Realizing ‘integral control’ in living cells: how to overcome leaky integration due to dilution?
A major problem in the design of synthetic genetic circuits is robustness to perturbations and uncertainty. Because of this, there have been significant efforts in recent years in finding approaches to implement integral control in genetic circuits. Integral controllers have the unique ability to ma...
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| Format: | Article |
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Royal Society Publishing
2018
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| Online Access: | http://hdl.handle.net/1721.1/119170 https://orcid.org/0000-0002-1097-0401 https://orcid.org/0000-0001-6472-8576 |
| _version_ | 1826213842255872000 |
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| author | Qian, Yili Del Vecchio, Domitilla |
| author2 | Massachusetts Institute of Technology. Department of Mechanical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Mechanical Engineering Qian, Yili Del Vecchio, Domitilla |
| author_sort | Qian, Yili |
| collection | MIT |
| description | A major problem in the design of synthetic genetic circuits is robustness to perturbations and uncertainty. Because of this, there have been significant efforts in recent years in finding approaches to implement integral control in genetic circuits. Integral controllers have the unique ability to make the output of a process adapt perfectly to disturbances. However, implementing an integral controller is challenging in living cells. This is because a key aspect of any integral controller is a ‘memory’ element that stores the accumulation (integral) of the error between the output and its desired set-point. The ability to realize such a memory element in living cells is fundamentally challenged by the fact that all biomolecules dilute as cells grow, resulting in a ‘leaky’ memory that gradually fades away. As a consequence, the adaptation property is lost. Here, we propose a general principle for designing integral controllers such that the performance is practically unaffected by dilution. In particular, we mathematically prove that if the reactions implementing the integral controller are all much faster than dilution, then the adaptation error due to integration leakiness becomes negligible. We exemplify this design principle with two synthetic genetic circuits aimed at reaching adaptation of gene expression to fluctuations in cellular resources. Our results provide concrete guidance on the biomolecular processes that are most appropriate for implementing integral controllers in living cells. |
| first_indexed | 2024-09-23T15:55:42Z |
| format | Article |
| id | mit-1721.1/119170 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T15:55:42Z |
| publishDate | 2018 |
| publisher | Royal Society Publishing |
| record_format | dspace |
| spelling | mit-1721.1/1191702022-09-29T17:07:16Z Realizing ‘integral control’ in living cells: how to overcome leaky integration due to dilution? Qian, Yili Del Vecchio, Domitilla Massachusetts Institute of Technology. Department of Mechanical Engineering Massachusetts Institute of Technology. Synthetic Biology Center Qian, Yili Del Vecchio, Domitilla A major problem in the design of synthetic genetic circuits is robustness to perturbations and uncertainty. Because of this, there have been significant efforts in recent years in finding approaches to implement integral control in genetic circuits. Integral controllers have the unique ability to make the output of a process adapt perfectly to disturbances. However, implementing an integral controller is challenging in living cells. This is because a key aspect of any integral controller is a ‘memory’ element that stores the accumulation (integral) of the error between the output and its desired set-point. The ability to realize such a memory element in living cells is fundamentally challenged by the fact that all biomolecules dilute as cells grow, resulting in a ‘leaky’ memory that gradually fades away. As a consequence, the adaptation property is lost. Here, we propose a general principle for designing integral controllers such that the performance is practically unaffected by dilution. In particular, we mathematically prove that if the reactions implementing the integral controller are all much faster than dilution, then the adaptation error due to integration leakiness becomes negligible. We exemplify this design principle with two synthetic genetic circuits aimed at reaching adaptation of gene expression to fluctuations in cellular resources. Our results provide concrete guidance on the biomolecular processes that are most appropriate for implementing integral controllers in living cells. United States. Air Force. Office of Scientific Research (grant no. FA9550-14- 1-0060) 2018-11-16T23:13:23Z 2018-11-16T23:13:23Z 2018-02 2017-12 2018-11-09T18:59:26Z Article http://purl.org/eprint/type/JournalArticle 1742-5689 1742-5662 http://hdl.handle.net/1721.1/119170 Qian, Yili, and Domitilla Del Vecchio. “Realizing ‘integral Control’ in Living Cells: How to Overcome Leaky Integration Due to Dilution?” Journal of The Royal Society Interface 15, no. 139 (February 2018): 20170902. https://orcid.org/0000-0002-1097-0401 https://orcid.org/0000-0001-6472-8576 http://dx.doi.org/10.1098/RSIF.2017.0902 Journal of The Royal Society Interface Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Royal Society Publishing MIT Web Domain |
| spellingShingle | Qian, Yili Del Vecchio, Domitilla Realizing ‘integral control’ in living cells: how to overcome leaky integration due to dilution? |
| title | Realizing ‘integral control’ in living cells: how to overcome leaky integration due to dilution? |
| title_full | Realizing ‘integral control’ in living cells: how to overcome leaky integration due to dilution? |
| title_fullStr | Realizing ‘integral control’ in living cells: how to overcome leaky integration due to dilution? |
| title_full_unstemmed | Realizing ‘integral control’ in living cells: how to overcome leaky integration due to dilution? |
| title_short | Realizing ‘integral control’ in living cells: how to overcome leaky integration due to dilution? |
| title_sort | realizing integral control in living cells how to overcome leaky integration due to dilution |
| url | http://hdl.handle.net/1721.1/119170 https://orcid.org/0000-0002-1097-0401 https://orcid.org/0000-0001-6472-8576 |
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