Viral Vectors as Containers and Their Importance to Gene Therapy

By: Danning Li

Hello everyone and welcome back to the big wide world of gene replacement therapy and medicine! On our last blog post, we tackled the general idea of gene replacement therapy, which was namely to put a working copy of a gene into a patient’s body, so that the gene product could be produced permanently. This idea of course sounds incredibly simple, but considering the lack-luster implementation of gene replacement therapy in medicine today, why hasn’t this idea become widespread? Well, this blog post is going to tackle that exact question, and look at some of the challenges facing gene therapy today.  

To start off, the main problem in gene replacement therapy is that the human body really hates taking in undigested DNA (if anyone wants to read about extracellular DNA in the body, here’s a good paper: The Origin and Properties of Extracellular DNA: From PAMP to DAMP). So, automatically, the idea of oral gene therapy pills is difficult to implement, since stomach acid and digestive enzymes would rapidly degrade incoming DNA into individual base pairs or base pair components. At the same time, injecting DNA directly into the blood stream or local tissue would meet a different problem; the immune system, which would rapidly detect the foreign DNA and then degrade it into all of its components (click here to see how the innate immune system detects DNA). Therefore, this leaves scientists and physicians with a problem, how can we create a therapy that can sneak past the immune system to deliver our uncompromised DNA to our target tissue?

Infective Solutions: The Virus

First thought: viruses, a common solution to a scientist’s dilemma. By the 1970s, it was already known that viruses are natural agents at injecting their genetic information into host cells for viral reproduction purposes. The goal then became to find a good viral candidate that could somehow be used as a gene delivery system to the human body. To be considered a good candidate, the virus must meet several criteria: it must be able to deliver the genetic information efficiently, it must be minimally immunogenic, it must be non-replicative, and it should have a low risk of insertion into the host genome (this article is a good summary of viral vectors for gene therapy).

The process to meet these goals requires the original viral DNA to be removed, and only the viral capsid to be used. Without going into a lot of details, since the virus has been rendered non-replicative, the production of the viruses would have to be split into multiple parts; this means that the DNA plasmid of our target gene would be given alongside our packaged plasmid expressing the viral capsid protein using a co-transfection protocol (triple transfection is the newer technique and has much better yield than double transfection). However, the question remains, just what kind of virus should be used? After all, there are so many types of viruses to choose from! For now, we will focus on 3 types of viruses that are of interest: retroviruses, adenoviruses, and adeno-associated viruses.

A) Retrovirus

As medical students, we have all heard of retroviruses, with HIV being the most widely known member of the retroviral family. For gene therapy purposes, lentivirus, a subtype of retrovirus, is used instead of a standard retrovirus, since a lentivirus can infect non-dividing cells. The good and bad thing about a lentivirus is that it will insert its own genome into the host genome-this is great because once the insertion occurs, the cell will have the DNA forever (no backsies)-but on the negative side, inserting DNA into random places within the human body will disrupt normal gene function and could lead to cancer. This was unfortunately shown when children given an experimental gene therapy to cure X-linked SCID-XI syndrome developed leukemia due to random insertion inducing mutagenesis (they were cured of their SCID-XI syndrome though, so mission success with unfortunate side-effect?).

B) Adenovirus

Our second virus of interest is the adenovirus, a virus responsible for many infections in the respiratory tract, among others. This early candidate for gene therapy however, had the tendency to spread throughout the body and become immunogenic. This was shown sadly in 1999, when Jesse Gelsinger died due to an immune reaction to adenovirus in a trial to cure ornithine transcaramylase, a metabolic disease that affects ammonia elimination,.

C) Adeno-associated Virus (AAV)

Finally, we arrive at our last viral candidate, the adeno-associated virus or AAV. The name is pretty straight forward, AAV depends on adenoviruses to reproduce (it’s like a virus of a virus). In fact, when AAV was first visualized under electron microscopy, scientists weren’t quite sure what it was due to its small physical size. Since AAVs are naturally non-replicative, they are minimally immunogenic, and there are no diseases that are known to be caused by AAV. The major limit of AAV usage however is their small size, since only about 2.5kb worth of DNA can be delivered with one virus, which significant limits the amount of treatable diseases with this strategy, since human genes are quite large in base pairs. However, since safety is the major concern of viral gene delivery, much of the focus on gene replacement therapy has focused on developing good recombinant AAV (rAAV) platforms because of their high safety features.

To conclude, I hope this post provided you a brief understanding of some of the current challenges in delivering gene replacement therapy in medicine and next time, our topic will be on the different types of rAAV vectors (delivery gene mechanisms), and how the choice of this rAAV subtype (there are a lot) is important for therapy development.

Author: Danning Li

Danning Li completed his BSc. majoring in Physiology at McGill University. Afterwards, he worked for two years on developing a gene replacement therapy for Canavan Disease, a rare inherited leukodystrophy, at the Horae Gene Therapy Center at the University of Massachusetts Medical School. Now a medical student at Schulich, he wants to bring attention to the interesting genetic therapies that will become available in the not so distant future.

Photo Credits: Creative Commons, Capsid

What is Gene Therapy?

By: Danning Li

On December 19th, 2017, Leber’s congenital amaurosis, an inherited disease that causes severe vision loss and blindness in children met its match in the form of voretigene neparvovec (AAV2-hRPE65v2, or Luxturna for ease of pronunciation), the first gene replacement therapy approved by the FDA for sale in the United States. The previous sentence might contain some words that are not part of the current medical curriculum, but they will become an increasingly important part of our future practice as technology develops. Already, the rate of approval for these novel therapies is ramping up. Last year, the FDA approved three new genetic therapies for public sale (for those interested, the FDA news releases are here in chronological order Kymriah, Yescarta, and finally Luxturna). So, for today’s blog entry, with the possible dawn of the genetic therapy age upon us, let us focus on just what a “gene replacement therapy” is, and why it is such a big deal.

