Silver Medal: mGEM Human Practices

Behind research lies an intrinsically human element – no discovery is made in a social or political vacuum. This year marked extensive development for mGEM’s Human Practices team, as we sought to address the gap between our project’s lab work and the transfer of scientific knowledge across communities. As our Wet Lab and Dry Lab subteams created diagnostic assays for antimicrobial-resistant strains of the notorious hospital-acquired infections, C. difficile and E. coli, Human Practices sought to understand the potential impact of this technology. Antimicrobial resistant infections thrive within healthcare settings, so we focused our efforts on the burden of C. difficile and AMR in the Canadian healthcare system on local, provincial, and national levels.

Our research began with compiling literature reviews on the ethics and policies surrounding synthetic biology in healthcare, as well as the statistics representing the expansion of C. difficile and AMR as a pressing issue in Canada and internationally. We then chose to interview national experts and organizations to help us understand differing perspectives within AMR, the need for rapid diagnostic assays, how to modify our project in order to best suit those needs, and the translation of scientific knowledge to facilitate public awareness and education.

Discussion Paper

Our interviews spanned six months, and we had the opportunity to speak with national stakeholders in AMR and C. difficile. Throughout this consultation process, we developed insights at various levels of the biomedical technology development pathway. This experience was particularly helpful to understand the complexity of bringing a clincial technology to market- let alone one grounded in novel scientific principles, and biological engineering. We wrote a discussion paper synthesizing our qualitative data, with the goal of presenting the overarching challenges in antimicrobial resistance and C. difficile diagnostics, and how pursuits in synthetic biology may fill those gaps. You can find our discussion paper here.

Below are summaries of our consultations with these industry experts and policy makers.

Dr. Yingfu Li

— Professor and Canada Research Chair; Dept. of Biochemistry and Biomedical Sciences

As our primary advisor for the 2016-2017, Dr. Yingfu Li has worked with us in developing the theme of antibiotic resistant bacteria during the early stage of the project. It made sense for us to go to him first and get his perspective on the current stage of research for antibiotic resistance. While interviewing him, we found that on the subject of resistance, there are two major branches of AMR research. One is improving the diagnostic method, to detect the bacterial strains with improved accuracy and timing. The other is developing new therapeutics to treat the novel strains. We determined that to grasp the full situation of antimicrobial resistance in Canada, we must approach researchers and clinicians who are involved in both branches of the issue.

Dr. Li also brought attention to a factor that must be considered in the wet lab design: balancing sensitivity and efficiency. He told us that a diagnostic tool that is fast in detection must sacrifice accuracy, while a tool that prioritizes accuracy sacrifices efficiency. The Human Practices and Wet Lab teams then opened a dialogue about the ramifications of sacrificing one component for the other.

Finally, Dr. Li encouraged us to find multiple stakeholders to understand the problem of antibiotic resistance. He provided names of researchers here at McMaster, whose work we would find especially interesting. We were able to interview some of them through his assistance.

Dr. Gerry Wright

— Director, Michael G. DeGroote Institute for Infectious Disease Research; Canada Research Chair in Antimicrobial Biochemistry

We had the opportunity to interview Dr. Gerry Wright, an expert in drug development and antimicrobial resistance, early in our project. The foundational knowledge we learned in this meeting heavily influenced our project direction, with the first section of our discussion addressing the basics of antimicrobial resistance. Dr. Wright justified his research, which aims to identify both new antibiotics and compounds which inhibit resistance. We learned that, although sometimes resistance is due to internal mutation of the bacteria’s DNA (which we thought occurred most often), the most common resistance mechanism is the acquisition of resistant genes from plasmids and transposons. That is, a bacterial organism’s resistance is more heavily influenced by external, rather than internal, factors.

Next, we discussed difficulties associated with a drug’s commercialization process. We learned that there is often a decade between the discovery of a compound and the “phase two” trials of experimenting on patients. In this decade lies the translational period referred to as the Valley of Death, wherein most discoveries will remain, since rigorous trials often prove the compound inefficient or harmful and the cost of the years of testing is enormous. This conversation led us to contact several research institutions, including the Canadian Institutes of Health Research, to deliberate solutions to the financial barriers within AMR research.

