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In January 2016 the National Science Centre announced the results of HARMONIA 7 call for proposals designed as collaborative transnational projects. One of the winners is Prof. Zuzanna Drulis-Kawa from UWr’s Faculty of Biological Sciences.

The project entitled „The phages recognising bacterial surface polysaccharides as their own receptors select for a bacteria population resistant to phages which simultaneously becomes more susceptible to protection mechanisms of the immune system”, has been granted funds totalling 1 173 600 PLN.

Prof. Zuzanna Drulis-Kawa
Fot. Dominika Hull/UWr/CC-BY-NC 2.0

What exactly are phages?

Prof. Zuzanna Drulis-Kawa: They are virus-infecting bacteria. Just as we get infected with viruses and come down with colds, phages attack only bacteria.

Does a phage have any specific structure?

A phage is adapted to its host organism – bacterium – and specialised enough to infect specific bacteria species, more precisely, specific strains within species. Bacteriophages are not universal and can’t kill all bacteria, like broad-spectrum antibiotics which can destroy many groups of bacteria. Phages attack only selected, „matching” bacteria.

Phages were being studied many years ago but the research stopped once antibiotics were discovered.

At the beginning of the 20th century scientists discovered in water samples something which killed bacteria, but they didn’t know what it exactly was. It turned out it was a virus – potential medicine for infectious diseases. We owe the discovery of those merciless bacterial parasites to independent researchers: Frederick Twort and Felix d’Herelle. The latter used phages to fight dysentery. In the heyday of phagotherapy ready-made phage preparations, in liquid or gel form, were widely available.

But once antibiotics were discovered, phages got forgotten. Antibiotics are easy to synthesise and mass produce, moreover, the range of their action is wider. One antibiotic can kill many bacteria species, which makes it easier for physicians to select the right medicine, because picking it is simple and the treatment is likely to be effective.

But antibiotics also kill the „good” bacteria.

Yes, because they don’t make any distinction between them. It may cause secondary symptoms, such as dysfunctions of the gastro-intestinal system or changes to the natural gut flora.

So are phages more „intelligent”?

They’re more selective in action and in order to administer phage therapy, the physician must know which bacterium has caused the disease. But on the other hand, preparations containing various bacteriophages attacking most frequently occurring bacteria (pictured) causing particular infections, such as purulent skin infections, are also available. One can prescribe „cocktail” formulations containing several kinds of phages.

So is phage therapy currently being used?

For example in Georgia, where EU guidelines don’t apply. In Poland it was fairly widely used until we joined the EU. Once EU principles on experimental therapy were introduced, it changed. In Wrocław we have the Phage Therapy Unit at the Medical Centre of the Institute of Immunology and Experimental Therapy of the Polish Academy of Sciences at Weigla street. This unit provides experimental phage therapy, which includes the classification of patients, selection of phages for treatment, and oversight of the therapeutic process. Phage therapy is no longer that accessible. Regulations were nonetheless necessary, as they minimise the risk of unwanted side-effects, which may occur in any kind of experimental therapy.

A physician administering such preparation to a patient is responsible for his or her safety. In the case of alternative therapies there have to be centres willing to undertake treatment and take responsiblity for the risk.

What diseases are treated at the unit at Weigla street?

Most often burns and postoperative wounds, lesions, infections resulting from diabetic foot syndrome.

Is therapy effective?

It’s not a miracle cure. Much depends on the route of delivery and way of administration, on the physiology of the affected organism, just as in antibiotic therapy. Sometimes bacteria are located in such a place that the medicine reaches it in too weak concentration or not at all, and there is no progress in treatment. Problems with persistent infections in such patients continue for years. Miracle cures don’t exist.

How phages work?

Bacteriophages are divided into two basic groups – one multiplies in bacteria, and then kills it (lytic phage). They are used in therapy. The second group doesn’t kill any bacteria, but becomes their companion. They live together, which is mutually beneficial – these are the temperate phages. Our task is to find phages able to destroy bacteria. The entire point is to find lytic phages which can be administered in preparations in the hope they will work. It is said that theoretically phages can’t harm us, because they don’t interact with human cells, as they are adapted to attacking bacteria, very much different from our cells. This is why phage therapy is thought to be safe. From the evolutionary point of view bacteriophages accompany bacteria all the time, they’re even ten times as numerous as bacteria. Our bodies are colonised by bacteria, accompanied by bacteriophages. We’re therefore constantly subjected to the relationship bacteriophages-bacteria-our organism. So if we’re selecting a bacteriophage, we multiply it in large numbers and use to treat the populations of bacteria which has colonised us, we do it only to reduce the pathogenic bacteria population as much as we can, and not harm the remaining ones. Similarly, wolves in a forest will never be numerous enough to kill all deer, because nature always strives for balance.

How long has this research been conducted at the University of Wrocław?

My team and I have been carrying out research at UWr for 10 years. We deal with the biology and genetics of bacteriophages, their production, isolation of their enzymes, and general profile. This is not directly related to phage therapy. At most such enzymes can be used as further application for therapy, because both entire phages and single proteins displaying enzymatic activity can be used as antibacterials. Our colleagues from the Institute of Immunology and Experimental Therapy PAS specialise in phage therapy, production of preparations, and running the therapy centre. In addition, they study the effect of bacteriophage action on the immune system. This amounts to research on the safety of phage therapy.

The centre at Weigla street in Wrocław is the only one working at this scale in Poland. Phage therapy is still in experimental phase, because it is difficult to get the permission of bioethics and drug accreditation commissions due to the theoretical possiblity that a phage may transfer genetic material and make changes to bacteria virulence. It is difficult to confirm whether a given phage is safe. Bacteriophages multiply and are subject to the same evolution processes as bacteria, but at a much faster pace. Such a formulation can’t be considered stable. It is therefore very hard to get the approval for using these preparations in humans. However, they’ve been successfully introduced to food industry as preservatives or to agriculture, where they prevent diseases in animals and crops.