Gene Replacement Therapy 

Gene replacement therapy, as its component words suggest, is a treatment that aims to provide a replacement copy of a gene to a patient’s body. It doesn’t matter if the patient doesn’t have this gene, protein or enzyme, or even if the patient has a mutant, non-functional or less-functional version of the enzyme; gene therapy seeks to rectify this issue. The goal of this therapy is for the replacement artificial gene copy to produce a functional enzyme or enzyme subunit that the patient’s own body needs, and can use effectively.

Now, some might be wondering why we don’t just supply the missing enzyme instead, after all, Enzyme Replacement Therapies (ERTs) are well-established treatments for several diseases already. However, the answer to this question is simple: economics. Remember how enzymes are constantly made and broken down in the body naturally? Well, this applies to inherited diseases too since the patient would break down the injected replacement enzymes overtime, and the effects would wear off. Since the replaced enzymes are made in a lab and have to be reinjected into the patient regularly, we would have to constantly produce the purified enzymes and the patient would be on the hook for the rest of their life. This might not sound like such a bad problem, a lot of medications are like this already, right? Unfortunately, it turns out treating someone for decades with regular ERTs cost around USD $9-10 million or more. Insurance companies and OHIP won’t be very happy if a lot of patients started lining up for therapies with these kind of price tags attached.

Looking Towards the Future

Naturally, when faced with such a tantalizingly difficult problem, scientists and physicians thought up a ridiculously simple solution in the 1960s. If making these enzymes outside of the body and then injecting it into the patient is too costly, why don’t we just give the patient’s body the genetic information it needs to make the missing enzymes inherantly? After all, the most efficient enzyme production facility is a living, breathing body that converts regular nutrients into precious enzymes. Even better, if we were lucky enough, and the inserted DNA managed to stick around inside the body somehow, we would have just cured the disease completely, improved the patient’s quality of life, and opened up a completely new world in science. Thus, the idea for gene replacement therapy was born, and brilliant minds around the world would spend the next half a century trying to make this ridiculously simple idea, a reality.

Author: Danning Li

 

Danning Li completed his BSc. majoring in Physiology at McGill University. Afterwards, he worked for two years on developing a gene replacement therapy for Canavan Disease, a rare inherited leukodystrophy, at the Horae Gene Therapy Center at the University of Massachusetts Medical School. Now a medical student at Schulich, he wants to bring attention to the interesting genetic therapies that will become available in the not so distant future.

Photo Credits: Creative Commons, Gene Therapy Infographic

Title: Cost and Effect: Do We Over-Regulate Drug Development?

By: James Payne

On one of my very first tests in medical school, I was asked which branch of government was responsible for approving new drugs in Canada, and I’m ashamed to say the question gave me pause.  One frequently hears about the actions of the FDA in the US; but is there even a comparable body in this country?  Of course, I’m being glib.  The Health Products and Food Branch of Health Canada (totally didn’t have to look that up) does indeed regulate which drugs are available for patients. So, we can all sleep safe tonight knowing we’re protected from the profit-hungry machinations of Big Pharma; but should we?

Government regulations are designed to keep us safe, and it’s not hard to see why they’re so important.  One needs only to recall the failure of the authorities to protect young mothers and their children from thalidomide in the early 1960’s.  Even after the drug was withdrawn from markets all around the world due to the terrible effects on fetal development, thalidomide was still legally sold in this country. Ironically, it was a Canadian physician, Dr. Frances Kelsey, who blocked approval of the drug in the United States even while up against enormous pressure; and so spared that country from suffering the same fate of her own.  In 1962, Health Minister J.W. Monteith specifically cited the thalidomide tragedy when pushing for a new bill with stricter regulations on drug development in Parliament.

Drugs are among the most important discoveries in the history of science.  How many lives have been saved by antibiotics?  By chemotherapeutics?  By the almighty beta-blocker!? But these drugs can also pose a danger to us all as well.  They are designed to change things within our bodies; yet our bodies are so complex that sometimes they may change the wrong things.  This is why thorough and extensive drug testing is so important to protect both patients’ safety, and their confidence in the healthcare system.  Regulation is essential.  But have we recently gone too far?

Big Pharma and Drug Development

People often look with contempt at big pharmaceutical companies.  Yet, we should also remember that these companies are responsible for many major drug breakthroughs over the past century.  They’re in the business of making money, but saving lives is a happy side effect.  I don’t expect you to feel sorry for Pfizer or Novartis or Roche, but I will ask you to consider that when they don’t make money, they don’t make drugs. Their bottom lines can be very much our problem.

Regulations on drug development increase drug costs (okay, fair enough; as we have discussed above, regulations are important!).  But the question of the day is: Do we over-regulate?  Over the past decades, evidence standards for drug efficacy and safety have steadily risen, and thus so have the costs of development.  Yes, this has likely prevented injury and even death from dangerous drugs (which cannot be undervalued); but if there is a steadfast rule of economics, it is that when firms pay more, we pay more.  Fifty years ago, the cost of developing a new drug was approximately $250 million USD (adjusting for inflation).  Today, it may be as high as $5 billion.

