UChicago PULSE Issue 6.2: Winter 2020

PULSE VOLUME 6, ISSUE 2. WINTER 2020.

EMERGENCE OF THE CORONAVIRUS

editors

writers

production

Swathi Balaji EJ Beck Natalie Choi Woojin Choi Allison Gentry Jean Kim Yifan Mao Abhijit Ramaprasad

Shayna Cohen Meagan Johnson Miles Kaufman Melody Leung Sanjana Rao Lindsay Romano Sofia Uranga Xiya Wu

Irena Feng Linus Park

graphics medicine Swathi Balaji Linus Park

pulse - winter 2020

cover design Olivia Shao

other contributors Gold Standard Kaplan Test Prep The Princeton Review

from the editor-in-chief Dear readers,

We have rapidly sailed into a new decade, and almost a quarter of 2020 is behind us. Nevertheless, this brief period has given way for new developments in science, medicine, and politics. In this issue, we update you on the progress of continual discoveries on the forefront of new medical practices and policies. We also direct your attention briefly to the more recent global crisis that the science and medical communities around the world have had to face.

As most of us are aware by now, the novel coronavirus (COVID-19) that has spread throughout the entire globe has created cultural, economic, and scientific panic. In efforts to best inform our readers about the virus and campus resources available, we have dedicated the first few pages of this issue to include the most recent update from UChicago’s Provost Ka Yee Lee and the CDC. We hope to contribute in this worldwide battle against COVID-19 through spreading awareness about what experts currently understand and listing the most up-to-date preventative measures. Unfortunately, mass media coverage concentrates heavily on such global phenomena and makes it easy for everyone to be swept up by the growing panic. It is our job to remind our readers that there are still exciting discoveries unrelated to this issue being made concomitantly.

And so, we bring you contents varying from new AI researched drug algorithms to gut bacteria and their implications on health to an inspection on the drug policies in Portugal. There are also informational pieces on adoptive cell therapy and traditional medicine. Finally, in this quarter’s issue, we introduce a major addition to PULSE magazine!

I am delighted to announce our new Graphics Medicine section! Graphics Medicine is an additional outlet for students to explore applications of healthcare and life sciences through the lens of visual art. Please look forward to the works of our many talented artists that provide us with insightful perspectives on medicine, patient care, and health education in the future.

With our mission to serve as a resource for undergraduates exploring science, we are very excited about this foray into a rapidly growing field. So, we hope that you enjoy the read, and we look forward to seeing everyone return healthy and refreshed from what will hopefully turn out to be an amazing spring break!

With Regards, Linus Park

pulse - winter 2020

CONTENTS COVID-19: UNIVERSITY UPDATES, GENERAL INFO

2

EDUCATION SO YOU WANT TO BECOME A DOCTOR MAKING AN MCAT STUDY SCHEDULE KAPLAN MCAT PRACTICE PROBLEM

6 8 9

POLICY THE HIDDEN PUBLIC HEALTH CRISIS THE NEXT FIX

10 12

RESEARCH FIRST DRUG MADE BY AI TESTED IN HUMAN TRIALS THE LINK BETWEEN GUT BACTERIA AND OBESITY BACTERIA AND VIRUSES AND FUNGI, OH MY! THE RESEARCH POTENTIAL IN TRADITIONAL MEDICINE

14 16 18 21

CLINIC CONNECTOMICS THE POWER WITHIN

24 26

GRAPHICS MEDICINE TRAUMA

32

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Full Statement from the President of the University of Chicago To: Members of the University Community From: Robert J. Zimmer, President As we continue to evolve the University’s public health precautions in response to developments with coronavirus (COVID-19), we are writing to update you on the University’s new travel guidelines and other health measures informed by the most recent assessments by the U.S. Centers for Disease Control and Prevention (CDC) and the Chicago Department of Public Health.

No students, faculty, staff, or others in our Hyde Park campus community have tested positive for COVID-19.

Our medical center is currently evaluating patients from outside the University for the virus and will continue to evaluate any patient with potential symptoms of COVID-19 in collaboration with local health department officials and the CDC. The medical center is taking all recommended public health precautions with any patient under evaluation.

For the general University population, the following updated travel guidelines are intended to lower the risk of exposure: •

•

•

•

With a growing number of countries reporting widespread transmission of COVID-19, the University strongly discourages travel to any country with a CDC travel health notice of Level 3 (currently, China, Italy, Iran and South Korea). Because these advisories have been extended to additional countries, we advise checking the University’s COVID-19 information page and the CDC’s travel notices for the latest information.

Any traveler who has returned from a country with a CDC Level 3 travel health notice should not attend school or work for 14 days after their return date, following Chicago Department of Public Health guidelines. This self-isolation period also applies to visitors to the University. Individuals should work directly with their departments to facilitate academic, research, or work continuity.

Anyone who has returned from a CDC Level 2 or Level 3 country in the past 14 days and going forward is strongly advised to fill out this simple form with information about their trip. This will help the University work with public health authorities to limit exposure in the event of a positive test case. If the CDC puts in place an additional designation for travel to domestic locations, we will communicate and follow those guidelines as well.

While Level 3 is the CDC’s highest alert, please bear in mind that the situation is continuing to change in many countries that have had COVID-19 cases. Following guidelines from the CDC, we are carefully monitoring the situation in countries where the University has study abroad programs. The University will follow up separately with study abroad participants to provide additional information related to planning for their spring programs.

Anyone who has traveled to an area with reported community spread and has developed respiratory symptoms including fever, cough, and difficulty breathing should stay home except to get medical care. People with such symptoms should call ahead before visiting your primary care provider, and contact coronavirusinfo@uchicago.edu. University representatives will immediately notify CDPH and help provide individualized guidance.

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COVID-19

FROM UCHICAGO Please continue to check the University’s COVID-19 page for more information about these travel guidelines and other public health measures. We ask that members of our community continue to support each other, avoid uninformed assumptions, and base your decisions about travel and health precautions on the best available information.

For additional information on COVID-19, please visit coronavirusupdates.uchicago.edu. Further health information is available from UChicago Medicine, CDPH, and the CDC. Please contact coronavirusinfo@uchicago.edu if you need guidance, resources, or assistance.

Helpful Resources: • https://www.cdc.gov/coronavirus/2019-ncov/summary.html • https://coronavirusupdates.uchicago.edu/ • https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public All past emails can be viewed here: https://coronavirusupdates.uchicago.edu/uchicago-archived-updates/

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COVID-19: INFO PROTECT YOURSELF AND OTHERS FROM GETTING SICK

WHO Basic Preventative Measures 1.

2.

3.

4.

5.

6.

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Wash your hands frequently.

Maintain social distancing.

Avoid touching eyes, nose and mouth.

Practice respiratory hygiene.

If you have fever, cough and difficulty breathing, seek medical care early.

Stay informed and follow advice given by your healthcare provider.

COVID-19

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SO YOU WANT TO BECOME A DOCTOR

DECISIONS, DECISIONS...

Becoming a doctor requires a real commitment, so your decision to pursue this career path should be an informed one. You should consider information from discussions with medical professionals. Talk to as many doctors as you can. Find out how they spend their days and what they love and do not love about their professions. Think about whether you could fill their shoes and whether you would thrive in doing so.

Always consider your source when gathering information. For example, television shows with exciting plots and attractive actors glamorize medicine, whereas newspapers can do the opposite by highlighting negative trends and emphasizing scandals.

While you are fortunate to have hundreds of career options to choose from, having so many choices can be confusing and overwhelming. Don’t let indecision paralyze you. Consider taking time off after college to work in medical and nonmedical fields, to travel, or volunteer before applying to medical school. This type of experience serves the dual purpose of allowing you to assess your interest in medicine, and it improves your medical school application; diversity of

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experience is a great way to improve your chances to get into medical school. In deciding whether medicine is the career for you, you should also reflect on the paths that you won’t be taking. Are you deciding between being a teacher or a doctor? Why not teach for a year or two and then reconsider medical school?

The skills you learn teaching will help you explain medical issues to patients, and many medical schools leave space for non-traditional medical students.

Perhaps you feel that there are too few rather than too many career possibilities from which to choose.

Some people consider medicine, law, and other obvious professions because they just don’t know what else is out there. In this situation, there is nothing like spending a couple of years in the real world. This will expose you to various professions and career options.

Even working for a temp agency can be beneficial; it can provide exposure to a few fields and organizations. Learning about other options might confirm your interest in medicine or could lead you in another direction. Either way, it will be valuable use of your time.

EDUCATION

WHAT IT TAKES TO BE A DOCTOR

Medical school takes considerable commitment, and the medical profession is very demanding. Few traits are essential, no matter where you are or what century you’re in. Consider the following questions: Do you want to spend your life helping others?

Doctors heal people, save lives, and help others – often through direct, face-to-face interactions. If this is your motivation, you’re in good company. However, there are other altruistic careers out there, all of which involve less schooling and less debt than medical school. The desire to help others should be one, but not your only reason for becoming a doctor.

