The traditional technological model of the pharma industry – finding small molecules that bind to big molecules and alter their activity – is dying. There simply aren’t enough undrugged proteins left to support the pharma and biotech industries under this paradigm. That particular gold mine is playing out, and it’s time to find a new one.
The microbiome is a logical next source of untapped riches. We know it to be associated with a host of diseases, particularly metabolic and autoimmune disorders. An emerging line of thought classifies hosts and their microbiomes together as the true natural unit of biology – the Holobiont – and ascribes all disease to its perturbation.
Whether you buy into holobiont theory or not, if you are a therapeutic company, the microbiome is just too big an opportunity to ignore. Not only are metabolic and inflammatory diseases (which include depression) huge market opportunities in affluent countries, they are diseases for which few small-molecule therapies provide satisfactory treatments. For instance, only one drug (orlistat) is FDA-approved for obesity. But its sales are underwhelming (~$100M/yr US) and its clinical value is dubious.
Common gut bacteria can be engineered to express both small-molecule metabolites and large-molecule signaling proteins that can alter metabolic and immune behavior. Here are some examples:
- E coli engineered to express a precursor lipid, N-acylphosphatidylethanolamine, have been shown to reduce fat in mice.
- Lactobacilli that secrete glutamic acid decarboxylase and Interleukin-10 reverse recent-onset diabetes in mice.
- Lactobacilli that express heat-shock protein 65 suppress atherosclerosis in mice.
- Lactobacilli engineered to express glucagon-like peptide improve cholesterol metabolism, glucose tolerance, and insulin sensitivity in rodent models
Cholesterol levels in treated mice, from Recombinant Incretin-Secreting Microbe Improves Metabolic Dysfunction in High-Fat Diet Fed Rodents. HFC and LFC are the high-fat and low-fat diet controls, GLP1 is the engineered Lactobacillus, PNZ is the not-engineered Lactobacillus control.
One engineered bacterium, a Lactobacillus that expresses the anti-inflammatory cytokine IL-10, has made it into clinical trials as a treatment for Crohn’s Disease. Although well-tolerated in Phase I, it apparently showed little therapeutic effect in Phase II trials.
No doubt there will be further setbacks, but success – and big profits – in these endeavors is inevitable.
One potential stumbling block is protection of intellectual property. Genetically engineered bacteria – like GMO crops – are inherently capable of reproducing and spreading. What’s to prevent treated patients from sharing their poop for DIY fecal microbiota transplantations?
Although there is no shortage of assholes in the pharma industry, I think it is too customer-facing to repeat the Orwellian tactics employed by Monsanto with its GMO crops. I just can’t see pharma companies sampling poop and suing unlicensed carriers of their bugs. More likely, they will develop kill-switches or nutrient dependencies to prevent unauthorized spread of proprietary bugs. They may even develop a razor-razor blade business model in which the bugs are free, but you have to keep buying pills that the bugs depend on.
I see no problems here that are insoluble. The markets are huge and affluent, the need is great, the technology is maturing. It’s only a matter of time until we are routinely ingesting modified bugs to fix what ails us.