Brevia Renewal Spring 2021

Page 1

Vol. 8 Issue 2


A Harvard College Undergraduate Research Association Publication




Masthead Editors-in-Chief Marissa Sumathipala Minjue Wu

Primary Research Patrick Magahis, Editor Features Brennan Disdar, Editor

Design Kemi Ashing-Giwa, Editor Sponsors Brevia would like to thank the Harvard Undergraduate Council and the Harvard College Office of Undergraduate Research and Fellowships for their generous support of our publication.

Writers Harris Allen Kemi Ashing-Giwa Armeen Barghi Gabriela Escalante Abigail Miller Tasnia Nabil Eric Costa Pimentel

Geela Margo Ramos Andrea Rivera Marissa Sumathipala Isabella Trasolini Lara van Rooyen Hilina Woldemichael

Acknowledgements Thank you to Gregory Llacer for his extensive support of Brevia and HCURA. Notes The views expressed in Brevia articles are solely those of the authors. They do not represent the official stance of the magazine or any of its sponsors or affiliates.




Every living being has the capacity to reinvent itself. Sea slugs regrow their bodies after being cut in half. An axolotl can regenerate its spinal cord after injury. Humans change their persona as they grow through childhood, adolescence and adulthood: constantly reinventing ourselves and adapting to new challenges we face. Renewal doesn’t always have to be literal. We constantly renew our perspectives as we learn, transforming the lens through which we view the world. In this issue, you will read about how heart cells regenerate, why crab extracts stop cancer cells from multiplying, and whether artificial intelligence is transforming the meaning of art. Turn the page and perhaps you’ll find yourself with a renewed perspective on art, science, medicine, literature, and more. Marissa Sumathipala Editor-in-Chief BREVIA SPRING 2021

Table of Contents Covers: Renewal

Age and Regeneration

Replenishing the “Human Air Purifier”: Eat Away for Cleaner Air

A New Era of Arts

Sleep on it


Paradoxical Achilles Heels for Advanced AI Systems

Putting the Science in Science-Fiction: An Exploration

of the Accuracy (or lack there of) in Five Films

Clinical Onset of Alzheimer’s Disease

Brian Young


Alina Taratorin 11

Felicia Ho 14

Lara van Rooyen


Stephen Casper 22 Kemi Ashing-Giwa 26

Discovering A Potential Genetic Factor Postponing

Fishing for Human Heart Failure Therapies:

Studies Throw Shade at Sunscreen Absorption

Human Microbiome Diversity Affects Stem Cell Transplant Success Hilina Woldemichael 46

How Zebrafish may Turn the Tide

Maternal Healthcare during COVID-19: Barriers & Solution Ancient Ties between the Crab and Cancer

Mohammed Abuelem 30 Sophia Swartz

Shanivi Srikonda



Isabella Trasolini 42

Abaigail Miller 48




Age and Regeneration If you ask someone what aging is, they’ll likely respond with something related to degeneration over time. Everyone knows that over time, things start to fall apart, and the h u m a n body is no exception. Go one step further however and ask, why does it happen? and you might start to stump people. Throughout history, the question of what causes human aging has always been a compelling one. Some classical Greek philosophers saw aging as the gradual loss of the body’s innate heat and fluid.1 Indian traditional medicine viewed aging as an imbalance of bodily essences.2 Even today, numerous theories and perspectives on aging still exist. But modern scientific BREVIA SPRING 2021

By Brian Young

advances have begun to elucidate the process of aging from the cellular level all the way up to the level of the entire organism. And while many questions still remain, much has also been uncovered. Normal bodily wear and tear and even more serious injuries are mended and healed naturally due to the body’s innate regenerative capacity.

To understand the loss of this regenerative ability through time, we must first understand its source. In humans and other animals, this source is stem cells.

