Team:ETH Zurich/core/human-practices
Contents
Human Practices
Human Practices is a procedure to ensure the responsibility and benevolence of our project. To achieve this, we first identified globally relevant topics and decided to work on <a class="a-link-neg-margin" href="#nav-antibiotics-resistance/" onClick="aaa('nav-antibiotics-resistance/');">antibiotics resistance </a> by the means of phage therapy. Secondly, we brainstormed societal concerns that are linked to our project, whereas we identified <a class="a-link-neg-margin" href="#nav-clinical-application/" onClick="aaa('nav-clinical-application/');">clinical application </a>, <a class="a-link-neg-margin" href="#nav-patient-safety/" onClick="aaa('nav-patient-safety/');">patient safety </a>, <a class="a-link" href="#nav-biosafety/" onClick="aaa('nav-biosafety/');">biosafety </a> and <a class="a-link" href="#nav-regulatory-process/" onClick="aaa('nav-regulatory-process/');">regulatory process </a> as significant issues to consider, whereas the following questions arose among others:
- How could our new method find an application in a clinical setting?
- Is phage therapy safe for the patient and if not, what needs to be done to ensure its safety?
- What happens if our newly created synthetic phages escape into the environment? Do they impose a danger on the ecosystem?
- How is the use of phage therapy regulated today and what would be necessary to obtain a good regulatory framework in the future?
Next, we met with stakeholders from the clinic and experts in safety and regulations to discuss these questions and get some general <a class="a-link-neg-margin" href="#nav-project-feedback/" onClick="aaa('nav-project-feedback/');">feedback </a> to our project. Finally, we <a class="a-link" href="#nav-integrated-human-practices/" onClick="aaa('nav-integrated-human-practices/');">integrated </a> all our gained knowledge to improve the design of our project. Furthermore, we used our platform to <a class="a-link" href="#nav-public-engagement/" onClick="aaa('nav-public-engagement/');">inform </a> the public about phage therapy as well as synthetic biology in general and in return get some valuable feedback from society.
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Antibiotic Resistance
<img src="https://static.igem.org/mediawiki/2019/b/b5/T--ETH_Zurich--AntibioticsResistance.svg" alt="antibioticsresistance" class="hp-icon"> Antibiotic resistant bacteria affect individuals independent of age, socio-economic status and country of residence and thus pose one of the biggest threats to global health today. It is an inevitable evolutionary response to antimicrobial usage. Susceptible pathogens are being replaced by more resistant variants by the process of natural selection [2]. However, despite the fact that this is a natural process, it is greatly accelerated by the misuse of antibiotics in humans and livestock [3][4]. An increasing number of infections such as pneumonia, tuberculosis and food borne diseases are becoming harder to treat as antibiotics become less effective against particular bacterial strains. Standard procedures such as organ transplantations, chemotherapy and routine surgeries like caesarean sections will involve more risk in the future if no alternative methods are developed. The length of hospitalizations will increase as a consequence, leading to higher medical costs and potentially increased mortality rates [1]. Therefore, the treatment of multi-drug resistant bacteria is highly relevant.
Dr. med. Andreas Kronenberg
Member of scientific board at the Swiss Center for Antibiotics Resistance
Group Leader at Institute for Infectious Diseases, University of Bern
- Andreas Kronenberg gave us a broad overview about the current situation in Switzerland, predictions for the future and available resources on this topic
- He sees the importance of our project and names phage therapy as one of many solving approach
- Challenges in phage therapy contain the high selectivity for specific pathogens, which makes an empiric therapy difficult and its standardization
- Current phage therapies have the disadvantage that the bacterium needs to be identified, which is not always possible in a clinical setting, and if so, identification needs 24 to 48 hours
- The immune system might degrade phages.