Do you enjoy working hard?

Medicine is an incredibly challenging field. This was the case a hundred years ago when doctors worked to fight yellow fever, polio, and influenza, and it is the case today as health professionals try to prevent and treat heart disease, cancer, AIDS/HIV, and influenza while dealing with the constraints of managed care. Consider medicine only if you love challenges and you know you want tremendous challenges in your professional life.

As you read through this article, think about whether the challenges involved in practicing medicine are the ones that appeal to you. For example, a physician who is 20 years out of medicine is still expected to fulfill 50 hours of continuing education a year, just like a first-year resident. One of the challenges of practicing medicine is a commitment to lifelong learning.

Are you interested in science and health issues?

If you enjoyed some aspects of your science courses and you find yourself drawn to health issues, there is a good chance that you will enjoy studying and practicing medicine. Although medicine has changed significantly over the years, its roots remain in basic science.

Do you like working with different people?

Except for a few fields, medicine involves working with people, many of whom may be very different from you.

If science interests you, but working with people does not, you may wish to consider a Ph.D. rather than an MD (this choice also involves less debt). You might also investigate an MD that allows you to do only research.

WHAT IT TAKES TO BE A DOCTOR IN THE 21ST CENTURY

Compassion – a critical part of the healing.

Advocacy – for your patients and for those without health care.

Leadership – in improving health care at the team, hospital and policy level.

Lifelong learning – there will always be more to know.

Interpersonal skills – communication with patients and among providers is key.

Negotiation – the ability to work around bureaucratic constraints.

Grasp – of increasing amounts of medical knowledge and of a health care system in flux.

ASK YOURSELF: IS MEDICINE YOUR CALLING? So, you still want to be a doctor…

Congratulations! The good news is that you are on your way to entering one of the most rewarding and respected fields, one of the few altruistic careers that pay livable wages. The bad news is that the MCAT and application process is still tough. The good news here, we can help you get into your dream medical school.

Let’s get you prepared for MCAT and your dream school!

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MAKING AN MCAT STUDY SCHEDULE One of the major factors essential to achievement in any field is planning. And the same thing applies when preparing for the MCAT. It is true that some students are capable of breezing through the MCAT exam and earning an excellent score without studying much beforehand. Nevertheless, most students require a structured MCAT study schedule to maximize their studying and ensure a solid performance on test day.

Considering that it is such an important preparation tool, an MCAT study schedule must be personalized to suit your specific circumstances. Therefore, designing your own MCAT study schedule requires careful thought and assessment on your part. So, follow along with these steps to help guide you through the planning process: Step 1: Determine your strengths and weaknesses Consider your undergraduate training or the amount of time that has passed since you graduated from undergraduate school. If you do not have a strong science background, then your study schedule should certainly start with an in-depth science review. If you do have a strong science background, then your study schedule should start with a review of material that applies to the Critical Analysis and Reasoning Skills (MCAT CARS) section. Your study schedule should start with you addressing your weaknesses.

Step 4: Develop daily and weekly schedules Schedule a minimum of 3 hours of study time each day. If you cannot fit MCAT study time in everyday, strive for every other day. In which case, you should increase the number of hours you spend studying on those days. Select your top two priority subjects and plot them into your schedule for two days a week.

Make sure you spend two-thirds of all your study time reviewing your top priority (most difficult) subject. And no later than one month prior to your test day, take 1-2 MCAT practice tests each week.

Step 2: Rank subjects according to personal difficulty This step touches on step 1 as well. Once you determine your strengths and weaknesses, you should go through and prioritize each MCAT subject accordingly. For instance, if you consider Organic Chemistry your hardest subject, then designate it as your number one priority. If Physics comes easy to you, then designate it as your last priority--but a priority nonetheless!

Step 5: Stick to your study schedule Once you get a way into your study schedule, you may feel like you do not need to study anymore. On the contrary, it is highly important that you stick to your schedule and review material often. It is also very important that you review material from earlier in your schedule as well as the questions you miss on practice exams.

Step 3: Determine how long you will study Look to your grades for direction in completing this step, as they are a good starting point for determining the amount of time you need to study. Students with a science background who earned an A in all of their science courses may only need three months or less to prepare for the MCAT. On the other hand, students without a science background or those who have not studied the sciences recently, would need to allow up to six months to prepare.

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For more tips on developing your personal MCAT Study Schedule, check out our advice pages on MCAT-prep.com

EDUCATION

Kaplan MCAT PRACTICE PROBLEM QUESTION Hypertension (high blood pressure) can be diagnosed by having two or more blood pressure readings higher than 140/90 on two difference occasions, separated by a week. Suppose that the criteria were changed to include anyone with a reading higher than 130/80 on at least one occasion. How would this change the prevalence of diagnosed hypertension in the population?

A. The prevalence would increase.

B. The prevalence would decrease.

C. The prevalence would remain the same.

D. There is not enough information to determine the change in prevalence.

THINK YOU’RE READY FOR TEST DAY? Find out with this fun and FREE way to tackle practice MCAT questions from Kaplan Test Prep. Register to receive one sample question a day for the next three months. You’ll get: • A new MCAT-style question each day to test your knowledge and skills • Complete explanations and expert strategies with every question • Compete against your friends to see who’s really ready for test day To get started go to: https://www.kaptest.com/mcat/mcat-practice/free-mcat-practice-question-a-day

A. If the threshold for hypertension (high blood pressure) were lowered, more individuals would fit the criteria for the disease. If the number of individuals with the disease increases and the population stays the same overall, there will be an increased prevalence of the disease.

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THE HIDDEN PUBLIC HEALTH CRISIS

A LOOK INTO HEALTHCARE IN MIGRANT DETENTION CENTERS

By

SOFIA URANGA WOOJIN CHOI

"Crisis" invokes images of widely broadcasted financial and political scandals. With news outlets constantly airing new socio-political turmoil, we often overlook public health concerns unless they are contagious and have documented incidences in the United States. However, one of the most pressing health concerns is happening in immigration detention centers and near the U.S-Mexico border.

At the Southern border, fear and a lack of resources and compassion have caused one of the gravest health crises in U.S history. On their journey to the United States, migrants often sustain life-threatening conditions and injuries with no means of treatment, even once they enter the country. In fact, some of the leading causes of non-violent death among migrants entering through the U.S-Mexico border have been heatstroke, dehydration, and hyperthermia.

However, in recent years, a larger public health crisis has arisen in detention centers due to a lack of proper healthcare and conditions necessary to treat migrants with infectious illnesses, such as the flu, mumps, and the chickenpox.

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And with the recent numbers of detained, unaccompanied minors reaching over 1,400, the lack of adequate health care is only becoming a more pressing issue. In the overcrowded detention centers, where adults and children lack resources for basic hygiene, disease easily spreads.

The effects of a lack of proper living conditions and overcrowding are best seen by the recent nationwide mumps outbreak in detention centers. In fact, despite the near eradication of the mumps in the United States, currently, several detention centers across the country are experiencing a mumps outbreak. The first five cases of the mumps in immigrant detention centers began in Texas and within mere months, multiple incidences of the mumps were recorded in dozens of facilities across the country. With migrants spending more time in detention centers and the rapid increase in overcrowding, the incidence of disease will only continue to rise.

In fact, according to Dr. Claire Bocchini, assistant professor of pediatrics (infectious disease) at Baylor College of Medicine, mumps spreads very easily in

groups of people who live right next to each other – a condition increasingly seen in detention centers nationwide. Moreover, response to disease outbreaks, such as mumps, often fails to resolve the problem. Incidences of the disease often go unchecked because of a lack of health services available, giving the illness more time to spread. Additionally, the practice of quarantine and isolation, even just in cases of exposure to infectious diseases, prolongs the detainees’ time in the facility and is detrimental to their mental health. In quarantine, individuals can’t have visitors and spend 25 days alone with little human contact. This isolation can lead to depression and anxiety. As more migrants are detained, the health crisis in detention facilities will only worsen.

The conditions in detention facilities and the health of detainees will only continue to deteriorate without policy intervention. Despite receiving millions of dollars in funds, detention centers continue to fail migrants in their facilities. And the plan of the current administration to expand detention and lower the

POLICY

healthcare budget for ICE facilities will further lead to illness and deaths among detained migrants.

However, multiple human and immigration rights groups have proposed policy plans to ensure migrants have access to adequate healthcare. According to the American Medical Association Journal of Ethics, "the United States government should restructure the detention system and reduce unnecessary detention."

Although no policy changes have been made to better healthcare for detained migrants, a class-action lawsuit has been filed against ICE and Trump administration officials in the U.S District Court for the Central District of California

for neglecting to address systemic failures.

Despite the lack of policy change, one of the most effective ways to make a difference in detention facilities is voting for legislators who understand the importance of providing detained migrants with accessible health services and sanitary living conditions.

