PULSE VOLUME 8, ISSUE 1. AUTUMN 2021.
THE PAST, PRESENT, AND FUTURE OF MEDICINE
from the editor-in-chief Dear Reader,
As our society moves forward towards new medical innovations and research developments, we take a look back at medicine in the past. This quarter's issue concentrates on the past, present, and future of medicine. I am elated to introduce our Autumn 2021 Issue and I hope that this issue brings refreshing insights of what has or will occur in our community. I am delighted to introduce eight articles that capture medicine throughout history. The issue includes a glance at how the COVID-19 pandemic is aiding the development of an HIV vaccine. Not only that but incorporated are interesting reads ranging from the rising costs of insulin to the future of human regeneration. Our partnered contributors, furthermore, have provided advice for medical school interviews as well as a comprehensive guide for students pursuing medical school. I would like to recognize the writers, editors, and partners for their significant contribution to this issue. As my last quarter as Editor-in-Chief, I have truly enjoyed collaborating with students of all years and being able to publicize each individual's work. I thank each and everyone of you for giving me this opportunity and I hope to see your success in future PULSE issues. Please enjoy! With Regards, Sophia Cao
editors Sophia Carino Ashley Chen Riley Hurr Areeha Khalid Emory Kim Michelle Ma Eve Tanios Helen Wei
writers
Sanaa Imami Caroline Kellogg Jack LeGrow Ayman Lone Marissa McCollum Eva McCord Neeharika Venuturupalli Rulan Zhang
managing editors Matthew Chen Charlotte Clulow Rachel Zhang
production Sophia Cao
incoming co-eics EJ Beck Jack Osborn
other contributors MCAT-prep.com Kaplan Test Prep The Princeton Review
pulse - autumn 2021
CONTENTS EDUCATION READY FOR MED SCHOOL INTERVIEWS? A COMPREHENSIVE GUIDE FOR FUTURE MED STUDENTS KAPLAN MCAT PRACTICE PROBLEM
2 6 8
MEDICINE IN THE PAST - LOOKING BACK SUBSTANCE ABUSE AND THE CRIMINAL JUSTICE SYSTEM THE RISING COSTS OF INSULIN
9 12
MEDICINE TODAY - LOOKING AT THE PRESENT INTELLECTUAL PROPERTY RULES FOR COVID-19 VACCINES LIMITS OF CHILD AUTONOMY WITHIN COVID-19 PANDEMIC SHOTS HEARD ROUND THE WORLD: HIV VACCINE
15 17 20
MEDICINE IN THE FUTURE - LOOKING FORWARD THE FUTURE OF HUMAN REGENERATION BEATING ALZHEIMER'S DISEASE: NEW FLUOROGENIC MARKER THE FUTURE OF CANCER TREATMENT
22 24 27
table of contents || 1
WHAT TO EXPECT IN MEDICAL SCHOOL: A COMPREHENSIVE GUIDE FOR FUTURE MED STUDENTS There are over 140 U.S. medical schools that award the Doctor of Medicine, better known as the MD, to graduates. These schools train students in allopathic medicine, an advanced system which encompasses the use of medications, surgery, and/or therapies to help treat individuals with a variety of conditions and diseases. Allopathic schools train tomorrow's MDs with a common (and rigorous!) core curriculum. But beyond that core, each medical school offers its own unique academic foci, teaching methods, and research opportunities to students, which means no two medical schools are exactly alike. As such, before entering medical school, it’s crucial for you to have a clear understanding of how long completing medical school will take, and perhaps more importantly, what each specific step of your medical school journey will entail.
HOW LONG DOES IT TAKE TO COMPLETE MEDICAL SCHOOL? Medical school itself takes 4 years to complete, but to become a doctor, you'll also spend 3–7 years in residency.
THE FIRST TWO YEARS The first two years of medical school are a mixture of classroom and lab time; students take classes in basic sciences, such as anatomy, biochemistry, microbiology, pathology, and pharmacology. They also learn the basics of interviewing and examining a patient. Traditionally, students take four or five courses in various disciplines at the same time. However, some schools focus on a single subject for a shorter block of time—say, three or four weeks—then move on to another subject. Other schools take an interdisciplinary approach to pre-clinical coursework, in which each class focuses on a single organ, examining all the anatomy, pharmacology, pathology and behavior relevant to that system. At the end of the second year, you'll take Step 1 of USMLE, a three-step test designed for students of allopathic medicine who are on the path to an MD. Step 1 of USMLE is a one-day, multiple-choice test that emphasizes knowledge of basic sciences, including anatomy, biochemistry, behavioral sciences, microbiology, immunology, pathology, pharmacology, and physiology. Topics such as nutrition, genetics and aging are also covered.
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EDUCATION
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THE CLINICAL EXPERIENCE: YEARS 3 AND 4 Third and fourth-year medical students do rotations at hospitals and clinics affiliated with their school, culminating with taking (and passing) USMLE Step 2. Step 2 is a two-day test with two components. The first, called Clinical Knowledge, or CK, requires you to answer multiple–choice questions on clinical sciences like surgery, internal medicine, pediatrics and obstetrics and gynecology. The second, called Clinical Skills, or CS, requires you to examine and diagnose actors posing as patients. Students doing rotations assist residents in a particular specialty such as surgery, pediatrics, internal medicine, or psychiatry. During this time, you'll interact with patients, perform basic medical procedures, and take on any tasks the resident requests you complete for them. While some rotations, such as Internal Medicine, are required at all programs, others have more unique clerkship requirements. The length of time you spend in a rotation depends on the hospital's focus or strength. At some schools, the surgery rotation is three weeks long; at others, it is three months. The character of the hospital will also color your experience. If the setting is a densely populated metropolis, you can expect increased experience with trauma, emergency medicine, or infectious disease, as well as exposure to a diverse patient population. Clinical rotations will not give you enough expertise to practice in any specialty (that's what a residency is for). They will give you a breadth of knowledge and help you consider potential career paths as a future health professional.
PATIENT CARE VS. RESEARCH You can train to be a primary care doctor at any medical school. However, programs that emphasize primary care tend to include more patient contact, coursework in patient handling, and longer clinical rotations in general fields. Many are actively involved in the surrounding communities, offering volunteer opportunities in the clinical care of historically underserved populations. If you're looking to pursue a career in academic medicine or biomedical research, you should look for schools with strong research programs. You will not have the same opportunities, facilities, mentors, or funding at a school focused on training primary care physicians.
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EDUCATION
COMBINED DEGREES If you want to complement your MD with advanced coursework in another discipline, some schools—especially those affiliated with a larger university—allow students to register for classes in other departments. Many also offer combined degree programs, such as pairing an MD with a Master of Science, Master of Public Health, or PhD.
AFTER MED SCHOOL Med students who make it through all four years (and don't worry, most do!) will be the proud owner of an MD. But your education doesn't end there; you will still need to pass the board exam and spend between three and seven years as a resident in a teaching hospital. Once your board exam and residency are complete, you’ll be all set to launch your medical career!
For more Med School Advice, visit Princetonreview.com/med-school-advice.
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800-273-8439 | PrincetonReview.com | 800-2REVIEW MCAT is a registered trademark of the Association of American Medical Colleges. The Princeton Review is not affiliated with Princeton University.
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READY FOR MED SCHOOL INTERVIEWS? Medical school interview season has arrived! And while you may be thinking your application season is coming to a close it is actually just beginning. Why are interviews even necessary? After toiling for hours over applications, receiving an invitation to interview may feel like the end goal; but, it is truly the time you need to refocus. Interviews offer you the opportunity to tie up loose ends from your application as well as further explain certain aspects of your personal statement or past activities. At the same time, an invitation to interview means medical schools want to meet you. They not only want to put a face to your name and application but also observe firsthand how well you fit into their institution and culture. So, here are five major tips to help you march into your interview with confidence and leave a good, lasting impression.