Dr. Dominik Mertz

— Medical Director Infection Control; Hamilton Health Sciences

The Human Practices team spoke with Dr. Dominik Mertz on August 2nd, 2017. Dr. Mertz is an associate professor at McMaster University in the Department of Medicine and Infectious Disease. Additionally, he is the Medical Director of Infection Control for Hamilton Health Sciences. We chose to interview Dr. Mertz because we were interested in hearing about the role of antimicrobial resistance and infection control in healthcare from an expert in the field. Foremost, we learned that the time it takes to diagnose C. difficile is a significant issue:

”When you have a patient in front of you who is not doing well, who needs antibiotics, the faster you know what [the infection] is, the better.” - Dr. Dominik Mertz, Hamilton Health Sciences

The turnaround of approximately 3-5 days between sending the sample to the lab and getting a result is a crucial period in patient treatment. In the time they are not receiving C. difficile-specific antibiotics, they are often taking broad-spectrum medications that can work to exaggerate the problem. Thus, a novel, faster technique of diagnosing C. difficile is clearly needed.

Dr. Nick Daneman

— Clinician-Scientist; Sunnybrook Research Institute

Dr. Nick Daneman specialized in AMR stewardship and C. difficile. With AMR bacterial strains of C. difficile being under investigation in our Wet Lab, Dr. Daneman could give us key insights on the burden on and scope of these pressing issues in healthcare systems and how we could tackle this. During our interview, Dr. Daneman revealed to us that in the case of C difficile,

“The majority of cases develop after admission [into a healthcare facility] or... an elderly person in a long-term care situation, or a recently discharged person who then develops symptoms in the community. The two [factors in the development of C. difficile as a disease] are: one needs to get the bug, which means oral ingestion of contaminants within the environment, and the second [factor] is antibiotics, because people have diverse, protective intestinal flora [that protect against sickness]... but antibiotics dilutes the normal bacteria and C. difficile has more of a niche to replicate and cause disease.” - Dr. Nick Daneman, Hamilton Health Sciences

Thus, with more infected patients in healthcare institutions, this induces colonization pressure and increases antibiotic usage. The standard diagnostic test for C. difficile being usage of immuno-sensitive PCRs sent to public healthcare labs, this took a lot of time. We discussed how shortened turnaround time on diagnostic results would lead to better and more proper prescription of antibiotics, should they be disease carriers, or omission of an unnecessary prescription of antibiotics, should they not have the disease. Additionally, quicker redirection to other tests for patients to find their proper diagnosis. In addition, Dr. Daneman explained that thousands of dollars could be saved per case of prevention. Morbidity and mortality were very high for this diseases, with the Ontario Burden of Infectious Disease Study showing C. difficile coming out in the top ten for these factors. After having explained our proof-of-concept, he saw that our project would fit into this needed aspect of diagnosis and prevention.

Finally, Dr. Daneman stressed that the issue of antibiotic and AMR stewardship and education were key in preventing C. difficile from developing into a bacterial disease.

“Any antibiotic can cause C. difficile [to become active], ...[including] the antibiotics we use to treat C. difficile. It is important to focus on when to start, how to choose, and when to stop treatment.”

Educating practitioners about antibiotic overprescription was vital, and we talked about how the public also needed to become more aware of this issue to prevent the widespread problems surrounding AMR. Since “90% of antibiotic use is in the community, ...better antimicrobial stewardship [is needed].” With us tackling important topics on local, national, and global scales, very important topic, he commended us and pressed us to move forward with our work.

Harpa Isfeld-Kiely

— Project Lead on AMR and AMS, Senior Project Manager; National Collaborating Centre for Infectious Diseases (NCCID)

To develop a stronger background in the broader policy dimensions of AMR, we interviewed Harpa Isfeld-Kiely, a Senior Project Manager at the Canadian National Collaborating Centre for Infectious Diseases (NCCID). Our conversations focused on understanding the complexities of public education on AMR, antimicrobial stewardship, the worldwide burden of disease, and Canada’s political role in combating AMR.

