Medical Humanities on Bacteriophage TherapyIntroduction In our experience, ordinary people are generally underexposed to bacteriophage therapy, let alone medical humanities. As a result, although there may be someone who has heard of both of them, it is difficult to link them together particularly using scientific thinking.
As iGEMers, we are able to apply our professional knowledge and critical thinking to go further into this field. Though we cannot find a specific concept of medical humanities, we come to a conclusion according our own understanding. Medical humanities is a therapy that require both medical techniques and humanistic care. To some extent, it is related to doctor-patient relationship, social contribution and ethics.
The purpose of this handbook is to illustrate the relationship between bacteriophage therapy and medical humanities, which will be presented into four major aspects, including exploration of the embodiment of humanistic medicine in pharmaceutical companies, inappropriate choice of volunteers, patients’ concerns and potential risks. Each aspect is consisted with both recent questions and possible solutions proposed by our team.
We hope that this handbook will serve as a first step for iGEMers into the world of bacteriophage therapy in medical humanities. As the scientists of tomorrow, in a field that less people had discussed about, we are making our best to promote its advancement.
Humanistic Medicine in Pharmaceutical Companies
The moral responsibility of a business
Archie B.Carroll, in his book Business and Society: Ethics and Stakeholder Management, subdivides corporate social responsibility into four responsibilities (Figure1): economic responsibility, legal responsibility, ethical responsibility and voluntary responsibility (later changed to charitable responsibility).
Figure.1
According to Archie, economic responsibility is the most fundamental social responsibility of enterprises, that is, to make profits while promoting the development of market economy. Philanthropic responsibility at the highest level represents a company's response to expectations that cannot be expressed directly, such as giving to charity. For the pharmaceutical enterprises, it is to promote the research and development of cutting-edge medical drugs and make contributions to the cause of human health that matter. In this regard, we can see this as the moral responsibility of pharmaceutical companies.
Drugs need to go through many steps from R&D to marketing (Figure 2), which is mainly divided into three processes: pre-clinical research, clinical trial and marketing approval. The time from R&D to marketing is different for different drugs. These processes show that the development and marketing of bacteriophage therapy require huge amount of time and investment , due to which as well as the strong specificity of bacteriophages, pharmaceutical companies' investment in research and development of bacteriophage therapy is extremely risky and unrewarding.
Figure.2
By introducing realistic scenarios, we can easily conclude that when an individual's sacrifice does not exceed a certain threshold, the realization of the greater public good becomes a moral obligation. Likewise, when the cost of bacteriophage therapy research and development does not exceed the threshold, we can assume that bacteriophage therapy research and development can be a moral obligation for pharmaceutical companies.
Conflicts between economic and moral responsibility
In the 1970s, most proponents of a market economy embraced Friedman's view that corporate social responsibility was only economic responsibility to increase profits, not to loosen the conditions for profit maximization for the wider good of society. However, divergence exists on the issue of whether corporations should undertake philanthropic responsibilities. While supporters, who often expect enterprises to have some empathy for patients, argue that pharmaceutical companies should be accountable not only to shareholders but also to the public interest, others who are more willing to treat patients as customers with interests think the opposite.
We believe that one of the reasons for this divergence may be that patients do not have direct contact with pharmaceutical companies in medical activities. On the one hand, it is precisely because of the "invisibility" of pharmaceutical companies in medical activities that pharmaceutical companies do not have the same direct moral obligation to patients as medical workers. On the other hand, zero communication between patients and pharmaceutical companies leads to the fact that pharmaceutical companies do not get the most direct feedback to arouse their desire to pursue spiritual demands, which is the most deficient part of pharmaceutical companies in humanistic medicine and affects their performance of undertaking charitable responsibilities to some extent.
Clearly, it is important to justify requiring the pharmaceutical industry to invest in the development and production of new medicines that can save patients' lives, but this is unrealistic from a purely commercial point of view, and most pharmaceutical companies do not want to sacrifice their own financial interests for this.
We don't have a clear conclusion here, but our point is clear: pharmaceutical companies have a moral obligation to invest in bacteriophage therapy.