"Border Crossers, and the Desert That Claims Them." USA Today. Gannett Satellite Information Network. Accessed February 20, 2020. https://www.usatoday.com/border-wall/ story/immigration-mexico-border-deathsorgan-pipe-cactus/608910001/.

Rebecca, Falconer. "ICE Sued for Failing to Provide Basic Health Care in Detention Centers."

Axios, August 20, 2019. https://www.axios. com/ice-detention-centers-health-care-lawsuitad8d94bb-af33-4ff8-9294-15251b461426.html.

Lyndon, Haviland. "Children at Southern Border Are Facing a Public Health Crisis." TheHill. The Hill, June 19, 2019. https://thehill.com/opinion/ immigration/448928-children-at-southernborder-are-facing-a-public-health-crisis.

Ryan Holeywell, George Cindy and Becker Alexandra. "Mumps Outbreak Causing Illness in U.S. Migrant Detention Facilities." TMC News, January 6, 2020. https://www.tmc.edu/ news/2019/09/mumps-outbreak-causingillness-in-u-s-migrant-detention-facilities/.

Ohta, Rie, and Clara Long. "How Should Health Professionals and Policy Makers Respond to Substandard Care of Detained Immigrants?" Journal of Ethics | American Medical Association. American Medical Association, January 1, 2019. https:// journalofethics.ama-assn.org/article/ how-should-health-professionals-and-policymakers-respond-substandard-care-detainedimmigrants/2019-01.

Elizabeth, Trovall. "Immigration Detention Facilities Can Be A Breeding Ground For Disease." NPR. NPR, September 23, 2019. https://www.npr.org/2019/09/23/763343004/ immigration-detention-facilities-can-be-abreeding-ground-for-disease.

Children Sitting in One of the Overcrowded Chain-Link Pens at a Facility in McAllen, TX. U.S. Customs and Border Protection's Rio Grande Valley Sector, n.d. Accessed February 21, 2020.

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THE NEXT FIX

THE DECRIMINALIZATION OF DRUGS IN PORTUAL 19 YEARS LATER

By

MEAGAN JOHNSON NATALIE CHOI

It’s the year 1980. Portugal is in the midst of their war on drugs. The drugs all came in at once, like a brutal wave. Lawyers, university students, socialites, blue collar workers – heroin and cocaine had reached every crack and crevice of Portugal. Some one in ten people roam the streets debasing themselves for their next fix – slowly facilitating the spread of HIV as used needles lay in the gutters and sidewalks.1 By the turn of the new millennium, Portugal is faced with a new crisis: opioids. Given the current opioid epidemic in the United States, Portugal’s solution to the drug crisis is both timely and valuable.

By July of 2001, Portugal had left behind its "Drugs are Satan" propaganda and introduced a national

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drug policy "which maintained the status of legality for using or possessing any drug for personal use with authorization, with an administrative offense if the amount possessed was more than a ten-day supply of a substance." This is a complicated phenomenon as boundaries between the "therapeutics" and politics of hard drugs become blurred. By destigmatizing the problem, Portugal hoped to reduce the prevalence of harm in heroin users. Statistically speaking, this policy reduced drug-related deaths to 3 per million – comparable to 10.2 per million in the Netherlands or 128.6 per million in Estonia. The number of people in drug treatment programs increased by nearly sixty percent.2 Cases of HIV went down from

POLICY

1,482 in 2000 to 40 drug users by 2014.1,2 The Portuguese government committed to tackling Hepatitis C by taking responsibility for one-hundred percent medical coverage of the disease.1,2 Currently, only five percent of persons living in Portugal aged 18-24 have reported using cannabis in the last month.2 As a bonus, "designer" drugs, often referred to as synthetics, cannot skirt the existing drug law by creating products with vastly dangerous side effects.

Technically, there may be flaws in data collection as differences in data collection have aggregated in the past eighteen years. The lack of concrete information makes it difficult to track the ramifications of "harder" drug usage over the course of several years, so it is best to look at Portugal in relation to the rest of the EU or United States. Without question, drugs will still exist and addictions will remain, but governments must address the underlying stressors that lead to usage.

Regarding the thousands of current drug users, Portugal’s drug policy is founded on three pillars of thought: "one, that there’s no such thing as a soft or hard drug, only healthy and unhealthy relationships with drugs; two, that an individual’s unhealthy relationship with drugs often conceals frayed relationships with loved ones, with the world around them, and with themselves; and three, that the eradication of all drugs is an impossible goal."2 This idea of a positively omnipresent government is completely unfamiliar to our modern nation. In spite of Portugal’s success, other countries have been hesitant to follow. This is again due to an end-all philosophy that results in absolute rejection of any alternative approach. The sum of all their efforts has been less than fruitful and turns a blind eye to the undeniable results of Portugal’s model. The disconnect lies in a government’s effort to make a profit off the addicted instead of directing their resources toward healing.

Some Portuguese politicians were critical of the newly-implemented policy, even going as far as believing Lisbon would become junkie nirvana or a drug Mecca for foreigners. People would get behind the wheel high, feral cats would roam the streets as the country turned into a slum, or people would wreak havoc in the street during a drug-induced high.

They argued that there appeared to be a push-andpull effect in the first few years after instituting the

policy: while drug seizures went up 500 percent, 63 percent of people did also check into rehabilitation centers.3 Personal drug use over an individual’s lifetime during this time was reported to have increased, by roughly 40 to 50 percent.3 This balancing report makes a case for Portugal having the same effects had they allocated a substantial budget for strong treatment and prevention programs. We must consider the most impactful humanist approach.

The question remains: Can Portugal’s experience lead to an incorporation of these ideas over to the United States? "In 2016 alone, an estimated 64,000 Americans died from opioid overdoses – more than the combined death tolls for Americans in Vietnam, Afghanistan, and Iraq Wars," according to a Time magazine report.1 The average cost to attend a rehabilitation center in the U.S. stands around $25,000 a month. Methadone treatment clinics are few and far between. Realistically, the United States has taken a laissez-faire attitude. Though it is not said, the drug trade fuels the U.S.’s economy. Although America has recently expanded the decriminalization of marijuana in certain states, it remains illegal by federal law. The United States would benefit from examining Portugal’s model more closely and determine what this approach implies about our national identity.

Perhaps it is an acknowledgement of a nation’s failures, nevertheless, a conversation about the potential determinants of complete decriminalization is worth investigating. The foundation to a discussion about drug legislation should question: Does dignity trump criminality?

Ferreira, Susana. "Portugal's Radical Drugs Policy Is Working. Why Hasn't the World Copied It?" The Guardian, Guardian News and Media, 5 Dec. 2017, www.theguardian.com/news/2017/dec/05/portugals-radical-drugs-policyis-working-why-hasnt-the-world-copied-it.

"Mixed Results For Portugal's Great Drug Experiment." NPR, NPR, 20 Jan. 2011, www.npr.org/2011/01/20/133086356/Mixed-Results-For-PortugalsGreat-Drug-Experiment.

"Cost of Rehab: Paying for Addiction Treatment - Addiction Center."

AddictionCenter, 7 Dec. 2018, www.addictioncenter.com/rehab-questions/ cost-of-drug-and-alcohol-treatment/.

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FIRST DRUG MADE

BY AI TESTED IN HUMAN TRIALS By

MELODY LEUNG EJ BECK

The first drug invented entirely by artificial intelligence (AI) is entering phase I clinical trials in March, a key milestone for machine learning in drug discovery. The compound, designed to treat patients with obsessive-compulsive disorder (OCD), was developed by U.K.-based AI startup Exscientia in partnership with the Japanese pharmaceutical company Sumitomo Dainippon Pharma. As opposed to conventional drug development techniques which require around four and a half years, the AI-designed drug completed its research exploratory phase in less than 12 months.

Developing new medications is no small feat. It takes many years of labor-intensive research and testing, with even more time devoted to testing its efficacy. Chemists estimate that there are 1060 possible compounds with drug-like characteristics – more than the number of atoms in the Solar System.

Therefore, finding potential molecules best suited for a target disease is extremely complex and challenging.

Moreover, early-stage drug discovery largely remains a trial-and-error process guided by researchers, and successful findings of a molecule viable in lab settings may not prove successful in patient populations.

The confluence of these factors has led to the FDA approving less than 40 new drugs per year, with only around 22 intended for public use.

Many decisions are required when finding the right molecules to target a disease. Exscientia’s AI Centaur Chemist uses a host of algorithms to narrow down which chemicals to synthesize and test by learning complex drug design rules from chemists. The

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algorithms sift through tens of millions of potential molecules and catalog, characterize, and compare their properties in computer models and simulations (in silico). Instead of using traditional statistical methods such as linear regression, through machine learning algorithms, AI can recognize complex patterns that are difficult to model using traditional methods and create its own logic. The computer algorithms emulate human cognition by representing data through a vast network of interconnected neurons similar to the human brain, with different weights assigned to each piece of evidence to reach a conclusion. In this fashion, AI can learn a lot faster and process more data than conventional approaches.

