking enzyme. Angewandte Chemie International Edition, 44(28):4358\u2013 4361, 2005.\r\n[2] Chris Berlind. California Institute of Technology, Computer Science Senior Thesis, 2011.\r\n[3] Victor A. Bloomfield, Donald M. Crothers, and Ignacio Tinoco, Jr. Nucleic Acids: Structures, Properties, and Functions. University Science Books, Sausalito, CA, 2000.\r\n[4] Yi Chen, Mingsheng Wang, and Chengde Mao. An autonomous DNA nanomotor powered by a DNA enzyme. Angewandte Chemie International Edition, 43(27):3554\u2013 3557, 2004.\r\n[5] Nadine L. Dabby, Ho-Lin Chen, Joseph M. Schaeffer, and Erik Winfree. The kinetics of toehold-mediated four-way branch migration. Nucleic Acids Research (submitted), 2012.\r\n[6] Robert M. Dirks, Justin S. Bois, Joseph M. Schaeffer, Erik Winfree, and Niles A. Pierce. Thermodynamic analysis of interacting nucleic acid strands. SIAM Review, 49(1):65\u201388, 2007.\r\n[7] Robert M. Dirks, Milo Lin, Erik Winfree, and Niles A. Pierce. Paradigms for compu- tational nucleic acid design. Nucleic Acids Research, 32(4):1392\u20131403, 2004.\r\n[8] Christoph Flamm, Walter Fontana, Ivo L. Hofacker, and Peter Schuster. RNA folding at elementary step resolution. RNA, 6:325\u2013338, 2000.\r\n[9] Daniel T. Gillespie. Exact stochastic simulation of coupled chemical reactions. J Phys Chem, 81(25):2340\u20132361, 1977.\r\n[10] Ivo L. Hofacker. Vienna RNA secondary structure server. Nucleic Acids Research, 31(13):3429\u20133431, 2003. [11] Kyozi Kawasaki. Diffusion constants near the critical point for time-dependent ising models. Phys Rev, 145:224\u2013230, 1966.\r\n[12] Nicholas Metropolis, Arianna W. Rosenbluth, Marshall N. Rosenbluth, Augusta H. Teller, and Edward Teller. Equation of state calculations by fast computing machines. J Chem Phys, 21:1087\u20131092, 1953.\r\n[13] Steven R. Morgan and Paul G. Higgs. Barrier heights between ground states in a model of RNA secondary structure. Journal of Physics A: Mathematical and General, 31(14):3153, 1998.\r\n[14] Larry E. Morrison and Lucy M. Stols. Sensitive fluorescence-based thermodynamic and kinetic measurements of dna hybridization in solution. Biochemistry, 32(12):3095\u20133104, 1993. PMID: 8457571.\r\n[15] Jonathan A. Othmer. Algorithms for mapping nucleic acid free energy landscapes. PhD thesis, California Institute of Technology, 2009.\r\n[16] Igor G. Panyutin and Peggy Hsieh. The kinetics of spontaneous DNA branch migration. Proceedings of the National Academy of Sciences, 91(6):2021\u20132025, 1994.\r\n[17] Charles M. Radding, Kenneth L. Beattie, William K. Holloman, and Roger C. Wie- gand. Uptake of homologous single-stranded fragments by superhelical dna: Iv. branch migration. Journal of Molecular Biology, 116(4):825\u2013839, 1977.\r\n[18] Paul W. K Rothemund, Nick Papadakis, and Erik Winfree. Algorithmic self-assembly of DNA sierpinski triangles. PLoS Biol, 2(12):e424, 12 2004.\r\n[19] John SantaLucia. A unified view of polymer, dumbbell, and oligonucleotide DNA nearest-neighbor thermodynamics. Proceedings of the National Academy of Sciences, 95(4):1460\u20131465, 1998.\r\n[20] John SantaLucia, Hatim T. Allawi, and P. Ananda Seneviratne. Improved nearest- neighbor parameters for predicting DNA duplex stability. Biochemistry, 35(11):3555\u2013 3562, 1996.\r\n[21] John SantaLucia and Donald Hicks. The thermodynamics of DNA structural motifs. Annual Review of Biophysics and Biomolecular Structure, 33(1):415\u2013440, 2004.\r\n[22] Joseph M. Schaeffer. The multistrand simulator: Stochastic simulation of the kinetics of multiple interacting DNA strands. Master\u2019s thesis, California Institute of Technology, 2012.\r\n[23] Georg Seelig, David Soloveichik, David Y. Zhang, and Erik Winfree. Enzyme-free nucleic acid logic circuits. Science, 314(5805):1585\u20131588, 2006.\r\n[24] Friedrich C. Simmel. Processive motion of bipedal DNA walkers. ChemPhysChem, 10(15):2593\u20132597, 2009.\r\n[25] Friedrich C. Simmel and Bernard Yurke. A DNA-based molecular device switchable between three distinct mechanical states. Applied Physics Letters, 80:883, February 2002.\r\n[26] Friedrich C. Simmel and Wendy U. Dittmer. DNA nanodevices. Small, 1(3):284\u2013299, 2005.\r\n[27] Betty J. Thompson, Merrill N. Camien, and Robert C. Warner. Kinetics of branch migration in double-stranded DNA. Proceedings of the National Academy of Sciences, 73(7):2299\u20132303, 1976.\r\n[28] James G. Wetmur. Hybridization and renaturation kinetics of nucleic acids. Annual Review of Biophysics and Bioengineering, 5(1):337\u2013361, 1976.\r\n[29] James G. Wetmur and Norman Davidson. Kinetics of renaturation of DNA. Journal of Molecular Biology, 31:349\u2013370, 1968.\r\n[30] Darren J. Wilkinson. Stochastic Dynamical Systems, pages 359\u2013375. John Wiley & Sons, Ltd, 2011.\r\n[31] Erik Winfree. Algorithmic self-assembly of DNA: Theoretical motivations and 2D assembly experiments. Journal of Biomolecular Structure and Dynamics, 11(2):263\u2013 270, 2000.\r\n[32] Peng Yin, Harry M.T. Choi, Colby R. Calvert, and Niles A. Pierce. Programming biomolecular self-assembly pathways. Nature, 451(7176):318\u2013322, 2008.\r\n[33] Bernard Yurke and Allen Mills. Using dna to power nanostructures. Genetic Programming and Evolvable Machines, 4:111\u2013122, 2003. 10.1023/A:1023928811651.\r\n[34] Joseph N. Zadeh, Conrad D. Steenberg, Justin S. Bois, Brian R. Wolfe, Marshall B. Pierce, Asif R. Khan, Robert M. Dirks, and Niles A. Pierce. NUPACK: Analysis and design of nucleic acid systems. Journal of Computational Chemistry, 32(1):170\u2013173, 2011.\r\n[35] David Yu Zhang and Erik Winfree. Control of DNA strand displacement kinetics using toehold exchange. Journal of the American Chemical Society, 131(47):17303\u201317314, 2009.\r\n[36] Wenbing Zhang and Shi-Jie Chen. RNA hairpin-folding kinetics. Proceedings of the National Academy of Sciences, 99(4):1931\u20131936, 2002.\r\n[37] Michael Zuker. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Research, 31(13):3406\u20133415, 2003." ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "National Science Foundation", "grant_number": "DMS-0506468" }, { "agency": "National Science Foundation", "grant_number": "CCF-0832824" }, { "agency": "Gordon and Betty Moore Foundation", "grant_number": "Caltech Programmable Molecular Technology Initiative" } ] }, "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "deposited_by": "Joseph Schaeffer", "deposited_on": "2013-02-14 22:07:06", "doi": "10.7907/JEBY-6X69", "divisions": { "items": [ "div_eng" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "chair" }, { "email": "niles@caltech.edu", "id": "Pierce-N-A", "name": { "family": "Pierce", "given": "Niles A." }, "role": "member" }, { "email": "umans@cms.caltech.edu", "id": "Umans-C-M", "name": { "family": "Umans", "given": "Christopher M." }, "role": "member" }, { "email": "barr@cs.caltech.edu", "id": "Barr-A-H", "name": { "family": "Barr", "given": "Alan H." }, "role": "member" }, { "email": "bruck@caltech.edu", "id": "Bruck-J", "name": { "family": "Bruck", "given": "Jehoshua" }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2012-09-28", "gradofc_approval_date": "2013-02-14", "review_status": "approved", "option_major": { "items": [ "compsci" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2013", "author_list": "Schaeffer, Joseph Malcolm", "advisor_list": "Winfree, Erik", "comittee_list": "Winfree, Erik; Pierce, Niles A.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/6718", "eprint_id": 6718, "rev_number": 24, "documents": [ { "id": "/id/document/13724", "doc_id": 13724, "rev_number": 4, "files": [ { "id": "/id/file/89102", "fileid": 89102, "datasetid": "document", "objectid": 13724, "filename": "EFrancoThesis.pdf", "mime_type": "application/pdf", "filesize": 17671392, "mtime": "2012-12-26 04:39:03", "url": "/6718/2/EFrancoThesis.pdf" } ], "eprint_id": 6718, "pos": 2, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": "other", "main": "EFrancoThesis.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final", "relation": { "items": [ { "type": "http://eprints.org/relation/hasVolatileVersion", "uri": "/id/document/27708" }, { "type": "http://eprints.org/relation/haspreviewThumbnailVersion", "uri": "/id/document/27708" }, { "type": "http://eprints.org/relation/hasVersion", "uri": "/id/document/27708" } ] } }, { "id": "/id/document/27708", "doc_id": 27708, "rev_number": 2, "files": [ { "id": "/id/file/89100", "fileid": 89100, "datasetid": "document", "objectid": 27708, "filename": "preview.png", "mime_type": "image/png", "hash": "94f5815afd4b3a0636d883a9f52baa2a", "hash_type": "MD5", "filesize": 35081, "mtime": "2012-12-26 04:39:03", "url": "/6718/3/preview.png" } ], "eprint_id": 6718, "pos": 3, "placement": 3, "mime_type": "image/png", "format": "image/png", "language": "en", "security": "public", "license": "other", "main": "preview.png", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/13724" }, { "type": "http://eprints.org/relation/ispreviewThumbnailVersionOf", "uri": "/id/document/13724" }, { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/13724" } ] } }, { "id": "/id/document/127086", "doc_id": 127086, "rev_number": 1, "files": [ { "id": "/id/file/372520", "fileid": 372520, "datasetid": "document", "objectid": 127086, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "2b928713ee3dfccf380ec6755412e5f7", "hash_type": "MD5", "filesize": 37194, "mtime": "2021-06-24 01:25:36", "url": "/6718/4/indexcodes.txt" } ], "eprint_id": 6718, "pos": 4, "placement": 4, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/13724" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/13724" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/13724" } ] } } ], "eprint_status": "archive", "userid": 2546, "dir": "disk0/00/00/67/18", "datestamp": "2012-05-15 23:44:25", "lastmod": "2019-10-03 23:53:40", "status_changed": "2012-05-15 23:44:25", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "efranco@ucr.edu", "id": "Franco-Elisa", "name": { "family": "Franco", "given": "Elisa" }, "show_email": "YES" } ] }, "title": "Analysis, Design, and in vitro Implementation of Robust Biochemical Networks", "ispublished": "unpub", "full_text_status": "public", "keywords": "feedback control, biochemistry, DNA, robustness, design", "abstract": "The functionalities of every living organism are wired in the biochemical interactions among proteins, nucleic acids, and all the other molecules that constitute life's building blocks. Understanding the general design principles of this \"hardware of life\" is an exciting and challenging task for modern bioengineers. In this thesis, I focus on the topic of molecular network robustness: I investigate several design rules guaranteeing desired functionalities in specific systems, despite their components variability. Experimental verifications of such design schemes are carried out using \\emph{in vitro} transcriptional circuits, a minimal analogue of cellular genetic networks.
\r\n \r\nThe first problem I consider is flux control, which is a fundamental feature for the correct performance of biochemical systems. I describe a simple model problem where two reagents bind stoichiometrically to form an output product. In the absence of any regulation, imbalances in the reagent production rates can cause accumulation of unused molecules, and limit the output flow. To match the reagents' flux robustly with respect to the open loop rates, I propose the use of negative or positive feedback schemes that rely on competitive binding. Such schemes are modeled through ordinary differential equations and implemented using transcriptional circuits; data are presented showing the performance of the two approaches.
\r\n \r\nThe second topic I examine is the functional robustness of interconnected networks. Molecular devices characterized in isolation may lose their properties once interconnected. This challenge is illustrated with a case study: a synthetic transcriptional clock is used to time conformational changes in a molecular nanomachine called DNA tweezers. Mass conservation introduces parasitic interactions that perturb the oscillator trajectories proportionally to the total amount of tweezers \"load\". To overcome this problem, we can use a transcriptional switch that acts as a buffer amplifier, achieving signal propagation and at the same time reducing the perturbations on the source of signal.
\r\n\r\nFinally, I describe a general class of control-theoretic methods to analyze structural robustness in natural biological systems. Using Lyapunov theory and set invariance, the stability properties of several well-known case studies are analytically demonstrated. The key feature of this analysis is its reliance on parameter-independent models, which only capture essential dynamic interactions between molecular species.