<img src="" alt="anresis" class="responsive-50 hp-logo">
Karin Waefler
Technical Officer at World Health Organization
- Although WHO has not published any official guidelines or recommendations regarding phage therapy, they provided us with general information concerning its potential and a statement about its use from the Federal Council of Switzerland
- Furthermore, WHO provided us the global list with bacterial strains that should be targeted with priority
- She points out the problem, that phage therapy has a reduced potential for low- and middle-income countries as their infrastructure is often poorly developed and shipped phages as well as the patients bacteria could have evolved multiple times in the time of shipment
<img src="" alt="who" class="responsive-50 hp-logo">
[1] Fact sheet on antibiotic resistance, WHO, https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance, Accessed: 12.06.2019
[2] Clinical Impact and relevance of antibiotics resistance, French GL, Advanced Drug Delivery Reviews, 57(10), pp. 1514-1527, 2005
[3] Prevalence of Inappropriate Antibiotic Prescriptions Among US Ambulatory Care Visits, 2010-2011, Fleming-Dutra KE et al., JAMA: The Journal of the American Medical Association, 315(17), pp. 1864-1873, 2016
[4] Antibiotics Overuse in Animal Agriculture: A Call to Action for Health Care Providers, Martin MJ, American Journal for Public Health, 105(12), pp. 2409 - 2410, 2015
Biosafety
<img src="https://static.igem.org/mediawiki/2019/0/01/T--ETH_Zurich--Biosafety.svg" alt="biosafety" class="hp-icon">
After injecting their DNA into a host, phages either multiply and induce lysis of the host cell or they are stabilized as prophages either integrated into the host chromosome (temperate phages) or as a free plasmid molecule. Temperate phages can mediate horizontal gene transfer that occurs in bacteria through transduction. Transduction is a mechanism by which a segment of the bacterial genome is inserted in a newly formed viral particle instead of the viral genome which can therefore be transferred to other bacteria and can recombine with the host’s genome by homologous recombination. From a biosafety point of view, the introduction of new genetic material from a recombinant viral particle into the bacterial gene pool may have positive, negative or neutral outcomes depending on the genetic marker introduced [1].
The survival of bacteriophages outside a host depends on the nature of the phage itself and is further influenced by the surrounding environmental conditions. Even if free phages can survive a rather long time in the environment, they need to infect susceptible bacterial hosts to replicate and propagate themselves. Many phages are known to be highly specific for their receptors and are therefore characterized by a narrow host range. However, some phages that are able to infect a large range of bacterial species have also been identified. These broad-host-range phages may promote genetic diversity and genetic exchange among a wider range of bacterial populations. Determination of the host range, virulence, resistance to environmental factors or the potential for gene transfer of the manipulated bacteriophage is therefore an important step in the risk assessment process to evaluate the probability of the phage’s propagation in a particular environment and its potential role in global gene transfer [1].
Dr. Ursula Jenal
Jenal & Partners Biosafety Consulting
- T7 phage is categorized as BSL-1. Its narrow host range among bacterial strains, incapability to infect eukaryotic cells and decreased efficiency of DNA packaging under UV light reduces its capacity to survive in nature and disbalance the ecosystem in case of an accidental release from the laboratory.
- If we randomize the tail fiber protein of T7 however, the situation has to be analyzed anew, as no laws are in place that regulates this case. Therefore, a risk assessment is necessary.
<img src="" alt="jenal" class="responsive-50 hp-logo">
Dr. Grégory Resch
Department of Fundamental Microbiology (DMF), University of Lausanne
- Evolved phages most probably already exist in nature, but haven't been find and characterized yet. Therefore, they should not be considered to be GMO and most likely do not affect environment.
- However, if a super phage is created, that can infect and lyse many bacterial strains, it can only be used in a highly controlled environment to prevent destabilization of the ecosystem.