The AI's selection process resulted in discovering 350 compounds needing to be made and tested, less than a fifth of the typical 2500 candidates.

This unprecedented productivity in selecting the best drug candidates has the potential to save vast amounts of time and money. In one study, Insilico Medicine, an AI-directed molecule screening platform from a startup, was compared with the past work of human researchers seeking fibrosis treatment options. While it took the researchers eight years to put forward viable candidates for trials, it only took the AI 21 days. Although further refinements with the algorithm were required to achieve a comparable quality in the drug candidate, this finding demonstrates the overwhelming efficiency and potency of AI. Exscientia estimates that their algorithms could reduce the cost of the drug discovery process by 30% from the current average of $2.7 billion, according to

RESEARCH

figures from the Food and Drug Administration.

Furthermore, AI could make drugs safer, increase the success rate of drugs in clinical trials, and lead to the discoveries in areas of therapeutics that were previously unexplored or assumed to be barren. Many adverse side effects or toxicity issues become apparent only after clinical trials, at a point where many patients may have already been exposed. AI systems can process and analyze vast sets of data about known compounds to generate predictions and create models to simulate how a new molecule may behave or interact in different chemical and physical environments.

These models could help us better understand how a new drug might affect different parts of the body.

Additionally, for each drug in the market, there are millions of compounds that are nearly chemically identical to it, with distinctions as subtle as an extra hydrogen or double bond. Some of these variations could work better than the approved drug, but are not conceived by chemists. AI could comb through all of these therapeutically promising isomers to search for compelling candidates for further exploration. Similar to the periodic table, these compounds are grouped with neighboring compounds that have related properties, but in multidimensional space. Positions are assigned according to a plethora of characteristics, such as the number of carbon atoms the compound has.

The key to algorithms is that they are agnostic and can be applied to any drug targets. Considering this fact and the heightened efficiency in the drug development cycle, drugs designed by Exscientia’s AI could be the start of a revolution in the way we develop new treatments for diseases.

Dovey, Dana. "For The First Time Ever, A Drug Developed By AI Will Be Tested In Human Trials." Forbes. Forbes Magazine, February 11, 2020. https://www.forbes.com/sites/danadovey/2020/02/11/first-time-everartificial-intelligence-develops-drug-candidate/#458926d160de.

Mullard, Asher. "The Drug-Makers Guide to the Galaxy." Nature 549, no. 7673 (2017): 445–47. https://doi.org/10.1038/549445a.

Murgia, Madhumita. "AI-Designed Drug to Enter Human Clinical Trial for First Time." Financial Times. Financial Times, January 30, 2020. https:// www.ft.com/content/fe55190e-42bf-11ea-a43a-c4b328d9061c.

Times, Eric Hamilton Tech. "Recent AI Developments Offer a Glimpse of the Future of Drug Discovery." Tech Times, February 12, 2020. https://www. techtimes.com/articles/247302/20200212/recent-ai-developments-offerglimpse-future-drug-discovery.htm.

Wakefield, Jane. "Artificial Intelligence-Created Medicine to Be Used on Humans for First Time." BBC News. BBC, January 30, 2020. https://www. bbc.com/news/technology-51315462.

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THE LINK BETWEEN GUT BACTERIA AND OBESITY By

MILES KAUFMAN JEAN KIM

In the United States, where calories are readily available, the evolutionary mechanisms intended to avoid starvation have somewhat backfired. With the expansion of fast food options and sedentary lifestyles, there have been a higher instances of obesity-related health problems like heart attacks and diabetes across the country1. Interestingly, obesity is one of the only diseases in which the microbiome of the gut is directly associated with the pathology3. Inside our large intestines sit trillions of bacteria including E. coli and E. faecium that serve important symbiotic roles in our biological systems. Our gut bacteria don’t just sit in our intestines and break down molecules like fiber. They also cause cravings and influence how fat is stored and broken down.

Over the past decade, many scientists have been working hard to discover how exactly our microbiomes influence our diets and susceptibility to weight gain.

One key role our gut microbiome plays in our digestive system is processing dietary polysaccharides, commonly known as starch.

In one study conducted by Dr.

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Fredrik Bäckhed, Swedish expert in microbiology and mouse physiology, investigated gut microbiota influence on fat deposition and storage4. The experiment consisted of two distinct mice colonies, the first of which was kept in a sterile, bacteria-free environment for eight weeks, while the second colony was fed the same diet in a non-sterile environment. After eight weeks, the mice belonging to the non-sterile environment with normal microbiome growth experienced a 42% increase in body fat, and their fat pads were 47% larger than the sterile mice. When the sterile mice were given microbes from the other group of mice, they had a 57% increase in body fat.

This increase was seen even when the mice were given less food.

Therefore, the study concluded that the presence of a gut microbiome was directly related to fat storage in mice, leading scientists to believe that bacteria are needed for proper fat storage even in humans4.

Although the microbiome plays a major role in weight gain and weight loss, there are also genetic markers attributed to obesity. In

an experiment by Ussar et al., mice that were either obesity prone or obesity-resistant were studied for possible connections between microbiome and metabolism.

When the researchers fed their mice with high-fiber diet, they showed weight gain, insulin resistance, and hyperglycemia. Even mice that were genetically resistant to obesity developed some of these symptoms5.

When looking at the gut microbiota of the experimental mice, Ussar et al. found correlations between prevalence of certain bacteria species and weight gain.

For example, mice with more M. schaedleri were on average leaner, and mice with more A. muciniphila experienced metabolic benefits including weight loss, reduced inflammation, and higher glucose tolerance. While obesity-resistant mice were healthier even with obesity-prone microbiomes, their genetics didn’t protect them from the medical and microbial side effects of an unhealthy diet. Dr. Ussar’s study concluded that while genetic factors can counteract an obesity-prone microbiome to an extent, having the wrong type of

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gut bacteria can still contribute to an onset of obesity and a host of other health issues5.

The bacteria in the human gut can be sorted into two categories— Vacteriodetes and Fermicutes.

In Ley et al., the proportion of Bacteriodes to Fermicutes was lower in obese subjects than in lean subjects. The researchers also found that by taking microorganisms from one mouse and placing them in the gut of another, they could cause the second mouse to gain body fat without altering its diet at all3. This was a groundbreaking discovery as it provided solid evidence for the idea that proportional abnormalities in the gut microbiome were not only linked to obesity but could be altered to treat the disease.

After that discovery, Dr. Ley began an experiment with 12 obese human subjects. Half of the subjects were assigned a low-carb diet, and the other half were assigned to a low-fat diet. Before the experiment began, the obese subjects had more Firmicutes and fewer Bacteriodetes than the control group. After a few weeks, the amount of Firmicutes began to

decrease and the amount of Bacteriodetes began to increase with both diets. There was no change in the diversity of the subject’s microbiomes, but the proportions of these bacteria types changed significantly. The loss of body weight seemed to affect the bacterial proportions while the type of diet did not3. Despite Ley’s low sample size of twelve, the results he saw were astounding, and further confirmed that changing the gut microbiome could be an effective treatment for obesity.

Although obesity is most commonly caused by an unhealthy diet, the role microbiota play in this disease is glaring. There have been many clinical trials recently that involve giving probiotics to both animal and human subjects with the hope that they will aid weight loss. These studies have been effective in improving gut integrity and shifting microbial populations in animals, but in humans the results have been inconsistent6. Studies involving human subjects are much more complex, because their behavior can’t be controlled in a lab environment, and a change in diet

can be difficult. Nevertheless, the results seen in these studies are quite promising. As scientists continue to discover more about microbes, we can hope to gain more insight into how obesity can be treated with a safe and efficient method.

Overweight & Obesity Statistics. (2017, August).

Retrieved February 6, 2019, from National Institute of Diabetes and Digestive and Kidney Diseases website: https://www.niddk.nih. gov/health-information/health-statistics/ overweight-obesity Broadfoot, M. V. (2016, February). Rise of the Microbiome. Discovery's Edge. Retrieved from https://discoverysedge.mayo.edu/2016/01/08/ rise-of-the-microbiome/ Ley, R. E., Turnbaugh, P. J., Klein, S., & Gordon, J. I. (2006). Microbial ecology: Human gut microbes associated with obesity. Nature, 444, 1022-1023. Retrieved from https:// www. nature.com/articles/4441022a Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004; 101(44):15718-23.

Ussar S, Griffin NW, Bezy O, et al. Interactions between Gut Microbiota, Host Genetics and Diet Modulate the Predisposition to Obesity and Metabolic Syndrome. Cell Metab.

2015;22(3):516-530.

Mazloom, K., Siddiqui, I., & Covasa, M. (2019).

Probiotics: How Effective Are They in the Fight against Obesity? Nutrients. Retrieved from https://www.mdpi.com/2072-6643/11/2/258

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BACTERIA AND VIRUSES AND FUNGI, OH MY!

