By Aoife Brennan, CEO of Synlogic, as part of the From The Trenches feature of LifeSciVC.
From the first time I heard the story of the American chestnut, I was fascinated. It is a story with threads from history, ecology, conservation and biotechnology- it was difficult for a scientist who loves the outdoors not to get sucked in.
The American chestnut was an important tree species in the eastern forests both ecologically and economically until it succumbed to chestnut blight, an imported fungus that invades the trees and has resulted in this once stalwart of the forest becoming functionally extinct. From a population of > 4 billion trees, there are only stump sprouts and about 100 trees remaining.
The American Chestnut Foundation is pursuing several strategies to achieve its mission of restoring the population to its former status including traditional cross breeding with blight resistant chestnut trees as well as genetic engineering. It turns out that the chestnut fungus, after it infects a tree, uses oxalic acid to spread. A transgenic species has been engineered that expresses an enzyme, oxalate oxidase, to consume the oxalic acid and prevent the fungus from spreading and killing the tree.
While I was learning about the American chestnut’s demise and potential recovery using biotechnology, our team at Synlogic were also pursuing our own oxalate consuming transgenic but for the treatment of a human disease. Oxalate, found in many foods, is also toxic to humans who either make too much (in primary hyperoxaluria) or absorb too much from their diet due to underlying gastrointestinal disease (in enteric hyperoxaluria- the application we are pursuing at Synlogic). There is currently no approved treatment for enteric hyperoxaluria and patients suffer with recurrent, painful kidney stones and have increased risk of chronic renal failure.
The scientists at the State University of New York inserted the gene encoding oxalate oxidase derived from a wheat species into the American chestnut genome. In our case, we inserted the gene encoding oxalate decarboxylase derived from Oxalobacter formigenes (a common gut commensal) into the genome of e. coli Nissle (a probiotic bacterial strain). In both cases, there was human exposure to the genes, enzymes and products of the metabolic pathway.
The transgenic OxO chestnut trees have undergone extensive study. They are resistant to the fungus but otherwise identical to the native American chestnut in every way. The tree is currently under regulatory review.
At Synlogic, we have also been diligently studying the activity of our engineered strain of e. coli (which we refer to as SYNB8802) in humans and in patients. So far, we have demonstrated that the engineered strain consumes oxalate in the human GI tract and reduces urinary oxalate levels in healthy volunteers. We are currently evaluating the safety and efficacy in patients with disease.
SYNB8802 is designed not to replicate outside of the fermenter and the data accumulated to date across pre-clinical and clinical trials confirm that it performs as designed. To re-establish the chestnut population, the hope is that the OxO chestnut tree will breed with the remaining wild- type stump sprouts to increase the diversity of the new population of trees that will and return the tree to its evolutionary trajectory.
In both programs, a biological solution has the potential to solve a critical problem but also faces potential opposition from those who resist genetic modifications as ‘unnatural. The American Chestnut foundation has done a fantastic job with education and has transparently shared the results of the research they have done to evaluate the OxO chestnut tree. They are currently running several pilot orchards to further evaluate the trees as they mature. Like our SYNB8802 strain, the OxO chestnut tree will undergo a thorough regulatory review by experts at government agencies before it is widely available.
To satisfy my appetite for updates on the project, I follow the blogs and posts from those involved in the work. For every ‘but it is a GMO’ comment, there are many more from landowners asking about ways to source seeds and reminiscences from those who remember the majestic beauty of a fully grown American chestnut tree.
I am looking forward to more updates from both oxalate programs in 2022, including progress in the review for the OxO chestnut and additional clinical data from our SYNB8802 program. In the longer term, I hope one day to stretch out beneath the shade of a fully grown oxalate transgenic and marvel at the progress we have made addressing important problems with biotechnology.