Project Description

Project Forget-Me-Not

The Problem

Neurodegenerative diseases are a unique challenge in a world with an increasingly aging population. In 2019, over 750,000 people were diagnosed with Dementia.The current treatment options for these diseases focus on alleviating damage rather than preventing the neurodegeneration in the first place.

Alzheimer’s Disease is the most common form of dementia,characterized by the progressive loss of neurons and the accumulation of abnormal protein deposits, such as amyloid plaques and tau tangles, in the brain. It affects 5-10% of the U.S population over 45 years (Mattson, 2004), it’s incidence is said to threefold in 50 years from now. The total number of people with AD dementia is projected to be 13.8 million in 2050 (Hebert et. al, 2013)

Unfortunately, the prevailing narrative surrounding Alzheimer's disease perpetuates the idea that it is an unstoppable force, overshadowing the potential of preventive strategies that are not only affordable but also effective. Instead of focusing solely on medications that offer fleeting months of slowed decline. Preventive measures have the potential to offer years of cognitive health.

By the time Alzheimer's disease is clinically diagnosed, significant damage has already occurred in the brain, and cognitive impairments are evident. Therefore, there is a critical need to develop diagnostics and treatments that target neuroprotection and disease modification at earlier stages, even before the onset of major cognitive symptoms.

Inspirations

Our solution- Project "Forget-Me-Not"

Logo

Wet Lab - Team NCSU is working on a Clostridia based platform to mitigate early signs of neurodegeneration through the gut-brain axis. As a proof of concept, we engineered Clostridium butyricum to mitigate early signs of AD. By leveraging the gut-brain axis, this clostridia-based therapeutic will be engineered to increase the amount of butyrate reaching neurons in the brain thus providing a baseline of neuroprotection to delay the onset of neurodegenerative diseases.

Dry Lab - Hypothesis 1: To determine the best time to deliver the synthetic biotic, our dry lab team used Quantum machine learning (QML) to classify a large dataset of MRIs into Mild Cognitive Impairment (MCI), Normal Cognition and AD. We hope to make this software open source as a clinician resource for the early diagnosis of AD.

Hypothesis 2: Using QML to classify Acetylcholinesterase inhibitor drug targets in Alzheimer’s disease.

Human Practices- Our human practices effort is a neuroethics report. This report is a deep dive into the ethics of Genetic Engineering, neuroethics and the ethics of our experiments in particular.

Integrated Human practices - More than 11 million family members provided 16 billion hours of care to AD patients in 2022. This number features a decline in the number of caregivers over the past decade, and a significant increase in the number of hours put in per caregiver (Report:2023 AD facts and figures).

For the integrated human practices section, we have surveyed AD patients and their caregivers to create an app. This houses essential patient information about their life and habits. Additionally, it integrates fragmented health data (the diverse medical records and prescriptions) from the physician teams in a HIPAA compliant manner using a NFC card.

References

  1. Mattson MP. Pathways towards and away from Alzheimer's disease. Nature. 2004 Aug 5;430(7000):631-9. doi: 10.1038/nature02621. PMID: 15295589; PMCID: PMC3091392.
  2. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. 2013 May 7;80(19):1778-83. doi: 10.1212/WNL.0b013e31828726f5. Epub 2013 Feb 6. PMID: 23390181; PMCID: PMC3719424.
  3. Alzheimer’s Association: 2023 AD facts and figures report.
  4. Sun J, Xu J, Yang B, Chen K, Kong Y, Fang N, Gong T, Wang F, Ling Z, Liu J. Effect of Clostridium butyricum against Microglia-Mediated Neuroinflammation in Alzheimer's Disease via Regulating Gut Microbiota and Metabolites Butyrate. Mol Nutr Food Res. 2020 Jan;64(2):e1900636. doi: 10.1002/mnfr.201900636. Epub 2019 Dec 23. PMID: 31835282.
  5. Liu J, Sun J, Wang F, Yu X, Ling Z, Li H, Zhang H, Jin J, Chen W, Pang M, Yu J, He Y, Xu J. Neuroprotective Effects of Clostridium butyricum against Vascular Dementia in Mice via Metabolic Butyrate. Biomed Res Int. 2015;2015:412946. doi: 10.1155/2015/412946. Epub 2015 Oct 7. PMID: 26523278; PMCID: PMC4615854.
  6. B. C. Simon, D. Baskar and V. S. Jayanthi, "Alzheimer’s Disease Classification Using Deep Convolutional Neural Network," 2019 9th International Conference on Advances in Computing and Communication (ICACC), Kochi, India, 2019, pp. 204-208, doi: 10.1109/ICACC48162.2019.8986170.

Project Inspiration

Team NCSU wanted to create a product that helped the increasingly aging population of the world. During our stakeholder interactions, we understood that the pandemic had brought down resources and research into dementia- one of the most common conditions plaguing old age. Inspiration from the UCL iGEM 2013’s website helped us document our journey as a neuroethics report. Further conversations with End Alzheimer’s Association and the University of Nottingham 2020 iGEM team strengthened our resolve to create a preemptive solution for neurodegenerative diseases.

Our scientific curiosity drove us to explore the ‘second brain’ or the enteric nervous system lining the human gastrointestinal tract and its role in Alzheimer’s Disease (AD). AD is caused by the deposition of Amyloid beta (Aβ) plaques in the brain. We decided that the best method of delivery was using the gut-brain axis. We chose our chassis organism, Clostridium butyricum through extensive literature reviews.

Recent research has shown that CB protects neuronal activity and reduces neuroinflammation in Vascular Dementia (Liu et. al, 2015). Our synthetic biotic is engineered to release butyrate treatment which reduces the levels of CD11b and COX-2 (inflammation factors in AD), and suppresses phosphorylation of NF-κB p65 pathway which ultimately lead to Aβ plaque deposition.

This synthetic biotic has to be administered at the Mild Cognitive Impairment (MCI) stage. The dry lab creates diagnostic resources to identify this stage.

Implementation

The QML model will be made an open source physician resource.The prophylactic synthetic biotic will be delivered in the form of capsules at the MCI stage.