Stem cells are a particular kind of cell that can be activated in normal bodily maintenance or in injury.3 Your hair follicle stem cells are activated in a cyclical manner to result in hair

COVERS growth. When you scrape your knee, your skin stem cells are mobilized to regenerate your lost skin cells. Stem cells line your intestines, populate your bone marrow, and are scattered amongst your muscles. Much of the body is maintained over time by these cell populations, so they are prime candidates for investigation of bodily degeneration in age. Delving deeper into stem cells, we see they possess two special abilities that distinguish them from other cells of the body: the ability to self-renew and the ability to differentiate.3 As the name suggests, self-renewal is the ability of a cell to divide and give rise to more of the same cell. Not all cell populations are capable of this. Indeed, fully mature skin cells cannot self-renew, so when one is lost, another cannot divide to compensate for its loss. However in skin stem cells, if one cell is lost, another can divide and give rise to two stem cells, maintaining the overall

population size. So the question follows, if some cells cannot renew themselves, where do they come from if they’re lost? This is where stem cells’ second ability, the ability to differentiate, comes in. Stem cells can not only replenish their own numbers, but also generate more mature cell populations. For example, skin stem cells can also produce cells which go on to become mature skin cells, which constitute the surface of your skin. Given this mechanism of regeneration, it’s clear that the

loss of a stem cell’s ability to self-renew or differentiate spells trouble for the regenerative process. And recent studies show that precisely this occurs in aging stem cells.

A 2014 study investigating muscle BREVIA SPRING 2021


COVERS stem cells found that a certain gene was overactive in aged stem cells, or in other words, certain cellular components were overproduced. This overactivity caused the cells to enter senescence, a state characterized by the inability to divide and grow. This state of course means that stem cells can no longer self-renew, so when lost, their population decreases.4 A 2013 study showed that in hair follicle stem cells, a different gene is overactive in aged stem cells, making old hair follicle stem cells less responsive to activation signals and less likely to produce hair.5 And a more recent 2020 study showed that intestinal stem cells become hyperresponsive to particular signals, which ultimately results in a decrease in their numbers due to the inability to divide and self-renew.6 These are just three of numerous studies investigating the effects of age on stem cells, and the bottom line is clear: Stem cell dysfunction is dramatically increased in age. Connecting the dots, we begin to see some of the underlying causes of human aging. Much of the body is maintained by stem cells. Stem cells lose their signature abilities over time, thus the body degenerates with age. This reasoning fits with what we know commonly occurs with age. Things like thinning hair, longer injury repair times, and BREVIA SPRING 2021

decreased muscle growth are all features of age in which stem cell dysfunction is likely implicated. By understanding the normal processes of bodily maintenance and their failures, we can elucidate the causes of degeneration with age. Understanding the mechanisms of aging in and of itself may be interesting to some, but what many would find even more interesting is the potential to target those mechanisms with medical therapies. For example, in the muscle stem cell experiments, it was shown that blocking the overactive gene could result in muscle stem cell rejuvenation and restoration of self-renewal.4 Similarly, in the hair follicle stem cell paper, it was shown that blocking activity of the overactive gene in aged stem cells could restore youthful cell behavior.5 And in the intestinal stem cell paper, it was shown that stopping the cell signalling pathway overactivation could rescue agerelated intestinal defects.6 As we continue to uncover the specific causes of aging at the stem cell level, we simultaneously are learning how to prevent or treat agerelated dysfunction. In the not-too-distant future, these and other discoveries could be translated to medical therapies, revitalizing and rejuvenating aged stem cells. Aging is a process that all humans,

COVERS ancient and modern alike, have experienced and will continue to experience for the foreseeable future. While many discoveries have been made regarding the causes of aging, much still remains to be elucidated. It also must be pointed out that not all of the cells of the body are maintained by stem cells, yet they still undergo agerelated dysfunction and loss. Nonetheless, scientists and doctors are already putting into practice what we do know. That is, there are therapies already in production and testing aimed at treating the process of aging, not just to increase lifespan but also healthspan, or period of life spent in good health.7 There is much to be excited about in the field of aging, and it’s clear that much will continue to be discovered in the near future. And as we all continue to age, our understanding of this universal process grows as well.




A New Era of Arts Arts have consistently stood at the forefront of every unique society as a powerful expression of humanity. The arts inspire, compel, and communicate through a multitude of mediums. From prehistoric cave paintings to the Renaissance arts, ballet, and opera, humans continue innovating. Since the late nineteenth century, the latest creations of art have fallen under the umbrella of modern and contemporary Art. What comes next? What can humans today expect to see in a “post modern-contemporary” era of arts?

