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Projects / Programmes source: ARIS

Designed cellular logic circuits

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Research activity

Code Science Field Subfield
1.05.00  Natural sciences and mathematics  Biochemistry and molecular biology   

Code Science Field
B001  Biomedical sciences  General biomedical sciences 

Code Science Field
1.06  Natural Sciences  Biological sciences 
Keywords
cell logic, synthetic biology, mammalian cells, gene switch oscillator, light sensors, TALE repressors, CRSIPR/Cas
Evaluation (rules)
source: COBISS
Evaluation of bibliographic research performance indicators according to ARIS methodology
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Researchers (12)
no. Code Name and surname Research area Role Period No. of publications
1.  14360  PhD Mojca Benčina  Biotechnology  Researcher  2014 - 2017  392 
2.  32254  PhD Rok Gaber  Biotechnology  Researcher  2014 - 2015  52 
3.  06628  PhD Roman Jerala  Biochemistry and molecular biology  Head  2014 - 2017  1,189 
4.  34252  Tina Lebar  Biochemistry and molecular biology  Technical associate  2014 - 2017  67 
5.  32984  PhD Jan Lonzarić  Biochemistry and molecular biology  Researcher  2014 - 2017  46 
6.  17917  PhD Andreja Majerle  Biotechnology  Researcher  2014 - 2017  92 
7.  29198  PhD Miha Moškon  Computer science and informatics  Researcher  2014 - 2017  258 
8.  13442  PhD Miha Mraz  Computer science and informatics  Researcher  2014 - 2017  366 
9.  37589  PhD Tina Tinkara Peternelj  Microbiology and immunology  Researcher  2016  39 
10.  38021  Bojana Stevović    Technical associate  2016 - 2017  12 
11.  39364  Anže Verbič  Biochemistry and molecular biology  Technical associate  2016 - 2017  9 
12.  05957  PhD Nikolaj Zimic  Computer science and informatics  Researcher  2014 - 2017  326 
Organisations (3)
no. Code Research organisation City Registration number No. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  20,942 
2.  1539  University of Ljubljana, Faculty of Computer and Information Science  Ljubljana  1627023  16,235 
3.  2992  EN-FIST CENTRE OF EXCELLENCE  Ljubljana  3664830  2,835 
Abstract
Cells are able to process different combinations of signals from the environment or signals originating from the normal or pathological internal processes, resulting in the response that allows the organisms to function and adapt to the changes in the environment. Understanding of those processes is one of the central challenges of molecular biology. Introduction of the designed information processing circuits into cells could be used for cell reprograming, cellular therapy, construction of sensors and as a powerful research tool. Designed gene regulatory circuits prepared by synthetic biologists have already demonstrated the ability to perform discrete Boolean logic functions both in prokaryotic and eukaryotic cells[1]–[10]. Logical functions, such as e.g. AND, OR, have been implemented using different combinations of natural transcriptional regulators[6]. As the universal logic gates of the same type are essential to construct complex electronic computing devices, in analogy, the universal biologic gate should be reliable and easy to construct. Most biological devices designed up to now are based on a handful of characterized bacterial regulators, such as LacI or TetR, which differ in their oligomerization states, affinity and structural motifs of DNA recognition. This heterogeneity of readily available transcriptional regulators hinders standardization, construction of more complex circuits and their interoperability. Discovery of the code underlying modular recognition of DNA sequence by Transcription activator-like effectors (TALEs)[11], [12] and CRISPR/Cas technology[13] is poised to revolutionize molecular biology through their application in genome editing. However, targeting designed protein domains towards almost any selected DNA sequence also represents a great opportunity to design complex genetic regulatory circuits. They are required to ascertain high level of control over the cellular response and to introduce new complex features into biological systems. We recently successfully optimized genetic NOR gates and constructed the complete set of 16 two-input logic functions for mammalian cells based on TALE repressors (Gaber et al, Nature Chemical Biology 2014)[14]. The CRISPR/Cas platform allows an even simpler selection of target sequences through selection of small RNA molecules; however advanced logic circuits based on the CRISPR/Cas technology have not been reported so far. In this project we propose to implement modular DNA binding domains to design complex regulatory circuits into mammalian cells including static logic, bistable switches and cellular oscillators. We plant to demonstrate the advantage of designable DNA binding domains in comparison to natural regulators used up to now, which is the ability to design an almost unlimited number of combinations required for complex genetic logic regulatory devices. Project is organized into three work packages that will a) prepare, characterize and optimize building blocks for designed discrete cellular logic, b) design and experimentally test bistable switch circuits and c) design and implement oscillators that will be modular, scalable and controllable by chemical signals or light. We plan to use designable TALE and CRISPR/Cas DNA binding domains fused to transcriptional activation (VP16) or repression (KRAB) domains as orthogonal regulators that could be wired into the selected logic topology. A bistable switch is a key element in the regulation, as it allows setting the system into the selected state with a pulse of the input signal and maintains this state based on the epigenetic memory. An oscillator is another fundamental device of complex systems, which introduces a periodicity and allows clocking of different processes and different oscillators are present in most cells and organisms. Successful realization of those goals will represent an important breakthrough in the design of biological systems.
Significance for science
The results of the project represent significant advances in the development of synthetic biology as they allow the use of designed transcription regulators to design cellular processes. Unlike most of the conventionally used natural regulators from other organisms with their limitations, several hundred thousand artificial regulators can be formed with our principle, with which we can edit any gene. We wish to emphasize the newly invented feature of TALE displacement and of locked TALEs, which we have presented first in the world.
Significance for the country
Within the project, we introduced a new technology of designing transcription regulators and preparation of cellular circuits on their basis, which was not present in Slovenia before. These findings will be continually used in our group for the engineering of human cell lines and for the preparation of cell therapy. The same technology can also be used to control the functioning of plant cells or yeasts, which would also be useful for other researchers. The research is important for the recognition of Slovenian science in the world and was presented by the principle investigator at several invited lectures abroad as well as in popular lectures in Slovenia. Several researchers were trained during the project tenure. Dr. Tina Lebar received several awards e.g. For Women in Science, Pregl award and IJS Gold Sign.
Most important scientific results Annual report 2014, 2015, final report
Most important socioeconomically and culturally relevant results Annual report 2014, 2015, final report
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