Controlled colonization of the human gut with a genetically engineered microbial medicine
Wow, July 16th, 2025 was Gut Microbiome Day in Nature and Science!
I am excited to see this Science paper (Controlled colonization of the human gut with a genetically engineered microbial medicine by Whitaker et al.) published -not only because it describes an intriguing application of synthetic biology (creating an engineered bacteria requiring a unique nutrient to colonize) but also because it reports on what many would consider a disappointing outcome.
Delivering engineered live biotherapeutics (eLBP) in the gut is an exciting frontier in drug delivery but it has been a fraught journey, as the unfortunate fates of such promising companies as Synlogic and Novome show. The eLBP engineered by Novome is the topic of the article: “a strain of Phocaeicola vulgatus, which is commonly found in the gut of healthy humans, with two genetic modules. One is therapeutic to rectify oxalate metabolism for preventing kidney stone formation, and the second adds multiple biosafety promoters that make the organism reliant on a [rare] essential nutrient, in this case porphyran.” (@Caroline Ash for Science) [rare is my addition, as is the renaming of porphyran from porphyrin, a very different molecule]. This is a clever approach, pioneered by @justin Sonnenburg at Stanford University.
Excellent preclinical data showed reversible engrafting (stop feeding porphyran and the eLBP disappears) and oxalate reduction, healthy human clinical trial participants showed the same... but in patients with hyperoxaluria (excess oxalate, a cause of kidney stones), abundant horizontal gene transfers lead the eLBP to lose its exclusive porphyran utilization ability (either by losing the gene or through other competing bacteria acquiring the gene and thereby gaining the ability to utilize porphyran). The oxalate-associated metabolic burden may have added to the differential fitness between the eLBP and other local microbial organisms.
These Phase 2a results led to the termination of the program and, ultimately, the leadership of Novome to close shop and return the remaining capital to investors -a sad ending for a promising startup and for its employees, although probably a rational decision from a purely financial perspective. The fact that the team decided to publish the results AND the fact that @science published it is a double miracle: although the results are disappointing, they are enormously useful.
@Weston R. Whitaker, @Zachary N. Russ, @Elizabeth Stanley Shepherd, @Lauren M. Popov, @Alexander Louie, @Kathy Lam, @David M. Zong, @Clare C. C. Gill,@ Jeanette Gehrig, @Harneet S. Rishi, @Jessica A. Tan, @Areta Buness, @Janeth Godoy, @Domenique Banta, @Sonia Jaidka, @Katheryne Wilson, @Jake Flood, @Polina Bukshpun, @Richard Yocum, @David N. Cook, @Tariq Warsi, @Lachy McLean, @Justin L. Sonnenburg, @William C. Deloache
Article: https://www.science.org/doi/10.1126/science.adu8000
Open Access: https://www.medrxiv.org/content/10.1101/2024.10.03.24314621v1