[1] Contained Use of Bacteriophages: Risk Assessment and Biosafety Recommendations. Verheust C. Pauwels K. Mahillon J. Helsinki DR. Herman P. Applied Biosafety, Vol. 15, No. 1, pp. 32 – 44, 2010
Regulatory Process
<img src="https://static.igem.org/mediawiki/2019/8/80/T--ETH_Zurich--RegulatoryProcess.svg" alt="regulatoryprocess" class="hp-icon"> Phages are currently classified as Medicinal Products (MP) under European Union (EU) legislation and as a drug by the Food and Drug Administration (FDA) in the United Stated, which necessitate that phages be produced under Good Manufacturing Practice (GMP) guidelines and require clinical trials. The few formal experimental clinical trials that have been completed to date have produced inconclusive results on the efficacy of phage therapy which contradicts the many successful treatment outcomes observed in recent individual case reports. Therefore, phages continue to lack any market approval in Western medicine as a recognized drug but are nevertheless increasingly used as an experimental therapy for the compassionate treatment of patients experiencing antibiotic failure [1].
Pia Stadelmann
Swissmedic
- Swissmedic explained us the legal framework for the use of bacteriophages
- Phages are considered as medicinal products and therefore the provisions of the Therapeutic Product Act (HMG) are used
- They must have a production authorization granted by Swissmedic and comply with Good Manufacturing Practice (GMP)
- For clinical trials a license from the ethics commission and Swissmedic is required
- The usage of the product under a temporary license (“compassionate use”) is only possible, if the product is already in clinical trial
<img src="" alt="swissmedic" class="responsive-50 hp-logo">
Dr. Jean-Paul Pirnay
Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital Brussels
- Regulatory issues include the declaration of phages as medicinal products, which presume Good Manufacturing Practice, preclinical studies, phase I, II and III clinical trials and centralized marketing authorization. This is too expensive as phages are biological entities that cannot be patented. Moreover, this process is also not feasibly for an evolving therapy.
- In Belgium phages were used earlier under the WMA declaration of Helsinki, Article 37, which enables their use for desperate cases without the need to perform clinical trials and work under GMP conditions. While demonstration of the efficiency of phage therapy is not feasible from compassionate use cases only, the generated data suggests that phage therapy is safe, as no adverse effects were detected. The main problem with this approach is however, that too much time is lost in case of critically ill patients.
- The Dedicated PT framework is a new concept elaborated by scientists in cooperation with Belgian Authorities. It includes the characterization of phages, their storage in a banking system, the production of a single phage (active pharmaceutical ingredient) using a suitable host according to a monograph and external quality testing by a "Belgian Approved Laboratory". Then approved phages can be bought in a pharmacy upon prescription as magistral preparations.
Dr. Grégory Resch
Department of Fundamental Microbiology (DMF), University of Lausanne
- The phage from which the library is derived needs to be well characterized and has to undergo a clinical trial
- The evolved phages don't have to undergo this procedure again, as they underwent only an accelerated natural selection process. Instead they only have to be sequences to exclude the existence of dangerous sequences
- A physic with no other treatment option can contact Swissmedic via a special demand formular. Phages that were authorized in another country with similar standards can be used in this case
[1] Clinical Indications and Compassionate Use of Phage Therapy: Personal Experience and Literature Review with a Focus on Osteoarticular Infections. Patey O. McCallin S. Mazure H. Liddle M. Smithyman A. Dublanchet A. Viruses, Vol. 11, No. 18, 2019
Public Engagement
<img src="https://static.igem.org/mediawiki/2019/a/a2/T--ETH_Zurich--PublicEngagement.svg" alt="publicengagement" class="hp-icon">
Scientifica
Scientifica is a fair that aims at educating the broad public about the newest scientific achievements. It includes special activities for children as well as a specific program for politicians and economists. Scientists have the opportunity to explain their projects and raise enthusiasm for science and get valuable feedback from a very diverse audience:
- The project was received well by the public and people were open to the concept to use phages to treat bacterial infections.
- People were particularly interested in the price of phage therapy, comparison to naturally occurring phages, biosafety issues as well as efficacy of treatment.
<img src="" alt="Scientifica" class="responsive-50 hp-logo">
Presentation at the Intra-Departmental Seminar
The Seminar is a series of talks that allows for optimal interaction and sharing of expertise with people from different scientific backgrounds.
<img src="" alt="VMB" class="responsive-50 hp-logo">
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