Which academic centres outside Europe have made most progress in this research?

There is currently a boom for phage therapy in the United States. Previously pharmaceutical companies were not interested in it, but because there has been a lot of talk about antibiotic resistance, they seek alternative treatments. They can be based on plants, but one of the ideas is to use phages. Many biotechnology companies have started developing phage formulations, and in recent years this research has been gaining momentum.

After years of „overfeeding” with antibiotics some move away from it and look for other remedies.

We can’t overreact. There was a heated dispute when some parents didn’t want to give their child with acute bacterial infection an antibiotic. Of course mild viral infections such as catarrh may be treated with natural remedies.

The same applies to vaccinations. Many parents don’t want to vaccinate their children.

We should ask how many children got sick from the vaccine, and how many died when vaccinations weren’t readily available. The saddest fact is that such decisions are made by the people who themselves were vaccinated. There is a phenomenon called „herd immunity”. If in a given population large percent of people have been vaccinated, then an infectious agent cannot transmit. But if the number of vaccinations decreases, then we’re at risk of epidemic. Today we use the latest generation of vaccines containing only the fragments of bacteria which are responsible for the emergence of protective antibodies.  

Antibiotics versus phages?

When the infection is serious, the doctor cannot refrain from using traditional antibiotic therapy. If he considers phage therapy, it can only be done in combination with antibiotics. However, he should be provided with recommendations developed by experts, groups of doctors. It is common to follow recommendations during therapy, such as guidelines on pneumonia treatment. By applying them, the physician knows he should select a specific sort of antibiotic as first- or second-line treatment. In case of phage therapy we don’t yet have such recommendations as it is only just emerging. Therefore the doctor has to be extremely knowledgeable about bacteria and phages in order to make the decision on therapy, which is very difficult.

Will your research under the recent Harmonia 7 grant help clinicians using phage therapy?

Bacteria change under the influence of phages, and vice versa. The race is still on and it’s impossible to completely eradicate bacteria. The objective of the recent grant is to assess if bacteria treated with phages become less or more dangerous (virulent) to us. We don’t know this for sure and that is one of the main objections expressed by the opponents of phage therapy, who argue that using phages produces the so-called resistant mutants of unknown virulence. I would like to answer this question.

And if it turns out they are less virulent, does that mean the large-scale application of phages will become possible?

We won’t be 100 percent sure. Bacteriaphages and bacteria are so different that we’ll never get the same, unambiguous result. The only question is how many results will be positive and how many negative.

How long does such research take?

A lot of time and resources are needed. With this one grant we won’t solve the entire problem of potential pros and cons of phage therapy, but at least a step forward will be taken.

How many people do you work with?

We have 7 permanent members of our team and several doctoral students. We have developed international co-operation, and work with institutions from Belgium, Italy, England, Ireland, USA, and Canada. Each of them specialises in one area, but if we come together we will be able to formulate more general conclusions. Without international co-operation it wouldn’t be possible. On this project we work in conjunction with Professor Miguel Valvano from  Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University of Belfast in Great Britain, who is an expert on bacterial virulence factors. We provide the bacteriophage part, and the third partner is professor Antionio Molinaro from the Department of Chemical Sciences, University of Napoli Federico II Complesso Universitario Monte S. Angelo in Naples, who in the final stage of the project will help us examine the chemical structures of bacterial surface polysaccharides. We hope that together we will find out if bacteria treated with phages become more dangerous or if their virulence decreases.

In the photo: Prof. Zuzanna Drulis-Kawa with a part of her team: Dr Barbara Maciejewska and doctoral student Agnieszka Łątka

Interview by Małgorzata Jurkiewicz

Prof. Zuzanna Drulis-Kawa, clinical microbiologist and laboratory diagnostician by education, is currently the head of the Department of Pathogen Biology and Immunology at the Institute of Genetics and Microbiology, consisting of six assistant professors, four doctoral students, and M.S. students. She delivers lectures and runs medical microbiology and bacteriophage biology practical classes. Since 2006 she has been a lecturer of Summer Microbiology School, Biol 4503, General Microbiology in English for  the students of the University of Minnesota Duluth. Prof. Drulis-Kawa graduated four doctoral students, eighteen M.S., and fifteen B.S. students. Between 2011 and 2012 she was the head of Doctoral Studies of the Faculty of Biological Sciences of the University of Wrocław and deputy director of the Institute of Genetics and Microbiology of the University of Wrocław.

She is the author of 65 papers published in Polish and international journals with total impact factor of 100. Among her achievements she considers the following the most important:

creating a collection of lytic phages specific to multiresistant clinical strains of Klebsiella pneumoniae and Pseudomonas aerungiosa; acquiring recombinant enzymatic depolymerase and endolysin proteins which have the potential to become antibacterial formulations used in medicine and food industry; developing an innovative method of monitoring the growth of Pseudomonas biofilm using piezoelectric sensors; participating in the European „COST  BM1003: Microbial cell surface determinants of virulence as targets for new therapeutics in Cystic Fibrosis” programme; organising a prestigious training conference as part of the project COST  Action BM1003: “The advantages and limitations of methods used in bacteria identification and typing”, Autumn Training School – COST BM1003, 23rd-25th September, 2013, Wroclaw, Poland.

Prof. Drulis-Kawa has repeatedly been awarded research funds in the calls for proposals organised by the State Committee for Scientific Research and National Science Centre, and her mentees have been winners of Grant Plus and FNP Ventures projects. She is a winner of the team award of the Minister of Science and Higher Education for educational achievements in 2013, and received the Medal of the Commission of National Education in 2014.