We learned a great deal around the breadth of qualitative research done by prominent biomedical research funders such as the Wellcome Trust around science communication, and public perception of antibiotic use. This resource was helpful for us to better understand the barriers to effective science communication commonly faced by research institutions and public knowledge brokers. We were additionally informed around the existing work completed by hospitals in Canada, primarily Mt. Sinai in Toronto around effective hospital antimicrobial stewardship. We were additionally referred to larger action plans being developed across Canadian health institutions to support work in antimicrobial stewardship.

We also discussed the large international health-economics studies projecting the estimated international number of deaths attributable to AMR bacteria, and the estimated worldwide cost for healthcare. Such arguments were particularly useful to scope the magnitude of the AMR problem in the broader context of other items on the global health agenda, such as non-communicable diseases (diabetes, cardiovascular diseases), and infectious diseases. We further discussed the functions of the Canadian government in supporting research towards point-of-care diagnostics like our wet lab project, and the leadership of Canadian policymakers on the national and international stages in strategizing against AMR. Such discussions yielded a greater understanding of the breadth of challenges presented on the policy and financing levels in supporting AMR research- and allowed us to contextualize our project in a broader AMR movement.

Dr. Cheryl Main

— Chair, Specialty Committee of Infectious Diseases; Royal College Canada

Dr. Cheryl Main was recommended to us by one of our past interviewees, due to her experiences of running educational programs in Hamilton on bacterial infections and sex education. One of the Human Practices team’s main interests is improving the public awareness and engagement on antimicrobial stewardship. By interviewing Dr. Main, we gained valuable insights on how public campaigns succeed and fail.

During the exchange, Dr. Main provided accounts of her work on educational programs at middle-high school boards, and of the challenges she experienced. She informed us that for change to occur in the minds of the public, educational programs need sustainability and longevity. She also emphasized the importance of carefully choosing words and visual aids to target the appropriate audience. For example, when catering to clinicians and other professional staff, the material can carry some scientific language. However, when addressing the general audience with mix of students, teachers and parents, basic terminology should be used to advance ideas clearly.

Furthermore, Dr. Main has executed informational campaigns for staff at the Hamilton General Hospital. Of the projects, she found installing posters at strategic locations in the wards to be especially helpful. Hearing this, the Human Practices team brainstormed initiatives that we could attempt to inform both the public and frontline staff on antimicrobial stewardship. We considered flyers such as the ones developed by Dr. Main’s team to be one of the most viable options for the resources that we had available.

Dr. Marc Ouellette

— CIHR III Scientific Director; Canada Research Chair in Antimicrobial Resistance

In Canada, CIHR (or Canadian Institutes of Health Research) is the main funding agency for health research. We were able to have a discussion with the Scientific Director of CIHR’s Institute of Infection and Immunity, Dr. Marc Ouellette. Dr. Ouellette’s extensive research on antimicrobial resistance, as well as his extensive oversight of the scientific community and research surrounding this topic, made him ideal for synthesizing the knowledge we gained and showing us where to go next.

During the meeting, several key themes emerged. Firstly, Dr. Ouellette’s insights on the gaps for detection assays reverberated with previous researchers’ statements: cost and rapidity were at the crux of the issue. Although there was a multitude of current diagnostic assays in the field of AMR, it was a necessity to make those technologies more affordable, so that more healthcare centres could have access to them, and more rapid. Specifically, if an assay could not determine an answer “within 30, 40 minutes, then it’s useless in that it has the same base as classic microbiology tests. The decision has been taken, the patient has moved on.” However, he also saw that “...adding a rapid diagnostic for general bacterial infection would have a huge impact. This is the quest to everyone involved in diagnostics: to distinguish between a bacteria and a virus. Right now, looking at the RNA-seeking test, we can determine this, but it’s not cheap or rapid... This is where an assay like [iGEM McMaster’s] could come in and really advance molecular medicine.”

