Team:RDFZ-China/Description

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Description

Background of the project

The current state of the problem

Depression, a common mental disease, is a serious problem for society. Depressed patients typically experience gloom, hypobulia, physical impairment, low mood, disproportionate situation, pessimism, world-weariness, and sometimes they even develop suicidal tendencies. According to a 2017 WHO survey, the number of people suffering from depression worldwide has reached 322 million, which means 4.3% of the world's population is affected. (1) Depression has serious impacts on individuals and society as a whole. About 50% of suicides are caused by depression and other mental disorders, including bipolar disorder, which affects 45 million people and has a depressed phase that resembles a lot to depression. (2, 3) Recently, the average age of such mental illnesses has long been declining, as more and more teenagers are suffering from these diseases. Such serious mental illnesses require in-depth investigation and research to find more effective treatments. According to our investigations, depression and bipolar disorder are both related to the imbalance of serotonin (4, 5). Serotonin is a monoamine neurotransmitter, also called 5-HT. Its functions are complex and diverse, including regulating mood, cognition, reward system, and memory (6). Studies have shown that low serotonin activity is one of the major causes of depression (4).

Status of related technology development

Currently, popular antidepressants include SSRIs (Selective Serotonin Reabsorption Inhibitors) and MAOIs (Monoamine Oxidase Inhibitors). Those drugs increase the extracellular concentration of 5-HT by limiting the reabsorption of synaptophysin in presynaptic cells, or by inhibiting monoamine oxidase, thereby increasing the concentration of 5-HT that can bind to postsynaptic receptors (7). However, according to the principle of those drugs, they cannot boost serotonin production (8). Hence, they cannot solve the fundamental problem of insufficient 5-HT secretion. Besides, antidepressants have many side effects. SSRIs may cause nausea, headache, dizziness, and insomnia (9). Patients taking MAOI must avoid eating foods containing tyramine. Otherwise, fatal hypertensive crisis might occur. (10). Moreover, taking medical treatment itself is also a problem. Due to the lack of medical knowledge and social stigmas on mental illnesses, patients often feel pressure and refuse to take antidepressants (11, 12). Studies have shown that 68% of patients stop taking medicine after 3 months (13). Only 33% of patients who insisted on taking medications completely followed the doctor's instructions (14).

Our solution

With the information provided above, we can see that the existing drugs have major defects, and directly taking medication is problematic. We hope to propose a solution to address both problems. First, to treat the root of depression, we plan to directly increase the content of 5-HT in the brain. Since 5-HT cannot cross the blood-brain barrier (15), we hope to achieve the same effect by having patients intake another substance, 5-hydroxytryptophan (5-HTP). 5-HTP is the precursor of 5-HT, which is produced by tryptophan hydroxylase (16) in the enterochromaffin cells of the human intestine. Many studies have shown that this substance has the effect of relieving depression (17, 18). Moreover, studies have shown that 5-HTP is more effective than existing drugs (19). It also has the effect of treating fibromyalgia (20) and migraine (21).

Second, dealing with patients' reluctance to take proper medication, we hope to find a way to enable the patients to obtain 5-HTP without requiring them to take drugs directly. As mentioned, 5-HTP is found and absorbed in the intestine (22). Therefore, to simulate this natural process, we hope that patients can also get 5-HTP directly in the intestine. To achieve this goal, we decided to implant engineered bacteria into the patient's intestine and engineer them to secrete 5-HTP. However, simply planting engineered bacteria in the intestine and allowing them to produce 5-HTP without external control could be hazardous. Therefore, engineered bacteria must adopt certain mechanisms so that they can be controlled externally. According to our design, the patients will ingest specific food to induce the engineered bacteria to produce the substance 5-HTP that the patient needs. This specific food should contain unique signal molecules that can be recognized by engineered bacteria, which can control the expression of drug-related protein genes. Under this design, the amount of drug produced can be controlled by food intake. Based on comprehensive considerations, we decided to use tea as the medium of new diet therapy.

As a common beverage, tea is more soothing and comfortable than taking medicine, thus it is more psychologically acceptable for patients. Moderate tea drinking has limited side effects and will not pose health threats, so it is relatively safe for the patients. Moreover, tea itself has the effect of regulating mood and even treating depression (27), which will be a good supplement to our project. As an integrated part of Eastern Asian/worldly culture, the public’s understanding and acceptance of tea culture are conducive to the popularization of our final results or products. With the nature of tea and the public's attitude towards tea drinking, this project is a good fit. After the patients' tea intake, the tea polyphenols and phenolic acid in tea will be metabolized into protocatechuic acid (PCA). This substance is very common in the intestines after people drink tea. For reference, for every 300 ml of tea consumed by a person, 1 mM of PCA is produced in the urine (28). Here, PCA is used as a signal molecule to stimulate engineering bacteria to produce 5-HTP.