\r\n \r\n", "date": "2012-06", "date_type": "degree", "id_number": "CaltechTHESIS:10192011-161454857", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:10192011-161454857", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "U.S. Army Research Office", "grant_number": "DAAD19-03-D-0004" }, { "agency": "National Science Foundation", "grant_number": "CCF-0832824" } ] }, "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "deposited_by": "Elisa Franco", "deposited_on": "2012-05-15 23:44:25", "doi": "10.7907/1C3S-FA59", "divisions": { "items": [ "div_eng" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "murray@cds.caltech.edu", "id": "Murray-R-M", "name": { "family": "Murray", "given": "Richard M." }, "role": "advisor" }, { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "co-advisor" } ] }, "thesis_committee": { "items": [ { "email": "murray@cds.caltech.edu", "id": "Murray-R-M", "name": { "family": "Murray", "given": "Richard M." }, "role": "chair" }, { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "member" }, { "email": "doyle@cds.caltech.edu", "id": "Doyle-J-C", "name": { "family": "Doyle", "given": "John Comstock" }, "role": "member" }, { "email": "pwkr@dna.caltech.edu", "id": "Rothemund-P-W-K", "name": { "family": "Rothemund", "given": "Paul W. K." }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2011-06-27", "gradofc_approval_date": "2012-05-15", "review_status": "approved", "option_major": { "items": [ "cds" ] }, "option_minor": { "items": [ "humanities" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2012", "author_list": "Franco, Elisa", "advisor_list": "Murray, Richard M. and Winfree, Erik", "comittee_list": "Murray, Richard M.; Winfree, Erik; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/6807", "eprint_id": 6807, "rev_number": 69, "documents": [ { "id": "/id/document/14183", "doc_id": 14183, "rev_number": 5, "files": [ { "id": "/id/file/91343", "fileid": 91343, "datasetid": "document", "objectid": 14183, "filename": "Joseph_Schaeffer_Masters_Thesis_Complete.pdf", "mime_type": "application/pdf", "filesize": 3982203, "mtime": "2012-12-26 04:40:10", "url": "/6807/1/Joseph_Schaeffer_Masters_Thesis_Complete.pdf" } ], "eprint_id": 6807, "pos": 1, "mime_type": "application/pdf", "format": "application/pdf", "format_desc": "Master's Thesis: Complete PDF (4Mb)", "language": "en", "security": 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"MD5", "filesize": 2238, "mtime": "2021-06-24 01:32:02", "url": "/6807/32/indexcodes.txt" } ], "eprint_id": 6807, "pos": 32, "placement": 32, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/14192" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/14192" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/14192" } ] } } ], "eprint_status": "archive", "userid": 2289, "dir": "disk0/00/00/68/07", "datestamp": "2012-02-17 21:38:17", "lastmod": "2019-10-03 23:54:19", "status_changed": "2012-02-17 21:38:16", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "thiryal@gmail.com", "id": "Schaeffer-Joseph-Malcolm", "name": { "family": "Schaeffer", "given": "Joseph Malcolm" }, "show_email": "NO" } ] }, "title": "The Multistrand Simulator: Stochastic Simulation of the Kinetics of Multiple Interacting DNA Strands ", "ispublished": "unpub", "full_text_status": "public", "keywords": "DNA nanotechnology; nucleic acid folding; stochastic simulation; continuous time Markov process; energy model; kinetics model; secondary structure;", "abstract": "DNA has been used in vitro as a computational substrate due to programmable base-pairing interactions. This allows the construction of logic gates, self-assembled shapes, motors, walkers and other nanoscale devices comprised of DNA strands. These strands must be carefully designed in order to correctly perform their function, which requires effective models of the DNA system. The thermodynamics of multiple interacting DNA strands is a well-studied model which can make equilibrium predictions on these systems, but many devices operate far from equilibrium. The prediction of large non-equilibrium systems requires the simulation of a kinetics model, as these are both stochastic and computationally difficult to solve in an exact form. We developed the Multistrand kinetics simulator, which extends the previous work by expanding the kinetics model to handle multiple nucleic acid strands, as well as using optimized algorithms in order to speed up the simulations. ", "date": "2012", "date_type": "degree", "id_number": "CaltechTHESIS:02022012-143934605", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:02022012-143934605", "referencetext": { "items": [ "Jonathan Bath, Simon J. Green, and Andrew J. Turberfield. A free-running DNA motor powered by a nicking enzyme. Angewandte Chemie International Edition, 44(28):4358\u2013 4361, 2005.", "Chris Berlind. California Institute of Technology, Computer Science Senior Thesis, 2011.", "Victor A. Bloomfield, Donald M. Crothers, and Ignacio Tinoco Jr. Nucleic Acids: Structures, Properties, and Functions. University Science Books, Sausalito, CA, 2000.", "Yi Chen, Mingsheng Wang, and Chengde Mao. An autonomous DNA nanomotor powered by a DNA enzyme. Angewandte Chemie International Edition, 43(27):3554\u2013 3557, 2004.", "Robert M. Dirks, Justin S. Bois, Joseph M. Schaeffer, Erik Winfree, and Niles A. Pierce. Thermodynamic analysis of interacting nucleic acid strands. SIAM Review, 49(1):65\u201388, 2007.", "Robert M. Dirks, Milo Lin, Erik Winfree, and Niles A. Pierce. Paradigms for computational nucleic acid design. Nucleic Acids Research, 32(4):1392\u20131403, 2004.", "Christoph Flamm, Walter Fontana, Ivo L. Hofacker, and Peter Schuster. RNA folding at elementary step resolution. RNA, 6:325\u2013338, 2000.", "Daniel T. Gillespie. Exact stochastic simulation of coupled chemical reactions. J Phys Chem, 81(25):2340\u20132361, 1977.", "Ivo L. Hofacker. Vienna RNA secondary structure server. Nucleic Acids Research, 31(13):3429\u20133431, 2003.", "Kyozi Kawasaki. Diffusion constants near the critical point for time-dependent Ising models. Phys Rev, 145:224\u2013230, 1966.", "Nicholas Metropolis, Arianna W. Rosenbluth, Marshall N. Rosenbluth, Augusta H. Teller, and Edward Teller. Equation of state calculations by fast computing machines. J Chem Phys, 21:1087\u20131092, 1953.", "Steven R. Morgan and Paul G. Higgs. Barrier heights between ground states in a model of RNA secondary structure. Journal of Physics A: Mathematical and General, 31(14):3153, 1998.", "Jonathan A. Othmer. Algorithms for mapping nucleic acid free energy landscapes. PhD thesis, California Institute of Technology, 2009.", "Paul W. K Rothemund, Nick Papadakis, and Erik Winfree. Algorithmic self-assembly of DNA sierpinski triangles. PLoS Biol, 2(12):e424, 12 2004.", "John SantaLucia. A unified view of polymer, dumbbell, and oligonucleotide DNA nearest-neighbor thermodynamics. Proceedings of the National Academy of Sciences, 95(4):1460\u20131465, 1998.", "John SantaLucia, Hatim T. Allawi, and P. Ananda Seneviratne. Improved nearest- neighbor parameters for predicting DNA duplex stability. Biochemistry, 35(11):3555\u2013 3562, 1996.", "John SantaLucia and Donald Hicks. The thermodynamics of DNA structural motifs. Annual Review of Biophysics and Biomolecular Structure, 33(1):415\u2013440, 2004.", "Georg Seelig, David Soloveichik, David Y. Zhang, and Erik Winfree. Enzyme-free nucleic acid logic circuits. Science, 314(5805):1585\u20131588, 2006.", "Friedrich C. Simmel. Processive motion of bipedal DNA walkers. ChemPhysChem, 10(15):2593\u20132597, 2009.", "Friedrich C. Simmel and Wendy U. Dittmer. DNA nanodevices. Small, 1(3):284\u2013299, 2005.", "James G. Wetmur. Hybridization and renaturation kinetics of nucleic acids. Annual Review of Biophysics and Bioengineering, 5(1):337\u2013361, 1976.", "Darren J. Wilkinson. Stochastic Dynamical Systems, pages 359\u2013375. John Wiley &\r\nSons, Ltd, 2011.", "Erik Winfree. Algorithmic self-assembly of DNA: Theoretical motivations and 2D assembly experiments. Journal of Biomolecular Structure and Dynamics, 11(2):263\u2013 270, 2000.", "Joseph N. Zadeh, Conrad D. Steenberg, Justin S. Bois, Brian R. Wolfe, Marshall B. Pierce, Asif R. Khan, Robert M. Dirks, and Niles A. Pierce. NUPACK: Analysis and design of nucleic acid systems. Journal of Computational Chemistry, 32(1):170\u2013173, 2011.", "David Yu Zhang and Erik Winfree. Control of DNA strand displacement kinetics using toehold exchange. Journal of the American Chemical Society, 131(47):17303\u201317314, 2009.", "Wenbing Zhang and Shi-Jie Chen. RNA hairpin-folding kinetics. Proceedings of the National Academy of Sciences, 99(4):1931\u20131936, 2002.", "Michael Zuker. