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Bacteria busters

September 5, 2007
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Foodborne pathogens and other bacteria are devoured from within by viruses known as bacteriophages. This fall, food manufacturers will begin testing this food-safety weapon.

John D. Vazzana, CEO, Intralytix Inc., Baltimore

If bacteria-destroying viruses become the next defense against foodborne pathogens, the industry will have to thank a Canadian Commie.

Biologist Felix d’Herelle first discovered the existence of bacteriophage in 1910 while conducting research in Mexico. When d’Herelle smeared feces from sick locusts onto plates of agar, clear spots appeared after a while in the cultures. He deduced an organism was eating the coccobacilli bacteria that had infected the locusts. He modified the Greek word phagin (to eat) and dubbed these germ killers bacteriophage. A phage virus attaches itself to a specific bacterium and injects genetic material into the cell. The bacterium’s metabolism becomes an incubator, reproducing the phage until its cell wall bursts, releasing hundreds of new phages that attack more bacteria.

An admirer of Josef Stalin, d’Herelle accepted an invitation from the Soviet government in 1934 to join the Institute of Bacteriology in Tbilisi, Georgia, where he joined George Eliava, a microbiologist and founder of the Eliava Institute. Eliava scientists worked in obscurity for decades, isolating the phage that attacks specific pathogens and developing purified cultures, until the mid-‘90s, when the emergence of antibiotic-resistant germs revived interest in phages. A number of US and European start-up ventures, most involving Eliava alumni, have sprung up since. While medical applications are the primary focus, phages also hold promise for a number of nano-applications. Among the firms pursuing food pathogen control is Baltimore-based Intralytix Inc.

Intralytix was founded in 1998 by Alexander “Sandro” Sulakvelidze, a Georgian microbiologist, and J. Glenn Morris Jr., a doctor and professor of internal medicine and infectious disease at the University of Maryland School of Medicine. Sulakvelidze was doing post-doctoral work with Morris, who was treating patients, some terminal, who suffered from antibiotic-resistant infections. Phage treatment had promise, but the efficacy had never been demonstrated to the satisfaction of health regulators. Working with US Agricultural Research Service (ARS) scientists in nearby Beltsville, MD, they conducted research and petitioned FDA in 2002 to use phage on food. At the same time, John D. Vazzana, a retired business executive who had guided several start-up ventures to successful IPOs, developed a strategic business plan for Intralytix and was asked to execute it in 2003.

In this illustration of a phage, the blue area depicts the head, where genetic material is stored. The pink corkscrew tail is the point of attachment to a target bacterium. Genetic material feeds into the target, generating hundreds of new phages until the cell wall bursts. Source: Intralytix Inc.

FE: How did Intralytix get involved with the food industry?

Vazzana: In the company’s early years, we signed a research & development contract with Perdue Farms to isolate and ferment phages to attack Salmonella enteriditis and Listeria monocytogenes. We had a basic product by 2001 for Salmonella, but because people cook raw chicken and destroy salmonella, a Listeria control was deemed more useful. At the encouragement of Perdue, we pursued regulatory approval for the Listeria phage, which we named LMP-102.

We’ve also worked closely with ARS researchers in their lab in Beltsville, MD. In 2001, two ARS plant pathologists published a largely favorable report on the use of phages on whole and cut apples and melons. Ultimately, we’d like to get a sample of the E. coli 0157:H7 strain in last fall’s spinach contamination to test against our phage cocktail. So far we haven’t, and neither has ARS.



FE: Why did it take four years to win FDA approval for LMP-102?

Vazzana: It was partly our fault that it took until August 2006. We didn’t understand what scientific data they needed. The process should go more smoothly in the future.

FE: While you have been preparing for commercial testing, EBI Food Safety in the Netherlands entered the market with an anti-Listeria phage. How does that affect LMP-102?

Vazzana: After we educated FDA, these guys waltzed in and got limited approval, a letter of no objection for GRAS status. I’m a little hurt. But we don’t look at them as competitors. EBI started a year or two after us and has one product designed for cheese. They are helping to educate end-users and consumers about phage as a food safety tool.



FE: How will phage be applied to food safety?

Vazzana: We’ve developed a mixture of six phages that, to date, have been clinically tested and proven effective against 278 strains of Listeria. We used our library of 30 different phages in developing the final cocktail. We can’t say the six phages will kill all Listeria bacteria because there may be rogue strains that we haven’t tested against, but it is quite efficacious.

We’re working with equipment makers on engineering a system to deliver phage to the surface of food immediately before packaging. Once we scale up phage manufacturing, we can experiment with different ways to deliver the product.

In test environments, we’ve had 2.5-3 log reductions of the target bacteria, but those tests were with sample inoculated to high bacterial concentrations. In real-world concentrations, product might be contaminated to 1-2 logs. The phage keeps multiplying as long at there is bacteria present to infect.

We’ve had phone calls, mostly from QA people, about testing LMP-102 at 70 US food companies and some international firms. Most of them make encased meats or import smoked fish and other ready-to-eat foods. They either have had a recall or are sensitive to that possibility. Some see phage as a way to improve their risk classification and do business with top echelon foodservice and retail customers.



FE: What are the human risks with phage?

Vazzana: Phages don’t infect mammalian or plant cells; they only infect bacteria. However, unless the strain is pure, they leave behind debris that could be fatal to humans. Our most important proprietary intelligence is techniques that are a slam-dunk for purification of phage on a commercial scale.

Phages are the most ubiquitous organisms on the planet, with many millions of varieties. In a milliliter of unpolluted water, there are an estimated 2 billion phages. Isolating the ones that control Staph, E. coli, Salmonella and Listeria out of nature was the focus of our early work. We know every gene in every phage in our library and constantly monitor for rogue genes.



FE: Scientists at Tbilisi’s Eliava Institute complain Western biotech companies are exploiting their work and will reap all the profit. Is that a fair assessment?

Vazzana: There are a lot of very smart people at Eliava, and we have a lot of respect for their technology. It’s just difficult to convert it to something we can get approval for here. There are steps you have to take early in the process to get that approval, and those weren’t taken in Georgia.

We had some early development agreements with Eliava, but it became evident, in order to meet Western regulatory requirements, we had to apply advanced techniques to isolate and characterize phages. The technology has to yield consistent results, meet quality standards and be reproducible.



FE: The inventors of a 2004 patent assigned to Intralytix are from Tbilisi. How would you characterize the relationship?

Vazzana: From time to time we have formal arrangements with the Georgian scientists, and we hope to collaborate more with them. Some of their cultures have been used for 30 years to treat chronic wounds, and from an anecdotal view are very effective. The only point you can fault them on is purification. But there are a lot of smart people there. Sandro Sulakvelidze, our founder, is in Georgia as we speak and will be visiting Eliava to see how we can have a closer relationship.



FE: How stable are the phage cocktails that food companies will test?

Vazzana: We will ship in a refrigerated state and in very concentrated form. Companies will dilute the liquid with purified water. In a refrigerated environment, phages will retain their strength for up to six months. They cannot multiply outside the presence of the target bacteria.

We were making cultures in 10-liter fermenters until June, when we contracted with a firm to make 1,000-liter batches. By the fall, we hope to scale up to commercial quantities for shipment to plants for pilot tests. Ultimately, the phage will be in powder form that can be warehoused for two to three years. We keep all master seed stocks in our lab in a powder form. Converting fermented stock to powder is one of our challenges, and we will meet it.

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