Transforming investment into a risky project into a moral responsibility
There are two different kinds of methods to transform investment into bacteriophage therapy into a moral obligation. One is to find out where the threshold is, and the other is to make up for the cost loss of pharmaceutical companies to achieve enough commercial incentives to start the development and production process of bacteriophage therapy, or even improve. As for the threshold value, we believe it is determined by the actual situation of pharmaceutical companies, and currently we have no way to study this aspect for the time being. But we hope to explore the second aspect to find a way to make up for the loss of drug companies and sufficient commercial incentives.
In access to relevant data, we analyzed the existing bacteriophage therapy operation mode and briefly sources of funds for the research and development company, we found that the existing bacteriophage therapy R&D company mostly depend on the market to obtain sufficient research funding, which has quite a number of commercial incentive that is due to the investor, recognition of bacteriophage therapy and investment can help drug companies to solve the status of the research and development funding shortages. This is the result of market selection.
We also believe that the development of enterprises is also in line with Malos' demand theory(Figure3) and we learned that it’s important to stimulate the desire of enterprises for self-actualization, so as to stimulate capable enterprises to engage in bacteriophage therapy research and development for the purpose of obtaining social benefits and fulfilling self-actualization needs. We would love to make a few suggestions on how to stimulate the self-actualization desire of the enterprises.
Figure.3
1.Make good use of the media
Let the general public realize that the pharmaceutical enterprises have the willingness to undertake moral obligations, and actually make contributions to human health, so as to build the mass foundation for the pharmaceutical enterprises, and let the work done by the pharmaceutical enterprises appear in the public's vision.
2.Promote science communication of basic medical knowledge
By doing so the public can have a deeper understanding of the efforts made by the pharmaceutical enterprises and deepen the impression of the pharmaceutical enterprises in the hearts of the people. In fact, we are conducting science communication activities in response to the first questionnaire feedback.
3.Establish the relationship between the public and pharmaceutical companies
This which requires pharmaceutical companies to listen to patients' feelings of medication in clinical treatment during market product research, and have direct contact and communication with patients, so that pharmaceutical companies can feel their social value. Inappropriate Choice of Volunteers
Children in underdeveloped countries as volunteers for clinical trials
A phenomenon that caught our attention is that the clinical trials of bacteriophages are mostly done in extremely underdeveloped areas such as Bangladesh, even on young children. In order to prove the safety for phage preparations and their clinical efficacy, a group of scientists explored the behaviour of orally applied T4-like phages in and in healthy adults from Bangladesh (Sarker et al., 2012). Also, there was isolation of T4-like Escherichia coli-specific bacteriophages from stool samples of children from Bangladesh (Chibani-Chennoufi et al., 2004), for the sake of exploring the characterization and standardization of phage preparations. Moreover, scientists conduct regular clinical examinations and multiple clinical chemistry tests in healthy and diarrheal children from Bangladesh(Sarker et al., 2016), so as to describe that the T4-like and the Russian oral coliphage cocktails are safe in both kinds of children for treatment.
All these cases trigger our thinking: clinical trials in children from developing areas definitely violate humanistic care and ethical standards. First of all, young children often have no idea of how to treasure their own bodies and health, which means they may not fully understand the risks of being volunteers. Besides, it is commonsense that volunteers for clinical trials can receive a payment for their sacrifice, which is why volunteers from underdeveloped areas usually take up a large scale. However, that is not the case in underdeveloped area. It is heartbroken to learn that these volunteers are taking part in clinical trials while being poorly paid and without concept of the risk, which is not in line with humanistic care and ethical standards, standing in these volunteers' shoes.
Joint efforts are in need to improve the situation
As for the conductor of the clinical trials, they should consider adults instead of children when choosing potential volunteers, for adults have the ability to take responsibility of their own choice and have a clear idea about the consequences.
More importantly, no underage volunteers should be allowed to take part in clinical trials. More often young children do not choose to become a volunteer according to their own will. Cases exist where their family pressure them to do so for the payment. We believe organizations that aim to defend children’s right like UNICEF should pay attention to this kind problem and step in to save innocent children from being used as a tool to make money.