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Research, 31(13):3406\u20133415, 2003." ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "National Science Foundation", "grant_number": "DMS-0506468" }, { "agency": "National Science Foundation", "grant_number": "CCF-0832824" } ] }, "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "deposited_by": "Joseph Schaeffer", "deposited_on": "2012-02-17 21:38:17", "doi": "10.7907/BBH8-CG37", "divisions": { "items": [ "div_eng" ] }, "institution": "California Institute of Technology", "thesis_type": "masters", "thesis_advisor": { "items": [ { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "name": { "family": "Unknown", "given": "Unknown" } } ] }, "thesis_degree": "MS", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2012-01-27", "gradofc_approval_date": "2012-02-13", "review_status": "approved", "option_major": { "items": [ "compsci" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2012", "author_list": "Schaeffer, Joseph Malcolm", "advisor_list": "Winfree, Erik", "comittee_list": "Unknown, Unknown" }, { "id": "https://thesis.library.caltech.edu/id/eprint/6676", "eprint_id": 6676, "rev_number": 20, "documents": [ { "id": "/id/document/13630", "doc_id": 13630, "rev_number": 4, "files": [ { "id": "/id/file/88501", "fileid": 88501, "datasetid": "document", "objectid": 13630, "filename": "thesis.pdf", "mime_type": "application/pdf", "filesize": 1020260, "mtime": "2012-12-26 04:38:51", "url": "/6676/1/thesis.pdf" } ], "eprint_id": 6676, "pos": 1, "mime_type": "application/pdf", "format": "application/pdf", "format_desc": "Complete Thesis", "language": "en", "security": "public", "license": "other", "main": "thesis.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final" }, { "id": "/id/document/127048", "doc_id": 127048, "rev_number": 1, "files": [ { "id": "/id/file/372482", "fileid": 372482, "datasetid": "document", "objectid": 127048, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "0be890e94986c4b65048461bc9492b1a", "hash_type": "MD5", "filesize": 20061, "mtime": "2021-06-24 01:22:41", "url": "/6676/2/indexcodes.txt" } ], "eprint_id": 6676, "pos": 2, "placement": 2, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/13630" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/13630" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/13630" } ] } } ], "eprint_status": "archive", "userid": 6728, "dir": "disk0/00/00/66/76", "datestamp": "2011-09-19 19:17:56", "lastmod": "2019-10-03 23:53:23", "status_changed": "2011-09-19 19:17:56", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "seungwoo.theory@gmail.com", "id": "Shin-Seung-Woo", "name": { "family": "Shin", "given": "Seung Woo" }, "show_email": "YES" } ] }, "title": "Compiling and Verifying DNA-Based Chemical Reaction Network Implementations", "ispublished": "unpub", "full_text_status": "public", "keywords": "DNA computation; compiler; software verification; model checking", "abstract": "One goal of molecular programming and synthetic biology is to build chemical circuits that can control chemical processes at the molecular level. Remarkably, it has been shown that synthesized DNA molecules can be used to construct complex chemical circuits that operate without any enzyme or cellular component. However, designing DNA molecules at the individual nucleotide base level is often difficult and laborious, and thus chemical reaction networks (CRNs) have been proposed as a higher-level programming language. So far, several general-purpose schemes have been described for designing synthetic DNA molecules that simulate the behavior of arbitrary CRNs, and many more are being actively investigated.
\r\n\t\t\r\nHere, we solve two problems related to this topic. First, we present a general-purpose CRN-to-DNA compiler that can apply user-defined compilation schemes for translating formal CRNs to domain-level specifications for DNA molecules. In doing so, we develop a language in which such schemes can be concisely and precisely described. This compiler can greatly reduce the amount of tedious manual labor faced by researchers working in the field. Second, we present a general method for the formal verification of the correctness of such compilation. We first show that this problem reduces to testing a notion of behavioral equivalence between two CRNs, and then we construct a mathematical formalism in which that notion can be precisely defined. Finally, we provide algorithms for testing that notion. This verification process can be thought of as an equivalent of model checking in molecular computation, and we hope that the generality of our verification techniques will eventually allow us to apply them not only to DNA-based CRN implementations but to a wider class of molecular programs.
", "date": "2012", "date_type": "degree", "id_number": "CaltechTHESIS:09182011-215125061", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:09182011-215125061", "referencetext": { "items": [ "[1] Leonard Adleman. Molecular computation of solutions to combinatorial problems. Science, 266:1021\u20131024, 1994.\r\n[2] Charles H. Bennett. The thermodynamic of computation - a review. International Journal of Theoretical Physics, 21(12):905\u2013940, 1982.\r\n[3] Muffy Calder, Vladislav Vyshemirsky, David Gilbert, and Richard Orton. Analysis of signalling pathways using continuous time markov chains. Transactions on Computational Systems Biology VI, 4220:44\u201367, 2006.\r\n[4] Luca Cardelli. Strand algebras for DNA computing. Natural Computing: an international journal, 10(1):407\u2013428, 2011.\r\n[5] Luca Cardelli. Two-domain DNA strand displacement. Mathematical Structures in Computer Science, 2011. In press.\r\n[6] Luca Cardelli, Marta Kwiatkowska, Matthew R. Lakin, David Parker, and Andrew Phillips. Design and analysis of DNA circuits using probabilistic model checking. Preprint, available at http://lucacardelli.name, 2010.\r\n[7] Luca Cardelli, Andrew Phillips, and Simon Youssef. Exploring DNA strand-displacement com- putational elements. In The 16th International Conference on DNA Computing and Molecular Programming, 2010. Two-page abstract at conference proceedings.\r\n[8] Nathalie Chabrier-Rivier, Marc Chiaverini, Vincent Danos, Franois Fages, and Vincent Schchter. Modeling and querying biomolecular interaction networks. Theoretical Computer Science - Special issue: Computational systems biology, 325:25\u201344, 2003.\r\n[9] Ehsan Chiniforooshan, David Doty, Lila Kari, and Shinnosuke Seki. Scalable, time-responsive, digital, energy-efficient molecular circuits using DNA strand displacement. 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Theoretical Computer Science - Special issue on Converging Sciences: Informatics and Biology, 391:239\u2013257, 2008.\r\n[15] Andrew Hinton, Marta Kwiatkowska, Gethin Norman, and David Parker. PRISM: A tool for automatic verification of probabilistic systems. Lecture Notes in Computer Science, 3920:441\u2013 444, 2006.\r\n[16] Ivo L. Hofacker, Walter Fontana, Peter F. Stadler, Sebastian L. Bonhoeffer, Manfred Tacker, and Peter Schuster. Fast folding and comparison of RNA secondary structures. Monatsh. Chem., 125:167\u2013188, 1994.\r\n[17] Jongmin Kim. In vitro synthetic transcriptional networks. PhD thesis, California Institute of Technology, 2006.\r\n[18] Jongmin Kim and Erik Winfree. Synthetic in vitro transcriptional oscillators. Molecular Systems Biology, 7:465, 2011.\r\n[19] Matthew R. Lakin and Andrew Phillips. Visual DSD. Microsoft Research.\r\n[20] Matthew R. Lakin, Simon Youssef, Luca Cardelli, and Andrew Phillips. Abstractions for DNA circuit design. 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Public Library of Science Biology, 2:424, 2004.\r\n[32] Ph. Schnoebelen and N. Sidorova. Bisimulation and the reduction of Petri nets. Lecture Notes in Computer Science, 1825:409\u2013423, 2000.\r\n[33] Georg Seelig, David Soloveichik, David Yu Zhang, and Erik Winfree. Enzyme-free nucleic acid logic circuits. Science, 314:1585\u20131588, 2006.\r\n[34] Nadrian C. Seeman. DNA in a material world. Nature, 421:427\u2013431, 2003. [35] Phillip Senum and Marc Riedel. Rate-independent constructs for chemical computation. PLoS\r\nONE, 6:e21414, 2011. [36] Adam Shea, Brian Fett, Marc D. Riedel, and Keshab Parhi. Writing and compiling code into\r\nbiochemistry. In Pacific Symposium on Biocomputing, volume 15, pages 456\u2013464, 2010.