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dc.contributor.author
Stefanov, Bozhidar-Adrian
dc.contributor.supervisor
Fussenegger, Martin
dc.contributor.supervisor
Martin, Ivan
dc.date.accessioned
2022-09-14T10:20:59Z
dc.date.available
2022-09-14T09:34:24Z
dc.date.available
2022-09-14T10:20:59Z
dc.date.issued
2022
dc.identifier.uri
http://hdl.handle.net/20.500.11850/570592
dc.identifier.doi
10.3929/ethz-b-000570592
dc.description.abstract
Personalized medicine is the science for developing remedies tailored to the individual necessities of each and every patient. The regulatory approval of the first engineered mammalian cell therapies enhanced the anticipation that these are to become the next pillar of medical care for complex and chronic disease. Although such cells are biological entities, they are modified using engineering principles in what is now established as the field of synthetic biology, and could thus be better described as biocomputing units. The foundations of these systems lie in the integrated therapeutic circuitry, which may provide an open or closed-loop control over the beneficial cellular functions. Open-loops would allow for more flexibility as the input strength and processes can be varied, while closed-loops are rigid and closely emulate the natural physiology. A common feature of every cellular circuit are the input converters, which may also be transcription factors activated by specialized cues. In this work we engineered the first mammalian transcription factor directly sensing temperatures in the physiological range from 38 to 40 °C. This enabled its use as a fever sensor in pyrexia animal models as well as for precise thermoelectrical control over therapeutic implants of engineered cells for controlling glycemia in a type-1-diabetes model. Capitalizing on this work, we envisioned natural energy sources such as sunlight as facilitators for temperature-based cellular control. In particular, we engineered endocrine cells to accumulate diverse therapeutic proteins in their storage granules and release them within minutes upon thermal stimulation in physiological saline. This generated injection ready solutions in an emergency biopharmaceutical process for production of therapeutics in remote areas. Finally, we engineered a closed-loop circuit capable of sensing cardiac troponin I, a protein considered as a gold standard biomarker for myocardial infarction, and responding to it with the secretion of a half-life optimized cardioprotective peptide.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
ETH Zurich
en_US
dc.rights.uri
http://rightsstatements.org/page/InC-NC/1.0/
dc.subject
medicine
en_US
dc.subject
synthetic biology
en_US
dc.subject
Diabetes type 1
en_US
dc.subject
Insulin
en_US
dc.subject
erythropoietin
en_US
dc.subject
biopharmaceutical production
en_US
dc.subject
BIOPROCESS ENGINEERING (BIOTECHNOLOGY)
en_US
dc.subject
Sunlight
en_US
dc.subject
myocardial infarction
en_US
dc.subject
thermometry
en_US
dc.subject
Gene switch
en_US
dc.subject
Synthetic receptors
en_US
dc.subject
Transcription factors
en_US
dc.subject
Thermal treatment
en_US
dc.subject
Closed-loop control
en_US
dc.subject
personalized medicine
en_US
dc.title
Synthetic biology circuits: temperature and myocardial infarction sensors for precision therapeutics
en_US
dc.type
Doctoral Thesis
dc.rights.license
In Copyright - Non-Commercial Use Permitted
dc.date.published
2022-09-14
ethz.size
201 p.
en_US
ethz.code.ddc
DDC - DDC::5 - Science::570 - Life sciences
en_US
ethz.identifier.diss
28588
en_US
ethz.publication.place
Zurich
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.::03694 - Fussenegger, Martin / Fussenegger, Martin
en_US
ethz.relation.cites
10.3929/ethz-b-000505804
ethz.date.deposited
2022-09-14T09:34:39Z
ethz.source
FORM
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2022-09-14T10:21:31Z
ethz.rosetta.lastUpdated
2022-09-14T10:21:31Z
ethz.rosetta.exportRequired
true
ethz.rosetta.versionExported
true
ethz.COinS
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