'The sick organ will always get freshly produced proteins'

Israeli team pioneers bacteria ‘factories’ to produce medicine inside the body

In peer-reviewed study on mice, Technion scientists say novel method using harmless microneedle patches ‘opens the door’ to treat war wounds, diabetes, and inflammatory skin diseases

Israeli researchers have developed an innovative method that enables medicine to be manufactured within the body itself.

The pioneering approach, not yet tested on humans, uses live, harmless bacteria that act like tiny factories, producing therapeutic proteins inside the body, exactly where they are needed.

“We are accustomed to thinking that to introduce a drug into the body, it must be manufactured in a factory and then delivered via a capsule or an injection,” said Prof. Boaz Mizrahi of the Technion-Israel Institute of Technology’s lab for biomaterials in the Faculty of Biotechnology and Food Engineering.

“This could be a turning point in the world of pharmaceuticals, and a new paradigm for both drug production and consumption,” he added.

Mizrahi recently spoke with The Times of Israel in a joint interview with Dr. Adi Gross, the study’s lead researcher.

Proteins are used in a variety of medicines, Mizrahi said. One example of a medical protein is insulin, used to help control blood sugar. Another hormone helps people with kidney disease make red blood cells. There are also antibodies and growth hormones made with proteins.

However, “proteins are very fragile, and their configuration is critical,” Mizrahi explained. If they are swallowed, for example, the stomach and intestines treat them like food and break them down, so they are ineffective.

The researchers’ novel method enables bacteria to produce and release perfectly configured, ready-for-use proteins within the body.

After testing on mice, the approach was written up in a peer-reviewed study which appeared in the journal Advanced Healthcare Materials. The research was co-directed by doctoral student Caroline Hali Alperovitz and supported by the Israel Science Foundation and the Russell Berrie Nanotechnology Institute at the Technion.

The technique “opens the door to a new kind of treatment,” Mizrahi said, including therapeutics for severe burns, war wounds, diabetes wounds, and inflammatory skin diseases such as psoriasis.

The importance of bacteria

Mizrahi said his lab is “inspired by nature, using knowledge collected by nature for centuries.”

He explained that for the past several years, scientists worldwide have been exploring the use of engineered bacterial therapies. The bacteria, which are genetically modified, can then deliver medicines and therapeutics to treat cancer, metabolic disorders, and inflammatory bowel disease.

In their earlier research, the scientists were able to use what Mizrahi called this “living materials” approach with a microneedle patch system that produced useful polymers, or large molecules, inside the skin. The method formed the basis for the current research.

“We needed something that can both synthesize and secrete in situ, within a specific place in the body, giving it the best condition, to produce and release therapeutic agents,” Mizrahi said.

For their study, the Israeli scientists used a harmless bacterium, Bacillus paralicheniformis, and engineered it to produce the protein γ-PGA (gamma-PGA). This protein plays a vital role in the healing of severe wounds and in reducing inflammation.

They then used a microneedle patch, which the scientists designed and manufactured, to deliver the bacteria.

“This is the simplest patch that you can think of,” Mizrahi said. “It’s like a Band-Aid.”

Once the patch is applied to the skin, the microneedles penetrate the inner layer of the skin and then dissolve. They do not harm nerves or blood vessels. Inside the body, the bacteria act as a “factory,” exactly where they are needed, according to Gross.

This “allows the bacteria to start producing and releasing the therapeutic protein right at the treatment site,” Gross said.

The researchers used detailed chemical analysis to confirm that the bacteria produced a “pure and active therapeutic substance.”

Treating mice in the lab, the scientists found that their skin remained healthy. The patch dissolved within just two hours, with no signs of inflammation or tissue trauma.

In the future, Mizrahi envisioned patients being able to use the patch “like a sticker.”

“It causes zero pain, and unlike an injection, it doesn’t require medical staff,” he said.

‘Huge benefit’

The new technology offers several advantages to traditional medicines.

“The diseased organ will always get freshly-produced proteins because they’re produced inside the body,” Mizrahi said. “That’s a huge benefit.”

Since some proteins are unable to be absorbed into the body, and others are sensitive to exposure to air, this approach circumvents those issues.

Because the bacteria multiply within the tissue, the researchers said, a single dose of bacteria introduced into the target organ can be sufficient for days, thereby reducing treatment costs.

For example, insulin is a protein hormone that a healthy body makes in the pancreas. Diabetes patients, who are unable to produce their own insulin, are given insulin, mostly by injection.

“In the future, we could treat patients using this ‘living’ system,” Mizrahi said. Currently, the researchers are experimenting with different bacteria to release other proteins.

Asked if they were surprised by the success of their experiment, Mizrahi said, “We never know if it’s going to work. That’s part of the excitement.”