\r\n[37] Jong-Shik Shin and Niles A. Pierce. A synthetic DNA walker for molecular transport. Journal of the American Chemical Society, 126:10834\u201310835, 2004.\r\n75 [38] David Soloveichik, Matthew Cook, Erik Winfree, and Jehoshua Bruck. Computation with finite\r\nstochastic chemical reaction networks. Natural Computing, 7:615\u2013633, 2008. [39] David Soloveichik, Georg Seelig, and Erik Winfree. DNA as a universal substrate for chemical\r\nkinetics. Proceedings of the National Academy of Sciences, 107:5393\u20135398, 2010. [40] Ye Tian, Yu He, Yi Chen, Peng Yin, and Chengde Mao. A DNAzyme that walks processively\r\nand autonomously along a one-dimensional track. Angewandte Chemie, 44:4355\u20134358, 2005.\r\n[41] Suvir Venkataraman, Robert M. Dirks, Paul W. K. Rothemund, Erik Winfree, and Niles A. Pierce. An autonomous polymerization motor powered by DNA hybridization. Nature Nan- otechnology, 2:490\u2013494, 2007.\r\n[42] Erik Winfree. Algorithmic self-assembly of DNA. PhD thesis, California Institute of Technology, 1998.\r\n[43] Brian R. Wolfe. Wolfe enumerator specification: Version 4. A project as a graduate student on rotation, 2009.\r\n[44] Peng Yin, Harry M. T. Choi, Colby R. Calvert, and Niles A Pierce. Programming biomolecular self-assembly pathways. Nature, 451:318\u2013322, 2008.\r\n[45] Peng Yin, Rizal F. Hariadi, Sudheer Sahu, Harry M. T. Choi, Sung Ha Park, Thomas H. LaBean, and John H. Reif. Programming DNA tube circumferences. Science, 321:824\u2013826, 2008.\r\n[46] Peng Yin, Hao Yan, Xiaoju G. Daniell, Andrew J. Turberfield, and John H. Reif. A unidirec- tional DNA walker that moves autonomously along a track. Angewandte Chemie, 43:4906\u20134911, 2004.\r\n[47] Joseph N. Zadeh, Conrad D. Steenberg, Justin S. Bois, Brian R. Wolfe, Marshall B. Pierce, Asif R. Khan, Robert M. Dirks, and Niles A. Pierce. NUPACK: Analysis and design of nucleic acid systems. Journal of Computational Chemistry, 32:170\u2013173, 2011.\r\n[48] David Yu Zhang. Cooperative hybridization of oligonucleotides. Journal of the American Chemical Society, 133:1077\u20131086, 2011.\r\n[49] David Yu Zhang, Andrew J. Turberfield, Bernard Yurke, and Erik Winfree. Engineering entropy-driven reactions and networks catalyzed by DNA. Science, 318:1121\u20131125, 2007." ] }, "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF" }, { "agency": "SURF" }, { "agency": "Caltech Computer Science dept. " } ] }, "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "deposited_by": "Seung Woo Shin", "deposited_on": "2011-09-19 19:17:56", "doi": "10.7907/QM4N-KX17", "divisions": { "items": [ "div_eng" ] }, "institution": "California Institute of Technology", "thesis_type": "masters", "thesis_advisor": { "items": [ { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "name": { "family": "Unknown", "given": "Unknown" } } ] }, "thesis_degree": "MS", "thesis_degree_grantor": "California Institute of Technology", "review_status": "approved", "option_major": { "items": [ "compsci" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2012", "author_list": "Shin, Seung Woo", "advisor_list": "Winfree, Erik", "comittee_list": "Unknown, Unknown" }, { "id": "https://thesis.library.caltech.edu/id/eprint/6502", "eprint_id": 6502, "rev_number": 31, "documents": [ { "id": "/id/document/13011", "doc_id": 13011, "rev_number": 6, "files": [ { "id": "/id/file/207300", "fileid": 207300, "datasetid": "document", "objectid": 13011, "filename": "2011-Jun-06-draft.pdf", "mime_type": "application/pdf", "filesize": 22329347, "mtime": "2016-08-22 21:22:55", "url": "/6502/1/2011-Jun-06-draft.pdf" } ], "eprint_id": 6502, "pos": 1, "format": "application/pdf", "format_desc": "Original version. 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"type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "id": "Hariadi-Rizal-Fajar", "name": { "family": "Hariadi", "given": "Rizal Fajar" }, "show_email": "NO" } ] }, "title": "Non-Equilibrium Dynamics of DNA Nanotubes ", "ispublished": "unpub", "full_text_status": "public", "keywords": "DNA, nanotechnology, nanotube, cytoskeleton, the origin of life, bond breakage, drag reduction, polymer dynamics, DNA rupture, cytoskeleton", "abstract": "Can the fundamental processes that underlie molecular biology be understood and simulated by DNA nanotechnology? The early development of DNA nanotechnology by Ned Seeman was driven by the desire to find a solution to the protein crystallization problem. Much of the later development of the field was also driven by envisioned applications in computing and nanofabrication. While the DNA nanotechnology community has assembled a versatile tool kit with which DNA nanostructures of considerable complexity can be assembled, the application of this tool kit to other areas of science and technology is still in its infancy. This dissertation reports on the construction of non-equilibrium DNA nanotube dynamic to probe molecular processes in the areas of hydrodynamics and cytoskeletal behavior.
\r\n\r\nAs the first example, we used DNA nanotubes as a molecular probe for elongational flow measurement in different micro-scale flow settings. The hydrodynamic flow in the vicinity of simple geometrical objects, such as a rigid DNA nanotube, is amenable to rigorous theoretical investigation. We measured the distribution of elongational flows produced in progressively more complex settings, ranging from the vicinity of an orifice in a microfluidic chamber to within a bursting bubble of Pacific ocean water. This information can be used to constrain theories on the origin of life in which replication involves a hydrodynamically driven fission process, such as the coacervate fission proposed by Oparin.
\r\n\r\nA second theme of this dissertation is the bottom-up construction of a de novo artificial cytoskeleton with DNA nanotubes. The work reported here encompasses structural, locomotion, and control aspects of non-equilibrium cytoskeletal behavior. We first measured the kinetic parameters of DNA nanotube assembly and tested the accuracy of the existing polymerization models in the literature. Toward recapitulation of non-equilibrium cytoskeletal dynamics, we coupled the polymerization of DNA nanotubes with an irreversible energy consumption reaction, analogous to nucleotide hydrolysis in actin and microtubule polymerization. Finally, we integrated the DNA strand displacement circuits with DNA nanotube polymerization to achieve programmable kinetic control of behavior within artificial cytoskeleton. Our synthetic approach may provide insights into natural cytoskeleton dynamics, such as minimal architectural or reaction mechanism requirements for non-equilibrium behaviors including treadmilling and dynamic instability.
\r\n\r\nThe outgrowth of DNA nanotechnology beyond its own boundaries, serving as a general model system for biomolecular dynamics, can lead to an understanding of molecular processes that advances both basic and applied sciences.
", "date": "2011", "date_type": "degree", "id_number": "CaltechTHESIS:06062011-122322347", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:06062011-122322347", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "suggestions": "Rizal F. HariadiNucleic acids, the \"NA\" in DNA and RNA, have long been known to be vitally important molecules within biological cells and organisms. However, they are interesting for more than just their known roles in biology: their predictable Watson-Crick base pairing properties allow nucleic acids to be powerful nanoscale engineering tools. Additionally, nucleic acid-based devices are particularly attractive as biotechnological tools, because nucleic acids naturally exist within all life, and thus nucleic acid devices more easily function in cellular environments. It is for these reasons that nucleic acids have emerged as a frequent star in recent synthetic biology, biotechnology, and nanotechnology research papers.
\r\n\r\nThis thesis is a collection of 6 experimental papers, 3 theoretical papers, and 1 review paper that demonstrate and characterize novel nucleic acid-based devices such as catalysts, logic gates, and allosteric switches. Particular effort was placed in ensuring that all the designs are generalizable in sequence and that all the devices are modular in nature; this allows many different components to be integrated into higher-complexity devices.