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Make a list of your strengths and weaknesses
While most medical schools have transitioned to the multiple-mini interview or MMI format, many common questions are recycled from the one-on-one or group interview styles. And the strengths and weaknesses prompt is at the top of the list. This question can be styled in several ways such as: a. What is your greatest strength? Greatest weakness? b. What are some of your strengths and how will they make you a good physician? c. How will you overcome your weaknesses to ensure success in medical school? You never really know how this question will be posed, so plan ahead by making a list of your strengths and weaknesses. Keeping three strengths and three weaknesses in mind will give you plenty to discuss in your response.
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EDUCATION
THEY'RE A GAME CHANGER!
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Reflect your produest moment
Another great interview question to prepare for relates to your achievements. The interview prompt may inquire about your “proudest moment” or “greatest achievement.” Either way, you should be honest and humble as you answer. Talk about something you are truly proud of...not what you think the interviewer wants to hear. Some good examples could be learning to play an instrument, adopting a pet, earning a degree, being a caregiver to a relative, or making a difference in the life of a stranger.
3
Think about some of your greatest challenges
Medical school is challenging -- not just for its curriculum, but for all the distractions and demands of everyday life you must navigate as well. Facing those challenges without falling apart in the process comes only with practice. Therefore, interviewers like to hear about the challenges you have faced. It is entirely okay to share something personal here (i.e. a learning disability, death in the family, financial hardship); just do your best to avoid crying. Strive to convey at most two difficulties and how you overcame them while remaining composed.
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Check your biases
Cultural competency, diversity, and health equity have risen in importance to medical school programs in recent years. So, you surely can anticipate multiple questions regarding your exposures to diversity, views on access to healthcare, and even your innate biases. For instance, do you automatically visualize a nurse as a woman, a prisoner as a minority, or a disabled person in a wheelchair? Are you familiar with recent state and federal legislation affecting the LGBTQ+ community or undocumented immigrants?
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Dress the part
Last, but not least, make sure to dress the part of a professional student who will soon be a professional physician. In general, you will want to aim for clean, business casual with comfortable dress shoes.
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Kaplan MCAT PRACTICE PROBLEM QUESTION The formation of α-d-glucopyranose from β-d-glucopyranose is called:
A. glycosidation B. mutarotation C. enantiomerization D. racemization
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B. Mutarotation is the interconversion between anomers of a compound. Enantiomerization and racemization, choices (C) and (D), mean the same thing as each other: the formation of a mirror-image or optically inverted form of a compound. Glycosidation, choice (A), is the addition of a sugar to another compound ANSWER 8 || pulse
MEDICINE IN THE PAST
SUBSTANCE ABUSE AND THE CRIMINAL JUSTICE SYSTEM By
Neeharika Venuturupalli Riley Hurr
Approximately 50% of current inmates have been incarcerated for drug related offenses and almost 70% of current inmates have met the criteria for substance abuse or dependence. As of 1992, the Substance Abuse and Mental Health Services Administration (SAMHSA) recognizes substance abuse as a mental disorder that requires professional medical attention. In other words, manyare currently serving time for circumstances beyond their control due to their poor mental health instead of actually receiving treatment or rehabilitative services. Statistically, there also seems to be a direct correlation between those imprisoned for drug related crimes and increased re-offending (recidivism) rates.
Penrose Hypothesis
in the 1960s. This movement responded to growing critiques of the dehumanizing and overall poor treatment of those with mental illness in their so-called “insane asylums”. The goal was to shut these institutions down and create more outpatient resources aimed to better integrate patients with mental illness. However, the lack of research that linked neuroscience with mental illness led to the decline of proper mental healthcare. A large portion of these populations ended up unhoused which made them an easy target for arrests in heavily policed areas. The lack of affordable and accessible mental healthcare led to the increased arrests of those with mental health issues. This displays the transition from hospitals to prisons that the Penrose Hypothesis highlighted.
The Penrose Hypothesis, which was developed in 1939, proposed that a decrease in mental health infrastructure has led to an increase in incarcerations. The theory, by Lionel Penrose, was developed when observing this relationship amongst 18 European countries, and it has continued to prove substantial when it comes to the American psychiatric deinstitutionalization movement
The War on Drugs and opioid epidemic exacerbated this issue and further substantiated the Penrose Hypothesis. These events left a large part of the American population vulnerable to a substance abuse disorder, unable to receive proper recovery resources. This article aims to explain both rehabilitative solutions and preventative measures to help mitigate the prevalence of substance abuse
disorders within American populations. However, before exploring the policy-oriented aspect of this issue, it is important to establish addiction as a neurobiological issue. Researchers have spent decades to prove this connection before they could advocate for legislation that properly addresses the issue.
Science Behind Addiction An addiction can neurologically develop even after just one instanceof using a drug. If someone already has another mental illness, they are more susceptible to developing an addiction at a faster rate than someone who does not have a mental illness. A family history of addiction can also predispose someone to addictive tendencies. Many drugs cause a person to experience heightened levels of dopaminergic activity which can increase the threshold for satisfaction. This can lead individuals to require the drug in order to feel the high that they are achieving which they can no longer naturally produce. Therefore, sober satisfaction levels are relatively much lower and this is how a dependency develops.
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Research has shown that addiction affects the parts of the brain that deal with reward, motivation, memory, inhibitory control, mood and interoception. Even just one usage of a drug can drastically affect how each of these systems interact with one another. These neurobiological changes that develop during addiction remain even after recovery which explains the risk of relapse.
Rehabilitative Solutions Some solutions proposed by a study conducted by the National Institute of Health (NIH) include drug treatment interventions during one’s prison sentence. This intervention system will ensure both prisons and community behavioral health centers work together and help individuals with substance abuse disorders. Along with the integration of healthcare and prison systems, the study stated that punishment alone is
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not effective in the case of a mental disorder. Therefore it is ideal for mental illness to be properly addressed while the individual is serving time. A solution implemented on a small scale in Columbus, Ohio in 2020 was a program which redirected nonviolent offenders to services which would alleviate the need for re-offending. For example, people who stole due to hunger were redirected towards food banks; people who stole because of being jobless were redirected towards educational programs aimed to get them a stable job. The program saw that less than 10% of the people re-offended, suggesting that none of these crimes had malicious intent but rather just a need due to lack of resources. While this program hasn’t been tested on a larger scale, it can be implemented for drug related crimes as well. Formerly incarcerated persons can be redirected to harm reduction centers,
community health initiatives, and rehabilitative centers which can help significantly decrease recidivism due to drug related crimes.
Preventative Measures There are several preventative measures which can be implemented to reduce imprisonment for drug related crimes as well. One movement that has recently been getting a lot of support is the decriminalization of drugs. It is important to decriminalize before substance abuse disorder can be properly destigmatized. This allows for people to be more open to receiving help for their addiction rather than fearing legal consequences of it. In the process of decriminalization, it also naturally removes the “criminal” label from those with substance abuse issues. However, decriminalization only removes the legal ramifications of it and does not necessarily promote usage.
