Bacteria can be engineered to fight cancer in mice. Human trials are coming.

There are trillions of microbes living in and on our bodies-and we might be able to modify them to help us treat diseases. Scientists have altered the genomes of some of these bacteria that live on skin, essentially engineering microbes that can prevent or treat cancer. It appears to work in mice, and human trials are in the cards.

I think this is really a major breakthrough," says Julie Segre, a geneticist and skin biologist at the National Human Genome Research Institute in Bethesda, Maryland, who was not involved in the research. The idea of harnessing microbes to treat cancer, and potentially other diseases, is a very exciting new avenue for the microbiome," she says.

Most research into the microbiome has focused on the trillions of bugs that live in our guts. But our skin is also home to multiple microbial ecosystems. The community that lives in your armpit could look quite different from the community that lives on your eyelids. We are still figuring out exactly what these microbes are doing, but they seem to feed on our secretions, possibly produce some beneficial secretions of their own, and protect us from infections.

They also appear to influence the way our immune systems work. A growing body of research suggests that microbes living in and on our bodies can amplify or turn down the immune response to something that might potentially cause us harm-whether it's an infection, a tumor, or something more benign.

Simply introducing a microbe to the skin of an animal can also trigger an immune response-albeit one that doesn't cause all the usual signs of an infection, like pain, fever, or sickness. This is somewhat surprising, says Michael Fischbach at Stanford University, because these microbes don't tend to be harmful: They're our friends." Adding a microbe to the skin of a mouse, for example, can have an effect similar to giving the same mouse a vaccination, he says.

Modified microbes

Fischbach and his colleagues wondered if they might be able to hijack this effect to tweak the immune response.

The team started the investigation by choosing a microbe that is commonly found on human skin. S. epidermidis is thought to be a member of the human microbiome, and it doesn't typically cause disease. The microbes the researchers used were originally collected from behind the ear of a human volunteer, says Fischbach.

The researchers modified these microbes by inserting a new gene into them. The gene codes for a protein that sits on the surface of some cancer cells. The idea is that if the immune system generates cells that recognize the microbe, these cells will also recognize tumors.

The team then applied these designer bugs" to mice by wiping them over the heads of the animals with a cotton bud. Another group of mice had regular, unmodified samples of the bacteria smeared onto them. In both cases, the microbes quickly made a home for themselves on the mice's skin, says Fischbach.

At the same time, the mice were injected with skin cancer cells. These cells were taken from other mice that had cancer, so they had the target protein on their surface.

Tumor target

Over the following days and weeks, these cancer cells grew into tumors in the mice that had been given the regular microbe. But the progression of the cancer was significantly slowed in mice that had been given the engineered microbe.

You could see these huge tumors growing on the side of the mice that had been swabbed with normal S. epidermidis," Fischbach recalls. But you couldn't see anything" in the mice that had been given modified microbes, he says. He points out that this particular type of cancer is notoriously aggressive and difficult to treat in mice.

We were surprised by the magnitude of the response," says Fischbach. It's surprisingly potent, given how mild a treatment it is." The treatment also worked in mice that already had tumors. The tumors appeared to shrink in animals swabbed with the engineered microbes. The team's findings were published in the journal Science.

Fischbach and his colleagues have a bit of work to do before they start trialing engineered microbes in people. First, they'll need to find a good candidate microbe. They don't yet know if S. epidermidis triggers the same immune response in people-it's possible that another microbe might work better.

They'll also have to choose a suitable cancer protein to target. This has proved a major challenge in the development of mRNA vaccines for cancer, which also rely on triggering an immune response to a cancer protein: there's often no obvious candidate.

Once the researchers have worked out which microbe they'll modify, and how, they'll trial it in animals to check that it's safe. Fischbach has plans to start trials of designer microbes in people with cancer within the next few years.

And while the team will focus on cancer, engineered bacteria could be used to treat other diseases, as well as allergies, Elaine Fuchs at the Rockefeller University in New York and her colleagues write in an accompanying commentary in Science. More research into the use of modified microbes could pave a way to safer, more effective and widely applicable therapeutics," the team writes.

What's exciting to us is the idea that you could just rub this behind somebody's ear and walk away," says Fischbach. And then, 10 days later, you might see a potent immune response that, in principle, persists indefinitely."