Besides, government should also play a part in supervising the selecting process of volunteers for clinical trials and even formulate regulations that punish adults who force children to take part in clinical trials to as a mean of financial income. Patient's Concerns over Bacteriophage Therapy
1.Public ignorance of bacteriophage therapy
The general public only know little about phages
Though there may be someone who has heard of bacteriophage therapy, they can’t really tell what it exactly is, what its use and in what situation we should take it. The reasons can be mainly separated into two aspects. First of all, up to now, bacteriophage therapy is a treatment regimen involving complex and poorly understood risks which is still at clinical trials. Therefore it is of great difficulty to secure patients’ consent.
In addition, the concept of bacteriophage therapy has not been widely spread. For example, in 2013, Henein came to a conclusion from experiencing the outbreak of E. coli 0104 that no bioethical bacteriophage therapy debate had has been published(Henein, 2014). Even the physicians have only a little grasp of bacteriophage therapy, needless to say how it was like for the patients.
Science communication can serve as a practicable solution
Science communication would be an effective approach to introduce bacteriophage therapy to the general public. We have already made long-term cooperation with BETTER Life Science Institution. For example, we have published an online article about antibiotics and superbacteria on the official account on Wechat, which is the most widely used application in China. Also, we have done several interviews with the Meng Wu, the founder of BETTER Life Science Institution, and through our pleasant conversations we have grasped his view on the science communication industry and understood deeply how professional institutions carry out science communication. What’s more, we are planning for designing and uploading some courses about bacteriophage therapy as well, for the sake of letting the general public to have the chance and approach to learn more about bacteriophage therapy. Given that BETTER is a professional institution doing excellent science communication work, through this platform could we help to spread knowledge of phage therapy.
2. High expenses for a new treatment
New treatment with promising outcome may bring out financial burden to patients
Given that bacteriophage therapy is a rather new treatment curing bacterial infections, many patients are concerned about its expenses. Drug pricing actually involves strong pharmaceutical economics. That is to say, drug pricing also involves patent fees, marketing costs, and local government policies. In addition, the relationship between supply and demand in the market plays a vital role as well, the drug in need absolutely could sale at a high price. Moreover, the patent period for a drug is usually 20 years, but it usually takes 10 to 12 years to develop a drug and costs about $15 to $2.5 billion, which means pharmaceutical companies only have 8-10 years to make money before cheaper generics are put on the market. The measure taken is usually selling for a high price due to the short profit period, so that there is no doubt the patients are concerned about the price of a new drug.
Bacteriophage therapy is actually more affordable than antibiotics
There was a group of Polish scientists who analyzed the approximate cost of treating staphylococcal infection on the basis of six cases in which good clinical effect of the phage therapy was seen. According to their research, the aggregate cost of the therapy was divided into medical service, laboratory and diagnostic tests, bacterial culture, phage typing, preparation of the phage formulation, and the medication for neutralizing stomach acid. They came to a conclusion that the total cost of phage treatment ranged from 1,444PLN to 4,044PLN(1PLN≈0.2625USD), with an average treatment period of 6 weeks. Also, they listed the most expensive antibiotics on the Polish market recommended for the therapy of multidrug-resistant staphylococcus infection (Table1)(Miedzybrodzki et al., 2007). Comparing the cost of phage therapy and antibiotic therapy, phage therapy was approximately 50% cheaper, which means that a wider application of phage therapy could lead to substantial savings in healthcare costs and improve bacteriophage therapy accessibility for patients in need(Miedzybrodzki et al., 2007).
Moreover, according to Chinese policy, biological cell immunotherapy, which is under medical insurance and NCMS, is a designated project of national health insurance. Hopefully, it is possible for bacteriophage therapy to become one of the designated projects as well, which will definitely make it more affordable.
Table1. The most expensive drugs used in the therapy of MRSA infection on the Polish market
3. Moral problem of subjecting a patient to a not yet approved therapy
It is morally unacceptable to offer patients a not fully-studied therapy
According to the Polish law, bacteriophage therapy is considered an experimental treatment, which occurs when a physician introduces new or only partially tested diagnostic, therapeutic, or prophylactic methods for the direct benefit of the person being treated. Two basic items are prerequisites for experimental therapy: one is the written informed consent of the patient and the other is the approval by an institutional review board (bioethics commission). Besides, it may be implemented only by a qualified doctor and when available treatment has failed(Miedzybrodzki et al., 2007). It is because this is the first time to apply phages for therapy, and the patient who is treated needs to be informed and to give permission ahead. Imagine being treated with a not yet approved therapy without any permission, needless to say it is not only dangerous and illegal, but will also makes bacteriophage therapy a social antipathy as well, thus making the road of marketization for bacteriophage therapy more bumpy.