MEDICINE IN THE PAST
Further measures that can prevent the development of a substance abuse disorder include widespread education about mental health and drug usage. It is crucial to educate the younger population on recognizing mental illness and the tendency of developing it during adolescent stages before it can develop into a larger issue. Potential solutions could include regular mental health check ups in all K-12 schools to help alleviate socioeconomic disparities in mental healthcare. It is also important to train school faculty on recognizing mental health issues and how to properly address such emergencies. For many students, school is one of the safest environments and it is crucial for faculty and educators to be properly equipped to make sure they can safely promote proper physical, mental, and educational development. Society’s goal is to properly expand mental health treatment
so that mentally ill individuals are not abused in the criminal justice system. However, as many experts phrase it: if there was an easy solution, it would have already been implemented. This is an issue that has been persisting for decades and we are now moving towards legislation that can hopefully alleviate its negative effects and help the populations that need it. If you or anyone you know is struggling with substance abuse, here are some helplines and resources you can use: - https://www.samhsa.gov/findhelp/national-helpline - https://www.therecoveryvillage.com/drug-addiction/ drug-abuse-hotline/ - https://drugabuse.com/addiction/drug-abuse/hotlines/ - https://americanaddictioncenters.org/rehab-guide/ alcohol-drug-hotline
Chandler, Redonna K et al. “Treating drug abuse and addiction in the criminal justice system: improving public health and safety.” JAMA vol. 301,2 (2009): 183-90. doi:10.1001/ jama.2008.976 “Federal Laws Related to SAMHSA.” SAMHSA, Substance Abuse and Mental Health Services Administration, 4 October 2021, www.samhsa.gov/about-us/who-weare/laws-regulations#:~:text=The%20 regulation%20acknowledges%20that%20 addiction,accreditation%20standards%20 and%20certification%20processes Grecco, G.G., Andrew Chambers, R. The Penrose Effect and its acceleration by the war on drugs: a crisis of untranslated neuroscience and untreated addiction and mental illness. Transl Psychiatry 9, 320 (2019). doi.org/10.1038/ s41398-019-0661-9 “Inmate Statistics: Offenses.” BOP, Federal Bureau of Prisons, 6 November 2021, https://www. bop.gov/about/statistics/statistics_inmate_ offenses.jsp Klein, Zach. “Opinion: nonviolent offenders need help, not jail. That’s what my city is giving them.” The Washington Post, The Washington Post, 4 December 2020, www.washingtonpost. com/opinions/2020/12/04/columbus-ohiononviolent-offenders-help-not-jail/. “What happens to drug addicts in jail?” Aspenridge Recovery, 22 March 2021, www. aspenridgerecoverycenters.com/what-happensto-drug-addicts-in-jail/
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THE RISING COSTS OF INSULIN By
Sanaa Imami Sophia Cariño
There are very few medicines more well-known than insulin, and for good reason. Insulin is an essential hormone that constantly controls glucose levels in the bloodstream. The hormone also is responsible for regulating glucose levels in the body’s liver, muscle, and fat cells. While insulin is produced naturally in the human body, people afflicted with diabetes are unable to produce adequate levels of insulin. Most diabetics need insulin in order to keep their blood sugar levels in check, so the hormone is synthetically produced by pharmaceutical companies to help them live life normally. However, due to significant price increases and noncomprehensive insurance plans, many diabetic Americans are unable to access this life-saving drug. While insulin is a commonplace medicine today, the drug wasn’t identified as a lifesaving tool until a hundred years ago. Insulin was first extracted and used by researchers Frederick Banting and Charles Best in 1921. The two originally determined
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that they could keep a diabetic dog with no insulin production capability alive by giving it insulin produced from another dog’s pancreas. From there, Banting and Best, along with J.B. Collip and John Macleod, produced a more refined version of insulin from the pancreata of cattle. The first insulin injection was given to a diabetic teen named Leonard Thompson, and within 24 hours of injection, his formerly life-threateningly high blood glucose levels dropped to a normal amount. From there, pharmaceutical company Eli Lilly began to mass-produce insulin, and by 1923, the drug was widely-available across North America. The availability of insulin was life-changing for diabetics — prior to the production of the drug, most diabetics were put on restrictive low-calorie and low-carb diets that rarely helped them control their glucose levels. Oftentimes, diabetics would die from starvation rather than extreme blood sugar levels. Some of the most common insulin brands, like Humalog
and Admelog (both of which were insulin lispro, or artificially produced insulin), were originally produced in the 1990s. Since their creation, their prices have increased exponentially. For example, the original price of one vial of Humalog was $21. Twenty years later, in 2019, the same amount costs $332, which is an increase of over 1000%. While inflation naturally causes all goods to increase in price, this sharp increase is much more severe. In comparison, prices in other developed countries have remained roughly the same, even as inflation and production costs have changed throughout the years. Ultimately, the added financial barrier in acquiring insulin has dramatically changed how diabetic Americans are able to live their lives, especially when compared to other countries where the drug is more accessible. What are the reasons for this drastic increase in insulin price for Americans? There are two main issues, both of which boil down to the pharmaceutical companies developing these drugs. There are
MEDICINE IN THE PAST
The average out-of-pocket cost of treatment in the US is roughly three times higher than that of India, the country with the second-most expensive out-of-pocket costs.
three pharmaceutical companies that control the insulin market in the US: Novo Nordisk, Sanofi-Aventis, and Eli Lilly. These companies have a monopoly on insulin, which means that they’re able to price their insulin at whatever price they’d like - this is because they have no competition nor do they have any restrictions or regulations imposed on them by the US government. Because of this monopoly on this life-saving commodity, corporations are able to abuse this lack of restriction and raise the price exponentially for their own financial gain.. In other words, because they know that diabetics will always continue to need insulin, they have no fear of falling demand due to price increases. The insulin price increases have caused many diabetic Americans to resort to drastic measures when it comes to the drug. On average, most diabetics need 2-3 vials of insulin a month, which currently amounts to $450 on average per month with no insurance. Oftentimes, insurance companies will
not fully cover these costs, and the price decrease is oftentimes not enough for Americans to comfortably afford. Many diabetic Americans skimp or altogether skip doses of insulin, which often causes erratic spikes and drops in blood sugar levels. In severe cases, diabetics who do not have enough insulin in their system experience diabetic ketoacidosis, a deadly condition that develops when the body does not have enough insulin to control where the blood sugar goes in the body. When the body does not have enough insulin, it can’t get energy from blood sugar, and instead, it resorts to breaking down fat. A byproduct of this process is the buildup of acids called ketones. When there is an excess of ketones, the body will go into shock, and oftentimes, diabetics will die from it. Technology has provided the solution to diabetes, yet due to significant financial barriers, many are still unable to access it. As insulin has become increasingly less accessible and affordable, the government and insurance
companies are now involved. The Trump administration ran on the campaign promise that many essential prescription drugs would be less expensive. During his term, Trump began negotiations with many big-name pharmaceutical companies, and many agreed to lower costs. By the end of the administration’s time in office, they had cut upfront insulin costs for seniors and lowered the co-pay (a fixed out-of-pocket cost for insurance-holders) for Medicare to a $35 monthly payment, which is roughly 7% of the average monthly cost of insulin for those without insurance. Beneficiaries who used Medicare would have a significantly cheaper copay but still have access to insulin. Many insurance companies have also pledged to lower copays and make insulin accessible to beneficiaries who need it but don’t have insurance plans where the drug is affordable for them. This year, the Biden administration has introduced the Comprehensive Plan for Addressing High Drug Prices that aims
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to regulate fair prices for live-saving medications, which includes insulin. With this plan, the administration works towards creating a more accessible Medicare program and enforcing regulations on the pharmaceutical companies that hold monopolies in America. By ensuring “equal and affordable access” (McConnell, 2021) for medications like insulin, many Americans will no longer need to sacrifice financially for their basic health necessities. Diabetes — a severe condition shared by over 10% of the American population — is treatable and manageable, but the politics behind insurance and pharmaceutical companies alike leaves countles diabetic Americans in danger of severe health complications. The livelihoods of millions of Americans should not be treated
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so trivially;policy makers and pharmaceutical companies must work together to eradicate barriers of access for all diabetic Americans, regardless of insurance plan or socioeconomic status.
McConnell, M. (2021, September 13). Biden administration targets out-of-control US drug prices. Human Rights Watch. Retrieved November 2, 2021, from https://www.hrw. org/news/2021/09/13/biden-administrationtargets-out-control-us-drug-prices.
Cohen, J. (2021, January 5). Insulin's out-ofpocket cost burden to diabetic patients continues to rise despite reduced net costs to pbms. Forbes. Retrieved November 2, 2021, from https://www.forbes.com/sites/ joshuacohen/2021/01/05/insulins-out-ofpocket-cost-burden-to-diabetic-patientscontinues-to-rise-despite-reduced-net-costs-topbms/?sh=62db739d40b2.