These prices are astonishing, so it’s not hard to imagine some valuable areas of research being dismissed as unprofitable, especially for diseases more prevalent in the developing world. Of course, there is a strong argument to be made that regulations help drug companies to an extent; getting to claim an FDA stamp of approval can be used as justification to charge more per pill, and skyrocketing drug costs are not solely a function of increased regulation. However, stringent regulations may be costing us even more than mere dollars and cents.

Understanding the Process

As standards rise, so does time of development.  The time required to take a new drug from discovery to distribution has increased steadily since the 1960’s; currently, the average ‘bench to beside’ period for a new drug is 14 years.  Let us consider the implications of this delay: drugs limit mortality and morbidity.  Therefore, does increasing the time required to produce a new drug lead, in the interim, to increased death?  Basic logic suggests that it does, and some studies have estimated the numbers to be in the hundreds of thousands.

Moving forward, should the drug approval process become a simple matter of guessing whether it will kill or save more people?  Of course not.  Medicine is more than arithmetic; public confidence and peace of mind depend on the knowledge that what doctors prescribe is safe.  But can we reduce those regulations without seriously undermining the efficacy of authorities like the FDA?  Several ideas have been proposed, and I encourage you to read some of them here.

To leave some food for thought: are we so preoccupied with making sure our medications don’t kill us, that we allow diseases to do just that?  Is one worse than the other?  These are difficult questions.  But it may be time to ask ourselves: when it comes to regulating drugs, what is the cost, and what is the effect?

Author: James Payne

With a last name tailor-made for a future doctor, James really couldn’t have wound up anywhere but Schulich!  A London native, he did his undergrad at Queen’s, where he majored in Chemistry and Economics; the latter of which was the focus of his work for the UWOMJ journal.  James loves sports (he can catch a football better than Tom Brady), music, and, as you may come to find out, semi-colons.

 

Understanding the Health Impacts of Climate Change: Advancing the advocacy role of doctors and healthcare professionals

By: George T. Kitching

In 2009, a Lancet Commission on the health impact of climate change warned that climate change poses the greatest global health threat of the 21st century and has the potential to undermine the past 50 years of progress in global health. In June 2015, a second Lancet Commission on Climate Change, (this one focused on health policy implications), concluded that “tackling climate change could be the greatest global health opportunity of the 21st century.” In the same month, the Lancet published a joint commission with The Rockefeller Foundation entitled Safeguarding human health in the Anthropocene epoch, with the intent to create a new interdisciplinary, collaborative research field named Planetary Health.

Defining ‘Planetary Health’

There is no agreed upon definition of Planetary Health, however it was first envisioned, as the achievement of the highest attainable standard of health, wellbeing, and equity worldwide through judicious attention to the human systems-political, economic, and social-that shape the future of humanity and the Earth’s natural systems that define the safe environmental limits within which humanity can flourish. Time will tell whether this research field has staying power over the long term, however a PubMed search for ‘Planetary Health’ scientific journal articles identified 191 publications already since June 2015 regarding the topic. Much of the activity around Planetary Health has focused on defining the new field and attempting to distinguish it from Global Health and concepts of One Health and EcoHealth.

This process has been assisted by the launch of a new Lancet sub-journal in Planetary Health in April 2017. A scan of topics covered in the first eleven issues among others include the examination of the health co-benefits of action on climate change, and in the September issue, a focus on the health impact of pollution. A comparison between One Health (which focuses on the connections between humans, animals and their environment), EcoHealth (which values biodiversity, including all forms of life, and incorporates concepts of environmental sustainability), and Planetary Health, found commonalities between the various approaches to health, however there were differences identified between contributing sciences, core focus and core values. In particular, Planetary Health was noted to have a more anthropocentric approach to health, with greater focus on equity in human health. Planetary Health was identified to differ from Global Health through its emphasis on sustainability based on natural resources.

The Real-World Health Impact 

The development of the field of Planetary Health, with its direct focus on human health, speaks to the growing awareness of the impact of political determinants of health, mediated through the local and global environment. Air pollution and accumulating microplastics are two examples of factors that transcend national borders to contribute to global climate change and environmental degradation. The Lancet Commission on Pollution, published in October 2017, found diseases caused by pollution were responsible for an estimated 9 million premature deaths in 2015, with the greatest deaths being contributed to air pollution alone. Furthermore, these 9 million premature deaths are approximately 16% of all deaths worldwide, and three times higher than AIDS, tuberculosis and malaria deaths combined. A 2017 investigation by Orb Media found 83% of potable tap water samples, collected from locations around the world, were contaminated with microplastics. In addition, further research into human consumption of microplastics has identified other daily sources of microplastic ingestion, such as sea salt, commonly used in cooking. The impact of microplastics on human health is still unknown, however, they have been recognized as potential vectors for persistent organic pollutants.

So, what is the value of a new field such as Planetary Health? Well, it provokes the examination of climate change through a human health lens. It spurs reflection on the ways that human health is connected to the environment and affected by political, economic and social paradigms. It challenges the public and global health scientific community to engage in interdisciplinary research. AND it challenges physicians and healthcare providers to advocate on behalf of their patients, for the development of sustainable societies through aggressive climate change mitigation strategies.

Looking Forward 

In September 2015 Canada joined countries around the world in adopting the Sustainable Development Goals (SDGs) to ‘end poverty, protect the planet, and ensure prosperity for all’. While addressing climate change is recognized within the SDGs (Goal 13), it is interwoven into the meaningful attainment of every other SDG. Without addressing climate change, ending poverty (Goal 1) or ensuring health and well-being for all (Goal 3), may be transient victories, reversed rapidly for those displaced from lands no longer habitable.

