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. 2020 Sep 21;11:4758. doi: 10.1038/s41467-020-18455-z

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a Lineage tree representing a history-dependent program. Letters represent the presence of the two inputs (a and b) and numbers on nodes represent states of the system associated with the order of occurrence of the inputs. For two inputs programs, five states are possible. b Integrase-mediated excision or inversion. When integrase sites are in the opposite orientation (left panel), the DNA sequence flanked by the sites is inverted. If integrase sites are in the same orientation (right panel), the DNA sequence flanked by the sites is excised. c 2-input history-dependent scaffold. Integrase sites are positioned to trigger expression of an output gene (arrows) or not (empty gray squares) in the corresponding lineage. Programs are implemented by inserting genes corresponding to the ON states in adequate scaffold positions. d DNA transitions, recombination intermediates, and gene-expression states for the 2-input scaffold. The corresponding lineage tree is represented in the upper left. e Single-cell programs operate in a single lineage and can control expression of single or multiple outputs. Multicell programs operate in multiple lineages and can control the expression of a single or multiple outputs. f Automated design of history-dependent programs. The CALIN algorithm takes as input a history-dependent program written as a lineage tree. CALIN decomposes multilineage programs into subprograms, each corresponding to a different lineage (a then b; b then a). For each subprogram, the algorithm identifies the ON states and the order of inputs within the lineage. Based on this information, the biological design is computed, and the software provides input/integrases connections, the architecture of history-dependent scaffolds and their corresponding DNA sequences. Each subprogram is executed in a different strain as a DNA device (f₁, f₂). The full program is implemented by composing the different strains into multicellular systems.