Roberts, D. K. (2020, July 30). The deadly costs of insulin. AJMC. Retrieved November 2, 2021, from https://www.ajmc.com/view/the-deadlycosts-of-insulin.
The history of a wonderful thing we call insulin. The History of a Wonderful Thing We Call Insulin | ADA. (n.d.). Retrieved November 2, 2021, from https://www.diabetes.org/blog/ history-wonderful-thing-we-call-insulin. Jones, S. (2019, January 31). Rising insulin costs are a life-or-death political crisis. Intelligencer. Retrieved November 2, 2021, from https:// nymag.com/intelligencer/2019/01/risinginsulin-costs-are-a-life-or-death-political-crisis. html. March, R. (2020, March 19). Political promises won't lower insulin prices. TheHill. Retrieved November 2, 2021, from https://thehill.com/ opinion/healthcare/486995-political-promiseswont-lower-insulin-prices.
Rajkumar, S. V. (2020). The high cost of insulin in the United States: An urgent call to action. Mayo Clinic Proceedings, 95(1), 22–28. https:// doi.org/10.1016/j.mayocp.2019.11.013.
What is insulin? EndocrineWeb. (n.d.). Retrieved November 2, 2021, from https://www. endocrineweb.com/conditions/type-1-diabetes/ what-insulin.
MEDICINE TODAY
INTELLECTUAL PROPERTY RULES FOR COVID-19 VACCINES WHAT ARE THE CONSEQUENCES OF INTELLECTUAL PROPERTY RULES FOR THE COVID-19 VACCINES? WOULD IT BOOST GLOBAL ACCESS TO VACCINES AND PROMOTE VACCINE EQUITY? By
Rulan Zhang Emory Kim
Although scientists have worked to develop vaccines at lightning speed, the challenge now lies in the distribution of the COVID19 vaccine to as many people as possible as quickly as possible. The equation for successful vaccination of enough people globally against COVID-19 is extremely complicated, as it often involves many more uncertainties and factors that studies cannot necessarily encompass. On a surface level, we are already seeing how factors such as politics can cause delays in distribution, with countries imposing export controls on vaccine components. The complexity of vaccine production, often involving hundreds of parts, means that supply chains could easily break down, leading to shortfalls in fulfilling manufacturing targets. In terms of more deep-rooted problems, it is becoming increasingly clear that the distribution of global vaccination is distinctly unbalanced: those living in developed nations are gaining access to vaccines much faster than those in
developing countries. Currently, the majority of COVID-19 doses are going to wealthier countries, leaving many less economically developed countries (LEDCs) behind and almost entirely dependent on the COVAX scheme run by WHO. While COVID-19 vaccine rollout has now begun in more than 159 countries, vaccination rates in many low-resource nations remain low to nonexistent. As of December 2020, high-income countries representing 14% of the world population have 53% of the global supply of vaccines this included 100% of Moderna’s vaccine and 96% of the Pfizer-BioNTech vaccine. Due to the vast inequities in COVID-19 vaccine distribution, it would take approximately 4.6 years to gain worldwide herd immunity with the current rate of 6.7 million vaccine doses per day. Achieving herd immunity via vaccination requires enough people worldwide to be vaccinated, not just those in wealthier countries. It is clear that the status quo of vaccine roll-out simply may not
be sufficient to meet the ambitious targets that have been set, making it extremely challenging to end the current pandemic and prepare for ones to come. COVID-19 vaccines are by no means the first time that clear inequity has been seen with the distribution of crucial healthcare tools, therapeutics and efforts. Debates over the waiving of intellectual property (IP) rules for various healthcare therapeutics have persisted for years. While IP rights act as a critical incentive for pharmaceutical companies to invest in research and development (R&D) to constantly update and develop healthcare therapeutics, it allows companies to have monopolies over their products, which thus leads to an increase in price and exclusivity. The one regarding waiving IP rules for COVID-19 vaccines is in many ways no different and is bringing the dichotomy between IP rights and public health to the limelight. India and South Africa appealed to the World Trade Organisation
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(WTO) to relax IP protections for COVID-19 vaccines, highlighting the urgency of this debate. Subsequent to this appeal, there have been cries and letters of support from influential individuals and lawmakers urging for a temporary relaxation of the WTO IP protection rules. Proponents of temporarily waiving IP protection of COVID19 medical technologies argue that this would allow manufacturers across the world (including LEDCs) to join in vaccine production to ramp up supply. This would be done without the fear of infringing IP rights, which means it could be easier to bring in more producers and produce on a larger scale. It might also be more efficient for poorer countries to conduct vaccine manufacturing in their own country, meaning they are no longer reliant on pharmaceutical companies in more economically developed countries (MEDCs) and WHO programs that require the funding/charity of MEDCs. On the other hand, many experts argue that waiving IP protection will have limited impact and even cause harm to long-term vaccine investment and R&D. Experts argue that there is little proof waiving IP rights will increase vaccine production and vaccination rates in LEDCs. This
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relies on the premise that there are vaccine producers ready-to-go and capable of manufacturing if IP rights are waived. In addition, many LEDCs would have to make swift national legislative changes to accommodate for a change in WTO rules regarding IP rights, which would be extremely difficult and time-consuming and undermine the whole point of waiving IP rights. Furthermore, many policy makers argue that maintaining IP rights would continue to provide the financial incentive for pharmaceutical companies to keep licensing and cooperating with manufacturers, which would increase global production. They argue that waiving IP rights, even temporarily, would take away the commercial incentive and harm manufacturing collaborations that would increase production. IP rights are also key to maintaining R&D to keep vaccines up to date with new COVID-19 variants. Removing IP rights could result in less private sector research due to the lack of financial incentive, causing COVID-19 vaccines to fall behind on variants and undermine efforts for second generation vaccines. The debate surrounding the waiver of IP rights is more complicated than many proponents argue and may not necessarily lead to
as many benefits as they believe. However, one thing is clear: there is an urgent need to think about global vaccine rollout strategy. In order to lessen the vaccine equity gap, it is essential to view vaccines as a public good and global effort rather than undertakings that deny people or countries who cannot afford them. Enrico Bonadio Reader in Intellectual Property Law, and Dhanay M. Cadillo Chandler Postdoctoral research fellow. “Intellectual Property and Covid-19 Medicines: Why a WTO Waiver May Not Be Enough.” The Conversation, October 14, 2021. https://theconversation.com/ intellectual-property-and-covid-19-medicineswhy-a-wto-waiver-may-not-be-enough-155920. “How Vaccine Nationalism May Delay Global Herd Immunity.” Medical News Today. MediLexicon International. Accessed November 13, 2021. https://www.medicalnewstoday.com/articles/ herd-immunity-may-take-4-6-years-due-tovaccine-nationalism. Irwin, Aisling. “What It Will Take to Vaccinate the World against COVID-19.” Nature News. Nature Publishing Group, March 25, 2021. https://www.nature.com/articles/d41586-02100727-3. Padma, T. V. “Covid Vaccines to Reach Poorest Countries in 2023 - despite Recent Pledges.” Nature News. Nature Publishing Group, July 5, 2021. https://www.nature.com/articles/d41586021-01762-w. “Senators to Biden: Waive Vaccine Intellectual Property Rules.” NBCNews.com. NBCUniversal News Group, April 16, 2021. https://www.nbcnews.com/politics/ politics-news/senators-biden-waive-vaccineintellectual-property-rules-n1264256. “Urgently Waive Intellectual Property Rules for Vaccine.” Human Rights Watch, December 9, 2020. https://www.hrw.org/news/2020/12/10/ urgently-waive-intellectual-property-rulesvaccine. “Would Exempting COVID-19 Vaccines from Intellectual Property Rights Improve Global Access and Equity?” Center For Global Development. Accessed November 13, 2021. https://www.cgdev.org/debate/wouldexempting-covid-19-vaccines-intellectualproperty-rights-improve-global-access.