In summary, definitive, lasting attainment of the targets set out in the SDGs rests upon robust and aggressive climate change mitigation. We need increased research by the global health scientific community into the health implications of climate change and its mitigation, and increased advocacy by our physicians and healthcare providers in understanding and preventing the local and global impacts of unsustainable resource use. And to achieve this, the field of Planetary Health helps to remind us all of the inseparable link between our environment and our health.

Author: George T. Kitching

George Tjensvoll Kitching is of Canadian and Norwegian ancestry, originally from Toronto. He has completed a BSc. in Biochemistry (Dalhousie University) and a MSc. in Public Health specializing in Global Health (Norwegian University of Science and Technology). George is currently studying at Western as a first-year medical student at the Schulich School of Medicine and Dentistry, at the Windsor campus. He is interested in understanding the role of healthcare providers in mitigating the health consequences of climate change.

Photo Credit: Creative Commons, Wind Turbines 

Do I Spend My Last Day Studying the Brachial Plexus?

January 25th

This is one of the many questions racing through my head as I walk through Victoria Hospital, tail between my legs and eyes at the floor. I’m approaching the Obs/Gyn call room after calling my boyfriend in tears for the millionth time this week while he tries to get his daily 6 hours before returning to night float. The bags under his eyes remind me that I’m the worst. I’m selfish, needy and lifeless. I’m not the person he fell in love with, I’m not the friend my classmates have relied on, I’m not the student that got into medical school. That person has been stolen with the body left behind.

I feel like I’m watching my life through a screen while an unidentified figure presses random buttons on the remote. The brightness has been turned down, colour desaturated with random alternations between fast forward and slow motion. The volume has been cranked so much that light vibration of emails, messages and schedule alerts and the inner mumblings of eating disorders past overwhelm my senses. Everything real that occurs around me is muffled and agitating. I’m begging them to press pause but they would rather taunt me with the OFF button, caveat being that there is no button to turn it back on. The OFF button has never looked so temping.

We are now laying in the call room which could also be used as an industrial sized fridge. I don’t cover need to cover up. My skin has numbed itself, so it can no longer feel the sweat of anxiety or the tears of depression. My stomach tied itself in a tight knot. My body is on standby – unwilling to fall asleep but never completely awake.

The exhaustion from this morning weighs me down like a ton of bricks. How many calories did I burn smiling and laughing in all the right places? I’m not cut out for this. One clinical methods session feels like I ran a marathon and I want to be a doctor. Good luck.

How did I get here? Last week I was bouncing around from study spot to the gym to the next exam feeling on top of the world. I may have gotten through an exam week without failing at least one, this was huge. I developed a foolproof plan to rock MSK and was pumped to spend a weekend in Blue Mountain with my class. I was going to clean up the apartment and leave some special treats to give my hardworking clerk the weekend to himself. Now the thought of leaving the apartment ties the knot in my stomach tighter and tighter. The thought of telling people I’m not going doubles it. Disappointing my boyfriend and impinging on his need for rest and solitude sends me into a tail spin. I have nowhere to go. Nobody deserves to put up with me right now.  I don’t want to put up with me right now.

There has already been three episodes like this since September. I’ve been dealing with mental illness since I was a kid. I always got tremendous satisfaction when doctors, counselors, whoever would ask “have you ever thought of hurting yourself” because the answer was always a definite no. Through the panic attacks, critical weights and depressive episodes, suicide was never an option I explored. It was empowering to think that even though my brain hates me, it wasn’t going to kill me. So now that these thoughts have popped up after 15 years, they are hitting me hard. Maybe they were by the 22 pounds I’ve gained since starting medical school. Maybe it’s the fact that I’m walking on eggshells around the UME due to my failed exams and missed mandatory sessions last year. Mental illness has finally gotten the best of me and I wasn’t strong enough to stop it. Imagine fighting a war for 15 years and losing. Imagine doing ground-breaking research for 15 years and having it thrown in the garbage and discredited. Would you want to start over?

What I should be doing is going to class and learning about this dreaded and deadly brachial plexus everyone is raving about. Hypothetically, if I was to take my own life, how pissed would I be if I spend my last days worrying about the brachial plexus?

January 27th

I am someone who wants to dedicate their life to caring for others and alleviating their pain and suffering. I believe that is he goal of most medical students. I feel tremendous guilt when I’m having suicidal thoughts because my mind always goes back to the patients. There are children diagnosed with terminal illnesses. We lose mothers, fathers and loved ones to cancer every day. These people did not deserve their fate and would do almost anything for another day. And here I am telling myself I care for these people while I take my life for granted. I wonder if the other physicians struggling with mental illness feel this way. I wonder if these thoughts contribute to the shame and secrecy that pushes us into a corner.

January 28th

My class should be getting back from Blue right about now. I’m dreading the explanations of why I ghosted everybody. Double dreading the explanations on why I don’t know the brachial plexus yet. As you can tell, I did not spend the last couple days studying the brachial plexus but I’m happy to report that it is not because these are my last days. I can feel the fog lifting and I’m not ready to give up yet. I realized I wasn’t ready when I spent two hours planning my clerkship rotations and talking about all the opportunities I have. My eyes are wider, my feet are faster, and my head is higher. Once I open this textbook to the brachial plexus in a couple minutes we will be 100% certain that I’m not going anywhere fast.

I could go back, cut out all my run-on sentences and edit this into a clean reflective piece but I’m choosing not to for three reasons. First, I think my chaos narrative is best reflected this way. Second, reading my thoughts and feelings from three days ago is petrifying. I barely remember that day, I can only remember the overwhelming sense of guilt and darkness. Third, and let’s be honest probably the most likely, is that I’m lazy and words are hard.

