The Goal of Symbiotic Microbes in Tissues, Generating Additional Oxygen as Required

We live in an era of biotechnology, of tremendous year by year increases in the capacity to engineer the fundamental mechanisms of life and disease. The research community and funding institutions should aim high, aim at the new and the amazing, rather than slouching forward in the service of crafting yet more marginal, incremental improvements to existing forms of therapy. Sadly, mediocrity rules when it comes to all too much of the research community. Vision is lacking, and far too few people are willing to tread the roads yet untraveled.

Why is it necessary to spend so much time and effort to convince people to fund and work on rejuvenation therapies after the SENS model, based on the repair of cell and tissue damage? Because this strategy is comparatively new, because it is different from the largely futile efforts to paper over age-related diseases that have gone before. We humans are conservative, and favor existing strategies, even when they are poor, even when new directions are highly promising. Beyond the matter of rejuvenation, there are a thousand plausible new directions in medicine and biotechnology that are given little attention for all the same reasons, whether the DRACO approach to defeating viruses, or the topic of today's paper, the introduction of symbiotic bacteria capable of generating oxygen to supply ischemic tissues.

The researchers here focus on treatment of ischemia following heart attack or stroke, and on largely unmodified symbiotic organisms that might be used for this purpose. This is but a single step upon a long road of possibilities. Why not an enhancement biotechnology for healthy people, in which symbiotic bacteria dwell in the body, ready to provide oxygen on demand? A gene therapy to add a wholly artificial gene to human cells, one connected to a promoter that triggers only in hypoxic conditions, with the result that it supplies a protein that engineered symbiotic microorganisms consume as fuel for their oxygen-production engines. This sort of machinery could be described in some detail today, then built with today's technology, tested in animals, and delivered into human tissues with the robust gene therapy platforms that will emerge over the next decade. The result will people resilient to drowning, people with incredible endurance, people who can survive heart attacks, strokes, and other forms of blood vessel injury with little additional damage.

This will not happen any time soon, but not because it is technically infeasible. It will not happen because there is little overlap in this world between those with ambition on the one hand, and those with funding and power on the other. In this age of rapid, radical progress in biotechnology, there is all too little will to reach for the myriad possibilities offered.

Photosynthetic symbiotic therapy

Engineered O2-producing biomaterials represent an emerging field with enormous potential to address tissue ischemia and hypoxia without revascularization. The clinical applications span nearly the entire domain of medicine and include the areas of tissue engineering and regeneration, organ preservation, wound healing, diabetic microvascular disease, and cardiovascular, cerebrovascular, and peripheral vascular disease. Nature, however, evolved the most elegant O2-producing biomaterial 3.5 billion years ago in the form of photosynthetic cyanobacteria, which are responsible for the relative abundance of O2 in Earth's atmosphere today. These ancestors of the chloroplast convert CO2 and water into O2 and glucose using light as an energy source. Recently, teams have begun to engineer symbioses between cyanobacteria or other photoautotrophic algae and heterotrophic cells such as those of mammals. In this relationship, the photosynthetic microorganism recycles CO2 produced by heterotrophic cellular respiration and generates O2 that helps sustain the heterotrophic partner.

The first use of a photosynthetic microorganism to remedy tissue hypoxia in vivo was reported in 2012. By placing a gas-permeable pouch containing a light-emitting diode and the photosynthetic microalga Chlorella vulgaris in the perfluorocarbon-filled peritoneal cavity of hypoventilated rats, the team demonstrated that Chlorella could supplement gas exchange in rats with respiratory insufficiency. The researchers also explored the use of photosynthetic symbiosis to enhance the viability of heterotopically-transplanted rat pancreases harvested 3 hours after cardiac death. The team demonstrated that a majority of diabetic recipient rats receiving pancreases stored in traditional cold preservation solution for 30 minutes exhibited severe glucose dysregulation and died within 5 hours after surgery. All rats receiving pancreases stored similarly but with Chlorella in gas-permeable bags at mild hypothermia (22°C), however, had normal blood glucose levels and survived beyond 1 week after surgery.

Direct inoculation of host tissues with microorganisms in solution risks rapid loss of the symbiotic microbes. Although no in vivo study has yet to demonstrate a significant immune response against a photosynthetic symbiont (i.e. against S. elongatus or C. reinhardtii in zebrafish, mouse, or rat models), delivery via a bioengineered construct nevertheless reduces the rate of cell dispersal. To this end, researchers have conducted impressive pioneering work on the development of photosynthetic algae-seeded scaffolds. Using an FDA-approved collagen-based scaffold, the team demonstrated that C. reinhardtii seeded within the scaffold were able to photosynthesize effectively and even proliferate. Moreover, C. reinhardtii co-cultured with murine fibroblasts within the scaffold were able to supply the fibroblasts with O2 in hypoxic conditions.

Thus far, photosynthetic symbiotic therapies have not taken full advantage of the immense genetic adaptability of cyanobacteria and microalgae. While researchers engineered C. reinhardtii to express and secrete vascular endothelial growth factor (VEGF), resulting in O2 delivery as well as neoangiogenesis when delivered into zebrafish and rat tissues in vivo, nearly all attempts to treat tissue ischemia or hypoxia using photosynthetic symbiosis have focused solely on gas exchange alone. Future studies should aim to expand the arsenal of clinically useful compounds produced by the photosynthetic symbiont and thereby augment its therapeutic potential. Overall, photosynthetic symbiosis represents a valuable untapped strategy for the development of novel engineered O2-generating biomaterials.