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HONEY, I VAXXED THE KIDS THE LIMITS OF CHILD AUTONOMY WITHIN THE COVID-19 PANDEMIC By
Eva McCord Michelle Ma
As soon as children transition from toddlerhood to preschool age— from chewing on teething rings to “chewing on” the contours of language, opinion, and occasionally shrill outspokenness— we ask questions. What do you want to be when you grow up? Did you make any new friends today? If you could teleport to anywhere in the world at this very moment, where would you go? In our eagerness to prod, probe, and dote on young minds, unencumbered by the nuance and cynicism conferred by age and
experience, we transform children into miniature Oracles of Delphi. We find a peculiar comfort in questioning those who make up for a lack of life experience with boisterous, blind optimism— eyes glinting in the face of the future even when they cannot discern what exactly it holds. And now, standing at one of many turning points in the COVID-19 pandemic, we must ask our children another question. Do you feel your life is in your own hands? With Wednesday, November 3rd marking the newfound eligi-
bility of 28 million children aged 5 to 11 to receive Pfizer-BioNTech’s COVID-19 vaccine, there has been no time more pressing than now to discuss the complicated concept of “adolescent medical decision-making capacity.” This term encompasses the situation in which the already challenging task of making medical decisions butts heads with the very nature of being a child— lacking the experience and knowledge that would empower one to make an educated and independent decision— let alone one that is staring down the metaphorical barrel of a life-threatening disease. In investigating academic
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opinion on this issue, we can turn to a paper published by Grootens-Wiegers on medical decision-making in children and adolescents, which concludes that at age 12, children have the capacity to be competent at decision-making. However, the paper cautiously notes that the brain’s reward system generally develops faster than its control system, which means that adolescents may be less competent at decision-making in certain contexts, for instance, those involving peer pressure. Furthermore, all four criteria for decision-making competency that the study cites— communicating a choice, understanding, reasoning, and appreciation— are highly dependent on the maturity level of a given individual. However, regardless of individual maturity or other confounding factors in the issue of medical autonomy, most states still require parental consent to receive the COVID-19 vaccine up to age 18, and all require it for those aged 5 to 11 (with the exception of the
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District of Columbia and Philadelphia, which allow children 11 and older to self-consent). So even as younger and younger children gain access to preventative measures against the 8th leading cause of death of the past year in their demographic, it is parents who are tasked with the challenge of caring for children amid a health crisis and coming to terms with the weight of their words in relation to their child’s medical future. For most parents, there seems to be no question at all. According to the Kaiser Family Foundation, less than one third of parents will allow their children to be vaccinated immediately, with two-thirds being reluctant or even adamantly opposed to the vaccine altogether. In the face of parental directives like these, where do children’s voices fit, and how will their potential demand to be heard strain the family unit? This tension during a time of metamorphosed uncertainty is emblematic of the entire nation’s journey through
a post-vaccine world, with a long-standing individualistic society grappling with the implications of a personal choice that will affect not only themselves, but their community, state, and country as a whole . And as the pandemic draws on in the face of mask mandate lifts, decreased social distancing, and notably, school reopenings, children’s vaccination statuses will become harder and harder to avoid discussing, raising many questions that may call into dispute who gets the final say. For instance, when does the opportunity to experience a “next to normal” childhood outweigh parental beliefs, conceptions, or concerns? When should being “mature for one’s age” yield a genuine chance to take control over one’s young life? Is it anyone’s place to support the five-year-old, whose routine vaccinations now encompass a
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greater discourse that they have yet to fully understand? What about the immunocompromised ten-year-old with anti-vax parents, or the children who are simply scared and uncertain? What moral obligation do we have to protect a world where kids can interact and socialize with one another, when doing so without critical and careful thinking could endanger other equally vulnerable demographics—both physically and autonomously? And at the same time, other often weaponized aspects of the pandemic now have the opportunity to be examined critically, yet with compassion: what did it mean to spend a period of one’s childhood, one’s formative developmental years, amid the pandemic? Who is accounting for the long-term effects brought on by experiencing a dark period in medical history as a young child, both powerless to do anything and unable to take control over their own protection?
The contention that arises concerning parental consent pertaining to children’s medical futures is not rooted in “sides,” as some may assume. There is no inherent correctness wielded by parent nor child over whether or not to fit in a vaccine appointment between after-school sports and playdates. It boils down to questions, reserved for and between parent and child. And, ironically enough, the questions we ask children are often reflections of our own, albeit “grownup,” anxieties.
Aviv, Aubrey, Allison, and Selena Simmons-Duffin. “Some Parents Want to Wait to Vaccinate Their Kids. Here's Why Doctors Say Do It Now.” NPR, NPR, 3 Nov. 2021, https://www.npr.org/ sections/health-shots/2021/11/03/1051299050/ covid-vaccine-kids-5-11. Liz Hamel Follow @lizhamel on Twitter, Lunna Lopes, and Oct 2021. “KFF COVID-19 Vaccine Monitor: October 2021.” KFF, 9 Nov. 2021, https://www.kff.org/coronavirus-covid-19/ poll-finding/kff-covid-19-vaccine-monitoroctober-2021/ “State Parental Consent Laws for Covid-19 Vaccination.” KFF, 11 Oct. 2021, https:// www.kff.org/other/state-indicator/ state-parental-consent-laws-for-covid-19vaccination/?currentTi Grootens-Wiegers, Petronella, et al. “Medical Decision-Making in Children and Adolescents: Developmental and Neuroscientific Aspects.” BMC Pediatrics, BioMed Central, 8 May 2017, https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC5422908/.
To know the future. To be cared for by others. To find protection. And to not just be safe, but feel safe.