I also don’t know how to end this gracefully, so I’ll end it with some people I’d like to thank. The beauty of having a broken mind is that a somber reflection ends as an award acceptance speech.

To my mother, sisters, best friends and family: I am sorry I’ve been keeping this from 
you and not answering my phone.


To my niece: I could never leave you.


To my class: Even though I haven’t been open and honest with you guys please know 
that you are all the most welcoming and trustworthy people on the planet. I am 
in no way doubting your FIFE capabilities and I’m always here to FIFE you
right back.


To my favourite clerk and on-call superhero: I don’t know what I’d do without 
you these past months. Your confidence in my recovery makes me believe it’s 
possible. You are the love of my life.


To Learner Equity and Wellness and Schulich School of Medicine: You are doing a wonderful job. 
Thank you for caring about us.


And finally, to medical students and future colleagues: Be honest with each other, reach out 
when you need it. We got this.
If you or a friend is experiencing a mental health crisis, please contact 911 or visit your closest Emergency Department.
Visit Learner Equity and Wellness on-site or online for resources and support:
https://www.schulich.uwo.ca/learner-equity-wellness/learner_wellness/index.html

By: Cheyenne LaForme

Cheyenne LaForme is a second year medical student at Western University and the Local Officer of Indigenous Health.  She is using a portfolio-style reflection piece to raise awareness about, and cope with mental illness. She is originally from Hamilton and Mississauga’s of the New Credit First Nation and received a B.Sc. in Life Sciences at McMaster

 

Photo Credits: Creative Commons, Reaching

Remote Medicine: An Urban Medical Student’s Perspective

Last summer, I traveled to Northern Ontario with my colleague Amanda Sauvé to complete an elective in remote family medicine. After driving 1,300 kilometers and crossing many moose charging warnings, we pulled off the TransCanada highway and arrived at our destination: a town of 4,700 people in the Thunder Bay District, with fewer than two persons per square kilometer.

I had never been somewhere so remote; the next gas station was a forty-five minute drive away! I was stunned by the vast landscape of sparkling lakes and lush forestry. For the first time, I witnessed the majesty of moose and drove within meters of black bears. Despite being within my own province, this territory felt so foreign to me. It was so peaceful to be away from the hustle and bustle of urban living and to feel immersed within nature. At the same time, it felt eerily quiet and isolating. I was beginning to grasp the meaning of ‘remote’ that our peers at NOSM can appreciate.

We resided in the old nurses’ quarters adjacent to the town’s small hospital, the only hospital within a 180-kilometer radius. Three permanent family physicians and the occasional locum operate the hospital’s inpatient ward, its emergency department and the neighboring family medicine clinic. I formed my impression of health care in remote Ontario by working with these welcoming physicians, engaging with their patients and meeting with community members from a nearby First Nations reserve.

Unsurprisingly, a major barrier to accessing healthcare was geography. Back home in London, Ontario, patients can see specialists locally, and urgent CT scans and MRIs can be obtained in a flash. Conversely, in this remote town, the closest tertiary care center where these resources are available is over three hours away by car, or an hour by helicopter. We could arrange telemedicine appointments if physical examinations were not required, but otherwise, the commute to Thunder Bay was inevitable – as were the astronomical gas prices this commute entails.

Distance to amenities and associated travel costs are only two of many social determinants of health that differ up North. Employment opportunities are scarce, and small businesses struggle to survive in such low-density populations. Although housing is cheaper, it is unaffordable for many families to heat their homes comfortably in the wintertime, with temperatures dropping as low as a frigid minus forty degrees Celsius. Average monthly grocery costs are more than twice the cost in urban Ontario.1

My heart sunk at the realization that many small towns had one overpriced corner store (if any) for people to buy food, yet every town, without exception, had a liquor store. I was also deeply affected by two major public health issues in remote Northern Ontario: substance use and access to mental health services.

Regarding the former, the so-called ‘opioid epidemic’ is an inadequately addressed issue across the province, and it is particularly so in Northern Ontario. Typically, a methadone clinic provides patients with one dose per day and gradually increases the number of doses patients are allowed to take home (known as ‘carries’) as patients demonstrate that they do not divert their medicine to others. Where I worked, many patients live forty-five minutes from the methadone clinic, making daily pick-ups unfeasible for a working individual or for patients without a vehicle. As such, patients could be given a full week’s carries without undergoing the usual process of demonstrating reliability. Consequently, methadone in the area was frequently diverted, as was apparent by urine drug tests in the emergency department. Two patients have died from methadone overdose within the past couple of years at this site; in such a small population, this number is alarming.

Patients with substance use disorders or any other mental health concern have a right to reasonably accessible services under the Canada Health Act, yet patients can be forced to travel three hours or further to see a psychiatrist. The lack of mental health services is particularly apparent in the Emergency Department. For suicidal patients who are safe for discharge, it is a struggle to arrange appropriate follow up given the shortage of counseling and social work services and the distance patients may need to travel to see a family physician or psychiatrist. I remember my preceptor and I sent a teenager home with a prescription for an antidepressant and uncertain follow up, and I wondered concernedly, “Is anything going to change for her?” As for psychiatric patients who are not safe for discharge, they must be transferred to the nearest Schedule 1 facility. This means that their recovery will take place about 300 kilometers from their home and families. I can only imagine how unfamiliar that environment can feel without having a nearby support network.