THE GUT MICROBIOME

By

LINDSAY ROMANO ALLISON GENTRY

What is the gut microbiome?

Did you know that the number of microbial cells on your body is 10 times the amount of cells you have? With over 5,000 different species, the human microbiome has become a topic of significant interest in recent years. It is becoming increasingly apparent that the tiny microorganisms living in and on humans play a big part in many processes. These microorganisms, or microbes, include fungi, viruses, and bacteria. Many different species of these taxa exist together in various locations around the body. They participate in a symbiotic relationship with the individual, meaning that there are mutual benefits for both parties. Like fingerprints, each person’s microbiome is unique, there is a particular set of species present that will complement each other while also fitting the needs of the host. If they do not, they will be overrun by species that are better suited for the individual.

In the womb, we have little to no microbiome, and once babies are

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born through natural birth, they are first colonized by the microbiota of their mother. The newly established population of microbes will continue to grow and diversify based on the diet, genetic disposition, and environmental factors as they age.

There are many different microbiomes that exist all over the body including your skin, mouth, and gut. All of these are important and function to keep us healthy and aid in routine body processes. The gut microbiome is particularly interesting because it is strongly influenced by the diet. An individual’s diet determines what microorganisms are introduced into the body and determines what kind of nutrition is provided to them. This helps shape the microbiome by helping certain species flourish while others may not be as successful.

The different types of microorganisms that live in the gut make up the majority of the microbiome.

Bacteria are introduced through food but specifically probiotics, which contain live cultures of

bacteria, colonize the gut. Fungi take up only a small percentage of the microbiome but are still important for the biodiversity and effectiveness of gut health. They are usually consumed and then colonize the stomach and intestine area. Viruses are different because they require a host for survival, so they live within the bacterial populations. The viruses in the gut are different than the harmful infectious viruses that we are more familiar with. The gut contains more stable populations of viruses that reside in their host bacteria in a symbiotic relationship. This kind of relationship also exists between other microbes and with the cells of the individual to maintain a fruitful environment.

How are these

microorganisms helpful?

The microbes in your gut are an essential part of your digestive system, aiding in the breakdown of food during routine digestion.

They live off of consumed food as it travels through the digestive

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Esson, Alex. "Ohio State Scientists Explain How Gut Microbes Change after Spinal Cord Injury." Front Line Genomics, October 26, 2016. http://www.frontlinegenomics.com/ press-release/7983/gut-microbes-changespinal-cord-injury/.

system, specifically in the stomach and intestines. The microbes break down things like fiber through fermentation to synthesize shortchain fatty acids. This process is beneficial to the individual because these microbes contain enzymes not found in human somatic cells that are capable of digesting soluble fibers. The production of fatty acids helps support digestion by lowering pH, creating a more acidic environment. This process helps further the breakdown and absorption of other food products in the digestive tract. These molecules are also involved in maintaining energy homeostasis and encouraging the growth of other bacteria.

The gut microbiome is also important for disease prevention.

Diversity within these microorganisms is very important because it makes the gut more robust against harmful bacteria and viruses that might be consumed. There have been many studies showing that having a lack of certain

gut microbes is associated with diseases like inflammatory bowel disease, diabetes, and obesity.

This is due to the fact that many products released by the bacteria and fungi have effects on hormone regulation, glucose regulation, and inflammation. These are all important factors in maintaining homeostasis, so dysregulation can increase the susceptibility of an individual to diseases based on poor food choices.

How do superfoods

help maintain gut health?

Some popular items praised for improving microbiome health include kombucha, yogurt, and whole grains. These foods work in different ways to improve the health of your gut. For example, kombucha is a fermented drink that consists of a mixture of tea, sugar, yeast, and bacteria. The yeast and bacteria create a symbiotic colony that ferment the drink by metabolizing the sugar and

creating a byproduct of alcohol, acid, and gas. This process is what makes the drink iconic fizz and vinegary taste. Kombucha does contain probiotics which can help improve gut health, but there is still research being done to determine if it has any effects on overall health. Other popular food items known for promoting digestive health include yogurt and kefir.

Both of these are dairy products that contain bacteria that ferment sugars, however, not all yogurts have probiotic bacteria that are beneficial for helping your gut.

Only certain strains of bacteria are beneficial for gut health, and others will be unable to cooperate with the gut and will be digested.

So, when looking for a yogurt to help replenish your gut bacteria make sure to check that it is marked as probiotic. Whole grains are important because they are prebiotics that gut microbes need to consume to flourish. Prebiotics are generally carbohydrates such as fiber and oligosaccharides, which

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are composed of simple sugars bonded together. Whole grains are beneficial because they have higher levels of fiber than refined grains. Fiber is a food source for the bacteria and fungi that reside in the gut, but it is important not to ingest an overabundance of these foods since it could lead to a reduction in microbial diversity.

This would occur when certain species overpower others that may not depend on fiber as much.

Although all of these foods products are good ways to help improve your gut microbiome, moderation is important to keep balance and diversity.

With the increasing interest in how the gut microbiome works with the body to help keep us healthy, there is new research being conducted all the time. There are more novel studies looking into fungi population, as most research has focused on the bacterial populations. It has already been found that fungi populations vary significantly between individuals and scientists are working to determine why that might be. In general, it seems the message is clear – make sure to keep moderation in your diet and don’t forget about all of those microorganisms that work every day to sustaining your health.

Bilodeau, Kelly. "Fermented Foods for Better Gut Health." Harvard Health Blog, May 16, 2018. https://www.health.harvard. edu/blog/fermented-foods-for-better-guthealth-2018051613841.

Clemente, Jose C, Luke K Ursell, Laura Wegener Parfrey, and Rob Knight. "The Impact of the Gut Microbiota on Human Health: an Integrative View." Cell. U.S. National Library of Medicine, March 16, 2012. https://www.ncbi. nlm.nih.gov/pmc/articles/PMC5050011/.

Ferranti, Erin P, Sandra B Dunbar, Anne L Dunlop, and Elizabeth J Corwin. "20 Things You Didn't Know about the Human Gut Microbiome."

The Journal of cardiovascular nursing. U.S. National Library of Medicine, November 1, 2015. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC4191858/.

Forbes, Jessica D, Charles N Bernstein, Helen Tremlett, Gary Van Domselaar, and Natalie C Knox. "A Fungal World: Could the Gut Mycobiome Be Involved in Neurological Disease?" Frontiers in microbiology. Frontiers Media S.A., January 9, 2019. https://www.ncbi. nlm.nih.gov/pmc/articles/PMC6333682/.

Harvard Health Publishing. "Can Gut Bacteria Improve Your Health?" Harvard Health Publishing, October 2016. https://www.health. harvard.edu/staying-healthy/can-gut-bacteriaimprove-your-health.

Maxmen, Amy. "The Gut's 'Friendly' Viruses Revealed." Nature News. Nature Publishing Group, July 14, 2010. https://www.nature.com/ news/2010/100714/full/news.2010.353.html.

Valdes, Ana M, Jens Walter, Eran Segal, and Tim D Spector. "Role of the Gut Microbiota in Nutrition and Health." The BMJ. British Medical Journal Publishing Group, June 13, 2018. https://www.bmj.com/content/361/bmj. k2179.

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THE RESEARCH POTENTIAL IN TRADITIONAL MEDICINE

By SANJANA RAO ABHIJIT RAMAPRASAD According to a 2004 press release by the World Health Organization (WHO), nearly 80% of the populations of developing countries rely on traditional or alternative medicine for their medical needs. Traditional medicine, as defined by the WHO, refers to “the sum total of the knowledge, skill, and practices based on the theories, beliefs, and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health as well as in the prevention, diagnosis, improvement or treatment of physical and mental illness�.

Thus, when this article refers to traditional medicine, it is referring to the WHO definition, examples of which include Sowa Rigpa, Ayurveda, and Unani, while more modern, non-allopathic treatments are termed as alternative, or complimentary therapies. Most traditional medicine relies on therapies derived from trial-and-error over hundreds of years and on herbal/natural agents. As these agents have been used over centuries by these communities, they present an untapped trove of research potential for use in modern medicine.

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Research Potential

Haldi (or turmeric) has been traditionally used by communities in India to treat everything from digestive disorders to respiratory conditions to skin cancer. The active ingredients in turmeric (curcuminoids) have been shown to exhibit anti-inflammatory abilities and are well documented anti-oxidants. The anti-microbial properties of turmeric have also been documented thoroughly, with in vitro studies demonstrating varying levels of inhibition in multiple varieties of bacteria and fungi when treated with turmeric extracts. Due to these properties and its use in traditional medicine, extensive research is being conducted into curcumin derived drugs and their potential use in conjunction with chemotherapy to increase remission rates of certain cancers.

Traditional medicine often makes extensive use of venoms and toxins. Since the period of Ancient Egypt, hirudotherapy or leech therapy has been used to treat a slew of disorders from hypertension to varicose veins.