Taking a broader outlook on the issue, we learned that Canada invests approximately $20 million each year into the issue of AMR. With regards to C. difficile, there were no exact monetary figures, but this bacterial disease was also a recognized crisis in hospitals and long-term care facilities. As a complex global issue however, Dr. Ouellette shed light on the multi-national collaborations that were in place to tackle AMR’s three pillars: surveillance, stewardship, and innovation. Bringing up the severity and wide scope of the issue around the world, he said:

”The G7 has discussed AMR twice in a row, and it has also been discussed in their climate forum. Now, the G20 is trying to make a group with other countries for push and pull: push being the research effort, and the pull is prizes or tax breaks. The CIHR contributed more into the pull, and the JPIAMR is a group of mostly European funders which is trying to fund internationally. Committees are being put together every week for AMR, which means there’s a lot of stakes in it... Challenges in developing countries are that the health systems are not the same; here in Canada I think it’s reasonable, and we can use authorities to help. Some other places this system is broken, so resistant infections can spread further and complicate things. This is where I see some of the challenges. The technology we develop nearly impossible to make in low-income countries... The health systems [are] broken.” - Dr. Marc Ouellette, CIHR

Segueing into talks of Stewardship, the heart of this AMR pillar lay in “[giving] antibiotics to the people who need them, and the right one at the right time. It’s an art, not a science, when they look at you feeling terrible.” Having known Dr. Nick Daneman’s work surrounding the auditing of prescribers of antibiotics, Dr. Ouellette explained to us that he believed in targeting both the prescribers and the patients.

“Sometimes antibiotics save lives, remember that. It’s just like washing your hands — it’s the public and the healthcare worker. Except, this situation has dire consequences. Antibiotics are absolutely necessary, but sometimes they’re not. You’re a parent and you haven’t slept for three days, so you try to convince your GP to give your child antibiotics. But what if you knew that your child’s immune system could be harmed? It’s only recently that we found antibiotics would harm your good bacteria, your microbiome, and we had no idea the role that plays in the immune system at a young age. A young baby in the first 6 months of its life: this is where antibiotics are life-saving, but also the worst. So education for all partners would help.”

Finally, Dr. Ouellette foresaw future research in this field in Canada as being able to fill the niches in AMR research gaps. Dr. Gerry Wright’s research on using molecules to help circumvent resistance was specifically mentioned, alongside immunology and alternatives to antibiotics. He lastly reinforced that “[we] need to protect what we have, judiciously, [through stewardship, better education]... Research on strategies to limit antibiotic use will also have impact, and Canada has a lot to offer there too.”

With Dr. Ouellette’s powerful insights, we were able to further understand just how important the evolving field of AMR, and specifically AMR Stewardship, were in future directions of healthcare and research. He himself saw our work as perhaps being the next step that could be taken in diagnostics for such an issue of import. We can thus justify our work even more through both the scientific impact that we will have and through our decisions to now broaden education about AMR and conduct our own forms of stewardship in our local communities.

Dr. Marek Smieja

— Chief of Microbiology for the City of Hamilton; Founding Member, Ontario Working Group for the Rapid Diagnosis of Emerging Infections

On September 13th, the Human Practices team had the opportunity to interview Dr. Marek Smieja, the Chief of Microbiology for the City of Hamilton. Dr. Smieja’s extensive work with C. difficile made him an excellent resource. After interviewing him, the three most prominent lessons we learned from him were that: 1) hospitals are overflowing and the turn-around time for C. difficile tests is approximately 3-5 days; 2) a test that can be provided in a more consumer-friendly manner is much-needed; and 3) healthcare providers prescribing antibiotics should be providing patients with information regarding the risks of AMR and C. difficile.

After discussing the burden of C. difficile on the healthcare system, Dr. Smieja highlighted the importance of finding ways to redirect patients away from hospitals and move diagnostic testing upstream. In order to help alleviate this load, Dr. Smieja suggested designing a more consumer-friendly diagnostic test that can be purchased at a pharmacy, brought home by family members, or conducted by nurses in nursing homes. This would also shorten the time that patients often wait before seeking medical attention, and would hopefully allow the infection to be addressed before it worsens. Lastly, Dr. Smieja voiced concern about healthcare providers not providing patients with adequate information upon the prescription of antibiotics. He stated, “as long as people think that there are no antibiotics have no side effects, we have issues.” This prompted us to ask if a pamphlet that could be distributed by such healthcare providers alongside the prescription of antibiotics would be helpful. After hearing that he was fond of the idea, the Human Practices team decided to design such a pamphlet that could be given to healthcare providers for their use.

