"PHAGES, BACTERIAL VIRUSES, ARE ABLE TO DESTROY MULTIDRUG-RESISTANT BACTERIA"

Feb 5, 2021

Researcher Pilar Domingo-Calap, from the Institute for Integrative Systems Biology (I2SysBio), joint centre of the University of Valencia and the CSIC 

Researcher Pilar Domingo-Calap, at the Institute for Integrative Systems Biology (I2SysBio), joint centre of the University of Valencia and the CSIC, had planned to take part this week in the educational series 'Actualidad' to share her research on phages, bacterial viruses, as an alternative to antibiotics. 

Given the current situation, the talk has been postponed, but we spoke with her so she could tell us firsthand about her work in this field of research, how her vocation originated, her scientific career, as well as the projects she is leading in the analysis of wastewater and the presence of COVID in it. 

What has happened for there to be super drug-resistant bacteria?
The indiscriminate use of antibiotics, in humans as well as livestock and agriculture, has triggered the emergency situation of multidrug-resistant bacteria. Bacteria are living organisms that evolve, allowing them to adapt to new conditions (even extreme ones), as is the case of surviving in the presence of antibiotics. These bacteria, capable of growing in the presence of antibiotics, have produced a worldwide public health problem that no longer responds to current treatments, making it necessary to develop new tools to control them.

Your research is focussed on phages. What are they?
Bacteriophages, commonly known as phages, are bacterial viruses. In the biosphere, phages are the most abundant biological entities, there being 10 times more phages than bacteria. In fact, phages have coexisted naturally with bacteria since the beginnings of life in an on-going host-parasite relationship. This makes nature be an inexhaustible source of phages, with enormous, still-uncharted diversity, but of great interest in both basic and applied science.

Have they been used at any time in the history of medicine? 
The discovery of the phages more than 100 years ago, led directly to their use as a therapeutic tool. The phages were seen to be able to destroy bacterial cultures in the laboratory, and at that point they were tested against dysentery in France and cholera in India, with promising results. However, after the discovery of antibiotics, the phages were abandoned and, after the Second World War, their use was left to eastern countries like Russia, Poland and Georgia.  In fact, in these countries they are still used as a routine form of therapy. In the rest of the western countries, phage therapy is not accredited, and its use is only permitted as a compassionate treatment. Since the recent pandemic brought on by the SARS-CoV-2 coronavirus, the United States has allowed the use of phage therapy as a treatment for COVID-19 patients, now that it has been seen that the causes associated with a greater mortality in COVID-19 patients are nosocomial bacterial infections, many of them multidrug resistant.

Why are they an alternative to antibiotics? How do they work? 
As I have commented, the phages are bacterial viruses. This enables them to recognise bacterial targets specifically, being capable of destroying them very efficiently, including multidrug-resistant bacteria. Phages, being able to evolve, can adapt to the bacteria rapidly, making them a very interesting tool in their control. In addition, for being so specific, they leave the remaining bacteria intact, thus reducing the secondary effects and being ecologically safe. Lastly, it is worth noting that implementing large-scale industrial production would be fast, simple, and low in cost. Nevertheless, there is a long road ahead for their routine use as a therapy, due, in part, to the lack of suitable clinical trials and the lack of regulations on the part of the competent authorities. From the Spanish Network of Bacteriophages and Transducer Elements, FAGOMA, we are working to be able to implement the use of phage therapy in Spain.

What research are you carrying out in this area?
In this regard, at the Environmental Virology and Biomedical Laboratory of the Institute for Integrative Systems Biology, a joint University of Valencia-CISC centre, we are isolating and classifying new phages from the environment for their therapeutic use in fighting bacterial infections in humans as well as in plants and animals. In addition, we are going further, expanding the possibilities in the direction of diagnosis and prevention. We are also studying the emergence of possible resistance to phages and how to reduce it. To cite an example, in collaboration with the La Fe Polytechnic University Hospital, we are looking for phages against multidrug-resistant strains of Mycobacterium abscessus, an opportunistic bacterium that causes infections in patients with cystic fibrosis, for use as a compassionate treatment. We also have a project financed by the European Society of Clinical Microbiology & Infectious Diseases centred around the use of phages against multidrug-resistant Klebsiella pneumoniae, a nosocomial bacterium that causes opportunistic infections, and which has a very high incidence in Europe.