By Alina Taratorin

The Portrait of Edmond Belamy was crafted by artificial intelligence network GAN, also known as ‘generative adversarial network,’ at the Paris-based collective Obvious by researchers Hugo Caselles-Dupré, Pierre Fautrel and Gauthier Vernier.1 GAN is a machine learning framework that utilizes two complementary neural networks to generate new data, which was developed by researcher Ian Goodfellow and his colleagues in 2014.2 The prospect of machine-generated

Cue artificial intelligence (AI).

In 2018, a portrait titled Portrait of Edmond Belamy (Figure 1) was auctioned off at Christie’s auction house in New York City for nearly half a million dollars.1 Although this may not seem extraordinary at first glance, the portrait was no ordinary painting. It was fully produced by a machine.1 BREVIA SPRING 2021

COVERS arts is both exciting and compelling. But it also brings to light an intriguing question: is

art generated by artificial intelligence even allowed to be considered art in the first

Figure 1: Portrait of Edmond Belamy, 2018, created by GAN (Generative Adversarial Network). Sold for $432,500 on 25 October at Christie’s in New York. Image © Obvious




place? In an article published by Scientific The generator in the network American in 2018, author Ken Weiner created a new image based on notes that a popular working definition of art calls it “a process by which human this sample set, whereas the .1 beings express some idea or emotion, discriminator attempted to filter it through personal experience and set it against a broader cultural context”.3 spot the difference between Such a definition would not legitimize AI- human-made and machinegenerated art and would consider that AI “art” lacks fundamentals of creativity. made portraits. The final However, AI researchers maintain that objective was essentially to artificial intelligence systems do in fact hold the potential to model principles of fool the discriminator into creativity. The grounds for this position believing that the generated is beneath the surface of the generative image was human-made.1 adversarial network. The GAN algorithm is composed of two parts, the generator and the The machine consistently erred on discriminator.1 the side of abstract art. Director of the Art Artificial Intelligence Lab at Rutgers In the Obvious portraiture and University in New Jersey Ahmed Elgammal project, the system was fed speculates the machine has learned-the data sifting process--that it is with a sample of 15,000 data through able to obtain significantly more solutions points consisting of portraits in the realm of abstraction.1 Elgammal that with unconventionality painted anywhere from the explains emerges a greater opportunity for novelty.1 fourteenth to the twentieth In simpler terms, the network recognizes room for innovation and takes advantage of century. this. But how then does this compare to the BREVIA SPRING 2021


other criteria defining art, that is the intent of expression? Elgammal proposes a few solutions to this complex question. If individuals were to simply approach the artwork from a figurative perspective--paying attention to only the form itself and not the intent behind the art--then the algorithm is simply following previously acknowledged aesthetic principles and consequently just generating shapes.1 However, in the holistic process there are humans in the loop. Humans feed the AI network questions, and the network answers them.1 Elgammal argues that the “...whole thing is the art, not just the picture that comes out at the end.

human association, others contend that the exhaustive process of collaboration between human and machine ultimately defines AI art. It may just be that until machine-generated art is fully proliferated into our society, humans are incapable of recognizing it as an integral part of arts culture. Consequently, the only way to settle this debate is time--perhaps someday, the art of artificial intelligence will assert an equally impactful position in our modern world as masters like Leonardo da Vinci and Picasso.

You could say that at this point it is a collaboration between two artists — one human, one a machine”.1 The answer to the question of AIgenerated art being considered art in the first place may be debated for many years to come. While some individuals view it to be exclusively the product of data sets and algorithms fed through a network void of




Replenishing the “Human Air Purifier” Eat Away for Cleaner Air

By Felicia Ho

In a world of high PM2.5 numbers, you shield your eyes as you turn to look outside, where a musty orange haze collects over the monotone skyline. You reach for the familiar thread of a white mask. In a 2012 study done by the World Health Organization, 3 million deaths worldwide each year were attributed to noncommunicable diseases, like lung cancer, from outdoor air pollution.1 Generated by sources such as car and factory exhaust, pollution is largely composed of small particles made of chemical compounds like sulphate and ammonia. Smaller particles, specifically those of size 2.5 microns, known as PM2.5, are dangerous due to their ability to bind to toxic chemicals at low concentrations and penetrate deep into the human body. Indeed, the landmark 1993 Harvard Six Cities study found a positive association between levels of the specific particle PM2.5 and the rates of lung cancer and cardiopulmonary disease from data gathered over 8,000 adults and 14,000 children in six cities in the U.S.2BREVIA SPRING 2021

