Team:Newcastle/Description

Description

Project Description

Introduction

Parkinson’s Disease (PD) is a neurodegenerative disorder affecting an estimated 7 million people worldwide [1]. In this day and age neurological disorders are a leading source of disability and death [2]. The subsequent burden of disorders such as PD will continue to rise with both a global increase in population numbers and life expectancy [1, 3].

Current diagnostic procedures rely on observations of late-stage motor symptoms, meaning delays and misdiagnoses occur. For individuals, this means therapies which delay the severity of PD may not begin until physical symptoms are present. By the time motor symptoms are severe enough for a diagnosis two thirds of dopaminergic cells in the substantia nigra are damaged - resulting in significant irreversible neurological damage and physical impairment both of which severely impact the person’s quality of life [4].

Diffusion tensor tractography of the human brain with neurone fibre-tracking from the substania nigra and the surrounding basal ganglia.

Our project

Our project, ‘muninn’, aimed to design and test a suite of biosensors which could be used to indicate whether a person may be suffering from PD before motor symptoms arise. The project development was informed by patient groups, health professionals, and diagnosticians, resulting in a suite of biosensors targeting biomarkers found in clinical samples.

After speaking to various healthcare professionals as well as members in attendance at Parkinson’s UK events, it was interesting and sad to learn that the NHS does not offer support groups and relevant activities for people living with PD. There are only medical treatments to manage motor symptoms after a diagnosis.

The team also heard a range of different people’s experiences with PD; some had a sense of relief from a confirmed medical diagnosis, whilst others had never heard of PD before. It seemed that many people knew, or at least suspected for years before their diagnosis that they had PD. This highlighted the fact that a medical diagnosis mainly relies on the presentation of late-stage motor symptoms, and a need for both earlier diagnostic procedures and alternative medical treatments.

Through further research it became apparent that PD shared many biomarkers with other diseases such as seborrhoeic dermatitis in HIV patients, as well as dopamine levels associated with schizophrenia. Consequently, the team investigated the CRISPR SHERLOCKsystem for detection of CPLX1, a Parkinson’s Disease-specific mRNA biomarker associated with the toxic mutation of alpha-synuclein in people effected by PD. In addition, we investigated biosensors for the detection of Glutathioneand Eicosane to increase our confidence in an indicative diagnosis.

Although eicosane and glutathione are not specific to PD, our inspiration was greatly influenced by the research involving Joy Milne and investigated non-motor symptoms in association with PD. The suite of biomarkers chosen to be included as part of ‘muninn’ is reflective of the range of potential biomarkers outlined in current research. By integrating feedback from clinicians and charities, ‘muninn’ aims to provide a foundation for developing diagnostic tests for early-stage PD.

For further details on each biosensor, see our Design page!

𝛼 -Synucleins are mainly found in neurons

𝛼-Synclein monomers join together to make 𝛼-Synclein oligomers

In healthy people, chaperones alter the conformation of the oligomers and form non-toxic 𝛼-Synuclein conformations. This inhibits the interaction of 𝛼-Synuclein with other neurotoxic proteins which would lead to cell death

In people living with Parkinson’s, toxic 𝛼-synucleins interact with neurotoxic proteins which leads to dopamine motor damage. This leads to the motor symptoms associated with Parkinson’s Disease

Additionally, chaperones sequester into Lewy Bodies. The function of the chaperone depletes and this additionally leads to the motor symptoms associated with Parkinson’s Disease

Our Inspiration

“Super Smeller” Joy Milne had a unique ability to distinguish the “smell” of PD on her late husband. Joy described her husband Les as smelling “musky” up-to 10 years prior to his PD diagnosis [3].

Joy’s unique ability led to further research at both Manchester and Edinburgh University later concluded that the musky odour was linked to seborrhoeic dermatitis, a common inflammatory skin disorder. With further investigation, 'muninn' discovered that seborrhoeic dermatitis was only a secondary non-motor symptom caused by the immune deficiency in people effected by PD.

During the bootcamp phase of iGEM (our initial two weeks), the team received talks and workshops from various academic staff at Newcastle University. The idea was to introduce us to synthetic biology and to show us some potential fields which we could explore with our project. After hearing about Joy Milne's unique ability to 'smell' Parkinson's Disease (PD) we decided to investigate the option of a pre-motor symptom diagnostic test. At the end of our first week, we team voted our 3 favourite project ideas. After the second week of research and planning the team settled on a PD diagnostic project that later became known as 'muninn'.

To see how the team developed and refined our ideas, see our Notebook!

By the end of bootcamp, the team had our initial project idea and was keen to discover a biomarker unique to PD that could lead to a potential early diagnosis based on non-motor symptoms. Although the team could not discover a sole biomarker indicative of PD, we were able to identify various symptoms that in collectively suggested a need for further PD investigation. We realised that a multi-diagnostic tool may be more appropriate as it enables us to incorporate various other PD biomarkers and consequently improve the accuracy of a PD diagnosis.

Synthetic biology approaches allow us to design, build and test several biosensors for various PD biomarkers relatively easily due to standardised assembly methods and an open source registry of characterised parts. 'muninn' aims to lay the foundation work so that once a diagnostic test is able to accurately detect PD biomarkers we can begin transfer our diagnostic tool into a cell-free process which synthetic biology approaches allow us to do. This would allow 'muninn' to become a worldwide multi-diagnostic tool, and make PD diagnostics available in countries where medical laboratory equipment isn't as widely available.

To see how 'muninn' developed as a multi-diagnostic tool after our bootcamp, see our Design page!

Or to skip ahead to see our team's key findings, visit our Results page!
(includes our bronze medal requirement).

References

Dorsey ER, Elbaz A, Nichols E, Abd-Allah F, Abdelalim A, Adsuar JC, et al. Global, regional, and national burden of Parkinson's disease, 1990–2016: a systematic analysis for the global burden of disease study 2016. The Lancet Neurology. 2018;17(11):939-53.
Feigin VL, Abajobir AA, Abate KH, Abd-Allah F, Abdulle AM, Abera SF, et al. Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet Neurology. 2017;16(11):877-97.
Trivedi DK, Sinclair E, Xu Y, Sarkar D, Walton-Doyle C, Liscio C, et al. Discovery of volatile biomarkers of Parkinson’s disease from sebum. ACS Central Science. 2019.
Pagan FL. Improving outcomes through early diagnosis of Parkinson's disease. American Journal of Managed Care. 2012;18(7):S176.
Ravn A-H, Thyssen JP, Egeberg A. Skin disorders in Parkinson’s disease: potential biomarkers and risk factors. Clinical, cosmetic and investigational dermatology. 2017;10:87.