Team:UPF Barcelona/Description
ABSTRACT
One-third of the treated hypothyroidism patients do not respond correctly to current therapies. To solve that, a system capable of restoring hormonal feedback was designed, offering an alternative to the 10% of Spaniards and the 5% of the global population that suffer from this endocrine disorder. Its functioning is based on our successfully engineered intein-mediated Escherichia coli biosensor, which showed a great response to distinct T3 thyroid hormone levels giving rise to different superfolder GFP concentrations. This was designed to be coupled to a PID controller, which computes the dosage that compensates for hormonal disbalances. As a proof of concept for the validation of this regulatory mechanism, a lactone cell circuit incorporating a turbidostat was developed, showing a high correlation between the experimental and modelling results. Finally, a detailed future implementation plan was defined so that it included the necessary steps towards a feasible implementation of this innovative treatment.
DESCRIPTION
Background
Thyroid disease is a global health problem that can hugely affect well-being, since thyroid hormones are essential for growth and regulation of energy metabolism, among others [1]. Ninety-nine per cent of thyroid disorders are cases of hypothyroidism, a condition characterized by the lack of thyroid hormone. Hypothyroidism affects 1 out of 10 Spaniards, but it extends worldwide affecting 5% of the overall population and, what is more, its prevalence seems to be increasing during the last years [2][3].
To avoid fatal consequences such as cardiovascular disease and increased mortality that result from non-prompt treatment, diagnosis and therapeutics need to be started as soon as possible [4]. Currently, patients under hypothyroidism are prescribed levothyroxine (LT4) tablets, that is, fixed doses of synthetic T4 thyroid hormones that are metabolized into their active T3 form at the peripheral tissues. But the range of doses at which the drug is effective without adverse effects is quite narrow and one-third of the treated patients still exhibit symptoms [2][5]. Moreover, doses are initially adjusted by “trial-and-error” with several analyses and visits to the doctor and require an indefinite follow-up to readjust the doses over time [6].
Thyrotropic feedback control
Thyroid disease is hampered by abnormalities in the hypothalamic-pituitary-thyroid axis, leading to conditions such as hypothyroidism or hyperthyroidism. The hypothalamic-pituitary-thyroid axis is also known as thyroid homeostasis or thyrotropic feedback control, as thyroid hormone release is regulated by a negative feedback control (see Figure 1) [7].
Just in case you are not familiar with the feedback concept, here we describe an example to make it understandable. An air conditioner has a system which measures the actual temperature in a room, and it actuates in response to reach the desired temperature. As the input and output of this system are always the same, the temperature, we can say that this is a feedback system.
So now, it is easier to understand why thyroid hormone release is regulated by feedback control. The hypothalamus and the pituitary gland stimulate the thyroid gland to release thyroid hormones: triiodothyronine (T3) and thyroxine (T4). These hormones travel through the body and its level is sensed so that when their concentration is adequate, the hypothalamus and the pituitary gland stop stimulating its secretion. Having this regulation in which the control is kept by inhibiting the secretion of hormones when they are at an adequate level is what is called a negative feedback loop.
Triiodothyronine as a biomarker
Thyroid hormones are present in the human body in two different forms: T3 and T4. T3 is the active form of the hormone and the one involved in more processes, while T4 is much more present as the thyroid gland mainly secretes the hormone in this form. However, T4 has to pass a deionization process to become active in the T3 form at the peripheral tissues to participate in the great majority of biological processes [8]. Then, if one of the hormones wants to be sensed, T4 will be much easier to identify as it is present in a much higher concentration. However, since T3 tests are usually ordered to help monitor treatment of a person with a known thyroid disease [9] and, on top of that, they result decisive in those cases in which hyperthyroidism’s degree is determined when TSH is suppressed [10], we believe that T3 could be a much more accurate indicator on the activity exerted by thyroid hormones.
Approach
Based on successful past approaches to external hormone regulation as the insulin pump, Hormonic seeks to offer artificial thyroid homeostasis, sensing the systemic amount of thyroid hormone and regulating as the thyrotropic feedback control would do [11]. Gathering recent advances in synthetic biology, control systems and electronics, we attempt to offer a patient-specific solution to the determination of dosage administration of drugs.
Hormonic aims to quantify and release the needed amount of LT4 so that thyroid homeostasis of the patient is kept on a healthy level through time.
For that, our proposal is divided into three different stages:
Biosensor
An intein-engineered E. coli able to detect T3, the active form of the thyroid hormone and give a fluorescent response proportional to the detected T3.