Overall, in my experience, many physicians and patients up North enjoy the lifestyle and pace that the area offers. On the other hand, they often feel ignored or overlooked by government with regards to their health. Now that I have witnessed their system first hand, I feel the same way. If I felt helpless and infuriated during my brief remote medicine stint, I can only imagine how strongly that fire burns within those who live and work within that system every day. A passion to help change these circumstances has ignited within me; even though I am over a thousand kilometers away today, I have a social responsibility to keep that flame alive. I feel guilty that I cannot envision a full-time career for myself so far from where I call home. However, I can hold myself accountable by at least practicing as a locum and by advocating for technological advances and health care reform that may improve the care of these patients.

I encourage all medical students to take the initiative to plan an experience in remote medicine. Even as a pre-clerk, you can be a valuable asset to an understaffed team and underserviced patient population. Furthermore, I urge my fellow medical students in urban settings to care about the challenges faced by our peers and patients in remote settings and to join me in advocating for their health.

References
1. Source: Food Secure Canada. Paying For Nutrition: A Report on Food Costing in the North. 2016. Available from: https://foodsecurecanada.org/sites/foodsecurecanada.org/files/201609_paying_for_nutrition_fsc_report_final.pdf

“Gaming” CaRMS: the game theory and history of resident matching

Let’s face it: the sight and sound of this term is a stress-inducer for many. This charming acronym stands for Canadian Resident Matching Service and match medical students with residency programs across Canada. Each year, the participating students wait anxiously for their results, and the non-participants wait anxiously for the match statistics.

The main concern usually relates to building a competitive application. However, lurking in the back of people’s mind is the mysterious CaRMS match algorithm. To address people’s curiosity (read: stress), CaRMS has a special webpage titled “De-mystifying the Match Algorithm” that contains key words such as “Roth-Peranson algorithm”, “rank order lists” and “applicant-proposing”. But how does it really work? For a better understanding of the mechanism and history of this “globally-recognized and award-winning” algorithm, let’s take a look across the border where the algorithm was first developed.

Medical internship in the United States was introduced in the 1900s as a form of post-graduate training. The idea gained popularity quickly for obvious reasons, but the implementation had a more troublesome history. Initially, medical students and hospitals made internship arrangements privately. An overabundance of internship positions relative to the size of graduating class each year resulted in a race among hospitals to recruit medical students as early as possible; some students received binding offers by the end of second year. Such a pre-emptive decision on the hospital’s side was risky and costly. Hospitals could potentially make a more well-informed choice if they withheld their offers until later, but they would then risk losing the brightest students to the early-acting hospitals. Consequently, everyone acts early –a classical case of Prisoner’s Dilemma.

The cost of this recruitment race was even higher for students. Many were still uncertain about their specialties of interest by the time they received an offer; signing a binding contract meant they might lose out on better options or make the wrong career decisions.

To mitigate the problem, medical schools established policies that prevented student information from being released to hospitals until a set date, forcing hospitals to make offers at the same time. This created a phenomenon of “exploding offers”. As hospitals scrambled to secure their preferred candidates, they shortened the response time for students to decide from 10 days to as short as 12 hours. Imagine if you were on a trans-Atlantic flight, you might miss your offer!

By the 1950s, it became clear that a central clearing house was urgently needed to facilitate the matching process. At first, a “priority matching” algorithm was proposed. Students and hospitals submit their preference lists for each other. In the first round of matching, those who put each other as first choices are matched and eliminated from the matching (1-1). Then, hospitals will be matched with their 2nd preferred candidates who rank the respective hospitals as first choices (2-1). In the third round, remaining students will match to their 2nd preferred hospitals who reciprocate by ranking the students as their first choice (1-2). The process goes on (2-2, 3-1, 3-2, 1-3, 2-3…). This proposal was rejected, as students would essentially be “penalized” for ranking hospitals they preferred but unlikely to secure.

Ultimately, a “deferred acceptance” algorithm was put forth. In brief, the proposing side makes offer to their most preferred candidates of the other party, who then temporarily accept the offer until they get a better deal in subsequent rounds – hence the “deferred” acceptance. Let’s demonstrate this in an example.

Assume there are four students who are trying to match to four hospitals. The students have a preference list, or “rank order list” (ROL), for the hospitals as shown:

 

Adam: Chrawna>Hammie>Vancity>Purple land

Beth: Chrawna>Purple land>Hammie>Vancity

Charlie: Vancity>Hammie>Purple land>Chrawna

Doug: Purple land>Hammie>Chrawna>Vancity

 

Similarly, hospitals rank the candidates as:

Chrawna: A>C>B>D

Hammie: B>C>D>A

Purple land: C>A>B>D

Vancity: D>B>A>C

Let’s start with the students as the proposing side. Adam and Beth both like Chrawna the best, so they both apply there. Charlie and Doug apply to Vancity and Purple land respectively. Now, since Chrawna receives two offers, it will be matched to its more preferred student Adam. Purple land and Vancity only receive one offer each and will be matched automatically. In this first stage of matching, Beth is unmatched. In stage two, she will apply to her second favourite place – Purple land. Even though Purple land is currently matched to Doug, it can still change its mind. After comparing its current match Doug to the new applicant Beth, the hospital selects Beth. At a result, Doug is now unmatched. Adam and Charlie remain matched to the hospitals from the previous stage. In the third stage, Doug will apply to the next location on his ROL, which is Hammie. Since Hammie still has not received any offer, it will happily take on Doug. Now everyone is matched and the matching process is complete.