Bacteriophage therapy maybe the best option under certain circumstances
It is certain that to subject a patient to a not yet approved therapy needs to be in respect with the patient’s right to autonomy (legitimate authority). However, it should be noted that it is not the only criteria of subjecting a patient. At some point, it is appropriate to introduce the notion of an “Ethically Justified Medical Therapy”(EJMT)(Verbeken et al., 2014). In order to label bacteriophage therapy as an EJMT, six criteria need to be met (Table2)(Verbeken et al., 2014). Though subjecting a patient to an unapproved therapy is morally wrong, in such specific circumstances is acceptable.
Table2: Six criteria for bacteriophage therapy to be labelled as EJMT
Potential Risks
1.Ambiguity about the pathogenic bacteria
The bacteria causing the infection may be unclear
Phages are able to deteriorate the target bacteria with high precision and efficiency, but ambiguity about the pathogenic bacteria can still exist and cause confusion to doctors when they are deciding what kind of bacteriophage therapy should be prescribed to the patients.
For most cases, patients don’t even know whether their discomfort was caused by bacterial infection or not, let alone the fact that it is extremely difficult for them to say for sure what kind of bacteria has caused the infection even if they have a biological or medical background.
Besides, patients especially children are often ignorant and forgetful about the details of infection, like the possible place where the infection might happen. This leaves a wide range of bacteria suspicious and adds more challenge to the doctor’s prescription deciding process, since details like time and place can help doctors pinpoint the exact bacteria or narrow it down to several possible bacteria. If the wrong phages were injected into the patient’s body, they can threaten the well being of the general microbial environment and bring about more serious conditions (Anomaly, 2020).
A combination of both bacteriophages and antibiotics may solve the problem
It would be a shame if ambiguity about the bacteria causing the infection become an obstacle of the wide range application of bacteriophage therapy. However, we believe this problem can be solved by using cocktail therapy, where both antibiotics and bacteriophage therapy are used to treat infections. The publication of bacteriophage therapy does not equal the eradication of the application of antibiotics, but rather to reduce the overuse of antibiotics. In addition, antibiotics still stand out for their wide antibacterial spectrum. Therefore, a cocktail of both phages and antibiotics can help a lot if doctors cannot decide with 100% certainty what have caused the infection. If the doctor can luckily narrow it down to just a few possible bacteria, antibiotics won’t even be needed since a cocktail of several associated phages may be enough to cure the infection.
In a study, it has been proved successful to use a cocktail of two lytic bacteriophages as a rescue treatment for severe septic peritonitis in a mouse model, and a therapy of bacteriophages combined with antibiotics significantly improved the clinical status of the infected mice(Gelman et al., 2018). Besides, according to a different study, a single course of bacteriophage therapy with concomitant antibiotics as a treatment for severe musculoskeletal infections also proved effective with no recurrence of infection(Onsea et al., 2019).
2.Generation of new antibiotic-resistant bacteria
Certain bacteriophages can bring new antibiotic-resistance to other bacteria
It has been proposed that if lysogenic rather than lytic phages were used for bacteriophage therapy, more bacteria will be equipped with antibiotic resistance. The difference between lytic and lysogenic phages is that while lytic phages can infect and lyse the cell to release new phage particles, lysogenic phages will need to first incorporate their own DNA or RNA into the host’s chromosomes, replicate with them without destroying the cell, and enter lytic cycle only under specific conditions. For lysogenic phages, bacterial genes encoding drug resistance may also be packed into the new phage capsids during the lytic circle (Anomaly, 2020). This process produces a transducing particle that can bring antibiotic resistance to other bacteria, leading to the generation of new antibiotic resistant bacteria.
Lytic phages are the optimal choice for bacteriophage therapy
Even though cases where phage therapy consisted with lysogenic phages have been proved successful, lytic phages are still more recommended to be utilized during bacteriophage therapy according to our research (Loc Carrillo and Abedon, 2011).