Dr. Andrew MacArthur

— Cisco Research Chair in Bioinformatics

Our group was invited to attend the Michael G. DeGroote Institute for Infectious Disease Research (IIDR) Rounds, where we had the chance to discuss existing computational pipelines in the surveillance of C. difficile in St. Joseph’s Hospital in Hamilton, Ontario. While this discussion was focused on the epidemiological surveillance of C. difficile within the hospital wards, much of the clinical discussion was focused on existing tools for prevention of the spread of AMR. Spanning recommendations such as washing hands, isolating patients with diarrhea, diagnostic tools, and prophylactic antimicrobial use, we were fascinated with the host of clinical decisions required to manage C. difficile patients.

Recognizing the complexity of the clinical landscape helped us better recognize and understand the clinical context under which a technology like our prospective point-of-care diagnostic tool would fit within the broader architecture of clinical decision making. SImilar in many respects to the United Kingdom, Canada is pressured under its provincial single-payer, publicly funded healthcare systems to build diligent health technology assessment studies and protocol to ensure that clinical decisions are being informed by both clinical utility and cost-effectiveness. For us, this was a significant tipping point in our understanding of the broader policy context of biotechnology development- particularly in the Canadian healthcare context. While techniques such as immunoassays and rectal swabs yield strong results, it is difficult to assess at what point in the clinical algorithm they should be deployed to ensure the ideal balance of clinical utility and cost-effectiveness.

Mayor Fred Eisenberger

— Mayor, City of Hamilton

With insights from leading researchers across Canada, we reached out to Mr. Fred Eisenberger, the Mayor of Hamilton, to figure out how we could effectively convey this information to the citizens of Hamilton. Specifically, we wanted to know how we could create effective workshops for high school students, campaigns for the general Hamilton community and resources that could be given to patients receiving antibiotics in order to foster a scientifically literate community and to bring awareness to issues surrounding antimicrobial resistance. Mr. Eisenberger’s extensive work in the Hamilton community and his focus on developing the next generation of healthcare leaders made him the best choice to help us develop a platform to share our research.

We started the meeting off by discussing the McMaster iGEM team, our research and the negative effects of C. difficile in Hamilton. The mayor proceeded by asking a series of questions to determine the scope of the problem and those who are most likely to be affected. With new knowledge from l researchers such as Dr.Daneman we were able to explain that in the case of C difficile,

“the majority of cases develop after admission [into a healthcare facility] or... an elderly person in a long-term care situation, or a recently discharged person who then develops symptoms in the community. “

As a team we wanted to develop a point of care diagnostic tool to prevent patients from acquiring a C. difficile infection in the first place. While our Wet Lab team has made tremendous progress, the Mayor pointed out that we should focus our efforts on what we can do now.

So after our discussion of the wet lab project and the issues surrounding C.difficile that are relevant to Hamilton, we focused the remainder of our meeting on education and outreach opportunities. We started by asking Mayor. Eisenberger the most effective ways of communicating with the public and bringing awareness to antimicrobial resistance. He laughed and said that while social media platforms are a good starting point, “good old-fashioned tv and radio” are still a great way of communicating with a wider audience, especially those who may not be active on social media. He said that once we had a solid message and had fully developed our content, he would help us to broadcast our message using mass media platforms such as the Cable 14 news. He also connected us with a number of local community groups such as the Social Planning Research Council, and the Public Health Sector of Hamilton led by Dr. Elizabeth Richardson. The mayor showed tremendous support for our project and the work we are hoping to do in the community.

The mayor's encouragement, insight on our outreach initiatives and contacts with local community organizations and Dr. Elizabeth Richardson have been invaluable and showcases the impact a student can have. We look forward to contacting these organizations, engaging with community members and speaking to Dr. Elizabeth Richardson, the Medical Officer of Health, to better understand how the McMaster iGEM team can word to address issues in the Hamilton community.

