Team:BABS UNSW Australia/project/futureapps
The Dream: Platform Technology
The final aim of Endosynbio is to use endosymbionts to treat human disease. Much as sap-eating aphids rely on their Buchnera symbionts to produce essential amino acids, symbionts could provide in situ production and delivery of proteins, fatty acids, antioxidants, vitamins or hormones. For those affected by monogenic disorders that cause a deficiency in one protein (i.e. cystic fibrosis, muscular dystrophy), we present this as an alternative to gene therapy. To date, efforts to perform in vivo gene modifications in humans have been unsuccessful at their best, and disastrous at their worst. Cystic fibrosis and muscular dystrophy are fairly prevalent monogenic disorders, and billions of research dollars have been spent developing treatments and cures. The true strength of Endosybio lies in its potential as a platform technology, to treat a broad range of rare monogenic disorders (e.g. hereditary spherocytosis, mucopolysaccharidosis, Marfan syndrome). Once artificial endosymbionts are shown to be safe and stable inside human cells, protein production can be tailored to each disorder.
Next, gene circuits allow for dynamic responses to environments. Bacterial sensing is well developed in terms of environmental and research-enabling biosensors - but could it also be used to detect specific physiological states, and triggers specific responses? Hormone imbalances (caused by too much or too little hormone could be monitored by symbionts), and adjusted through protease activity or increase hormone production. For example, adrenal insufficiency syndrome is caused by the adrenal gland under-producing master regulator hormones cortisol and aldosterone. Almost too easy, no? Additionally, hormone-producing synthetic organelles could be used for to facilitate gender transitions, an increasing practice as acceptance becomes more widespread.
The intracellular production and delivery of molecules also inspires potential uses. For some beneficial molecules, delivery is not problematic. However, most molecules require processing, are lipid insoluble, or cannot access target cells when administered artificially. The most obvious example are antioxidants - the current market for antioxidant supplements is estimated to be $65 billion per annum, and none are proven to be very effective at reducing free radical levels. Synthetic endosymbionts could deliver antioxidants enzymes or other neutralising molecules. In fact, lactic acid bacteria have been shown to have high levels of antioxidative ability [1]. Oxidative stress, caused by normal aerobic cellular metabolism as well as certain pathological states, is associated with clinical conditions ranging from ageing and neurodegenerative diseases to cardiac failure and chronic fatigue syndrome. Antioxidants reduce oxidative stress, and efficient delivery to at-risk cells could therefore have an extremely wide ranging beneficial effect..
Case Study 1: Endosynbiology and Organogenesis
The inspiration for endosynbio came from the endosymbiotic relationship between pea aphids and Buchnera species. Buchnera inhabit specific cells in the aphid known as ‘bacteriocytes’ with the specific organ known as the ‘bacteriome’ (1). The bacteria synthesise a range of amino acids to supplement the aphid’s diet of sap. It was this simple idea of supplementation with in vivo protein expression that stimulated visions of synthetic human organs with supplementing or additive functions, and led to our current project. After some major bankruptcies in the early 2000s, the field of tissue engineering is beginning to re-emerge with biologic skin products currently available and tubular structures such as tracheas and arteries in development. Companies such as Organogenesis Inc. are leading the market in regenerative medicines and making the idea of transplantable organs grown in the laboratory a reality (2). Synthetic organelles – organelle engineering, if you like – is the perfect companion to emerge with tissue engineering technology. As we develop the ability to engineer hollow and glandular organs, endowing these with supplementary functions such as synergised insulin secretion or contraceptive oestrogen/progesterone secretion could become a huge component of future medicine. Immunogenicity of endosymbionts would also be less of a problem in this instance And who knows – maybe one day our Sychechocystis organelle will combine with engineered skin grafts to create the first photosynthetic humans! We can dream, right?
Case Study 2: In Vivo Biologic
The rise of targeted biologic therapies has dominated in the past few years. In the realm of autoimmune, inflammatory and neoplastic diseases, hundreds of new therapies are being developed to tackle disease from a new perspective [3]. The use of monoclonal antibody therapies and more recently, the development of chimeric antigen receptor (CAR) T cell therapies (4), has made a real difference to treatment by specifically targeting, with antibody affinity, molecules of pathogenesis. Examples of this include anti-TNF-alpha antibodies used in rheumatoid arthritis and trastuzamab, which binds to and blocks the HER2 receptor commonly amplified in breast cancer. One of many problems with this system is that regular injections are required to maintain antibodies within the system. Whilst this is perhaps okay for a disease such as breast cancer, which today has an 80% cure rate, chronic diseases such as rheumatoid arthritis, inflammatory bowel diseases and severe allergic diseases will require lifetime treatment, or substitution with other, less effective drugs. Even CAR T cell therapy, an ingenious in vivo system which exploits the strength of the immune system to tackle blood-borne and solid cancers using the chimeric B/T cell receptors maintained on autologous T cells, has its drawbacks – that it relies on multiple injections. A treatment, not a cure. Future work in endosynbiology provides a solution to this problems. Quickly and easily transforming a bacterial chassis (optimised for endosynbiosis) with the antibody sequence could supply a permanent source of therapy, which is essentially curative.
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