This is because lytic phages not only are unable to incorporate antibiotic resistance coding gene into other bacteria, leave no chance for the generation of more antibiotic resistant bacteria and will not add to the crisis of superbacteria, but also act much more quickly than lysogenic and phages which might revert to a lysogenic life cycle. Lytic phages won’t have to incorporate their DNA or RNA into the host’s genome and replicate with it, therefore saving a lot of time and release new phage particles much faster than lysogenic phages. Time is precious when it comes to saving lives, especially when the patient is undergoing a serious infection that is threatening his/her life.
Choosing lytic phages for bacteriophage therapy has become a consensus view and a more adaptable approach. Considering the above factors, we insist on engineering lytic phage vB_PaeM_SCUT-S1 to produce a possible bacteriophage therapy treatment for infections caused by antibiotic resistant Pseudomonas aeruginosa, commonly occurs in respiratory tract .
3.Lack of a standard administration protocol for bacteriophage therapy
There are not enough tests to guarantee the safe application of bacteriophage therapy
Currently, both the research of bacteriophages and bacteriophage therapy are still at an early stage. Even though phages were put into bacterial infection treatment ever since they were discovered in the 1915, which is earlier than the discovery of the first antibiotic in 1929, there are still a lot of problems unsolved about bacteriophages and bacteriophage therapy. It is sad to say only a few trials have taken place and the number is far from enough to prove the absolute safety of injecting phages into human bodies (Wright et al., 2009).
For the production process, it has been put forward that the bacteriophage production methods have largely neglected the impurities that might endanger human health(Luong et al., 2020). The production of bacteriophage require the lysis of bacteria, as well as the separation of target bacteriophage from other cell debris, which may be lipopolysaccharides(LPS), exotoxins and other compounds. These bacterial parts can cause serious side effects from fever to endotoxin shock. That it to say, an effective and controllable process for phage production that also meets safety and efficacy demands is yet to be studied and achieved(Luong et al., 2020).
Determining the ideal treatment plan and effective potency so as to formulate a standard treating strategy for each type of bacteriophage therapy also matters. Information like the best way of injection and target concentration should be concluded through numerous clinical tests, because all of them are vital to the decision of clinical therapeutic regimen. Infection can sometimes be serious enough to threaten people’s life, so it is also necessary to take these urgent cases into consideration where the patient’s life is at stake due to bacterial infection, and the ideal loading dose of bacteriophages should also be tested and controlled with great care.
Many first steps are taken for the establishment of a standard protocol for bacteriophage therapy
It is good to know that a systematic and practicable procedure for bacteriophage isolation, selection, liter-scale cultivation and purification has been proposed by Luong and colleagues. Modified classic techniques and modern membrane filtration successfully removed most of the impurities. The bacteriophage acquired through this method possess high phage purity measured by Limulus amoebocyte lysate (LAL) chromogenic assays, protein analysis and cell viability analysis and show excellent reproducibility(Luong et al., 2020).
Onsea and colleagues established “multidisciplinary phage task force” (MPTF) consisted with infectious disease specialists, pharmacists, microbiologists, surgeons, and phage scientists, which dedicates on forming standardized treatment pathways. They have formed a protocol for treating severe musculoskeletal infections using a combination of bacteriophage therapy and antibiotics, including isolation of pathogens and susceptibility testing, intraoperative and postoperative administration of bacteriophages as well as patient follow-up(Onsea et al., 2019). Their application through a draining system proved practicable and will be further optimized. It is wonderful that MPTF has taken on responsibility to contribute to the establishment of standard protocols for bacteriophage therapy, and we believe with encouragement and support, more and more facilities would start to do the same. Conclusion
Of course, the above views only represent the personal opinions of our team and certainly do not apply to all cases. However, we all believe these issues matter when we are trying to develop a new treatment for bacterial infections. Due to the limited conditions, we are temporarily unable to carry out further research. We couldn’t agree more that a long process and much more hard work and endeavor are inevitable for bacteriophage therapy to be finally used in hospitals and clinics. Moreover, we are more than proud to be able to contribute our efforts to the advancement of bacteriophage therapy and fight the war of antibiotics overuse and superbacteria. We believe that with the time going by, the society will pay more and more attention to bacteriophage therapy and the above issues can be properly addressed.
We warmly welcome any well-intentioned suggestions and corrections, and we would love to discuss this topic with other iGEMers interested in medical humanities over bacteriophage therapy. References
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