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Synchronized bacteria attack tumors

Engineered microbes grow and burst in cycles to release anticancer molecules

by Michael Torrice
July 21, 2016 | APPEARED IN VOLUME 94, ISSUE 30

Engineered bacteria cycle through growth and programmed death every 4 to 5 hours.
Credit: Jeff Hasty

In the 1890s, a surgeon named William B. Coley injected cancer patients with dead Streptococcus bacteria in hopes of coaxing the people’s immune systems to attack their tumors. Although these so-called Coley’s toxins had some success, doctors largely ignored them in favor of radiation and other therapies.

But the idea of enlisting bacteria to fight cancer lives on. In recent years, researchers have tried to exploit bacteria’s affinity for tumors’ low-oxygen and immune-cell-free environments, engineering the microbes to attack the malignant cells.

Now a team of synthetic biologists has designed bacteria that grow and die in programmed cycles, allowing for a controlled release of anticancer molecules and preventing unchecked bacterial growth (Nature 2016, DOI: 10.1038/nature18930).

“This is a fascinating paper that blows me away,” says Martin Fussenegger, a bioengineer at the Swiss Federal Institute of Technology, Zurich, who was not involved in the work. “It describes an unconventional, completely novel, yet highly promising strategy to use synchronized bacteria that invade and kill cancer cells by rhythmic ‘explosions.’ ”

If bacterial anticancer therapies ever make it to the clinic, such synchronized explosions would help avert harmful uncontrolled growth of bacteria, Fussenegger says.

To program Salmonella bacteria to execute these cycles, the researchers, led by Jeff Hasty at the University of California, San Diego, designed a genetic circuit with two basic functions. First, the circuit tells the microbes to produce an anticancer molecule as they grow. “Then we program them to commit suicide to deliver the drug,” Hasty says.

That second step involves quorum sensing, a process in which bacteria communicate via molecules to coordinate their actions, such as forming biofilms. In this case, the engineered circuit instructs the bacteria to make a small molecule called N-acyl-homoserine lactone. Once the bacteria reach a certain threshold population, the molecules activate quorum-sensing pathways in the genetic circuit and trigger the cells to lyse, or break open, spilling their anticancer cargo.

About 10% of the bacteria survive the resulting wave of destruction and go on to restart the cycle. In cultures, each cycle lasts about four to five hours and the bacteria keep cycling for 15 to 18 days, Hasty says. “There is a strong selective pressure for the bacteria to beat this cycle, and eventually they do,” he says.

The researchers tested three strains of these bacterial suicide squads in mice with metastasized liver cancer. Each strain synthesized one of three anticancer payloads: a molecule that lyses mammalian cells, a cytokine that initiates an immune response against the tumor, or a protein that triggers cancer cells to kill themselves.

After 12 days, tumors in mice receiving the engineered bacteria were about one-quarter the size of those in mice treated with normal Salmonella. And when the researchers treated mice with the cycling Salmonella and the chemotherapy drug 5-fluorouracil, the mice survived 50% longer than animals receiving either the drug alone or just the bacteria.

Hasty considers this study a proof of principle and cautions that before any bacteria therapy can be tested in people, researchers must understand how the immune system will respond to the engineered microbes.

Still, “it’s forward-thinking and novel and worth exploring more,” says Shibin Zhou of Johns Hopkins Medicine. Zhou also wonders if the bacteria’s controlled release of therapeutic payloads could be exploited to treat chronic diseases such as hypertension or diabetes.



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Georgev Meredith MD (April 22, 2017 7:37 PM)
George Meredith MD
This is but the tip of the iceberg!

Consider: the breast cancer death rate per 100,000 US women is essentially the same today as it was in 1970. The treatment then was some type of mastectomy and adjunctive radiotherapy (hopefully 5000 Rads as opposed today' more dangerous 6500 Rads).

Surgeons knew back then that adjunctive chemotherapy did not appreciably improve the 5 and 10 year survival rates and so no adjunctive chemotherapy was given back then.

Today, we have genetic testing, the Cancer Treatment Centers of America, a plethora of adjunctive chemotherapeutic agents and a host of oncologists who can cite statistics that indicate that the new chemotherapy that they have just been licensed to use....why this new chemotherapeutic agent offers real hope. Emphasis in the words fear and hope!

Go back and look at chemotherapy in Cecil and Loeb's textbook of Internal Medicine circa 1970 and you will find....surprise....surprise....the cancers that were being cured by chemotherapy back then, are the same ones that being cured today. Except for Lance Armstrong's testicular carcinoma and perhaps the rare Burkitt's Lymphoma
The Hodgkins Disease, some lymphomas, childhood luekemias are the same cancers that were being cured back in the seventies and about in the same proportions . But not the breast, lung, prostate and pancreatic cancers.

Read my lips! The adjunctive chemotherapy that oncologists are pushing off onto an incredibly naïve American public, do not work! Do not produce cancer cures! Play on patient fears. And simply feed patients' false hope. Prolong their misery. And wreck and bankrupt their families!

Wakeup America! This is but the tip of the iceberg! Many of you are being scammed by or are about to be scammed by your local oncologist!

George Meredith MD
Virginia Beach

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