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In The Glow: Luminescent Biosensors for Hormone Detection and Diagnosis

Overview

The human endocrine system is responsible for keeping the body in a delicate balance by controlling essential functions such as thermoregulation, thirst, satiety, sexual drive, and awareness. The body uses chemical messengers called hormones to maintain this delicate balance, by signaling to the cells throughout your body on how to behave. Examples of hormones include Estrogen, Oxytocin, and Cortisol. This year our team sought to produce engineered protein biological sensors for the detection and quantification of hormones present in saliva as tool for diagnosis of hormone disorders, monitoring endocrine function, and determining treatment efficacy. As a starting point for our biological sensors we have focused on detection of the steroid hormone cortisol. We have taken two approaches to the biologic sensors for the measurement of Cortisol. Firstly, we have constructed a glucocorticoid sensor utilizing changes in Fluorescence Resonance Energy Transfer (FRET) to detect hormones. Secondly, we have began developing a novel biological sensor which utilizes intein splicing, producing a signal for hormone quantification. In addition to our work in the laboratory, we developed complimentary hardware and software, which we aim to incorporated into the form of diagnostic pacifier device with a built in luminometer, allowing for portable, quick, and non-invasive collection, and measurement of salivary analytes in infants.

Why Cortisol?

Cortisol is a steroid hormone that is made in the cortex of the adrenal glands. It is released in the bloodstream and transported all around the body. This hormone is necessary for many bodily functions, as indicated by the majority of cells having a receptor for it. Although each individual has his/her own operating range of “normal” cortisol levels, naturally, cortisol levels undergo a diurnal rhythm: they are at a peak when one wakes up, and fall as the day progresses. Determining a normalized range of values for the population can help find abnormalities among individuals. Fluctuating cortisol levels that differ from this diurnal rhythm can serve as an indicator of various disorders. Thus, cortisol can be a very useful biomarker of health and wellness.

Some functions of cortisol include the regulation of blood sugar levels, metabolism, cardiovascular health, controlling inflammation and immune function. [1] Since cortisol enhances the production of glucose from the liver through gluconeogenesis, counterbalancing the effects of insulin, [2] it can potentially be used as a biomarker for conditions like hypoglycemia (low blood sugar) and insulinemia (abnormally elevated blood-insulin levels). In terms of metabolism, cortisol is an overall catabolic hormone which decreases lean body mass, muscle mass, and can increase energy expenditure. [2] Elevated cortisol production and a change in local regulation are associated with obesity, [3] further research on cortisol could be used to help combat this common condition. Using cortisol as a biomarker could potentially have an application in early diagnosis of metabolic disorders such as Cushing’s syndrome and Addison’s disease, which are caused by hyper- and hypo-secretion of cortisol, respectively. Early diagnosis for these disorders would be revolutionary for early treatment options to lessen symptoms including obesity, bone loss, and high blood pressure for Cushing’s, as well as weight loss, muscle/joint pains, and low blood pressure for Addison’s.

Another potential application of cortisol as a biomarker is to monitor fetal wellbeing in pregnant women. Highly stressed pregnant women have elevated glucocorticoid levels which can cause reduced growth, alter the timing of tissue development, and can cause mood disorders later in the child’s life. [4] In a study where maternal cortisol levels were observed during pregnancy and infant development rates were measured following birth, it was found that “exposure to elevated concentrations of cortisol early in gestation were associated with a slower rate of development over the first postnatal year and lower scores on the mental development index of the Bayley Scales of Infant Development (BSID)”. [5] In contrast, higher levels of maternal cortisol late in gestation showed opposite results. Monitoring cortisol levels in pregnant women could help predict developmental problems that may arise following birth.

Presently, the most common method of measuring cortisol levels is through blood work. Other methods however, such as salivary tests, are generating interest as they are far less invasive and easier for sample collection. One key difference between blood and saliva tests for hormones is that salivary tests are able to measure the amount of free, unbound hormone that is available to act on a given tissue because saliva contains unbound, bioavailable hormones. Since 95-99% of steroid hormones flowing in the blood are bound by carrier proteins rendering them inactive (because steroids are unable to dissolve in water, a large component of blood), blood tests may give a less accurate representation of how much hormone is actually available to target tissues. [6,7] In one study, researchers found a correlation between higher salivary cortisol and increased HbA1c levels (glycosylated hemoglobin, a metabolic factor), as well as high triglyceride and high density lipoprotein (HDL) cholesterol levels. These correlations were not found when cortisol levels were tested through blood. [8] This is where Queen’s Genetically Engineered Machinery (QGEM’s) product can be of great use. We are developing a pacifier that is intended to detect salivary cortisol in infants, and quantify the levels to a mobile application through bioluminescence and Bluetooth technology. This concept is not limited to infants, as the genetically engineered protein could be used to quantify salivary cortisol levels in youth and adults as well. Using saliva as a diagnostic method for cortisol abnormalities has great potential as it is non-invasive, accessible and self-administrable, meaning the general population might be more inclined for regular tests to have more control over their health and wellbeing.

References

[1] McKay LI, Cidlowski JA. Physiologic and Pharmacologic Effects of Corticosteroids. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003. Available from: https://www.ncbi.nlm.nih.gov/books/NBK13780/
[2] Effects of Cortisol on Carbohydrate, Lipid, and Protein Metabolism: Studies of Acute Cortisol Withdrawal in Adrenocortical Failure. Christiansen J, Djurhuus C, Gravholt C, Iversen P Christiansen J et. al. The Journal of Clinical Endocrinology & Metabolism 2007 vol: 92 (9) pp: 3553-3559
[3] Cortisol dysregulation in obesity-related metabolic disorders. Baudrand R, Vaidya A. Current opinion in endocrinology, diabetes, and obesity. 2015 vol: 22 (3) pp: 143-9
[4] Fetal exposure to excessive stress hormones in the womb linked to adult mood disorders -- ScienceDaily. (n.d.). Retrieved October 8, 2018, from https://www.sciencedaily.com/releases/2013/04/130407090835.htm
[5] Davis, E. P., & Sandman, C. A. (2010). The Timing of Prenatal Exposure to Maternal Cortisol and Psychosocial Stress is Associated with Human Infant Cognitive Development. Child Development, 81(1), 131–148. Read it here.
[6] The choice is clear: saliva vs. blood diagnostics for hormone testing. (n.d.). Retrieved October 8, 2018, from https://www.tecan.com/blog/saliva-hormone-testing-versus-blood-diagnostics
[7] Lewis JG. Steroid analysis in saliva: An overview. Clin Biochem Rev. 2006;27(3):139-146.
[8] Konishi S, O'Connor K. Salivary but not blood cortisol excretion is associated with metabolic biomarkers in healthy young women. Am J Hum Biol 2016; 28(4):539-544.