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The power of 'bacteriophage'

Date posted: March 16, 2006

Antibiotic alternative launched by CABIDF research offers a practical solution for safe food and healthy animals.

Canadian researchers are one step closer to launching a new type of animal treatment with breakthrough potential to benefit Canada's beef industry and beef consumers.

New "bacteriophage" treatments have unique advantages to protect cattle against major bacterial infections and provide an alternative to antibiotics, says Dr. Roger Johnson of the Public Health Agency of Canada. Several phages, including ones targeted at E. coli O157:H7 are performing well in advanced testing and could result in products on the market within three-to-five years. Other phages targeting Salmonella Typhimurium DT 104 also have potential. Early research with these phages was supported by the Canada Alberta Beef Industry Development Fund (CABIDF).

"The E. coli O157:H7 phages we're testing are producing very promising results," says Johnson. "Safety and efficacy results look very satisfactory, and we're working toward optimal formulations and delivery systems. We're optimistic this work will result in valuable animal treatment options that will be practical and cost-effective for beef producers, and provide great food safety and perhaps animal health advantages for Canada's beef industry."

Scientists have known about phages for 90 years, but as therapeutic agents, they have been largely placed on the back burner in the western world ever since the discovery of antibiotics for the treatment of bacterial infections, says Johnson. Rising concerns related to over-reliance on antibiotics and emergence of bacteria resistant to multiple antibiotics have sparked renewed interest internationally in developing phages as an alternative treatment.

"We have seen the emergence of new foodborne pathogens, such as E. coli O157:H7, that are difficult to control," says Johnson. "We have also encountered microorganisms that have rapidly developed resistance to many antibiotics, Salmonella Typhimurium DT 104 being a prime example. As a result, there is strong interested in exploring avenues that could replace antibiotics under these circumstances."

In the question and answer session below, Johnson provides a big picture outlook of the prospects for phages, including their benefits for beef producers.

Q: What is the current stage of progress toward a bacteriophage treatment for E. coli O157:H7 and Salmonella Typhimurium DT 104, and what are the key obstacles ahead?

A: In our CABIDF project a few years back, we identified some valuable phages for treating cattle for E. coli O157:H7, and also some with potential for treating Salmonella Typhimurium DT 104 infections in cattle. Since then we and our colleagues, including Dr Tim McAllister and Dr Susan Bach of Agriculture and Agri-Food Canada, have been addressing a number of questions that need to be answered before these phages can be used in a commercial operation. We are seeing good progress with the E. coli O157:H7 phages, particularly in ensuring their safety and efficacy, and looking at ways of producing them for safe use in cattle. We're optimistic a related product or products will become available to cattle producers within the next several years.

One focus has been developing the best formulations and delivery systems that would be simple and effective. The keys here are to ensure the dosage that reaches the intestinal tract of cattle is effective, that the viability of the phages is preserved and that we can provide the phages in a form that is easy for cattle producers to administer.

We've only done a small amount of work on this and we need to bring in some additional expertise in this area. But we have had good results in drying the phages and embedding them in a protective coating that resists stomach acids. We're hopeful we can develop a relatively dry product that could be added to cattle rations as a granular powder. Our focus has been looking at what kind of formulation would be the easiest for producers to use and control in the cattle environment. For example, such a formulation would be survive well and would be dense enough to not to blow around in the field. It would also be simple for producers to control which animals get the medication and which don't.

Once this work is near completion, the next step for us is applying for regulatory approval to conduct a field trial with these phages in naturally raised cattle. It would probably take one whole summer to do the trial and then another year to put the data together. If that is successful and the indications are good, then it would probably be another two or three years before there would be a product on the market. So, we're looking at another three-to-five years.

Q: What are the key questions to ensure the safety of this approach?

A: Because phage therapy is relatively new, particularly in the western world, there are a lot of questions we consider important.

For example, are the phages we selected able to transfer undesirable genes from one bacterium to another - a process called transduction. We have developed a system in which we can evaluate our phages to see whether in fact they do this or not, and whether they have a high or low risk of doing this.

Another question we've examined is whether there would be any detrimental effect on humans if these phages were used in cattle and got into the meat supply. This includes looking at the potential of these phages to trigger any undesirable effects when humans are exposed to them concurrently with bacteria such as E. coli O157:H7. In one specific example, we've looked to see whether or not the phages would switch on any of the virulence genes of E. coli O157:H7.

So far what we're finding is good news. The phages we've selected have a very low frequency of transduction, and we haven't found any evidence that they switch on key genes in affecting virulence for humans.

We've also found that these phages have little or no impact on other animal species that share cattle environments, such as birds and rodents.

Q: Will phage therapy be practical for cattle producers?