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SHOTS HEARD ROUND THE WORLD HOW THE COVID-19 PANDEMIC IS HELPING DEVELOP AN HIV VACCINE By
Marissa McCollum Areeha Khalid
While HIV has been a constant threat for over three decades, COVID-19 has surpassed its estimated death toll—700,000 people in the U.S.—in under two years. This does not mean, however, that COVID-19 will likewise go untreated. There are multiple vaccines already authorized by the FDA, and the efficacy of both Pfizer and Moderna vaccines is consistently rated above 88% against the alpha strain. With 66% of the U.S. population at least partially vaccinated, COVID-19 appears to have a much shorter historical period of unchecked infection than HIV. Even more optimistically, some new research is working toward a preventative immunization against HIV using the same mRNA technology responsible for the success of some of the COVID-19 vaccines. First clinically identified in
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1982, AIDS is one of the most well-known epidemics of the modern age. AIDS, or acquired immunodeficiency syndrome, strips the body’s natural immune system, leaving patients susceptible to illness or death from even minor infections. The pathogen behind this disease, HIV (human immunodeficiency virus) has infected over 1.1 million people in the United States as of 2019. Despite the prolific nature of the disease, the CDC estimates that around 15% of those infected are unaware and therefore liable to unknowingly spread HIV to others. AIDS has no cure, only treatments to mitigate symptoms and reduce communicability. Current trials are not the first attempts to curb HIV transmission. The first treatments used for HIV were direct acting dideoxynucleoside reverse transcriptase
inhibitors (NRTIs), a class of drugs that prevent the virus from inserting its own genome into host cells, the means by which HIV reproduces within an infected body. HIV is comparatively difficult to completely eliminate after infection has set in, as it produces latent “reservoirs” which allow the virus to persist through attempts to eradicate the active infection. However, current antiretroviral therapy has lowered the mortality of HIV to close to zero when treated quickly and adequately. Preventative measures also exist, such as preexposure prophylaxis (PrEP), a daily medication for high-risk populations, such as men and transgender women who have sex with men, or injection drug users. Despite these improvements, a single-dose prevention remains elusive. Even a vaccine efficacy as low as
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50% sustained for two years would lower infection rates significantly in high-incidence areas, according to Dr. Paul Stoffels, an HIV researcher and chief scientific officer for Johnson & Johnson. One promising vaccine trial, performed in Thailand in 2009, showed 60.5% efficacy one year after vaccination with RV144, but this protection decreased after three years to only 31.2%. Still, the Thai trial offers hope in the face of numerous failed trials since. A study completed in the U.S. from 2009 to 2013 used DNA prime–recombinant adenovirus type 5 boost (DNA/rAd5), a method similar to the mRNA system used in the COVID-19 vaccination. In this method, DNA for antigens, proteins that exist on the surface of a given virus, are injected, causing the host body to replicate solely those proteins used for recognition. This prompts the body to produce antibodies against the pathogen, which increases efficiency when dealing with a legitimate infection. Unfortunately, despite the success of COVID19 mRNA immunizations, the DNA HIV vaccine did not offer any substantial protection. As Dr. Anthony Fauci, director of the National Institute of Allergy
and Infectious Diseases (NIAID) remarked after a failed HIV vaccine trial, “The development of a safe and effective vaccine to prevent HIV infection has proven to be a formidable scientific challenge.” Nearly all viruses, including HIV and COVID-19, mutate as they are passed from one host to another. In order to limit such effects of mutations on vaccine efficacy, later HIV trials used “mosaic” molecules that include aspects of multiple variants’ antigens. A study that ran from 2017 to 2019 in sub-Saharan Africa saw 25.2% efficacy by using such a mosaic, a far cry from the 50% needed to effect lower rates of infection, but another promising foundation for future studies. Hopes could rest on one such clinical study in progress, which uses the same mRNA platform as the Moderna COVID-19 immunization. Known as mRNA-1644, the vaccine is sponsored by the Bill and Melinda Gates Foundation and the International AIDS Vaccine Initiative. The study will likely start recruiting adults without HIV before the end of the year, and is set to finish in May 2023. If successful, or even if only partially
effective, the results of the present studies will inform HIV treatment and prevention far into the future. Science is inching ever closer to a permanent solution for the HIV/ AIDS epidemic. Angel, C. J. L. (2020, September 10). Bringing the path toward an HIV-1 vaccine into focus. PLOS Pathogens. https://journals.plos.org/ plospathogens/article?id=10.1371/journal. ppat.1008663#ppat.1008663.ref001 CDC. (2021, October 1). Basic Statistics | HIV Basics | HIV/AIDS | CDC. https://www. cdc.gov/hiv/basics/statistics.html?CDC_ AA_refVal=https%3A%2F%2Fwww.cdc. gov%2Fhiv%2Fstatistics%2Fbasics.html JavanmardiI, N. (2021). Recent advancements in Graphene oxide-based for fight with HIV infection . Advances in Applied NanoBioTechnologies, 2(4), 47-52. https://www.dormaj. org/index.php/AANBT/article/view/436 Katella, K. (2021, November 3). Comparing the COVID-19 Vaccines: How Are They Different? Yale Medicine. https://www.yalemedicine.org/ news/covid-19-vaccine-comparison Madison, C. M. (2021, October 25). Using mRNA to Create the Elusive HIV Vaccine. Pharmacy Times. https://www.pharmacytimes.com/view/ using-mrna-to-create-the-elusive-hiv-vaccine Mathieu, E., Ritchie, H., Ortiz-Ospina, E. et al (2020, March 5). Coronavirus (COVID-19) Vaccinations - Statistics and Research. Our World in Data. https://ourworldindata.org/ covid-vaccinations?country=USA National Institute of Health. (2021, August 31). HIV Vaccine Candidate Does Not Sufficiently Protect Women Against HIV Infection. https:// www.nih.gov/news-events/news-releases/ hiv-vaccine-candidate-does-not-sufficientlyprotect-women-against-hiv-infection Steenhuysen, J. (2020, February 3). Trial of promising HIV vaccine halted after failing to show benefit. Reuters. https://www. reuters.com/article/us-health-hiv-vaccine/ trial-of-promising-hiv-vaccine-halted-afterfailing-to-show-benefit-idUSKBN1ZX2QO Vella, S., et al. (2012, June 19). The history of antiretroviral therapy and of its implementation in resource-limited areas of the world. Wolters Kluwer. https://journals.lww.com/aidsonline/ fulltext/2012/06190/the_history_of_ antiretroviral_therapy_and_of_its.12.aspx
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DENTAL PULP STEM CELLS THE FUTURE OF HUMAN REGENERATION By
Ayman Lone Helen Wei
Stem cell therapy has long been regarded as the apex of regenerative medicine, more so than organ transplants or synthetic body parts. Because they start as unspecialized cells, stem cells have the ability to either differentiate into various cell types or to self-renew and become new stem cells. These functions allow them to heal – or sometimes regrow – damaged tissue and organs in humans. One of the most commonly used stem cells, called mesenchymal stem cells (MSCs), are derived from specific areas in the body such as bone marrow, umbilical cords, and embryos (which is often the topic of many ethical debates). A new alternative to MSCs are dental pulp stem cells (DPSCs). Even though the use of DPSCs is a recent development, research has uncovered unique traits and increased applicability to treating diseases compared to MSCs. As the name implies, DPCSs reside under the third molar pulp where they are then extracted for use in stem cell therapy. Compared to MSCs, which are extracted from various organs as mentioned previ-
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ously, and induced pluripotent stem cells (iPSCs) that are created from scratch from somatic cells, DPSCs present a less invasive, complex, and ethically challenging option for treatment. For example, DPSCs may be extracted during a wisdom tooth surgery or another similar simple dental operation, whereas accessing the bone marrow would require surgery. Another concern regarding MSCs is that contemporary research suggests that stem cells from bone marrow may only be able to differentiate into a few types of cells, namely osteoblasts (bone cells), which are only useful in musculoskeletal regeneration. On the other hand, DPSCs, in addition to the properties of MSCs, can form into osteoblasts, odontoblasts (a type of tooth cell), neurons, and fat cells. This ability to differentiate into various kinds of cells is referred to as multipotency. Although embryonic stem cells (ESCs) are also multipotent, their use brings up many ethical concerns and controversy. ESC extraction involves the destruction of human embryos, sparking debates over whether this extraction would be
classified as murder. Many believe that embryos are humans with rights, while others view embryos as groups of cells with which it is permissible to conduct research. Even though the NIH created specific guidelines on stem cell use and research – with emphasis on ESCs – the issue remains a polarizing one in the US, similar to the “pro-choice” vs. “pro-life” debate. The use of DPSCs completely side-steps this debate and avoids these ethical hurdles, highlighting its practicality in research. Similarly, iPSCs – MSCs “reverse engineered” to resemble stem cells – have the flexibility of ESCs without the ethical baggage. As with MSCs, however, the procedure to obtain DPSCs is much simpler than the procedure to produce iPSCs. Overall, DPSCs represent a balance between simplicity and versatility, and have thus been the subject of many applications to specific diseases and fields of medicine. Three of the main applications of DPSC therapy include dentistry, neurology, and angiogenesis (the generating of new blood vessels).
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In terms of dentistry, DPSCs can differentiate into each of the four main components of teeth: enamel, pulp, dentin, and cementum. In fact, one of the earlier studies involving DPSCs showed how the cells could regenerate a dentin-pulp complex for immunocompromised mice, suggesting that perhaps human compatible lab grown teeth are on the horizon. This wouldn’t be too surprising, considering that a species of stem cells originating in dental pulp should be expected to differentiate into teeth-related organs. However, the ability of DPSCs to treat neurological diseases is unexpected. Due to how they express a variety of neurological growth factors, DPSCs have a surprisingly high rate of neurocyte differentiation. This would allow them to combat diseases such as dementia or schizophrenia. In 2019, a team at the University of Warwick conducted a study in which they concluded that DPSCs can effectively treat ischemic stroke. Another surprising trait of DPSCs is their angiogenic properties. Along with the numerous neurological growth factors,
DPSCs produce several pro-angiogenic factors that – combined with DPSCs’ high proliferation rate – stimulate the rapid growth of new blood vessels. These applications only touch the surface of what DPSCs are capable of. DPSC research has only just begun, and studies have shown differentiation into liver cells and beta cells (insulin makers), pointing towards potential diabetes and hepatitis treatments. Many of the possible setbacks of stem cell therapy – ethical questions, difficulty of cell extraction, differentiation versatility, etc. – are addressed and alleviated by DPSCs in some way. These cells are paving the way for a new wave of treatments for all kinds of diseases. After all, the study of DPSCs – and the field of regenerative medicine and tissue engineering in general – is only at its dawn, and the extent of their potential is yet to be fully discovered.