Women and science

Next 11 February the International Day of Women and Girls in Science is being celebrated. What are the main challenges that you have had to face in your career?
My career as a scientist can be described as a series of personal growth challenges. I wanted to be a scientist since I was very little. Things that are invisible to the human eye interested me, and already as a girl my parents bought me a microscope to be able to observe a new dimension of nature. That led me to study biology, and, little by little, I specialised in virology, an exciting world in which there are many brilliant female scientists. Over the years it has been difficult at times to balance my personal life with the professional, since the path to specialisation in the research world forces us to travel a lot (for example, I lived for many years in France), as well as having horrendous timetables.
As a woman, on certain occasions during my professional career I have detected inequality between men and women, which seems to me unacceptable in our current society. I hope that little by little certain barriers will be eliminated and we can feel equal as people, being judged for our abilities and not for our looks, which should not be taken into consideration.

Do you have a model, a female scientist who inspires you?
The truth is that I can't say that I have or have had a female scientist as such as a model. I believe that all those women who in the past managed to make great discoveries fighting against all odds to demonstrate that we women can be the same as men should be models for us and for society in general. Of course, if I have to choose someone, it would be Marie Curie, a brilliant scientist, recognised by two Nobel Prizes, who gave her life to and for science and, unfortunately, of whom I still hear it said at times that she got there thanks to her husband.... I would also like to mention Rosalind Franklin, who made possible the discovery of the structure of DNA and whose name is usually not mentioned.  Lastly, mentioning Margarita Salas, a Spanish virologist who introduced molecular biology to our country, who discovered the polymerase DNA of the Phi29 virus, and who was the first Spanish woman to be a member of the National Academy of Sciences in the United States, an international recognition for which very few researchers could opt.

What would you say to a young woman who wanted to devote herself to science? 
Anyone should be able to have the access and freedom to choose their professional future, without considering if they are a man or a woman. Luckily, the new generations are already near equality, although it is true that there is still much left to be done. There should be no careers or positions for men or for women. Anyone with the ability needed should be able to get a job. I try to convey this, that young women not see that there are barriers for being a woman, that they follow their calling and try to be the best at what they do; the same thing I would say to anyone.

 Covid-19
What do you think happened in the Valencian Community for us to have been worse in the first wave? 
It is difficult to know exactly what happened to reach that point because it is due to a combination of many things. From the start, I have supported the use of masks, avoiding contact with public surfaces, limiting personal relationships to the maximum and always outdoors. It was to have been expected that the virus was transmitted by air, although accepting the transmission via aerosols took a long time. It is that which facilitates the transmission of the virus in closed spaces. In the Valencian Community, good climatic conditions have allowed us to spend most of our time outdoors. However, the arrival of the cold encouraged social gatherings indoors, in many cases without masks or taking the proper ventilation measures. In addition, the new variants that are transmitted more easily could be responsible for the increase in cases, although we are still studying that hypothesis in the laboratory. Furthermore, I believe there was a relaxation of control measures on the part of citizens, above all at Christmas, which has meant a third wave with a high incidence rate. Compulsory strict confinement is not needed for us to stay home, reduce contact with friends and relatives or promote telecommuting. We must all do our bit.
 

You lead two projects on the study of wastewater and the presence of COVID in it. How did this idea come about, and what does the research involve? Has any trace of the British strain been found in Valencia? 
Well, the idea came up because in our laboratory we are looking for new phages in nature and in anthropogenic environments as well, including wastewater. We have been taking water samples from the city of Valencia's wastewater treatment plants for a while, and with that can relate the viral load found in the wastewater with the incidence of the virus in the population. As a virologist, I knew that other coronoviruses like SARS-CoV-1 were excreted in faeces, which implied that the new virus would be as well. The interesting thing is that we were able to recover genetic material from the SARS-CoV-2 virus in water dating back to February 2019, including before there were cases reported in Valencia. Thanks to that, we have several projects under way both in the epidemiological monitoring of COVID-19 through wastewater and to determine if, via faeces, the faecal-oral route might be facilitating transmission of the coronavirus. In addition, in our laboratory we are sequencing the genetic material of SARS-CoV-2 in wastewater to determine what variants are circulating in Valencia. The latest results, up to the beginning of November, have shown no sign of the British strain. The November-to-January study has just been sent for sequencing and we are hoping to be able to have the data as soon as possible.


 When do you think we will be able to return to living with a certain normality?
It all depends on the speed with which the vaccines are given, and that they continue creating immunity against the new variants as the emerge. I wouldn't venture giving a date, but like everyone, I hope that it is as soon as possible.