\r\n\r\nThe works presented in this thesis were designed using only non-covalent changes to nucleic acid complexes and structures via Watson-Crick base pairing--i.e. hybridization, branch migration, and dissociation. These three primitives are sufficient to construct an endless variety of circuits and devices, much like how resistors, capacitors, and inductors allow complex electrical circuits. One advantage of devices, reactions, and circuits engineered using only Watson-Crick interactions is their robustness to their environmental conditions. While enzymatic reactions require specific temperatures, salt conditions, and co-factors, nucleic acid hybridization works reliably in a variety of different solutions.
\r\n\r\nThese works are not meant to be final, optimized designs for devices, but rather demonstrations of the wide range of possibilities afforded by nucleic acid engineering and of problems that can be practically solved with dynamic nucleic acid devices in the near future.
", "date": "2010", "date_type": "degree", "id_number": "CaltechTHESIS:05262010-173410602", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechTHESIS:05262010-173410602", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Gayle Hammer", "deposited_by": "David Zhang", "deposited_on": "2010-06-03 16:33:10", "doi": "10.7907/Q4NR-CH87", "divisions": { "items": [ "div_eng" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "niles@caltech.edu", "id": "Pierce-N-A", "name": { "family": "Pierce", "given": "Niles A." }, "role": "chair" }, { "email": "bruck@caltech.edu", "id": "Bruck-J", "name": { "family": "Bruck", "given": "Jehoshua" }, "role": "member" }, { "email": "sefraser@caltech.edu", "id": "Fraser-S-E", "name": { "family": "Fraser", "given": "Scott E." }, "role": "member" }, { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_defense_date": "2010-06-14", "gradofc_approval_date": "2010-05-27", "review_status": "approved", "option_major": { "items": [ "cns" ] }, "copyright_statement": "Author's Rights Authorization: I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted here is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive license to archive and make accessible, under the conditions specified under \"Thesis Availability\" in this submission, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation, or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2010", "author_list": "Zhang, David Yu", "advisor_list": "Winfree, Erik", "comittee_list": "Pierce, Niles A.; Bruck, Jehoshua; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/2261", "eprint_id": 2261, "rev_number": 10, "documents": [ { "id": "/id/document/4228", "doc_id": 4228, "rev_number": 3, "files": [ { "id": "/id/file/24461", "fileid": 24461, "datasetid": "document", "objectid": 4228, "filename": "thesis.pdf", "mime_type": "application/pdf", "filesize": 2528018, "mtime": "2012-12-26 02:49:10", "url": "/2261/1/thesis.pdf" } ], "eprint_id": 2261, "pos": 1, "mime_type": "application/pdf", "format": "application/pdf", "format_desc": "Full thesis", "language": "en", "security": "public", "license": "other", "main": "thesis.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final", "relation": { "items": [ { "type": "http://eprints.org/relation/hasVolatileVersion", "uri": "/id/document/20823" }, { "type": "http://eprints.org/relation/haspreviewThumbnailVersion", "uri": "/id/document/20823" }, { "type": "http://eprints.org/relation/hasVersion", "uri": "/id/document/20823" } ] } }, { "id": "/id/document/16515", "doc_id": 16515, "rev_number": 3, "files": [ { "id": "/id/file/203003", "fileid": 203003, "datasetid": "document", "objectid": 16515, "filename": "Soloveichik_David_2008.PDF", "mime_type": "application/pdf", "filesize": 40947, "mtime": "2016-08-22 21:15:49", "url": "/2261/2/Soloveichik_David_2008.PDF" } ], "eprint_id": 2261, "pos": 2, "format": "application/pdf", "language": "en", "security": "internal", "license": "other", "main": "Soloveichik_David_2008.PDF", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "approvalform" }, { "id": "/id/document/20823", "doc_id": 20823, "rev_number": 2, "files": [ { "id": "/id/file/24459", "fileid": 24459, "datasetid": "document", "objectid": 20823, "filename": "preview.png", "mime_type": "image/png", "hash": "a0f58250579a4198c6ed40b9a71f4902", "hash_type": "MD5", "filesize": 12116, "mtime": "2012-12-26 02:49:10", "url": "/2261/3/preview.png" } ], "eprint_id": 2261, "pos": 3, "placement": 3, "mime_type": "image/png", "format": "image/png", "language": "en", "security": "public", "license": "other", "main": "preview.png", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/4228" }, { "type": "http://eprints.org/relation/ispreviewThumbnailVersionOf", "uri": "/id/document/4228" }, { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/4228" } ] } }, { "id": "/id/document/122494", "doc_id": 122494, "rev_number": 1, "files": [ { "id": "/id/file/367892", "fileid": 367892, "datasetid": "document", "objectid": 122494, "filename": "indexcodes.txt", "mime_type": "text/x-c", "hash": "6c02817e29b60c57b52191b7b7507e69", "hash_type": "MD5", "filesize": 35351, "mtime": "2021-06-23 21:58:42", "url": "/2261/4/indexcodes.txt" } ], "eprint_id": 2261, "pos": 4, "placement": 4, "mime_type": "text/x-c", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/4228" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/4228" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/4228" } ] } } ], "eprint_status": "archive", "userid": 2, "dir": "disk0/00/00/22/61", "datestamp": "2008-06-02", "lastmod": "2020-01-31 23:02:45", "status_changed": "2009-09-25 02:32:28", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "david.soloveichik@utexas.edu", "id": "Soloveichik-David", "name": { "family": "Soloveichik", "given": "David" }, "orcid": "0000-0002-2585-4120", "show_email": "NO" } ] }, "title": "Molecules Computing: Self-Assembled Nanostructures, Molecular Automata,and Chemical Reaction Networks", "ispublished": "unpub", "full_text_status": "public", "keywords": "benenson automata; chemical kinetics; complexity of shapes; DNA nanotechnology; self-assembly; stochastic kinetics; tile-assembly", "abstract": "Many endeavors of molecular-level engineering either rely on biological material such as nucleic acids and restriction enzymes, or are inspired by biological processes such as self-assembly or cellular regulatory networks. This thesis develops theories on three such topics: self-assembled nanostructures, molecular automata, and chemical reaction networks. The abstractions and underlying methods of the theories presented herein are based on computer science and include Turing machines and circuits. Toward engineering self-assembled nanostructures, we create a theory of scale-free shapes in which the complexity of their self-assembly is connected to the shapes' descriptional complexity. Further, we study patterns in terms of whether they can be self-assembled robustly without an increase in scale to accommodate redundancy. We also describe a new method of ensuring resilience to more types of error simultaneously. Toward creating molecular automata we study the computational power of a restriction enzyme-based automaton. Toward designing chemical reaction networks, we develop a technique of storing and processing information in molecular counts, which is capable of achieving Turing universal computation. We also study the computational complexity of simulating stochastic chemical reaction networks and formally connect robustness and simulation efficiency. Lastly, we describe nucleic acid implementations of Boolean logic circuits and arbitrary mass-action kinetics. The three areas of this thesis are promising realizations of molecular-level engineering, and the theories presented here inform the range of possibility or delineate inherent difficulties in these areas. ", "date": "2008", "date_type": "degree", "id_number": "CaltechETD:etd-05292008-142339", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechETD:etd-05292008-142339", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "deposited_by": "Imported from ETD-db", "deposited_on": "2008-06-02", "doi": "10.7907/ZGE0-AF38", "divisions": { "items": [ "div_eng" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "yaser@caltech.edu", "id": "Abu-Mostafa-Y-S", "name": { "family": "Abu-Mostafa", "given": "Yaser S." }, "role": "chair" }, { "email": "umans@cs.caltech.edu", "id": "Umans-C-M", "name": { "family": "Umans", "given": "Christopher