Scientists at the Department of Biosystems Science and Engineering (D-BSSE) are the first to have succeeded in artificially creating mechanisms analogous to the human body clock in mammalian cell cultures – a first step towards therapeutic use.
The process commonly referred to as the "body clock" and known to science as the "circadian rhythm" is a self-regulating mechanism and a kind of biological timekeeper in the human body. It follows a daily period of about 24 hours and forms the time base for biological and physiological processes in the majority of organisms. For example, circadian rhythm controls the formation of proteins vital to life. Thus to a certain extent, circadian rhythm also governs human behaviour., Until recently, however, exactly exactly how that was done was poorly understood.
ETH Zurich researchers have now succeeded in synthetically producing this kind of self-regulating cycle in cultured mammalian cells. It is the first time ever that this cycle has been synthetically produced. The most recent research results from the teamled by Martin Fussenegger and Jörg Stelling, Professors at the Department of Biosystems Science and Engineering (D-BSSE), were recently published in the scientific journal Nature.
Artificial mammalian oscillator
The work from Fussenegger and Stelling paves the way for the identification of the processes behind the body clock. In turn, the resulting knowledge could in future enable complex gene therapy treatments in which a controllable synthetic mammalian oscillator could be used to molecularly "automate" physiological processes which occur several times a day. For example, the artificial body clock could be used for insulin secretion in the human body, thus replacing the administration of insulin by injection.
The researchers used mammalian cell cultures for their study. Fussenegger explains that "We combined modules of artificial gene control systems in these cell cultures as you would in an electronic circuit." The laboratory work was supported by computer modelling that provided the researchers with information on how the function of the oscillator can be adjusted with respect to the strength of formation of certain proteins and their formation frequency. In this manner, the first controllable mammalian oscillator to replicate the process of a body clock was created.
Teamwork by genes
It was possible to produce proteins rhythmically in mammalian cells based on a sense-antisense transcription loop in the cell culture. Three genes with different tasks were used for this: two that regulate one another and one gene that renders the dynamic processes visible via a fluorescent product. If the genes are read in the direction in which we normally read, i.e. from left to right ("sense transcription"), a particular protein element is read and produced. On the other hand, this protein production is suppressed if read in the opposite ("anti-sense") direction.
The two mutually regulating genes interact with a time difference and thus form the time base for the oscillations. They switch the sense-antisense transcription on and off periodically. Stelling explains that, "Starting from this basic principle, the modelling also allowed us to design the oscillator in such detail that it functions reliably – even its frequency and amplitude are adjustable."
Fussenegger thinks that synthetic biology ultimately will enable specific further development of the oscillator that will allow it to be put to therapeutic use. However, he says that this is still a long way off.
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