bacteria-106583

by Benika Pinch

Fancy a pill packed with bacteria?

Researchers are investigating using genetically modified bacteria, taken in pill form, to treat human disease. Informally, they are called “designer probiotics”. But, unlike probiotics (microorganisms with known health benefits), they can’t be obtained via a serving of yogurt from your local supermarket. Rather, the bacteria in question are feats of genetic engineering and are specifically designed to produce drugs.

If the idea of ingesting a community of bacteria is a little off-putting, keep in mind that we already share our bodies with thousands of bacteria. In fact, the average adult is composed of more microorganisms than human cells – making each of us a walking microbial metropolis. So why not invite some microbial physicians to town?

Bacteria as Drug Factories

Bacteria aren’t newcomers to the drug discovery world. In fact, bacteria are routinely transformed into drug-producing factories using a technique known as recombinant DNA technology, in which DNA from difference species is combined and inserted into a host organism.

Take insulin, for example. In the late 1900s, scientists engineered bacteria to include the gene for the human insulin protein. After being grown in large vats, the bacteria pumped out insulin, which was then purified and given to humans.

The new “bacteria in a pill” approach does things differently. Instead of pumping out a drug and purifying it in the lab, the bacteria do their drug-producing act directly inside a patient!

This raises the question: why deliver a hoard of bacteria that will produce a drug, rather than giving the drug in its purified form? It turns out that using bacteria to deliver drugs has a number of advantages in treating various diseases, including cancer.

Bugs as Drugs: Using Bacteria to Fight Cancer

Employing bacteria to fight cancer dates back to the late 19th century when an oncologist, William B. Coley, deliberately infected his cancer patients with Streptococcus pyrogenes, the agent that causes strep throat. Talk about risky business – some patients experienced complete remission, but others battled dangerous systemic infections.

Coley’s work highlighted a remarkable phenomenon: a Streptococcus infection can help shrink tumors. How? It was subsequently discovered that tumors are extremely low in oxygen and many bacteria preferentially grow in environments without oxygen. Therefore, as the bacteria accumulated in the tumors of Coley’s patients, they triggered an immune response and competed with the tumor cells for nutrients, essentially starving the tumor cells to death.

Given that the mere presence of bacteria can effectively shrink a tumor, then infection with bacteria engineered to produce a cancer drug should be even more effective. Also, since many bacteria grow selectively in tumors, they could overcome one of the primary challenges in cancer therapy: delivering drugs to tumors, and not to surrounding healthy cells, which can cause nasty side effects.

So what specific bacteria are under consideration? Here’s one that may come as a surprise given its well-earned reputation: Salmonella.

Salmonella: Friend or Foe?

You probably know Salmonella as the bacteria that hides in undercooked meat, waiting to wreak havoc on the human body with diarrhea, vomiting, and chills. Not necessarily something you want to ingest by choice! Salmonella, as it turns out, is toxic to cancer cells. So in this case, our enemy’s enemy just might be our friend.

But before we can use Salmonella as a drug, it needs to be way less dangerous. Once again, genetic engineering comes to the rescue. Researchers engineered Salmonella to be safer, with far fewer side effects. In mice, this weakened Salmonella still kills tumors, but without causing systemic infections or harming healthy cells.

In a recent study, researchers further engineered Salmonella to produce toxins that target a protein, called epidermal growth factor receptor, which is highly expressed on cancer cells. This modified Salmonella not only effectively kills cancer cells, but also is remarkably selective, being 1000 times more likely to grow in tumors over healthy tissue.

Genetically modified Salmonella could therefore present a triple threat as a cancer therapeutic: the bacteria themselves are toxic to malignant cells, they selectively grow in tumors, and they secrete cancer-killing drugs.

Regulating Living Drugs

As you might imagine, deliberately infecting people with genetically modified bacteria requires thorough regulation.

To ensure safety, bacteria under consideration for therapeutics need to be susceptible to antibiotics so that they can be rapidly cleared from the patient if necessary. Also, as an added measure of precaution, researchers have created a built-in containment mechanism in genetically modified bacteria to prevent them from growing free in the environment. Specifically, they lack the machinery necessary to manufacture thymidine, a key building block for survival. The modified bacteria can therefore only survive in environments where thymidine is present – either in humans, or in culture in a laboratory.

Just a Spoonful of Bacteria

Genetically modified bacteria are currently being evaluated in human clinical trials for a variety of diseases in addition to cancer. Bacteria engineered to secrete an anti-inflammatory drug are showing benefit in patients with inflammatory bowel disease. In addition, researchers modified a normal resident of the human body, Lactobacillus jensenii, to secrete an antiviral protein that prevents HIV infection in women.

A new treatment for diabetes is also underway in the form of a harmless microbe used in dairy production, Lactococcus, which researchers engineered to secrete the precursor of insulin, proinsulin. This bacterium could save diabetic patients from frequent and painful insulin shots.

Ultimately, genetically modified bacteria are self-propelling drug factories, making them attractive vehicles for drug delivery. In addition to their ability to secrete therapeutics, the bacteria themselves exert beneficial effects: ranging from bacteria known to be good for health (probiotics), to the selective toxicity of Salmonella towards cancer cells.

So how about it – interested in that bacteria pill yet?

 

Benika Pinch is a Ph.D. student in the Chemistry and Chemical Biology program at Harvard University.

This piece was written with guidance from Friends of Joe’s Big Idea.

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