 

Adam Beth Charlie Doug
Proposes to

Match

Chrawna

Chrawna

Chrawna

unmatched

Vancity

Vancity

Purple land

Purple land

Proposes to

Match

 

Chrawna

Purple land

Purple land

 

Vancity

 

unmatched

Proposes to

Match

 

Chrawna

 

Purple land

 

Vancity

Hammie

Hammie

Final result Chrawna Purple land Vancity Hammie

 

As a result, Adam is matched to Chrawna, Beth to Purple land, Charlie to Vancity, and Doug to Hammie.

On a cautionary note, in practice, students do not actually have to propose to hospitals repeatedly. Instead, these “stages” of matching are simulated – presumably with powerful computers at National Matching Services Inc. – with only one round of ROL submission to the central clearing house. In the context of CaRMS, each submission of ROL is equivalent to one round of iteration.

One may then wonder: does it matter which side starts the process? In the example above, the students make the “proposal” first. If one starts the process with the hospital side, there will be only one round of matching. The results are: Chrawna with Adam, Hammie with Beth, Purple land with Charlie, and Vancity with Doug. Every hospital will get their first choice, but the students will be worse off with their less preferred hospitals (just compare the results according to the students’ preferences). In general, student-proposing will lead to better or at least equally good results for students, since they essentially get their picks before the hospitals.

Is there a way to “game” the system? The simple answer is, not really. There is no incentive to put your “safer” options higher on your list just so that you are matched to at least somewhere, because you may potentially miss out on better matches. There is also technically no penalty for putting your “dream” hospital as your first choice. Even if you are rejected during the first “stage” within a submission, you can still “propose” to your other options and be accepted in later stages. As a result, the Deferred Acceptance algorithm elicits “true” preferences: students have no incentive to submit a rank order list that does not reflect their wishes.

In addition to solving the recruitment race, exploding offers, and too-risky-to-dream-big problems, this algorithm also produces so-called “stable” matches. Going back to our example, there is no pair of hospital-student such that they prefer each other to their assigned partners. Even though Hammie prefers Beth to its current match, Beth is not willing to give up Purple land for Hammie.

There have been modifications over the years to incorporate match variations such as couples matching. Nevertheless, “deferred acceptance” concept remains central to the currently used Roth-Peranson algorithm. It is used for resident matching in both US and Canada. If this post has not been re-assuring enough, the algorithm was also pivotal to Roth winning a Nobel Prize for Economics in 2012 – a truly “globally recognized and award winning” match program. Indeed, not many matchmaking solutions can be quite a match for this one and its making.

 

Resources:

De-mystifying the Match Algorithm http://www.carms.ca/en/about/blog/de-mystifying-match-algorithm/

The Match Algorithm http://www.carms.ca/en/residency/match-algorithm/

Alvin Roth “The Origins, History, and Design of the Resident Match”

Alvin Roth and Elliot Peranson “The Redesign of the Matching Market for American Physicians: Some Engineering Aspects of Economic Design.”

 

Take a Hike – In Canada’s National Parks

Hello everyone! I hope that the holiday season had been restful and delicious for everyone. Today I’m going to write about something fun, outdoorsy, and provide information that may be more applicable for warmer weather. However, it’s fun and temperatures that I for one am looking forward to.

For now, we celebrate a brand new year. As a member of the class of 2017, one thing I had not anticipated is how much I identify with the date every time I see it written. After three and a half years of calling myself a 2017, it’s extra exciting that “The” year is finally here! First and second years, prepare yourselves for an onslaught of humans in MSB whom you have never seen before, as we walk around the VERC and lounge with an eerie poise of familiarity. I am really looking forward to being back and all the socialness that it entails, so feel free to say hello (we’re not that scary).

Now for my topic au jour – Canada’s National Parks! What are these national parks, specifically? Webster’s Dictionary (just kidding, the Canadian government website) describes them as “a country-wide system of representative natural areas of Canadian significance”, or in other language, bits of land that together represent the various natural regions of Canada. These regions include boreal forests, temperate rainforests, prairie grasslands, and more words that I bet you didn’t think that you would hear post-Grade 9 Geography. These parks are protected for public understanding, appreciation and enjoyment, and are maintained for future generations to likewise enjoy.

The park system’s origins date back to November 1885 (the year that the first appendectomy was thought to be performed), when the Canadian government designated 26 km2 of Alberta’s Sulfur Mountain to be preserved for the benefit of all Canadians. This area today is part of Banff National Park and is the Cave and Basin Hot Springs.

Pictured: A postcard by Harmon Byron showing the Government Pool at Cave and Basin, Banff National Park (produced before 1942).

The pool shown in the postcard closed in 1992 and the location has since received a multimillion dollar renovation. Interestingly, these hot springs were regarded as having healing properties and were used for thousands of years by the First Nations peoples. In 1883, they were “re-discovered” by three railway employees who were working on the construction of the first transcontinental railway through the Rocky Mountains. I highly doubt that spelunking was part of that original job description.

Picture2

Pictured: Interior pool post-renovation

Following the government’s designation in 1885, it was found that the area surrounding the original reservation was even more admirable and this led to The Rocky Mountains Park Act being passed in the House of Commons in June 1887 to establish what is now the Banff National Park, the first national park in Canada.

The history of the following development of the park system is (in my opinion) very interesting, detailed, and less fitting for a short, nothing-to-do-with-medicine blog. I found a lot of information on The Canadian Encyclopedia website and would direct you there if you are looking for more procrastination-worthy fodder!

Now, I’ve chosen (with difficulty) three National Parks to give as examples of places that you can and should visit. Many of Canada’s National Parks are also UNESCO world heritage site, which are locations listed by the United Nations Educational, Scientific and Cultural Organization as something of special cultural or physical significance. If the UN thinks they’re important, you should too!

