Team:Oxford/Description
Project Description
Overview
Rare, or “orphan”, diseases are frequently ignored by the pharmaceutical industry. They encompass a huge range of disorders, from ALS to Tourette’s Syndrome, but individually have a relatively low number of patients. The low patient numbers mean that there is very little impetus for the pharmaceutical industry to research and produce novel, innovative therapeutics. This means that patients are often left with unsatisfactory treatments. Our goal is to produce a probiotic therapeutic to treat one such disorder: Wilson’s Disease.
The Problem
Wilson’s Disease is a genetic disorder characterised by an inability of the body to fully metabolise copper. Normally, when copper is ingested, it is taken up from the small intestine into the liver and subsequently transported into the blood or excreted into the bile. In Wilson’s Disease, there is a mutation in the gene: ATP7B. ATP7B encodes a copper-transporting protein that is responsible for loading copper onto ceruloplasmin for transport in the blood, and into the bile for removal from the body. In the absence of a functional form of this protein, copper is unable to be removed from the liver after absorption. This results in toxic accumulation, as cuprous ions react with hydrogen peroxide to produce dangerous free radicals that damage the tissue. This allows copper ions to leak into the blood and eventually accumulate in, and damage, other tissues, such as the kidneys and brain.
Current treatments are regarded by patients as unsatisfactory. From discussions with these individuals, we have surmised that there are 3 main problems with current treatments:
Our CuRE aims to address these limitations.
Probiotics
A probiotic constitutes a microorganism that is introduced into the body for its beneficial properties. The concept of a probiotic, meaning “for life”, was introduced by Elie Metchnikoff in 1907, when he hypothesised that replacing or diminishing the populations of ‘putrefactive’ bacteria in the gut with lactic acid bacteria could positively affect bowel health.
Products that are commonly sold as probiotics include food stuffs, such as yoghurts and cheeses. However, recently there has been an increase in the amount of research going into the use of probiotics as therapeutics, with the genetic engineering of organisms to produce useful substances. Currently there is limited legislation regarding probiotics, as probiotics sold as dietary supplements do not require FDA approval. A genetically-engineered probiotic therapeutic would require more stringent legislation and FDA approval to ensure, through clinical trials, that it works as expected.
Although advancing rapidly, the field of probiotics still requires significant research particularly in areas such as safety. Although regarded as safe for relatively healthy humans to consume, there have been some reports of probiotic-related side effects in people with serious underlying medicals conditions. We carried out a comprehensive safety review when completing our project.
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Parts
In order to detect and chelate dietary copper we investigated the copper sensing systems of E. coli and attempted to redesign them to fit our requirements. We also looked for copper chelating proteins. You can read about how we chose our parts here.
Delivery
From discussion with patients and the public, and the work carried out by previous Oxford iGEM teams, we decided to investigate the use of a bead to deliver our bacteria to the small intestine. Our bacteria will initially be encapsulated in an alginate matrix, and then be alternately coated in layers of alginate and chitosan. The goal of the multiple polymer-coatings is to protect the bacteria from the harsh conditions of the stomach, whilst having the ability to degrade in the more alkaline pH of the small intestine. This degradation releases our bacteria into the favourable conditions of the small intestine, where they can colonise the area and chelate dietary copper.