Dr. Elizabeth Richardson and Mr. Jordan Walker

— Medical Officer of Health, City of Hamilton; Manager, Hamilton Infectious Disease Prevention and Control Program (respectively)

With Mayor Eisenberger’s help, we arranged a meeting with Dr. Richardson and Mr. Walker with the intention of further integrating McMaster iGEM with the City of Hamilton and its healthcare communities. The preparation for this meeting involved an inter-subteam assessment of the future of McMaster iGEM, and how to commit to projects which will truly benefit our city. We had the opportunity to discuss upcoming initiatives within Hamilton’s Public Health sector, and our interviewees’ own goals in the execution of these projects.

An issue we discussed in depth was the recent spike of Legionnaires’ disease which occurred in Hamilton and the Greater Toronto Area over the past summer. Mr. Walker expressed that the largest obstacle in combating Legionella bacteria was the difficulty researchers face in tracking the source of the infection, since the bacteria exists in warm water sources and airborne mists. The current diagnostic method involves a urine antigen test which, although providing a sufficient diagnosis, does not give any hint to where an individual contracted the disease. Legionnaire’s struck our team as an intricate and pressing issue, with the potential for synthetic biology application in both diagnostic and therapeutic techniques.

Other prevalent issues we discussed within Hamilton’s healthcare system include:

Lyme disease from tick bites

Tobacco consumption and smoking in youth

Sexually transmitted infections and antibiotic delivery for syphilis, gonorrhea, and chlamydia

Opioids and safe injection sites

Mental health determinants

We recognise the potential of mGEM’s future projects to connect with the City of Hamilton’s public health sector, and for our Human Practices and Outreach teams to provide support to their own campaigns. This meeting was invaluable for our careful consideration of the future of McMaster iGEM as a community-integrated, education-based research team.

Dr. Theresa Tam

— Chief Public Health Officer, Public Health Agency of Canada

After interviewing many researchers from across Canada, speaking with the Mayor of Hamilton and most recently meeting with Dr. Richardson and Mr. Walker from the public health sector in Hamilton, we decided to contact the Public Health Agency of Canada (PHAC) to better understand Antimicrobial resistance on a national scale. Dr. Theresa Tam, Chief Public Health Officer, provided us with a number of resources including the Canadian Antimicrobial Surveillance System 2016 Report, the Antimicrobial Resistance in Common Hospital Pathogens in Ontario Report, and the Federal Action Plan on Antimicrobial Resistance. These resources have been invaluable in helping us better understand the scope of AMR. After all, “AMR is a cross-cutting issue with roles and responsibilities shared by the federal, provincial, and territorial governments”.

After we have had a chance to thoroughly analyze all the information we have received, we will be contacting Dr. Chris Archibald the Director of the Surveillance and Epidemiology Division, in the Centre for Communicable Diseases and Infection Control to discuss our project, outreach initiatives and how we can continue to address healthcare issues such as AMR in Canada. With insights from both Dr. Tam and Dr. Archibald, we will be able to continue the development of our outreach initiatives for both students and communities and be able to broaden the scope of our project.

The Future of mGEM Human Practices

mGEM Human Practices is looking to continue discussions with Hamilton Public Health, the city of Hamilton’s Public Health Division. The long-standing objective is to align the topical focus of mGEM’s project with a public health concern in our city. This strategic alignment affords mGEM the opportunity to apply synthetic biology to problems with deep relevance to our broader community. This approach also expands opportunities for critical reflexivity within the basic science research arm, as well as the broader scope of human practices. By engaging critical stakeholders working at various levels of technology development, implementation, and regulation- such insights can enhance processes of technological innovation, towards a form of integrated innovation that conscientiously marries scientific discovery to its worldly implications. After all, the development of technology is not in a vacuum: it has demonstrable interactions within a broader system that deploys technological tools to make decisions with human consequences. This year, our group developed experience and built a cursory understanding of the complex network of actors within clinical technology. In future years, our hope is to expand upon our understanding of complex networks and actors involved in the series of steps translating biomedical technology from bench to bedside.

Team:McMasterU/HP/Silver