Synthetic biologists are developing “smart” bacteria they want you to swallow

Biomedicine

Companies Bet on Designer Bacteria as New Way to Treat Disease

Synthetic biologists are developing genetically modified bacteria that you swallow, but no one knows yet how they should be regulated.

Sometime next year, volunteers in the U.S. could start swallowing capsules stuffed with genetically engineered E. coli.

The experimental pills, designed by Synlogic, a Cambridge, Massachusetts, synthetic biology startup, contain bacteria designed to treat a rare metabolic disease by recognizing when they reach a person’s stomach and then soaking up large amounts of ammonia.

The treatment, slated for its first clinical test during 2017, is an early example of what the company’s founders call “synthetic biotics”—or intestinal bacteria endowed with genetic programs that allow them to sense something going on in the body and then take an action, like deliver a drug or release a colored chemical useful in a diagnostic test.

The idea of swallowing genetically modified bacteria might seem odd. But purpose-built germs could be a new way to take over physiological functions that people’s own bodies can’t perform if they are sick, and a substitute for pills or injections.

Developing Modified Bacteria as Drugs
  • Ernest Pharmaceuticals, Amherst, MA Engineered salmonella to treat cancer
  • GenCirq, San Diego, CA Cancer-killing bacteria
  • Synlogic, Cambridge, MA E. coli pills for various illnesses
  • Trayer Biotherapeutics, Rockville, MD Yogurt bacteria to treat phenylketonuria
  • ActoGenix/Intrexon, Ghent, Belgium Testing GM bacteria pills in Europe

The smart bacteria could be the first medical use of a form of synthetic biology popularized by Synlogic cofounder and MIT professor James Collins starting in 2000. That year, Collins, taking his cue from electronics, constructed what’s essentially a toggle switch in E. coli—a circuit involving two genes that could flip-flop between states. It was nifty demonstration, and soon after, Princeton scientists announced they’d made a fluorescent bacterium that could flash on and off.

The idea was to program cells to carry out all kinds of new and useful functions. It proved irresistible—there have been countless experts panels, a TED Talk, and an international student competition.

But Synlogic’s plan for a genetically modified pill is one of the first concrete medical applications of such ideas. It involves deleting and adding several genes to a harmless strain of E. coli, the gut bacterium, so that it develops an unquenchable appetite for ammonia, formed from the nitrogen we get from eating protein.

Normally, extra nitrogen is turned into urea and we just pee it away. But some people can’t process it fast enough. They end up instead with ammonia levels that can be toxic enough to kill newborns and in kids and adults can cause delirium and angry behavior. Synlogic’s E. coli would take ammonia and turn it into arginine, a harmless amino acid.

A person would probably swallow a capsule once a day containing about 100 billion bacteria, says J.C. Gutierrez, the company’s CEO. The company has so far raised $70 million from venture capitalists.

It’s not just rare diseases being targeted with redesigned bacteria. Startups like Ernest Pharmaceuticals, recently formed by University of Massachusetts professor Neil Forbes, plan to fight cancer using salmonella, a bacterium best known for causing food poisoning that also has a habit of congregating in tumors.

Forbes thinks the germs can be programmed to recognize they’re in a tumor and release anti-cancer drugs too toxic to be given as an injection.

Previously, one European company, ActoGenix, tested pills containing genetically modified bacteria, but no GM germ pill has yet gone on sale, and the idea remains novel enough that there’s no agreement on what to call such medicines. The U.S. Food and Drug Administration has designated them as “living biotherapeutic products.”

Currently, as many as eight to 10 GM bugs are awaiting a green light from the FDA for early testing in the U.S., estimates Yamil Hernandez, cofounder of Thayer Pharmaceuticals, a startup in Maryland that intends to engineer a yogurt bacteria, lactobacillus, to consume phenylalanine, an ingredient in milk, nuts, and Coke Zero and other diet sodas that some people can’t digest. Hernandez says a germ designed to metabolize it could be sprinkled as a powder on food.

“It’s like hungry, hungry hippo, just with a very strong preference for phenylalanine,” he says.

Using bacteria as a treatment isn’t new to medicine. The vaccine against tuberculosis is made with weakened germs. And the U.S. probiotics market—those pills and yogurts at health food stores containing healthy gut bacteria—is worth $3.5 billion.

But no one is quite sure how to regulate a GM pill whose contents are both alive and likely to end up in toilet bowls. Gutierrez says in some cases, depending on how the germ is modified, the U.S. Environmental Protection Agency may have to sign off in addition to the FDA.

One risk is that bacteria can exchange DNA with one another, which means companies’ genetic alterations could end up in a completely different organism. In practice, scientists say organisms with engineered genomes stand little chance against their wild bacteria siblings. The germs usually die off and their genetic cargo goes extinct.

Synlogic says its germs have some additional features programmed into the genome that make them safer. Gutierrez says the ammonia-eating program will turn on only in a low-oxygen environment like the human gut. It’s also dependent on a nutrient, thymidine, that’s not found at high levels in the digestive tract. He says that because of this, the germs will divide only once before dying.

Credit

Illustration by JooHee Yoon

Antonio Regalado

Antonio Regalado Senior Editor, Biomedicine

I am the senior editor for biomedicine for MIT Technology Review. I look for stories about how technology is changing medicine and biomedical research. Before joining MIT Technology Review in July 2011, I lived in São Paulo, Brazil,More where I wrote about science, technology, and politics in Latin America for Science and other publications. From 2000 to 2009, I was the science reporter at the Wall Street Journal and later a foreign correspondent.


SHARE THIS
Previous Post
Next Post