M." }, "role": "member" }, { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "member" }, { "email": "bruck@paradise.caltech.edu", "id": "Bruck-J", "name": { "family": "Bruck", "given": "Jehoshua" }, "role": "member" }, { "email": "doyle@cds.caltech.edu", "id": "Doyle-J-C", "name": { "family": "Doyle", "given": "John Comstock" }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_submitted_date": "2008-05-29", "thesis_defense_date": "2008-05-05", "thesis_approved_date": "2008-06-02", "gradofc_approval_date": "2008-05-30", "thesis_awards": "Milton and Francis Clauser Doctoral Prize, 2008", "review_status": "approved", "option_major": { "items": [ "cns" ] }, "copyright_statement": "I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive\nlicense to archive and make accessible, under the conditions specified below,\nmy thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2008", "author_list": "Soloveichik, David", "advisor_list": "Winfree, Erik", "comittee_list": "Abu-Mostafa, Yaser S.; Umans, Christopher M.; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/1554", "eprint_id": 1554, "rev_number": 11, "documents": [ { "id": "/id/document/2405", "doc_id": 2405, "rev_number": 3, "files": [ { "id": "/id/file/14884", "fileid": 14884, "datasetid": "document", "objectid": 2405, "filename": "thesis.pdf", "mime_type": "application/pdf", "filesize": 3123632, "mtime": "2012-12-26 02:39:11", "url": "/1554/1/thesis.pdf" } ], "eprint_id": 1554, "pos": 1, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": "other", "main": "thesis.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "final", "relation": { "items": [ { "type": "http://eprints.org/relation/hasVolatileVersion", "uri": "/id/document/19145" }, { "type": "http://eprints.org/relation/haspreviewThumbnailVersion", "uri": "/id/document/19145" }, { "type": "http://eprints.org/relation/hasVersion", "uri": "/id/document/19145" } ] } }, { "id": "/id/document/16465", "doc_id": 16465, "rev_number": 3, "files": [ { "id": "/id/file/201462", "fileid": 201462, "datasetid": "document", "objectid": 16465, "filename": "Schulman_Rebecca_2007.PDF", "mime_type": "application/pdf", "filesize": 41333, "mtime": "2016-08-22 21:14:57", "url": "/1554/2/Schulman_Rebecca_2007.PDF" } ], "eprint_id": 1554, "pos": 2, "format": "application/pdf", "language": "en", "security": "internal", "license": "other", "main": "Schulman_Rebecca_2007.PDF", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "content": "approvalform" }, { "id": "/id/document/19145", "doc_id": 19145, "rev_number": 2, "files": [ { "id": "/id/file/14882", "fileid": 14882, "datasetid": "document", "objectid": 19145, "filename": "preview.png", "mime_type": "image/png", "hash": "e01ed4df4da5a0f706e8577bf109a683", "hash_type": "MD5", "filesize": 14264, "mtime": "2012-12-26 02:39:11", "url": "/1554/3/preview.png" } ], "eprint_id": 1554, "pos": 3, "placement": 3, "mime_type": "image/png", "format": "image/png", "language": "en", "security": "public", "license": "other", "main": "preview.png", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/2405" }, { "type": "http://eprints.org/relation/ispreviewThumbnailVersionOf", "uri": "/id/document/2405" }, { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/2405" } ] } }, { "id": "/id/document/120896", "doc_id": 120896, "rev_number": 1, "files": [ { "id": "/id/file/366284", "fileid": 366284, "datasetid": "document", "objectid": 120896, "filename": "indexcodes.txt", "mime_type": "text/plain", "hash": "7474538624ab8ef96ba6515b74c1512f", "hash_type": "MD5", "filesize": 35518, "mtime": "2021-06-23 21:09:07", "url": "/1554/4/indexcodes.txt" } ], "eprint_id": 1554, "pos": 4, "placement": 4, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from application/pdf to indexcodes", "language": "en", "security": "public", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/2405" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/2405" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/2405" } ] } } ], "eprint_status": "archive", "userid": 2, "dir": "disk0/00/00/15/54", "datestamp": "2007-05-30", "lastmod": "2020-03-24 20:29:11", "status_changed": "2009-09-25 02:07:37", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "rebecca.b.schulman@gmail.com", "id": "Schulman-Rebecca-Beth", "name": { "family": "Schulman", "given": "Rebecca Beth" }, "orcid": "0000-0003-4555-3162", "show_email": "NO" } ] }, "title": "The Self-Replication and Evolution of DNA Crystals", "ispublished": "unpub", "full_text_status": "public", "keywords": "Cellular automata; chemical computation; DNA nanotechnology; evolution; origin of life; self-assembly; self-replication", "abstract": "How life began is still a mystery. While various theories suggest that life began in deep sea volcanic vents or that a world where life consisted predominantly of RNA molecules preceded us, there is no hard evidence to give shape to the chain of events that led to cellular life.
\r\n\r\nPerhaps the fundamental enigma of our origins is how life began to self-replicate in such a way that evolution could produce Earth's \"endless forms most beautiful.\" With the exception of biological organisms, we have no examples of self-replicating, evolving chemical systems, despite an extensive research program with the goal of identifying them.
\r\n\r\nIn this thesis, I construct a chemical system that is capable of the most basic self-replication and evolution. The system uses no enzymes or biological sequences, can support and replicate a combinatorial genome, and is completely autonomous. There are no fundamental obstacles to the replication by this system of much more complex sequences or to open-ended evolution.
\r\n\r\nThe design of the system is inspired by the work of Graham Cairns-Smith, who has proposed that life began with clay. Clays are tiny layered crystals; some clay crystals can contain one of several different patterns of atoms or molecules in each layer. The choice of patterns for the layers could be viewed as a sort of genome: it would be copied as the clay grew, and if the crystal broke, each new piece would inherit its pattern from the old piece and could replicate it in the same manner. If some patterns of layers could grow and reproduce faster than other patterns, crystals with faster-growing patterns would be selected for.
\r\n\r\nInstead of the atoms or small molecules of which clay consists, I use molecules consisting of 4-6 interwoven, synthetic DNA strands called DNA tiles to construct crystals that replicate and evolve as Cairns-Smith imagined. While the choice of construction material was influenced by ease of use -- in contrast to clay crystals, DNA tile crystals have been previously characterized and are easy to crystallize and image in the laboratory -- the choice was fundamentally made because DNA tile monomers are programmable, allowing us to create novel crystal morphologies rationally.
\r\n\r\nThe crystals I construct, termed \"zig-zag ribbons\", contain a sequence of information (\"a genome\") in each row. Growth of the ribbon adds rows, one at time, each of which contain an arrangement of DNA tiles that encode the same information sequence as the previous row. Altering the set of \"tiles\" used to assemble ribbons allows us to alter the alphabets for and the permitted lengths of sequences that can be copied.
\r\n\r\nI describe how to design tile sets that can replicate genomes with different alphabets and the kind of sequence evolution that is in theory possible with some simple tile sets. Altering the tile set can not only change the kinds of sequences that may be replicated, it can also make growth and splitting more robust. I show how to make changes to the crystals' design to prevent errors during growth and splitting and to reduce the rate of spontaneous generation of new crystals.
\r\n\r\nIt has been previously shown that DNA tile crystallization can be used to perform universal computation; I show that in theory crystals that can compute can undergo open-ended evolution as they try to produce more and more complex programs to take advantage of available growth resources. This mechanism is simple enough to potentially observe in the laboratory in the near future. In experiments, I demonstrate a much more basic kind of replication and evolution, in which zig-zag ribbons maintain a preference for a certain width into a second generation.