Bronckaers, Annelies et al. “Angiogenic properties of human dental pulp stem cells.” PloS one vol. 8,8 e71104. 7 Aug. 2013, doi:10.1371/journal. pone.0071104 https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC3737205/ Potdar, Pravin D, and Yogita D Jethmalani. “Human dental pulp stem cells: Applications in future regenerative medicine.” World journal of stem cells vol. 7,5 (2015): 839-51. doi:10.4252/wjsc. v7.i5.839 https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC4478630/ Tatullo, Marco et al. “Dental pulp stem cells: function, isolation and applications in regenerative medicine.” Journal of tissue engineering and regenerative medicine vol. 9,11 (2015): 1205-16. doi:10.1002/term.1899 https:// pubmed.ncbi.nlm.nih.gov/24850632/ Lan X, Sun Z, Chu C, Boltze J and Li S (2019) Dental Pulp Stem Cells: An Attractive Alternative for Cell Therapy in Ischemic Stroke. Front. Neurol. 10:824. doi: 10.3389/fneur.2019.00824 https://www.frontiersin.org/articles/10.3389/ fneur.2019.00824/full Mayo Clinic Staff. “Frequently Asked Questions about Stem Cell Research.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 8 June 2019, https://www.mayoclinic. org/tests-procedures/bone-marrow-transplant/ in-depth/stem-cells/art-20048117. “Dental Pulp Stem Cells.” Dental Pulp Stem Cells - an Overview | ScienceDirect Topics, Science Direct, 2021, https://www.sciencedirect.com/ topics/medicine-and-dentistry/dental-pulpstem-cells. “Types of Stem Cell: Stem Cells: University of Nebraska Medical Center.” UNMC, University of Nebraska Medical Center, 2020, https://www. unmc.edu/stemcells/educational-resources/ types.html
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BEATING ALZHEIMER'S DISEASE A NEW FLUOROGENIC MARKER PUTS ROUTINE TESTS FOR ALZHEIMER'S IN REACH By
Jack LeGrow Ashley Chen
Alzheimer’s disease (AD) and other neurodegenerative disorders pose some of the most concerning threats to an aging population. According to the World Health Organization, there are approximately 55 million people worldwide currently living with AD or some related form of dementia. The 7th leading cause of death internationally and the 4th among those aged 70 and older, Alzheimer’s not only induces stress and fatigue among
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its victims but also weighs a heavy burden on the family members of patients. Caretakers and loved ones report constant physical and emotional stress, feeling on-duty 24/7, and statistically disproportionate frictional unemployment. Considering the distress placed on patients and their families, the Alzheimer’s Association championed clinical trials and extensive research to treat and understand
AD beginning in 1978. Since then, several AD medications have proved efficient at delaying the onset of neuronal damage. Molecular causes for AD have been identified as the buildup of amyloid-beta (Aβ) and tau neuritic plaques in the cerebral cortex. Unfortunately, finding a cure for AD presents a challenge to the medical community despite massive investment and decades of research.
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The primary roadblock preventing the development of a comprehensive cure for dementia has been the difficult timeline implicated in AD clinical studies. Alzheimer’s has a long prodromal period. Patients appear asymptomatic while plaques and neurofibrillary tangles accumulate in the gray matter of the brain. By the time the first symptoms appear, AD is often too far advanced to effectively treat in clinical trials. Therefore, early detection of AD is critical for meaningful advances in its treatment. Conventionally, cerebrospinal and ocular fluid are used to sample Aβ, tau, and other biomarkers associated with the onset of AD; however, these techniques often yield inconclusive concentrations or are too invasive for early diagnoses. Conversely, AD can be effectively diagnosed throughout its early stages using amyloid-positron emission tomography (PET) and magnetic resonance imaging (MRI) to map regions of plaque buildup and neuronal damage. Unfortunately, these techniques implicate other disadvantages, including high cost and exposure
to radionucleotides. To better diagnose asymptomatic AD, there is a need for low-cost, non-invasive, and spatially precise imaging to identify amyloid and neurofibrillary tangle buildup in the cerebral cortex. With such leverage, the hope is that frequent AD testing could be integrated into check-ups at the doctor’s office for patients over a certain age—as standard as blood work. Recently, reactive oxygen species (ROS) have also become promising candidate indicators for AD diagnostics research. These species are critical in cellular and genetic signaling, and their concentration is strictly controlled for homeostatic balance. If not properly regulated, however, excessive ROS can build up and cause cellular damage in a process called oxidative stress. The buildup of Aβ plaques in AD has been directly linked to oxidative stress. Oligomer Aβ can insert itself in the cell membrane of neurons, inducing an effect called lipid peroxidation. This generates highly reactive aldehydes like acrolein, malondialdehyde, and 4-hydroxynonenal (HNE). HNE is of particular
importance in AD pathology because it can readily react with cellular components containing thiol (–SH) and amine (–NH2) groups, such as nucleotides and proteins. Oxidative stress generating HNE has been shown to result in multiple deleterious events like RNA and DNA inhibition, the disruption of protein functions, and stagnated protein synthesis. These events interfere with typical neuron signaling and can initiate premature apoptosis, contributing to cognitive impairment in AD. Oxidative stress is directly correlated with the progression of AD, and therefore, its detection can provide the same confidence as the presence of amyloids and tau in the cerebral cortex. Furthermore, ROS are direct products of plaques interacting with brain tissue, so their detection would offer the same relative spatial mapping as MRI or amyloid-PET. The advantage of ROS is that they are much more reactive than Aβ, tau, and the other biomarkers linked to AD. Thus, indicators can be designed to react with ROS in a manner that makes them detectable in the presence of ROS
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and undetectable otherwise—an approach that has not previously been possible. Considering the role of oxidative stress in Alzheimer’s pathology, researchers have developed a fluorogenic molecular probe that senses O2^˙−, a major ROS produced by oligomer Aβ and HNE reactions. They achieved this by chemically “caging” resorufin—a fluorescent dye used in bioimaging—so that nonfluorescent derivatives have their fluorescence recovered in the presence of O2^˙− through selective nucleophilic cleavage of a chemical cage unit. They appended several benzene-sulfonyl chlorides with various electron-donating and electron-withdrawing substituents to examine which resorufin probes would generate the best sensitivity to inflammatory oxidative stress stimulation in HeLa cancer cells and mice. Pentafluorobenzenesulfonyl cage units were found to produce ideal resorufin fluorescence sensitivity in the presence of O2^˙−. With a 2.6 × 10^-7 M limit of detection, its sensitivity sits comfortably between the O2^˙− concentration expressed under normal (10^-10 –10^-12 M) and abnormal/inflamed (10^-6 M) conditions. Compellingly, this pentafluorobenzenesulfonyl-caged resorufin derivative was used to identify oxidative stress in an array of demonstrations. Human cervical epithelioid carcinoma cells stained with the molecular probe produced a strong fluorogenic response when intentionally placed under oxidative stress. The
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probe was given to mice who had simulated inflammatory-induced oxidative stress in their peritoneal cavity where it was capable of spatiotemporally visualizing the affected tissue in-vivo. Justification that this fluorogenic response was oxidative stress-induced was provided when the same conditions were generated and when Tiron, an O2^˙− scavenger, was introduced. These experiments produced no fluorogenic response, indicating the O2^˙−-specific fluorescence. This new molecular probe shows promise to provide the necessary early imaging for conclusive AD diagnosis. Microglial cells, known to cause neuronal death in dementia through the release of inflammatory cytokines, were tested with the caged resorufin derivative. The molecular probe produced the same fluorogenic response when the microglial cells were placed under oxidative stress from Aβ presence. Indeed, this suggests that the probe is effective under the exact conditions of neurofibrillary tangle and plaque buildup in the early stages of AD. Noninvasive and cheap molecular probes like pentafluorobenezenesulfonyl-resorufin open doors to a new age in Alzheimer’s treatment and the pursuit for a cure. With the potential to conclusively diagnose AD in its earliest stages by imaging oxidative stress in the cerebral cortex, patients will be able to receive preemptive treatments and participate in new studies that can eventually lead to cures starting from the disease’s asymptomatic, prodromal period.