According to a study by the Vascular Disease Foundation, every five minutes a person dies due to a blood clot. Leech venom contains blood thinners, which can be used to stave off thrombosis. In 2000, FDA approval was granted for an anticoagulant drug derived from leeches, for use during surgery.

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Other drugs derived from venom include Tirofiban and Integrilin, which are made from compounds isolated from the venom of the saw-scaled viper and the dusky pygmy rattlesnake respectively.

These drugs work by inhibiting the same receptor preventing the formation of blood clots.

Obstacles to the Spread of Traditional Medicine

If traditional medicine has such beneficial potential, why isn’t it more widespread and recognized by modern medicine? There are multiple obstacles to mass production/use of traditional therapies, including the difficulty of regulating quality, conducting clinical trials, and the risk of drug interactions. As traditional medicine often favors a "holistic view" of the affliction, and tailors the treatment to a particular individual based on his/her lifestyle and medical history, it becomes nearly impossible to properly conduct a randomized, double blind trial.

Although the difficulty associated with performing randomized trials presents a large barrier, there are still potential avenues of research into establishing a basis for these traditional practices. This research is usually directed toward extracting the active ingredient (the compound responsible for the desired effect) from herbal remedies (e.g. curcumin from turmeric) and then conducting in vivo and in vitro experiments using just the active ingredient. Other forms of research delve into the field of complementary therapy, wherein traditional medicinal practices are combined with modern therapy in order to minimize side effects (e.g., combining massage and radiation

therapy), or to increase the effectiveness of the therapy (e.g., using herbal products and chemotherapy in conjunction). Moreover, there is a large grey area regarding what constitutes a 'supplement', and the quality regulation of supplements across countries.

The Ecological Aspect

The use of animal parts and secretions presents many ecological problems. Pangolins are the most trafficked animal, for their large keratin scales. These scales are believed to have medicinal properties and are used in traditional medicines all over the world. As with the use of pangolin scales (and the corresponding near extinction of pangolins), tiger phalluses are consumed in China to ward off impotence and increase fertility. Resources are finite, and traditional medicines can permanently damage populations of endemic species. Similarly, tiger bones are sold in China due to their perceived health benefits, although scientifically, none have been proven. Many species whose parts are used in traditional medicine are now classified as critically endangered due to overexploitation. Furthermore, if these endemic species are bred in countries where they are not native, they may become invasive, and destroy the native species in that area. The same is true of diseases and bacteria which can wreak havoc on the native species that do not have immunity to them.

Health Policy

Although the World Health Organization regulates these medicines worldwide, many countries (especially those with large

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Global use of herbal traditional medicine.

traditional/alternative medical systems) have their own legislation regarding these issues. These range from countries with minimal regulation (as in the case of New Zealand) to those with entire ministries dedicated to the proper regulation of traditional and alternative medicines (as in the case of India). There are many factors that must be taken into account when crafting health policy. For many communities, their medical practices have formed an integral part of their history and identity, and as they often utilize herbs and other resources from their indigenous land. However, if these drugs are to be mass produced, an ecological problem is presented as well. Furthermore, the question of property — both intellectual as well as in terms of resources — is brought into focus. For instance, Captopril is a drug used to control blood pressure and was derived from the venom of a Brazilian viper (the arrowhead viper).

However, the tribes who first used this venom weren't given a penny; their traditional knowledge were packaged for the masses without compensation, in one instance of biopiracy. On the other hand, in the Kalahari Desert, the South

African government worked hand in hand with the San tribe to develop dietary supplements based on hoodia, a cactus well-known to the San for its appetite-suppressant qualities.

Snake Oil

Over the course of this article, the words "snake oil" may have come to mind. The phrase "snake oil" now refers to fraudulent drugs with no medicinal value used to mislead. However, true "snake oil," or the fat content of the Chinese water snake, has anti-inflammatory properties which justify its use to treat arthritis in traditional Chinese medicine, and contains omega-3-fatty acids, and 20% eicosapentaenoic acid (EPA), both of which are easily used by the human body. The modern connotation arises from the passage to the Western hemisphere. Due to the rarity of Chinese water snakes in the USA, your average 19th century peddler was most likely not selling traditional snake oil.

Instead, it was either a mixture of mineral oils and herbs, with no snake component or medicinal properties, or rattlesnake oil, which contains a third of the fatty acid content of traditional snake

oil. Thus, "snake oil" became associated with falsehoods, rather than its origins as a genuine product.

Prasad S, Aggarwal BB. Turmeric, the Golden Spice: From Traditional Medicine to Modern Medicine. In: Benzie IFF, Wachtel-Galor S, editors. Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2011. Chapter 13.

Available from: https://www.ncbi.nlm.nih.gov/ books/NBK92752/ Mason, Su, Philip Tovey, and Andrew F Long.

"Evaluating Complementary Medicine: Methodological Challenges of Randomised Controlled Trials." BMJ: British Medical Journal 325.7368 (2002): 832–834.

Zhang Q. Traditional and Complementary Medicine in Primary Health Care. In: Medcalf A, Bhattacharya S, Momen H, et al., editors.

Health For All: The Journey of Universal Health Coverage. Hyderabad (IN): Orient Blackswan; 2015. Chapter 12. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK316267/ "National Policy On Traditional Medicine And Regulation Of Herbal Medicines - Report Of A WHO Global Survey: 2. National Policy On Traditional Medicine And Complementary/ Alternative Medicine: 2.1 National Policy On TM/CAM". Apps.Who.Int, 2005, http://apps. who.int/medicinedocs/en/d/Js7916e/6.html.

Accessed 28 Oct 2018.

Vascular Disease Foundation. "Every five minutes someone dies from a blood clot or deep vein thrombosis." ScienceDaily. ScienceDaily, 5 March 2011. www.sciencedaily.com/ releases/2011/03/110305105233.htm.

Clinical Significance of Leech Therapy in Indian Medicine - Kumar, Syal : Journal of Evidence-Based Integrative Medicine doi:10.1177/2156587212466675 Venomous: How Earth’s Deadliest Creatures Mastered Biochemistry. By Christie Wilcox.

New York: Scientific American/Farrar, Straus and Giroux. ISBN: 978-0-374-28337-7 (hc); 978-0-374-71221-1 (eb). 2016.

Frank, Kurtis et al. "Curcumin Research Analysis".

Examine.Com, 2020, https://examine.com/ supplements/curcumin/.

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CONNECTOMICS

THE FUTURE OF PERSONALIZED MEDICINE

By

SHAYNA COHEN YIFAN MAO

“Human Connectome Project marks its first phase,” National Institutes of Health, June 8, 2016. https://www.nih.gov/news-events/news-releases/human-connectome-project-marks-its-first-phase

In 1990, the U.S. Federal Government embarked on a billion-dollar journey to do what was once thought impossible: sequence the human genome.

With the ambitious goal of identifying genetic variants involved in diseases like cancer and diabetes, researchers quickly began their work on the project, sequencing

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small portions of anonymous donors’ genomes. Eventually, the project was completed in 2003, with a reference genome established based on those anonymous donors. This served as a springboard for future work in genomics.

Through the Human Genome Project (HGP), scientists now have the ability to identify genetic

variants consistent with certain diseases for only $1,000 instead of billions. As research continues and questions of the origins of disease become more complex, an interesting question arises: what if, along with mapping the human genome, we are also able to map the connections in the human brain?

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Scientists like Dr. Bobby Kasthuri at the University of Chicago focus their work around that very question, working in a field known as connectomics. Connectomics, previously known as hodology, is the study of connectomes, which are comprehensive maps of the connections in an organism’s nervous system. With roughly 100 billion neurons in the human brain and an estimated 1 quadrillion connections between them, this is certainly no easy feat. Nevertheless, there are techniques currently in use. Macroscopically, diffusion MRIs can be used to show fiber crossings in regions like the optic chiasm or the caudate nucleus, which neighbors the internal capsule, a white matter tract with many myelinated axons that are important for signaling. Another more widely used technique, and particularly important to Dr. Kasthuri’s research, is electron microscopy. By slicing extremely thin segments of the brain and using fluorescent or molecular markers to identify different neurons, a map of connections in a specific brain region or the retina can be mapped. A world where an individual’s neuronal connections could be mapped for $1,000 may still be rather far into the future, but the field of connectomics surely leads an interesting inquiry into how our brains are connected and function.

Despite the rapid expansion of initiatives like connectomics and the Human Genome Project, they are rarely without controversy. For the HGP, many critics center their arguments around privacy and the possible perpetuation of stereotypes based on ethnicity, which

helped pave the way for HIPAA to be created in 1996. These same questions are also prevalent in connectomics. On the issue of privacy, there are implications about the brain and the mind. If an individual’s connectome could be coded into a computer, is that computer sentient in the same way the individual is? Would the individual and the computer have the same consciousness? Additionally, the possibility of mapping brains of individuals of different races, religions, genders, sexual orientations, etc. could unintentionally aid discourse promoting physiological distinctions between demographics. These questions remain concerns of the distant future, but the implications of this research and possible regulations they may bring about should be discussed as an intrinsic part of connectomics as a field.

