Medicines from engineered bacteria offer promise — and pitfalls

Medicines change when theories of disease change. Since the mid-20th century, the dominant theory of disease has been that of chemicals misbehaving. It followed that medicines were largely comprised of chemicals formulated in purified form, intended to rectify the lack or surfeit of other chemicals.

Genomics and microbiomics have done little to change or augment this paradigm and have yielded surprisingly few new drug targets. In part that’s because the supply of targets is limited, and most of the best ones have already been exploited. These disciplines did, however, create new appreciation for the dependence of health on autonomous or semi-autonomous agents in our bodies, particularly gut bacteria and immune cells.

We’ve already seen the first cellular medicines, human immune cells genetically reprogrammed to attack cancer cells. Now the first bacterial medicines — bacteria programmed to dispense therapeutics — are on the horizon. Although they represent an exciting opportunity, they raise questions about their use, their control, and their financing.

So far, three therapies based on engineered bacteria have made it to early clinical testing in humans. The results have been mixed. A mouthwash made from a protein secreted by recombinant Lactococcus bacteria successfully reduced inflammation of the inner lining of the mouth in patients undergoing chemotherapy for head and neck cancer. Bacteria programmed to make the anti-inflammatory cytokine IL-10 were orally administered to patients with Crohn’s disease, but the results were disappointing and the trial was terminated. A company called Synlogic is now testing bacteria engineered to reduce blood ammonia levels in patients with liver disorders.

Other bacteria-based treatments in the pipeline are aimed at reversing early-onset diabetes, reducing the formation of cholesterol-filled blockages in the arteries that nourish the heart, preventing colon cancer, and treating obesity.

Medicines comprised of purified chemicals cure none of those diseases and control most of them poorly, if at all. Despite the enormous toll that obesity takes on human health (offering an unmatched market opportunity), there is only one anti-obesity drug approved in both the European Union and the U.S., and it is of questionable effectiveness.

To date, gastric bypass surgery is the most effective intervention for obesity. Surprisingly, the theory on which it was developed — reducing the absorption of nutrients — appears to play little role in its effectiveness. Instead, gastric bypass changes the suite of microbes in the gut and, more importantly, changes the set of small molecules they secrete. These molecules initiate a cascade of signals that result in a feeling of satiety, leading to reduced appetite and body fat.

These observations lead to an obvious medical proposition: Why not skip the surgery and give patients genetically engineered bacteria that would take up residence in the gut? A number of researchers and biotech startups are taking on this challenge.

• A group at Vanderbilt University programmed E. coli bacteria, a common inhabitant of the gut microbiota, to generate precursors of N-acylethanolamide, an appetite-suppressing compound. High-fat diets cause gut bacteria to cease production of these molecules, leading to increased appetite and obesity. Mice given these genetically engineered bacteria along with high-fat diets showed substantial reductions in food intake, fat buildup, and insulin resistance compared to controls. These effects persisted for weeks after administration of the engineered bacteria.
• Glucagon-like peptide is an effective therapy for increasing insulin production in people with type 2 diabetes. But this peptide can’t be taken by mouth. Instead, it must be injected intramuscularly, and is quickly degraded in the bloodstream, seriously limiting its usefulness. Mice fed Lactobacilli engineered to make glucagon-like peptide showed increased insulin production in response to glucose, and also displayed reduced levels of harmful LDL cholesterol and triglycerides.

The emergence of bacteria as medicines raises questions that our current drug development paradigm is ill-equipped to answer.

Maintaining control over an inert chemical — whether it’s a small, simple molecule like aspirin or a large, complex one like a monoclonal antibody — is relatively easy. Either the body breaks it down or, if it gets into the environment, microbes break it down. In either case, the substance disappears.

Control isn’t so easy when the medicine is a living entity capable of growing and reproducing on its own. Scientists have devised kill-switches and genetic dependencies to limit the spread of genetically modified organisms in the environment, and these tools appear to be effective. But engineering microbes to live only in the guts of patients who have paid to receive them may not be so easy. Instructions for DIY fecal microbiota transplants are readily available online and have developed their own user communities. What’s to stop treated individuals from sharing their engineered microbiota with others?

Monsanto discovered how difficult it can be to control living organisms when the company began selling engineered plant seeds. To protect its investment in genetically modified crops, Monsanto relies on aggressive — sometimes abusive — legal tactics against unauthorized users. Pharmaceutical companies might be reluctant to follow suit. Suing sick people whose poop was found to contain proprietary therapeutic bacteria they hadn’t been prescribed would likely ignite a political backlash.

The pharmaceutical industry is increasingly addicted to a business model in which it charges extremely high prices for niche drugs. Orphan drugs (those with a market of less than 200,000 patients) comprise nearly half of all new approvals, and carry a median price tag of $83,000. Bacterial medicines don’t fit this paradigm. Premium pricing, even if justified by cost-benefit analysis, would merely spur revenue-draining micropiracy efforts.

Bacterial medicines hold immense potential to provide durable therapies for chronic diseases. They may well succeed where traditional pharmaceuticals have largely failed. But they may also require new economic models to fund their development. The standard pharma business model relies heavily on exclusivity. If for-profit drug developers are not confident that they will get paid by every user of bacterial medicines, they may never invest the effort needed to perfect them.

Our market-based system of drug development has been wonderfully productive. But markets have their blind spots, and bacterial medicines may be one of them. Governments and nonprofits should fill this gap.

Drew Smith is a molecular biologist and long-distance hiker who has held positions at several biotech and medical technology startups. He writes about science and hiking at Walking to the Light.