Reference

1. World Health Organization. Depression and Other Common Mental Disorders Global Health Estimates[M]. World Health Organization,2017
2. https://www.who.int/news-room/fact-sheets/detail/mental-disorders
3. Bachmann, S (6 July 2018). "Epidemiology of Suicide and the Psychiatric Perspective". International Journal of Environmental Research and Public Health. 15 (7): 1425. doi:10.3390/ijerph15071425. PMC 6068947. PMID 29986446. Half of all completed suicides are related to depressive and other mood disorders (wikipedia)
4. Ruhé HG, Mason NS, Schene AH (April 2007). "Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies". Molecular Psychiatry. 12 (4): 331–59. doi:10.1038/sj.mp.4001949. PMID 17389902. （wikipedia）
5. Studies assessing the binding potential of the serotonin transporter or serotonin receptors have also been inconsistent, but generally point towards abnormal serotonin signalling. Manji & Zarate 2011, p. 112.
6. Young SN (November 2007). "How to increase serotonin in the human brain without drugs". Journal of Psychiatry & Neuroscience. 32 (6): 394–9. PMC 2077351. PMID 18043762.
7. "Mechanism of Action of Antidepressants" (PDF). Psychopharmacology Bulletin. 36. Summer 2002.
8. https://nutritionreview.org/2013/04/5htp-5hydroxytryptophan-prozac-ssris/
9. (Handbook of Experimental Pharmacology 250) Matthew Macaluso, Sheldon H. Preskorn - Antidepressants_ From Biogenic Amines to New Mechanisms of Action-Springer International Publishing (2019)
10. Grady MM, Stahl SM (March 2012). "Practical guide for prescribing MAOIs: debunking myths and removing barriers". CNS Spectrums. 17 (1): 2–10. doi:10.1017/S109285291200003X. PMID 22790112. Archived from the original on 7 July 2017.
11. Bucci KK, Possidente CJ, Talbot KA. Strategies to improve medication adherence in patients with depression. Am J Health Syst Pharm. 2003;60(24):2601–2605.
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13. Bull SA, Hu XH, Hunkeler EM, et al. Discontinuation of use and switching of antidepressants: influence of patient-physician communication. JAMA. 2002;288(11):1403–1409.
14. Boudreau DM, Capoccia KL, Sullivan SD, et al. Collaborative care model to improve outcomes in major depression. Ann Pharmacother. 2002;36(4):585–591.
15. Nakatani Y, Sato-Suzuki I, Tsujino N, Nakasato A, Seki Y, Fumoto M, Arita H (May 2008). "Augmented brain 5-HT crosses the blood-brain barrier through the 5-HT transporter in rat". The European Journal of Neuroscience. 27 (9): 2466–72. doi:10.1111/j.1460-9568.2008.06201.x. PMID 18445233.
16. Turner EH, Loftis JM, Blackwell AD (March 2006). "Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan". Pharmacology & Therapeutics. 109 (3): 325–38. doi:10.1016/j.pharmthera.2005.06.004. PMID 16023217.
17. l-5-Hydroxytryptophan in depression: the first substitution therapy in psychiatry? The treatment of 99 out-patients with 'therapy-resistant' depressions
18. Tryptophan and 5-hydroxytryptophan for depression
19. W. Poeldinger, et al. A Functional-Dimensional Approach to Depression: Serotonin Deficiency as a Target Syndrome in a Comparison of 5 -Hydroxytryptophan and Fluvoxamine. Psychopathology. 1991; 24: 53-81.
20. Caruso I, Sarzi Puttini P, Cazzola M, Azzolini V (1990). "Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome". J Int Med Res. 18 (3): 201–9. doi:10.1177/030006059001800304. PMID 2193835.
21. Boiardi A, Crenna P, Merati B, Negri S, Tansini E, Bussone G (1981). "5-OH-Tryptophane in migraine: clinical and neurophysiological considerations". J Neurol. 225 (1): 41–6. doi:10.1007/bf00313460. PMID 6164755.
22. Manocha, M. and Khan, W. Serotonin and GI Disorders: An Update on Clinical and Experimental Studies. Clinical and Translational Gastroenterology, 2012, 3(4), p.e13
23. Yin J, Yang L, Mou L, et al. A green tea–triggered genetic control system for treating diabetes in mice and monkeys[J]. Science translational medicine, 2019, 11(515).
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25. R. Chait, A. C. Palmer, I. Yelin, R. Kishony, Pervasive selection for and against antibiotic resistance in inhomogeneous multistress environments. Nat. Commun. 7, 10333 (2016).
26. S. Valentin, A. Morales, J. L. Sánchez, A. Rivera, Safety and efficacy of doxycycline in the treatment of rosacea. Clin. Cosmet. Investig. Dermatol. 2, 129–140 (2009).
27. Gilbert, N. (2019). The science of tea’s mood-altering magic. Nature, 566(7742), S8–S9. doi:10.1038/d41586-019-00398-1
28. P. G. Pietta, P. Simonetti, C. Gardana, A. Brusamolino, P. Morazzoni, E. Bombardelli, Catechin metabolites after intake of green tea infusions. Biofactors 8, 111–118 (1998).