Controller
An electronic circuit which incorporates an ARDUINOTM that has already implemented the response that has to be given to the sensed T3.
Release
A system able to close the loop and give LT4 (or not) responding to the answer given by the controller.
Inspiration
The problems caused by the initial undefinition of a clear dosage in current treatments for thyroid dysfunction seem to be a hot topic among affected people. Just by asking some familiars and acquaintances, we realized about the relevance of this issue, as they were not fully satisfied with the received treatment. Moreover, the tracking methodology employed has evidenced to not properly adapt to the requirements of the current COVID pandemic situation: given the non-risky character of the disorder, many patients have got their clinical appointments cancelled, disabling this way adequate monitoring. Furthermore, according to the study carried out by the Spanish Endocrine and Nutrition Association (SEEN), there has been an increase in the demand (19,5% to 77,4%) for an alternative such as Telemedicine (TM) [12].
During the brainstorming sessions, we tackled concerns of our environment and tried to propose solutions involving synthetic biology. Having clear the different necessities of the proposed ideas, when the final decision needed to be given, we finally balanced our preferences towards Hormonic because of the multidisciplinary character of our team between electronics, synthetic biology and computation perfectly matched the needs that this therapeutic approach appeared to have.
References
[1] Taylor, P. N., Albrecht, D., Scholz, A., Gutierrez-Buey, G., Lazarus, J. H., Dayan, C. M., & Okosieme, O. E. Global epidemiology of hyperthyroidism and hypothyroidism. Nature Reviews Endocrinology, 14(5) 2018, 301–316. DOI:10.1038/nrendo.2018.182
[2] Chiovato, L., Magri, F. & Carlé, A. Hypothyroidism in Context: Where We’ve Been and Where We’re Going. Adv Ther,2019, 36, 47–58. DOI:10.1007/s12325-019-01080-8
[3] Valdés, S., Maldonado-Araque, C., Lago-Sampedro, A., Lillo, J., Garcia-Fuentes, E., & Perez-Valero, V. et al. Population-Based National Prevalence of Thyroid Dysfunction in Spain and Associated Factors: Di@bet.es Study. Thyroid, 27(2),, 2017, 156-166. doi: 10.1089/thy.2016.0353
[4] Maldonado Araque, C.Prevalencia de disfunción tiroidea en la población española. Implicación del hierro en la fisiología tiroidea. Doctorate, 2019, Universidad de Málaga.
[5] Fliers, E., Demeneix, B., Bhaseen, A., & Brix, T. H. European Thyroid Association (ETA) and Thyroid Federation International (TFI) Joint Position Statement on the Interchangeability of Levothyroxine Products in EU Countries. European thyroid journal, 7(5), 2018, 238–242
[6] American Thyroid Association, Endocrine Society, & American Association of Clinical Endocrinologists.U.S. Food and Drug Administration's Decision Regarding Bioequivalence of Levothyroxine Sodium. Thyroid, 14(7),, 2004,486-486. doi: 10.1089/1050725041517138
[7] Dietrich, J. W., Landgrafe, G., & Fotiadou, E. H. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. Journal of Thyroid Research, 2012, 1–29. DOI:10.1155/2012/351864
[8] Abdalla, S. M., & Bianco, A. C. Defending plasma T3 is a biological priority. Clinical Endocrinology, 81(5) 2014, 633–641. DOI:10.1111/cen.12538
[9] American Association for Clinical Chemistry C, 2020. T3 (Free And Total) | Lab Tests Online. [online] Labtestsonline.org. Available at:
[10]Sheehan, M., 2016. Biochemical Testing of the Thyroid: TSH is the Best and, Oftentimes, Only Test Needed – A Review for Primary Care. Clinical Medicine & Research, 14(2), pp.83-92.
[11] Weissberg-Benchell, J., Antisdel-Lomaglio, J., & Seshadri, R. Insulin Pump Therapy: A meta-analysis. Diabetes Care, 26(4), 2003, 1079–1087. DOI:10.2337/diacare.26.4.1079
[12]Gorgojo Martínez, J., Zugasti Murillo, A., Rubio Herrera, M. and Bretón Lesmes, I., 2020. TELECONSULTA En Endocrinología Y Nutrición En Tiempos De La Pandemia COVID-19 Y Más Allá. [online] Seen.es. Available at: https://www.seen.es/ModulGEX/workspace/publico/modulos/web/docs/apartados/1433/160620_105727_7128864936.pdf [Accessed 22 October 2020].
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