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IGEM: Intelligently Genetically Engineered Microglia

Our ambitious project concerns bringing synthetic biology to the brain in order to try a novel approach to tackling Alzheimer’s Disease (AD). Microglia are mobile brain cells, making them an ideal chassis. To do this, our proposed treatment would involve extracting microglia from a patient, or using a specially bred immortalised line of human microglia, to avoid rejection, and transfecting it with our new genetic circuit. Implantation into the brain could be performed surgically or using a viral vector - but in order to better control the numbers of genetically engineered microglia (GEM) in the brain micro-neurosurgery may prove best. Our circuit is designed to detect detect amyloid plaques, attract other microglia, degrade the plaques, reduce neuroinflammation and support dying neurons. Theoretically, this should halt the progression of Alzheimer’s disease and could lead to other forms of neuro-genetic engineering.

Our GEM have zeocin resistance would be injected into the key areas of pathology in the AD brain; the neocortex, limbic structures, hippocampus, amygdala, and some of the brainstem nuclei. Microglia are naturally drawn towards the senile plaques characteristic of AD. Senile plaques create free radicals, so as the GEM near the plaques oxidative stress increases. In response, our oxidative stress promoter will increase the transcription of key genes. Their protein products are matrix metalloproteinase 9 (MMP-9) , vasoactive intestinal peptide(VIP), brain derived neurotrophic factor (BDNF) and a chemoattractant called interferon gamma-induced protein 10(IP-10).

Brain cell death in AD is engendered by neuroinflammation due to microglia activation. VIP is able to de-activate GEM and native microglia. Activated microglia do not, however, produce proteases to clear plaques or attract other microglia. MMP-9 is capable of degrading β-amyloid fibrils and soluble β-amyloid in situ (Yan et al. 2006). Many theories of AD causation see amyloid build up as key to pathogenesis. Increasing clearance could therefore halt disease progression, and synthetically expressing MMP-9 in volume will ensure greater than natural plaque degradation even after microglial inactivation. In order attract more GEM to increase clearance rate, the chemoattractant is produced. AD may also arise due to insiufficient BDNF signaling (Frade & Lopez-Sanchez 2010), and BDNF is able to support dying neurons, which is why we also propose its production.

IGEM: Major Circuit Componenets

Zeocin Resistance

Zeocin is a glycopeptide antibiotic capable of killing most bacteria, fungi, yeast, plant, and animal cells by intercalating DNA and inducing double strand breakage. This makes zeocin resistance an ideal selective maker for our project, which involves both bacterial and mammalian chassis. The product of the Sh ble gene, isolated from the bacterium Streptoalloteichus hindustanus (Gatignol et al. 1988), confers zeocin resistance to transfected/transformed cells. Sh ble is a small binding protein with strong affinity for antibiotics on a one to one ratio. It prevents zeocin from being activated by ferrous ions and oxygen, meaning it cannot react in vitro with DNA.

Oxidative Stress Promoter