Regardless of the ethical quandaries, there are undeniably practical uses to connectomics that would greatly benefit healthcare as a whole, similar to the HGP. Through comparing connectomes of healthy patients to connectomes of patients with various conditions and neuropathies, scientists could gain insight into synaptic origins of neuropathic pain and possible treatments. While this would require a great deal of standardization related to how connectomes are developed, the principle of comparing connectomes seems to be a rather fundamental aspect of any clinical applications. Additionally, as precision medicine becomes increasingly more popular, the ability to affordably map a person’s neuronal connections could greatly individualize patient

care, just as we have seen with the HGP in providing therapies to treat some cancers and rare childhood disorders. The exact future of clinical use of connectomics is unwritten, but some potential benefits lie clearly within view.

Though the Human Genome Project required billions of dollars and a large team of scientists, along with facing a fair amount of criticism, the applications at both the lab bench and the patient bedside are progressively manifesting themselves as research fields advance. Connectomics may be new and comparatively more unheard of, but it seems likely that continued investment in the field can only benefit the biomedical field as a whole. There may be a difficult road to navigate ahead, with questions of regulations, standardization, and ethical implications, but connectomics has potential to promote further insights into the workings of the human brain and most importantly, to help many people living with neurological conditions.

James R. Anderson, "Exploring the retinal connectome," Molecular Vision 17 (2011): 355-379. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC3036568/ "About the Human Genome Project," Human Genome Project Information, July 18, 2011. https://web.archive.org/web/20110902062606/ http://www.ornl.gov/sci/techresources/ Human_Genome/project/about.shtml V.J. Weeden, "Diffusion spectrum magnetic resonance imaging (DSI) tractography of crossing fibers," NeuroImage 41, 4 (2008): 1267-1277. https://www. sciencedirect.com/science/article/pii/ S105381190800253X?via%3Dihub

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THE POWER WITHIN

FIGHTING CANCER WITH ADOPTIVE CELL THERAPY

By

XIYA WU SWATHI BALAJI

In 2012, a clinical trial made headlines throughout the nation as 7-year-old Emily Whitehead became the first pediatric patient to undergo T-cell therapy.

For Emily, CAR T-cell therapy was a last resort, after chemotherapy had twice resulted in relapse. The weeks following the reintroduction of the engineered T-cells into her veins were difficult. She developed a high-grade fever and her blood pressure dropped dangerously in what we now know are the effects of an inflammatory response known as cytokine release syndrome (CRS)3. Ultimately, the treatment was a success, paving the way for T-cell therapy to be recognized as one of the most promising fields in the future of cancer treatment.

In the last decade, adoptive cell therapy (ACT) has taken the world of cancer treatment research by storm. A type of ACT, CAR T-cell therapy has made remarkable strides from its use in small clinical trials

Emily Whitehead and her mother Kari Whitehead.

Taken by Jeff Swensen for the New York Times4.

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to its use in the United States as the first type of gene-based therapy approved by the Food and Drug Administration (FDA)1.

At the core of ACT is the idea of harnessing the patient’s own immune system to fight against cancer.

For the standard cold or flu, the immune cells in our bodies are usually able to mount a highly effective response, and the accompanying symptoms are only temporarily uncomfortable. More impressively, the immune system has memory of the diseases it has encountered before. If the same virus comes knocking again, the secondary response from the immune system is both faster and stronger because the accumulated memory cells "remember" the antigens in question. Recognition of outsiders is crucial to the immune system's function. To prevent our immune system from turning on the body, immune cells must be able to distinguish "self " from "non-self." Failure to do so is what results in autoimmune diseases, where the immune system launches an immune response against its own antigens.

Cancer, however, hinges on the opposite problem. Because cancer cells are the descendants of our normal cells, they can evade the immune system by disguising themselves as "self " despite their existence being harmful to the body. They are wolves in sheep's clothing. T-cell therapy, then, involves the shearing away of this disguise. Researchers generate CAR T-cells by genetically engineering the patient’s T-cells to produce chimeric antigen receptors (CARs) on the cell surfaces1. Like the Greek Chimera that existed as a hybrid of animal forms, these receptors are a fusion of different components decided by the researcher.

The modified cells are then reintroduced into the patient and allowed to proliferate, truly earning them

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T-cell activation or immune cell lysis as the result of T-cell therapy induces release of various cytokines. These cytokines activate other immune cells, leading to greater cytokine release and a positive feedback loop that results in a "cytokine storm." Graphic by Shimabukuro-Vornhagen et al (2018)12.

the moniker of a "living drug." The presence of CARs gives the T-cells new vision, allowing them to recognize common antigens present on cancer cells. The cancer cell's disguise is stripped away, and the T-cells now see the wolf for what it is2.

Nevertheless, with every new treatment comes new side effects and downsides that need to be overcome with more research. Around the same time that Emily was declared to be in remission, another child, Poppy*, was treated with the new therapy.

Poppy improved similarly for a period of time before her cancer relapsed and no longer responded to the same treatment. The cause? Her leukemia cells had returned with new antigens, made once again invisible to the CAR T-cells engineered to look for different markers4. Finding solutions to this "antigen escape,"

along with mitigating the effects of CRS that many patients who undergo T-cell therapy experience, are one of the primary goals of new research in this field.

In recent years, T-cell therapy has evolved beyond the comparatively simple constructions of before, now including new lines such as bispecific T-cell engagers (BiTEs), and engager T-cells, and dual CAR T-cells.

Too Much of a Good Thing: Cytokine Release Syndrome

As described in Emily's case, a common side effect of T-cell therapy is cytokine release syndrome (CRS). As the name suggests, CRS involves the release of cytokines in the body. Under normal conditions, these cytokines are critical for effective functioning of the immune system. They are responsible for modulating

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the activation, proliferation and differentiation of various cell types and regulating antibody production.

When functioning as expected, cytokines can control the intensity and length of the immune response5.

However, CRS occurs when immune cells release quantities of inflammatory cytokines many times, sometimes thousands of times higher than expected.

This is when problems arise. The various cytokines flood the body and can even prompt other immune cells to produce additional cytokines in what is known as a positive feedback loop, a vicious cycle of immune cell activation and cytokine release that culminates in a "cytokine storm." Clinically, CRS presents as a range of symptoms, including anything from mild, flu-like symptoms to severe symptoms such as hypotension, high fever and eventually multiple organ failure. Children in particular are at a higher risk of developing CRS, hypothesized to be the result of their more immature immune systems6.

CRS can be deadly. In Emily’s case, were it not for immediate and fortunate interventions taken to treat the syndrome, the happy story may very well have taken a different turn. At the same time, Emily didn’t have very many good options left; CAR T-cell therapy had been the last resort. However, the problem with CAR T-cells is that it is administered in a single dose and it is hard to predict how much the cells expand once inside the body6. There would be no way to stop the treatment midway if, for example, the effects of CRS became too severe. It's all or nothing.

Thus, researchers turned their attention to ways to address this problem. How do we make T-cell therapy safer for patients? In one clever treatment alternative, CAR T-cells are discarded in favor of smaller, injectable proteins called bispecific T-cell engagers (BiTEs).

These BiTEs consist of two single-chain variable fragments connected by a short linker, and their name, much like many other inventions in this field, is highly suggestive of their function. Since BiTEs are proteins, not cells themselves, they work by directing T-cells already present within the patient's body to

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kill tumor cells. These resident T-cells are normally, as discussed, oblivious to the tumor threat. BiTEs force the T-cells to pay attention by binding to both tumor cells and T-cells simultaneously. One of the fragments in its structure is specific to a tumor antigen and the other specific to a cell-surface molecule on the T-cells.

Once both cell types have been lassoed, BiTEs mediate T-cell responses and the killing of the tumor cell7.

Unlike CAR T-cells, BiTEs can be given in multiple doses, so treatment can be interrupted if necessary, such as if a patient experiences severe CRS. Despite this safety benefit, BiTEs unfortunately have a very short half-life and are unable to proliferate in the body. Since one of the biggest draws of ACT is that they involve living drugs, BiTEs by themselves suffer a comparative disadvantage.

Another common safety feature now engineered into T-cells used in immunotherapy is the inclusion of a "safety switch," usually in the form of a suicide gene that responds to the addition of some drug.

For example, for T-cells engineered to have a CD20 suicide gene, addition of the anti-CD20 antibody rituximab resulted in significant T-cell death8. With this safety feature, even though CAR T-cell therapy functions along the lines of "all-or-nothing," there is at least the option to pull the plug on the treatment if circumstances, such as uncontrollably severe CRS, necessitate such action.