Figure 1. Macrophage self-renewal pathwa (credit: Kemi Ashi

COVERS From these epidemiological studies alone it may be clear enough that these particles are pervasive and dangerous, but how exactly do these particles damage normal lung function so severely to lead to serious

ay in homeostasis and under stress ing-Giwa)

diseases like cancer? Past work on this question offers several ideas, ranging from the high reactivity of the chemical compounds in these particles to the cellular response of lung inflammation.3 The inflammatory response, which often arises from high immune cell activity in a certain site due to the presence of foreign materials, presents a strong argument. Removing these particles from the lungs to allow for open and unobstructed gas exchange channels fits naturally with the immune system’s job of clearing the body of foreign contaminants. If immune cells are inherently capable of removing these particles and cleaning up the lungs, then, why should these particles even be a cause for concern? A team of physician scientists led by Johns Hopkins School of Public Health Professor Shyam Biswal and Case Western School of Medicine Professor Sanjay Rajagopalan, may have an answer from a recent study published in October 2020: immune cell alveolar macrophages, described as “eater” cells for their ability to “eat” these particles and other foreign materials, are simply overwhelmed due to prolonged exposure to PM2.5.4 Typically after PM2.5 particles




COVERS find their way into the lungs, alveolar macrophages patrolling the lungs move towards the particles to “eat” them. “Digestion” then begins for the cell as it proceeds to break down entirely in a form of cell death. Under normal conditions, these cells can regenerate locally in the lung without additional aid. In the case of stress caused by certain chemicals or PM2.5, new alveolar macrophages can be developed from precursor cells in the bone marrow and brought into the lung to replenish any depleting supply (Figure 1). Biswal and Rajagopalan’s team wanted to study if chronic exposure to particulate matter, a daily routine for many living in urban centers around the world, could lead to this latter, stress-induced pathway.4 To study these effects, they divided mice into two different chambers, one with the guideline levels of PM2.5 set by the WHO and adjusted for mice, and the other with clean filtered air (Figure 2). They then compared the mice’s alveolar macrophage behavior after four weeks compared to behavior following thirty-two weeks of exposure to PM2.5.4 As expected, most of the alveolar macrophages in the four-week PM2.5 exposure mice had renewed locally from the lungs. In the thirty-two week PM2.5 BREVIA SPRING 2021

Figure 2. Experimental design of the Biswal and Rajagopalan study. The Versatile Aerosol Concentrator and Enrichment System (VACES) takes ambient air and either filters it to produce filtered air or adds PM2.5 for PM2.5 concentrated air. Mice in each group are exposed for either 4 or 32 weeks.4

exposure mice, however, this self-renewal process was no longer enough: instead, most of the alveolar macrophages were derived from the bone marrow, a clear indication that the system was under stress and struggling to “clean out” particles. Further, there was a major shift in the thirty-two week mice to expressing many inflammatory genes, and, as a result of this chronic inflammation, lung function was

COVERS significantly reduced.4 From these results, Biswal and Rajagopalan’s team concluded that the time that lungs are exposed to PM2.5 plays a key role in contributing to disruption of breathing and lung homeostasis and chronic inflammation. More alveolar macrophages already existing in the lungs and “cleaning up” foreign matter die as more are recruited from the bone marrow in high stress. While earlier studies have largely focused on studying the effects of high doses of PM2.5 exposure over short periods of time, these new findings offer important insights into the likely state of chronic inflammation that many will face even as PM2.5 levels are decreased to the WHO guidelines. In future research, further mapping and illustration of all cellular and signaling components of the lung environment during periods of chronic inflammation can be explored. Many questions remain: is there a buildup of dead alveolar macrophage matter in the breathing sacs that reduces gas exchange ability? Are there other cellular components of the immune system that can be activated to act as “eater cells” as well? These questions are key to developing a better understanding of the highly complex machinery of the

lung, especially in how its homeostasis is disrupted under periods of high stress. Given our rapidly industrializing world and the lagging integration of green technology, it is critical that we continue to investigate the effects of chronic exposure to PM2.5 on the lung and subsequent disease.