  1. Bruce Peninsula National Park, located between Lion’s Head and Tobermory, Ontario: phenomenal camping and hiking, and only three hours away. Easily weekend-able!

Picture3

(Disclaimer: I did not take this picture)

  1. Cape Breton Highlands National Park on Cape Breton Island, Nova Scotia: it contains one-third of the world famous Cabot Trail. I was lucky enough to take a short trip here during my emergency medicine elective this fall in Sydney, Nova Scotia. Even though it was a wet day and the weather changed between drizzle, rain and snow every 500 m, the vistas were incredible and I will definitely be visiting again.

Picture4

(Disclaimer: I did take this picture)

On a less rainy day, courtesy of the internet:

Picture5

  1. Elk Island National Park, 35 km west of Edmonton, Alberta: this park hosts the densest population of ungulates (hoofed mammals) in Canada, and it is high on my list to visit this summer with my handy national park pass (what is this? Keep reading, my friends).

Picture6

I will hike, canoe and make friends with bison (interestingly, both the singular and plural form of the word. How many bison will I make friends with? It’s a mystery).

Now for the final, exciting news that you hopefully already know: To celebrate Canada’s sesquicentennial (your twenty-five cent word of the day, meaning 150th anniversary) in 2017, admission will be free to all of Canada’s National Parks, Historic Sites and Marine Conservation Areas. I feel this is all the more reason to pick somewhere where you haven’t been before, or even somewhere where you have been and would love to revisit, and make a trip of it. I’ve conveniently included a link below so that you can order your free season’s park pass!

Picture7

Picture8

Happy exploring!!

http://www.commandesparcs-parksorders.ca/webapp/wcs/stores/servlet/en/parksb2c

10 Tips on Choosing a Specialty

In undergrad, you’ve spent countless hours studying for exams, perfecting your immaculate GPA, and preparing for the MCAT – to become the ideal candidate for medical school. Now that you are medical students – congratulations! – you are studying to become the best doctors. But what type of doctor do you want to be?

Some of you already know the answer before entering medical school. You may have heard your friends say “I’ve always wanted to be a cardiologist”, or “I was born to do neurosurgery”, or “I came to medical school to become a family physician to serve my community”. But no matter if you are set on a career path, or are undecided, keeping an open mind is perhaps the most important. Through personal experience in medical school, I’ve compiled the following 10 tips on choosing a specialty:

1. Keep an open mind, as discussed above. This is a point worth emphasizing. About half of my friends changed their specialty of interest through the course of medical school. A few announced a new interest at the end of each inspirational block.

2. Explore each specialty that interests you. For example, do an observership, take a summer non-credit elective, or participate in research (SRTP, SROP, SWORP)… But if you do not find an opportunity to do so, there is still Year 3 Clerkship where you will rotate through the major areas of medicine.

3. Ask yourself, what do you like about this specialty? You might have seen an exciting procedure such as stent-deployment in the cardiac cath lab, or enjoy talking to people about their struggle with depression and mania, or gain satisfaction by identifying features of nuclear atypia on a pathology slide that lead to the diagnosis.

4. On the other hand, what are the undesirable aspects of the specialty? For example, will you still be happy, at the age of 50, to be paged at 3 am for an emergency appendectomy? Will you be bored of titrating furosemide in the heart failure clinic? On the contrary, some people find these aspects of their job the most rewarding.

5. Will you enjoy the “bread and butter” work of this specialty, and not just the rare and exciting cases? After all, you will be doing this job every day for rest of your medical career. While it’s theoretically possible to “see the light” and change your specialty mid-career; it is generally not advised.

6. If you are unsure, use the process of categorization and elimination. Some common contrasting themes are: Generalist vs. specialist. Primary care vs. consultant. Doctor’s office vs. hospital care. Medicine vs. Surgery. Procedural vs. non-procedural. Adult medicine vs. Pediatrics. etc. Here is an algorithm from the BMJ.

7. If you are still undecided, like many students, then reflect on what fits your personality. Some people prefer working with their hands such as in orthopedic surgery, while others enjoy contemplating complex concepts such as hormonal pathways in endocrinology. Each year, the Learner Equity and Wellness (LEW) Office offers the Myers-Briggs personality test that may help you determine a suitable specialty.

8. Sometimes there are more than 1 path to becoming the doctor you want to be. For example, the family medicine 2 + 1 residency program is an attractive but competitive career path. For example, you can do 2 years of family medicine + 1 year emergency medicine, obstetrics, or anesthesia, to name a few.

9. If you are torn between 2 (or more) specialties and it’s almost 4th year, some students split their elective time in both subjects. Others choose multidisciplinary electives, such as ICU which involves internal medicine, anesthesia, and surgical critical care. But it’s riskier to match into a competitive specialty, that may sense your ambivalence.

10. Although it’s never too late to decide on a specialty, ideally you want to make a decision before applying for 4th year electives, and at the latest before the CaRMS residency match. Never be afraid to seek help. Talk to your peers, upper year students and residents, or make an appointment at the LEW Office, if you would like more guidance.

Choosing a specialty is a career-defining decision. You came to medical school from diverse backgrounds, for a variety of reasons, to become a doctor. I hope that you will soon find the specialty that suits your calling! This blog post covers the main points, but is by no means an exhaustive list. To the upper year students, if you have other considerations that helped you choose a specialty, please feel free to comment below! To the junior students, you will be surprised at how quickly medical school passes, despite the lengthy lectures, mountain of notes, and seemingly endless exams. So may the wind be behind your sails as you set off on a voyage of discovery in the vast ocean of medicine!

Pei Jun Zhao

Meds 2017