Proper diagnostics serve as the pillar for effective treatments. This cutting-edge research presents a substantial addition to the toolkit in the fight against AD and neurodegenerative disorders. The future for oxidative stress biomarkers is vast. By demonstrating resorufin’s ability to fluoresce in cells with Aβ-induced oxidative stress, researchers can tap into the studies of cancer, Parkinson’s disease, Lou Gehrig’s disease and heart failure. Identifying localized oxidative stress in regular exams could help to diagnose dormant tumors, increased risk for organ failure, and asymptomatic neurodegenerative disorders alike. Having the benefit of early diagnosis in any disease helps save lives, not only to help delay or prevent symptoms and disease progression but also in more robust clinical trials for future cures. Jawon Shin, Dong Min Kang, Jounghyun Yoo, Jeongyun Heo, Keunsoo Jeong, Ji Hyung Chung, Ye Sun Han, Sehoon Kim. “Superoxideresponsive fluorogenic molecular probes for optical bioimaging of neurodegenerative events in Alzheimer’s disease.” Analyst 146, no. 15 (2021): 4748-4755. https://doi.org/10.1039/ d1an00692d. Scott Counts, Milos Ikonomovic, Natosha Mercado, Irving Vega, Elliot Mufson. “Biomarkers for the Early Detection and Progression of Alzheimer’s Disease.” Neurotherapeutics 14 (2016): 35-53. https://doi. org/10.1007/s13311-016-0481-z. Lee, J.C., Kim, S.J., Hong, S. et al. “Diagnosis of Alzheimer’s disease utilizing amyloid and tau as fluid biomarkers.” Exp Mol Med 51 (2019): 1-10. https://doi.org/10.1038/s12276-0190250-2. Mao P., Reddy P.H. “Aging and amyloid betainduced oxidative DNA damage and mitochondrial dysfunction in Alzheimer's disease: implications for early intervention and therapeutics.” Biochim Biophys Acta 1812, no. 11 (2011): 1359-1370. https://doi.org/ 10.1016/j.bbadis.2011.08.005. Wilson, Jessica. Alzheimer’s Disease. Digital image. 30.5 MB. Science Photo Library, https:// www.sciencephoto.com/media/447399/view/ alzheimer-s-disease.
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THE FUTURE OF CANCER TREATMENT By
Caroline Kellogg Eve Tanios
An effective treatment for cancer has eluded scientists and doctors for centuries. For as long as we have studied cancer, it remains the second-leading cause of death globally and a disease that half of men and a third of women will develop in their lifetimes. But why is it so difficult to find an effective treatment? Because there isn’t one. As each tumor has its own set of mutations and variations, they respond differently to chemotherapy, radiation, and other known cancer treatments. While a single universal cancer treatment remains elusive, scientists are developing methods to personalize the treatment of cancer instead of searching for a cure-all. The central philosophy behind the personalization of cancer treatment is predicting the effectiveness of treatments through models. However, modeling human cancer
is extremely difficult. The wide variety of potential mutations combined with the randomness of cancer development makes it impossible to predict exactly how a tumor will develop. So, why not observe it in real time? The most accurate model involves taking a sample of a human tumor and implanting it into immunocompromised mice. Following implantation, several therapeutic strategies are tested on the mice to determine which one most effectively limits tumor growth and should be administered to the patient. While it seems impossible to grow human tissue within a mouse, these tumors have been shown to have similar molecular profiles to those grown in humans. There are many benefits of growing a tumor in real-time, including the ability to study the tumor at
various stages of development or understand the changes that lead to metastasis. However, there are several drawbacks that cause these models to be inefficient. Unsurprisingly, one of the most significant limitations is the fact that oftentimes implanted tumor cells do not grow in specific mice. Testing immunotherapies is also impossible when working with immunocompromised mice, and the human tumor microenvironment can’t be perfectly replicated in mice. The financial burden of creating and maintaining multiple mouse generations also cannot be understated; it can cost up to $25,000 to propagate tumors in mice, all of which is not covered by insurance. In response to these difficulties, scientists have developed an alternative for modeling human cancers: organoid models. Grown in specialized media
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conditions and a 3D matrix, organoid models aim to address the issues associated with 2D cell cultures by more accurately replicating the tumor environment. Already, organoid models have proven successful, with one group finding a 90% success in replicating 22 cases of colon cancer. However, the same central limitation remains: the inability to replicate cancer development in humans with reliable accuracy. Organoid models fail to model specific kinds of cancer such as prostate cancer. Further, for certain tissue types, the specialized media used in the creation of organoid models still needs to be developed.
to screen drugs and predict drug combinations that can reduce the size of tumors. Using genomic information from patient tumors, a model is created that can predict the response of the tumor to different therapeutic strategies. This specific model has shown success in treating four cases of multiple myeloma (MM), a kind of cancer notorious for developing drug-resistance and having unpredictable responses to treatment. As with every predictive cancer model thus far, however, AI models still struggle to accurately predict how a tumor will develop and therefore have not been used on a large scale.
Stepping away from in vitro and in vivo models of human cancer or anything physical at all, AI models represent another potential avenue for the personalization of cancer treatment. One popular AI model is simulating cancer physiology
The future of cancer treatment is highly personalized. However, regardless of the model, it is difficult to predict the development of tumors with 100% accuracy. While the aforementioned methods are far more advanced than the simple
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2D cell cultures used just 50 years prior, they still remain unreliable. It’s important to emphasize the gravity of cancer and the reason why it’s so important that we find a cure for it. Billions of dollars have been donated to cancer research over several centuries, and for good reason: it is one of the most grave human diseases that we have yet to find a truly effective cure for. Doudican, Nicole A, Ansu Kumar, Neeraj Singh, Prashant R Nair, Deepak A Lala, Kabya Basu, Anay A Talawdekar, et al. “Personalization of Cancer Treatment Using Predictive Simulation.” Journal of Translational Medicine 13, no. 1 (2015): 43. https://doi.org/10.1186/ s12967-015-0399-y. Francies, Hayley E, and Mathew J Garnett. “What Role Could Organoids Play in the Personalization of Cancer Treatment?” Pharmacogenomics 16, no. 14 (2015): 1523–26. https://doi.org/10.2217/pgs.15.114. Malaney, Prerna, Santo V. Nicosia, and Vrushank Davé. “One Mouse, One Patient Paradigm: New Avatars of Personalized Cancer Therapy.” Cancer Letters 344, no. 1 (2014): 1–12. https:// doi.org/10.1016/j.canlet.2013.10.010. Sudhakar, Akulapalli. “History of Cancer, Ancient and Modern Treatment Methods.” Journal of Cancer Science & Therapy 01, no. 02 (2009): i-iv. https://doi.org/10.4172/19485956.100000e2.
ulse p THE PRE-MEDICAL STUDENTS’ ASSOCIATION the university of chicago FACEBOOK /uchicagopmsa WEBSITE pmsa.uchicago.edu
