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Needles be Gone for T1D

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Insulin delivery using infusion pumps can be effective for treatment of T1D, but it does not completely protect T1D patients from the long-term effects of the disease or enable a normal non-diabetic lifestyle. Diabetes research has focused on using insulin-producing cells isolated from cadavers or made from stem cells in T1D patients. While some of the research has yielded promising results, nothing yet has radically changed general approaches to treat patients.

Our approach is to give bacterial cells that naturally live in our body the ability to function like our insulin-producing cells, to synthesize insulin when blood glucose levels are high to maintain proper glucose levels in T1D patients. In the proposed project, we will establish the feasibility and safety of this approach by making bacterial strains with this function and testing them in mouse systems. If successful, our research will form the basis for a bacterial treatment that can circumvent the struggle of injected insulin therapy and the issues regarding rejection of transplanted human cells.

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Needles be Gone for T1D

  1. 1. Needles Be Gone for T1D Yo Suzuki, Assistant Professor J. Craig Venter Institute
  2. 2. Long-term goal: Make deep-skin bacterial cells that function as beta (insulin producing) cells in T1D patients No struggle of injected insulin therapy No autoimmune issue of pancreas transplants This project: Proof of concept: a skin bacterium that (1) produces a potent insulin analog (engineered insulin), (2) responds to glucose, and (3) resides only in a designated individual to be validated in mouse systems Beta cells Glucose Insulin Glucose uptake Not diabetic Beta cells Glucose Insulin Glucose uptake Diabetic Beta cells Glucose Insulin Glucose uptake Insulin analog Engineered bacteria Not diabetic
  3. 3. Bacteria live at least 3 mm into the skin in our body in a layer of the skin previously thought to be sterile (nothing could live there)! Platform: deep-skin bacteria Nakatsuji et al., Nat Commun. 2013; 4: 1431. Detection of bacteria in dermis using Gram staining (arrows) Advantages: Deep-skin bacteria are in close association with capillary vessels of the skin They are non-toxic (in a native form) They can enter the skin in a non-invasive manner They can be engineered to be better They are easier to understand than human stem cells Abundance of bacteria Depth(mm) Detection of bacteria in deep skin samples using PCR (for 16S DNA) Negative control
  4. 4. Platform: deep skin bacteria Tool 1: potent single-chain insulin analog (engineered insulin) Bacteria cannot make native insulin made of two peptide chains, but it can make single-chain insulin analogs (SCIs) SCIs that are as robust as native insulin have been developed SCIs are not proinsulin (an intermediate in insulin production) and unlikely to share the safety concern of proinsulin Tool 2: glucose sensor Genetic circuits can be constructed to make SCI production dependent on glucose sensing We will implement the Trz1 system, which can convert a glucose signal into the activation of any gene via the action of three proteins Tool 3: biocontainment Engineered bacterial cells stay only in designated hosts We will delete the thymidylate synthase gene and make the cells dependent on thymidine supplied from outside Engineered bacteria Thymidine application Mouse
  5. 5. Platform: deep skin bacteria Tool 1: potent single-chain insulin analog Tool 2: glucose sensor Tool 3: biocontainment Synthetic biology brings these tools together Constructed bacteria will be tested for their abilities to (1) induce glucose uptake in cultured adipocytes and (2) reduce blood glucose levels in treated mice (1) Expression of SCI (2) Expression of 3 genes to make a glucose sensor (3) Deletion of the thymidylate synthase gene Deep-skin bacteria Beta cells Glucose Insulin Glucose uptake Insulin analog Engineered bacteria Not diabetic

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