\r\n\r\nThis work suggests that the concept of a self-replicating chemistry is closely related to the concept of a chemistry that can store information and compute. It is only by clearly understanding how chemistry can perform these latter tasks that we can hope to understand how self-replication and evolution can occur, and by implication, understand how life might have begun.
", "date": "2007", "date_type": "degree", "id_number": "CaltechETD:etd-04302007-164103", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechETD:etd-04302007-164103", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Melissa Ray", "suggestions": "rschulman@berkeley.edu", "deposited_by": "Imported from ETD-db", "deposited_on": "2007-05-30", "doi": "10.7907/3F8C-9D50", "divisions": { "items": [ "div_eng" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "winfree@dna.caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "yaser@caltech.edu", "id": "Abu-Mostafa-Y-S", "name": { "family": "Abu-Mostafa", "given": "Yaser S." }, "role": "chair" }, { "email": "yurke2@aol.com", "id": "Yurke-B", "name": { "family": "Yurke", "given": "Bernard" }, "role": "member" }, { "email": "winfree@dna.caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "member" }, { "email": "gjoyce@scripps.edu", "id": "Joyce-G", "name": { "family": "Joyce", "given": "Gerald" }, "role": "member" }, { "email": "bruck@vangogh.paradise.caltech.edu", "id": "Bruck-J", "name": { "family": "Bruck", "given": "Jehoshua" }, "role": "member" }, { "email": "zgw@cheme.caltech.edu", "id": "Wang-Zhen-Gang", "name": { "family": "Wang", "given": "Zhen-Gang" }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_submitted_date": "2007-04-30", "thesis_defense_date": "2007-05-11", "thesis_approved_date": "2007-05-30", "gradofc_approval_date": "2007-05-30", "review_status": "approved", "option_major": { "items": [ "cns" ] }, "copyright_statement": "I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive\nlicense to archive and make accessible, under the conditions specified below,\nmy thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2007", "author_list": "Schulman, Rebecca Beth", "advisor_list": "Winfree, Erik", "comittee_list": "Abu-Mostafa, Yaser S.; Yurke, Bernard; et el." }, { "id": "https://thesis.library.caltech.edu/id/eprint/5044", "eprint_id": 5044, "rev_number": 12, "documents": [ { "id": "/id/document/8001", "doc_id": 8001, "rev_number": 4, "files": [ { "id": "/id/file/49232", "fileid": 49232, "datasetid": "document", "objectid": 8001, "filename": "thesis.pdf", "mime_type": "application/pdf", "filesize": 18696961, "mtime": "2012-12-26 03:14:14", "url": "/5044/1/thesis.pdf" } ], "eprint_id": 5044, "pos": 1, "mime_type": "application/pdf", "format": "application/pdf", "language": "en", "security": "public", "license": "other", "main": "thesis.pdf", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", 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"pos": 6, "placement": 6, "mime_type": "text/plain", "format": "other", "format_desc": "Generate index codes conversion from text/plain to indexcodes", "language": "en", "security": "internal", "license": "other", "main": "indexcodes.txt", "media_duration": "0", "media_aspect_ratio": "0", "media_sample_start": "0", "media_sample_stop": "0", "relation": { "items": [ { "type": "http://eprints.org/relation/isVersionOf", "uri": "/id/document/10532" }, { "type": "http://eprints.org/relation/isVolatileVersionOf", "uri": "/id/document/10532" }, { "type": "http://eprints.org/relation/isIndexCodesVersionOf", "uri": "/id/document/10532" } ] } } ], "eprint_status": "archive", "userid": 2, "dir": "disk0/00/00/50/44", "datestamp": "2007-01-11", "lastmod": "2020-02-25 21:42:26", "status_changed": "2009-09-25 03:31:35", "type": "thesis", "metadata_visibility": "show", "creators": { "items": [ { "email": "jongmin.kim@postech.ac.kr", "id": "Kim-Jongmin", "name": { "family": "Kim", "given": "Jongmin" }, "orcid": "0000-0002-2713-1006", "show_email": "YES" } ] }, "title": "In Vitro Synthetic Transcriptional Networks", "ispublished": "unpub", "full_text_status": "public", "keywords": "neural network; oscillators; synthetic biology; transcriptional network", "abstract": "Information processing using biochemical circuits is essential for survival and reproduction of natural organisms. Construction of synthetic biochemical circuits from simple components provides a useful approach to establish the minimal determinants required for complex logical functions. As stripped-down analogues of genetic regulatory networks in cells, we engineered artificial transcriptional networks consisting of synthetic DNA switches, regulated by RNA signals acting as transcription activators or repressors, and two enzymes, bacteriophage T7 RNA polymerase and Escherichia coli ribonuclease H. The synthetic switch design is modular with programmable connectivity and allows dynamic control of RNA signals through enzyme-mediated production and degradation. The switches support sharp and adjustable thresholds using a competitive hybridization mechanism, analogous to a biological threshold mechanism, \"inhibitor ultrasensitivity,\" thus allowing arbitrary analog or digital circuits to be created in principle. Theoretical correspondence of our biochemical network to neural networks where synaptic weights and thresholds are encoded by concentrations of DNA strands greatly facilitates network design and analysis. Experimentally, we have constructed and analyzed several simple networks: positive and negative autoregulatory circuits, a mutual inhibitory circuit, and oscillators with positive and negative feedback. Reasonable agreement between experimental data and a simple mathematical model was obtained for switch input/output functions, phaseplane trajectories, the bifurcation diagram, and oscillation periods. A systematic quantitative characterization lead to identification of important network properties such as the saturation of degradation machinery and challenges to understand such as the interference by incomplete RNA signals. Construction of larger synthetic circuits provides a unique opportunity for evaluating model inference, prediction, and design of complex biochemical systems and could be used to ontrol nanoscale devices and artificial cells.", "date": "2007", "date_type": "degree", "id_number": "CaltechETD:etd-12182006-115817", "refereed": "FALSE", "official_url": "https://resolver.caltech.edu/CaltechETD:etd-12182006-115817", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechTHESIS", "reviewer": "Kathy Johnson", "deposited_by": "Imported from ETD-db", "deposited_on": "2007-01-11", "doi": "10.7907/Q9YA-N192", "divisions": { "items": [ "div_biol" ] }, "institution": "California Institute of Technology", "thesis_type": "phd", "thesis_advisor": { "items": [ { "email": "winfree@caltech.edu", "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "advisor" } ] }, "thesis_committee": { "items": [ { "email": "pws@caltech.edu", "id": "Sternberg-P-W", "name": { "family": "Sternberg", "given": "Paul W." }, "role": "chair" }, { "email": "woldb@caltech.edu", "id": "Wold-B-J", "name": { "family": "Wold", "given": "Barbara J." }, "role": "member" }, { "email": "melowitz@caltech.edu", "id": "Elowitz-M-B", "name": { "family": "Elowitz", "given": "Michael B." }, "role": "member" }, { "id": "Winfree-E", "name": { "family": "Winfree", "given": "Erik" }, "role": "member" } ] }, "thesis_degree": "PHD", "thesis_degree_grantor": "California Institute of Technology", "thesis_submitted_date": "2006-12-18", "thesis_defense_date": "2006-12-06", "thesis_approved_date": "2007-01-11", "review_status": "approved", "option_major": { "items": [ "biology" ] }, "copyright_statement": "I hereby certify that, if appropriate, I have obtained a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee.\n\nI hereby grant to California Institute of Technology or its agents the non-exclusive\nlicense to archive and make accessible, under the conditions specified below,\nmy thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.", "resource_type": "thesis", "pub_year": "2007", "author_list": "Kim, Jongmin", "advisor_list": "Winfree, Erik", "comittee_list": "Sternberg, Paul W.; Wold, Barbara J.; et el." } ]