Team:UPF Barcelona/Design


This section describes the design of the three main components conforming Hormonic, together with a description of our proof of concept for our system validation.

Hormonic design

The heart of Hormonic lies in the ability to quantify the levels of T3 hormone in vivo. That's why our amazing team, conformed by multidisciplinary scientists, successfully came up with an innovative and completely new way to carry out these measurements: an intein mediated T3 biosensor engineered using synthetic biology. But Hormonic goes beyond that, it is designed to restablish the hormonal feedback system thanks to an external software coupled to our modified bacteria to achieve a groundbreaking therapy approach for hormonal disbalances.

Figure 1. Scheme of the different components of Hormonic: the biosensor, the PID controller and the device.

The following block explains the three main components of Hormonic:

T3 biosensor
PID control software

How can we measure the amount of T3 hormone in the patient?

Bearing in mind that the design of a robust T3 hormone biosensor is a key component of Hormonic, the first thing we need is a biological agent capable of translating the biological information into measurable values, that will be interpreted by the external controller previously explained.

For this we used E. coli bacteria, and to be able to sense T3 , we decided to engineer a protein called intein. Inteins are a naturally occurring type of protein-segment that, at a post-translational level, are able to remove themselves from the peptide-chain, joining the two remaining portions at both sides.

Figure 2. Scheme of the interactions of our Intein Mediated T3 (IMT3) sensing protein, before (left) and after splicing (right).

Since the main characteristic of inteins is their ability to reconstruct virtually any split protein, we thought that, if split correctly, we could use a Fluorescent Protein. So, what we did was to split different GFPs, and couple them to the intein.

Using light as a reporter we can quantitatively and continuously know the amount of hormone. This way, when T3 is present in the media, fluorescent proteins are formed and the light signal can be detected by our computational unit.

Lactone Proof of concept

How can we prove that Hormonic would correctly restablish the feedback loop?

Knowing the 3 components that create Hormonic, it is necessary to know if the whole regulation mechanism works. The endocrine system is very complex: the triple feedback that rules the hypothalamic-pituitary-thyroid axis makes the thyroid hormonal levels not constant, thus possibly producing unknown temporal cycles. The fact that we could not know the effect of levothyroxine in our system (the release drug would not be metabolized into T3 hormone, because we are not working with human cells) and the uncertainties related to thyroid behaviour made it impossible to close the loop.

Consequently, we had to design a closed mockup system to test the ability of our PID to maintain the stability of the feedback. A minimal hormonal regulation model was created with lactone as the target hormone of the system. Different cellular types have been used to create a whole genetic circuit with Lactone Producer Cells (acting as the Thyroid gland), Lactone Sensing Cells (acting as our Biosensor) and two different effector molecules, that will act upon the Lactone Production to increase or decrease it. In this way, we are able to test and prove the ability of our PID to regulate hormonal levels, while guaranteeing the health and security of the patients.

But the most interesting thing of being a general circuit is the fact that if Hormonic can regulate an hormone cycle, it can be extrapolated and used to regulate any other hormonal feedback.