A: The prospects are very positive. Regarding the production of phages - growing and preparing them for use - we've found two important things

First, we've been able to select non-pathogenic host bacteria on which we can grow these phages. Typically they would be grown in E. coli O157:H7, but when it comes to production for commercial use we don't want to have to be handling a potent human pathogen. Second, we have gone to using a completely plant-based media on which to grow these host bacteria. To grow bacteria you need some sort of bacteriological culture medium, and most of these contain animal products. But because of the risk of BSE, for example, there would be regulatory issues on the oral administration of a product to cattle that was derived from bacteria cultured in medium that might contain animal products. So, we have gone to a plant-based media and these non-pathogenic hosts to avoid those issues.

Q: Obviously it's important we have alternatives to antibiotics, for a number of reasons. Aside from being an alternative tool, what is the key advantage of phages?

A: One very appealing feature is that phages are very easy and economical to produce in large quantities. Also, phages are unique and exciting because they actually evolve in response to changes in their target bacteria. For example, bacteria may become resistant to phages. But, unlike antibiotics, phages respond to finding that their host has become resistant by mutating themselves so that they can re-infect the new type of bacterium. This takes place in a very short time, so it's often easy to find new phages in the presence of bacteria that have become resistant to the original phage.

One challenge, then, is that the regulatory system has to allow for that evolution in some way. But if we can figure out the safety implications, that unique activity is potentially very advantageous.

Q: How would you describe the evolution of bacteriophage research in general?

A: We've seen a lot of research progress that I expect will result is some key advances in veterinary and human medicine over the next several years.

The history is very interesting. Since phages were first discovered in the early 20th century, there's been a lot of excellent work done in Eastern Europe, in Poland, Russia and the Czech Replubic, and especially in the Republic of Georgia.. Those regions frequently use these kinds of therapies in people. Recently, I was actually over at the Eliava Institute in the Republic of Georgia, which is named after George Eliava who, with Felix D'Herelle, a French Canadian, first developed phages for therapeutic use in humans. It's quite remarkable what they're doing with phages over there. There's a whole body of science published in the languages of these countries, but for numerous reasons, including the language barrier, it has not been used widely in the western world. We should not forget that science was conducted at a very high level in these countries. They put the first satellite into space and they were very advanced in chemistry and biology.

Now, a lot of that science is finally coming forward and being used. I think in the next four or five years we'll see a lot of information drawn from past science, and verified by current research, that will help to establish the credibility of the work and the benefits and potential of phages.

In the West, the application of bacteriophage therapy in animal health and food safety goes back to work of Hugh Williams-Smith in the late 70's in the UK. Our group in Canada is part of the new wave of science that is picking up the ball, and we hope to make some major advancements over the next decade and beyond.

Q: What are other uses of phages we can look forward to?

A: There are other potential applications in the food area that are very interesting. For example, researchers are now beginning to investigate the potential for spraying meat and produce such as sprouts with phages, as a way of controlling contamination should the bacteria start to grow.

There's also a tremendous amount of interest in the proteins that the phages make that kill bacteria by causing them to burst. Specifically, there are two basic compounds or substances. One is a group called holins, which actually put holes in the bacterial membranes. The other is called lysins, which actually help to dissolve the membrane of the bacterium - that's how the phages, which have multiplied inside the bacteria, burst the bacterium and get out and go on and find another host bacterium. Researchers are beginning to exploit these proteins and their activities, because they are incredibly effective -- they're fast, they're simple and they're also quite specific.

Overall, there's a broad interest in these substances produced by phages as antimicrobial agents. There's the whole area of diagnostic technology. For example, and we have already looked at this in our laboratory, if you have phages that are highly specific for something like E. coli O157:H7, you could put a luminescence gene in the phages that would produce a light signal every time the phage was able to find and replicate in E. coli O157:H7. This could be result in very sensitive testing of foods for numerous bacteria, including E. coli O157:H7 and other foodborne pathogens. There's lot of interest in that area.

Also, there's considerable interest in bacteriophage therapy in treating diseases of plants. Intensive production of produce - tomatoes, sprouts and those types of plants - is associated with the same kind of problems we see in animal agriculture, where high intensity farming results in a higher risk of infectious disease. Environmentally friendly, targeted phages could be an important tool for that kind of production.

Q: Bacteriophage therapy has largely been under the radar to this point. Is it ready to break out?

A: We're seeing a lot of momentum with the interest in this area now. Western science in some respects is like any other business, where people gravitate to where the money is, and I think that will happen in the short term as we see a greater investment in bacteriophage research. It's a new wave of potentially powerful technology and there's no doubt it will be exploited commercially. The process is already happening.

For Canada, it's going to be important in the fields of agriculture and medicine, in the life sciences and environmental sciences, to develop a capacity to do world-class work in this field. Much of the work on phages in the western world has been not been in phage therapies, but in molecular biology, and to date, there's only been a small number of people who have worked with other applications of phages. I think it's going to be important, both provincially and nationally, to have a capacity to research and exploit this potentially valuable technology in the very near future.

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