What Goes Up: CAR T-cell Exhaustion

Though the selling point of CAR T-cell therapy is that it involves the use of living T-cells themselves, this fact is also a potential weakness. T-cells, like all cells in the body provided they're functioning correctly, cannot proliferate forever, nor are their existence static. The types of T-cells in a T-cell pool changes over time. With increasing age, there is a shift towards more effector and memory T-cells as opposed to undifferentiated naïve T-cells. Naïve T-cells are essentially "younger" T-cells. Compared to

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their differentiated, older counterparts, naïve T-cells have improved proliferation and cytotoxicity, the ability to kill tumor cells. Before being injected into the patient’s body, T-cells need to first be extracted and engineered into CAR T-cells. The process takes days, so when the cells are reintroduced into the patient, they are older and thus more susceptible to exhaustion. Though the mechanisms of CAR T-cell exhaustion are not completely understood, researchers have found that exhausted CAR T-cells have poor expansion and cytotoxicity, which makes the therapy less likely to work.

In other words, time is of the essence. Methods have been used to improve T-cell expansion and persistence modifying the structure of the receptor.

Another option is to rely on more than just the engineered cells. Patients often have T-cells present within the body, known as resident or bystander T-cells, that are unmodified but have potential to be recruited by engineered cells to help attack the tumor burden.

These types of engineered T-cells, capable of recruiting resident T-cells, are called engager T-cells.

Engager T-cells can be thought of as a balance between BiTEs and CAR T-cells. BiTEs can redirect resident T-cells to tumor cells, but they are incapable of self-amplifying and have a relatively short half-life.

Meanwhile, CAR T-cells have a much longer half-

life but are not able to take advantage of the resident T-cells within the body. Engager T-cells possess the strengths of both of these alternatives. They are engineered T-cells, so they can proliferate in the body just like CAR T-cells, but engager T-cells are also capable of secreting engager molecules, which function just like BiTEs in recruiting resident T-cells.

In other words, engager T-cells have both direct cytotoxic effects on tumor cells as well as indirect effects through the secretion of these engager molecules11. In these ways, T-cell therapy is paving promising paths to overcome and circumvent T-cell exhaustion.

Catch Me If You Can: Antigen Escape

Poppy hadn’t been as lucky as Emily. Her cancer initially responded well to CD19 CAR T-cell therapy, but it relapsed, returning with a different uniform.

The same CD19 CAR T-cells that worked so well were now useless because the relapsed cancer no longer expressed CD19 antigens. The antigen had escaped.

The reasoning behind this occurrence is simple despite its devastating implications. Even if 99% of tumor cells express the CD19 antigen and are successfully targeted and killed by the CD19 CAR T-cells, the 1% that survive would be CD19 negative. The surviving tumor cells are capable, then, of proliferating and forming a new growth that is now 100% CD19 negative, effectively "immune" to the old treatment.

This is an all too common problem with T-cell therapy, one that's provoked many different suggestions on how to improve the treatment. One such suggestion involves the production of dual CAR T-cells. These T-cells, once again as the name suggests, would be engineered to target two different tumor antigens at once. For example, one Stanford team has engineered a CAR T-cell that would simultaneously target both CD19 and CD229. The thought is that even if some percentage of tumor cells are CD19 negative, they can still be identified by this dual CAR T-cell if they express CD22.

Engager T-cells in action. Engager T-cells (green) secrete engager molecules, which consist of two fragments. One fragment (neon green) binds to antigens on both engager T-cells and the patient’s resident T-cells (blue). The other fragment binds to antigens on the tumor cell. In this way, engager T-cells can "teach" resident T-cells to recognize and kill tumor cells. Graphic by Iwahori et al (2015)11.

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Though the potential of these T-cells is great, there are still many variables that need to be considered when engineering something like dual CAR T-cells.

Though CD19 has been a tried and true tumor antigen to target, choosing a second antigen requires careful scrutiny. First, is this antigen highly expressed on tumor cells? More importantly, is this antigen not expressed on other tissue cells in the body or other T-cells? To choose an antigen that may be highly expressed on tumor cells but is also highly expressed elsewhere may lead to a phenomenon known as fratricide, where the engineered T-cells may end up killing fellow T-cells or even attacking healthy cells in the body10. Furthermore, dual CAR T-cells are, simply put, difficult to engineer. For some patients, even regular CAR T-cell therapy is not an option. Their T-cells do not respond to attempts to engineer them with necessary receptors, either because the cells are too fragile or exhausted from chemotherapy treatment or due to other unavoidable causes.

Nevertheless, advancements in T-cell therapy continue to persist as one of the brightest hopes for the future of cancer treatment. Evolving from CAR T-cells to now a whole host of different adoptive cell therapies, this field of research has only scratched the surface of its potential. *Note: The real name of this patient has not been released to the public. She is referred to as "Poppy" in this article.

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1.

"CAR T Cells: Engineering Immune Cells to Treat Cancer." National Cancer Institute. Accessed February 23, 2020. https://www.cancer.gov/ about-cancer/treatment/research/car-t-cells.

9.

"Two Is Better Than One: Arming the T-Cells with Dual CancerTargeting Antibodies." Stanford Medicine BMT, n.d. http://med.stanford. edu/bmt/news/news-archive/two-is-better-than-one.html.

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Ruella, Marco, and Marcela V Maus. "Catch Me If You Can: Leukemia Escape after CD19-Directed T Cell Immunotherapies." Computational and structural biotechnology journal. Research Network of Computational and Structural Biotechnology, September 28, 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061074/.

10. Breman, Eytan, Benjamin Demoulin, Sophie Agaugué, et al.

"Overcoming Target Driven Fratricide for T Cell Therapy." Frontiers in immunology. Frontiers Media S.A., December 12, 2018. https://www. ncbi.nlm.nih.gov/pmc/articles/PMC6299907/.

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"Relapsed Leukemia: Emily's Story." The Children's Hospital of Philadelphia, January 28, 2014. https://www.chop.edu/stories/relapsedleukemia-emilys-story.

4.

Grady, Denise. "In Girl's Last Hope, Altered Immune Cells Beat Leukemia." The New York Times. The New York Times, December 9, 2012. https://www.nytimes.com/2012/12/10/health/a-breakthroughagainst-leukemia-using-altered-t-cells.html.

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Cohen, Marion C, and Stanley Cohen. "Cytokine Function: A Study in Biologic Diversity. Retrieved from Cytokine Function A Study in Biologic Diversity." American Journal of Clinical Pathology, May 1996. https://academic.oup.com/ajcp/article-pdf/105/5/589/24878191/ ajcpath105-0589.pdf.

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Shimabukuro-Vornhagen, Alexander, Philipp Gödel, Marion Subklewe, Hans Joachim Stemmler, Hans Anton Schlößer, Max Schlaak, Matthias Kochanek, Boris Böll, and Michael S von Bergwelt-Baildon. "Cytokine Release Syndrome." Journal for Immunotherapy of Cancer. BioMed Central, June 15, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC6003181/.

7.

Slaney, Clare Y, Pin Wang, Phillip K Darcy, and Michael H Kershaw.

"CARs versus BiTEs: A Comparison between T Cell–Redirection Strategies for Cancer Treatment." Cancer Discovery. American Association for Cancer Research, July 16, 2018. https://cancerdiscovery. aacrjournals.org/content/candisc/8/8/924.full.pdf.

8.

Griffioen, Marieke, Esther H M van Egmond, Michel G D Kester, et al.

"Retroviral Transfer of Human CD20 as a Suicide Gene for Adoptive T-Cell Therapy." Haematologica. Ferrata Storti Foundation, September 2009. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738728/.

11. Iwahori, Kota, Sunitha Kakarla, Mireya P Velasquez, et al. "Engager T Cells: a New Class of Antigen-Specific T Cells That Redirect Bystander T Cells." Molecular therapy: The Journal of the American Society of Gene Therapy. Nature Publishing Group, January 23, 2015. https://www.ncbi. nlm.nih.gov/pmc/articles/PMC4426792/.

12. Shimabukuro-Vornhagen, Alexander, Philipp Gödel, et al. "Cytokine Release Syndrome." Journal for Immunotherapy of cancer. BioMed Central, June 15, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC6003181/.

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GRAPHIC MEDICINE: TRAUMA

By Andrew Trandai

Andrew Trandai is a graduate of the University of Chicago and the Johns Hopkins Bloomberg School of Public Health. He is also an advocate for mental health and suicide prevention, seeking to address health disparities and cultural stigma.By exploring the intersection of art and medicine, he hopes to improve health literacy and make health information more accessible.

Find more of his work at andrewtrandai.com. : Shaw, B. (2018). Trauma-Informed Behavioral Healthcare [Powerpoint Slides].

Retrieved from Johns Hopkins Bloomberg School of Public Health 330.664.01 Introduction to Mental Health Services CoursePlus site.

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ulse p THE PRE-MEDICAL STUDENTS’ ASSOCIATION the university of chicago FACEBOOK /uchicagopmsa WEBSITE pmsa.uchicago.edu