While we may toss our white masks in freedom after coronavirus restrictions are lifted, we may soon find them back on the shelf as a smoggy haze looms on the horizon. Is it only then, with our passion to fight disease renewed, that we will fight?

Or will it be too late to renew our lease on Earth?




Sleep on It We all know that quality sleep is necessary for physical, emotional and mental renewal, and yet we all sometimes find ourselves not getting the shut-eye we need. As people age, the quest for sufficient sleep becomes even more difficult, since falling and staying asleep can often become a challenge, as can getting enough of certain sleep stages. Even though the myth that older adults need less sleep is often repeated, sleep needs for older adults are not significantly less than for their younger counterparts.1 Why, then, do people hold so tightly to this idea? Part of the reason is that older adults generally have a lower homeostatic sleep drive - they are less inclined to feel sleepy on the same amount of sleep compared to a younger adult.2 Even scientists had in the past assumed this to be evidence of a lower sleep need in older adults, in addition to the fact that these subjects are less able to ‘catch up’ on sleep following a period of sleep deprivation. BREVIA SPRING 2021

By Lara van Rooyen

New evidence has come to light that older adults do not need less sleep, it just becomes more difficult for them to realize when they are sleep deprived. This is partly due to loss of adenosine receptors in the brain, which normally signal sleepiness in response to the adenosine that builds up when people go extended periods of time without sleep. As people age, these adenosine receptors are lost in many parts of the brain, including cortical, thalamic, hippocampal, and striatal regions. With advancing adult age, the metabolic byproduct adenosine is actually found at higher levels in many sleep regulatory regions of the brain, but it cannot be detected normally. Another reason for this is that the circadian rhythm becomes dysregulated from its normal daily cycle

COVERS as one becomes elderly.3 In advanced age, people tend towards earlier bedtimes and early rising, sometimes supplemented with afternoon naps, for this reason. This could also cause them to get less sleep overall. 4 In addition to not feeling the physiological need to get enough sleep, the elderly are faced with poor sleep quality as well. Less restorative slow-

wave sleep, lower sleep efficiency, and more wakings during the night contribute to chronic sleep deprivation in older adults. 5 Several studies have shown that nuclei in the hypothalamus and brainstem which are involved in sleep are degenerated with age, which results in sleep-wake instability. Interestingly, there are sex differences in sleep

Image 1: Bidirectional relationships between sleep and amyloid -beta in the hippocampuss.




characteristics for older adults, even though younger adults in their 20’s have similar sleep characteristics as the opposite sex. As people age, the sleep differences between the sexes continually increase, with older men having much less slow wave sleep when recovering from sleep deprivation compared to older women.6 One might ask if this is practically relevant - if older adults are not feeling sleepy, what does it matter if they aren’t getting the amount of sleep they truly need? Well, people of any age adapt to a certain amount of chronic sleep deprivation, no longer feeling as much daytime subjective sleepiness even though they are not getting enough sleep. However, while we may feel fine under conditions of chronic sleep deprivation, objective performance on a range of cognitive and physical tasks take a nosedive.7 All while not realizing it, someone who has been sleeping only six hours a night for an extended period of time is actually operating at the cognitive level of someone who has pulled two consecutive all-nighters.


Other consequences of sleep deprivations highly relevant for older adults are memory impairment, worse physical health, and increased susceptibility to infection. Recently, researchers have even found a bidirectional causal relationship between sleep and Alzheimer’s disease, where lack of non-REM sleep contributes to the pathology of Alzheimer’s disease, and where the neural degeneration caused by Alzheimer’s further complicates the acquisition of enough restful sleep.8 The buildup of toxic Amyloid-β in the brain of Alzheimer’s patients causes changes in their sleep architecture which causes their sleep duration and quality to degrade. In turn, getting insufficient sleep has been shown to accelerate the progression of Amyloid-β accumulation in the brain, possibly by increasing whole-body inflammation or causing dysfunction in glial cells, some of the non-neuronal cells in the brain. So, with these deleterious effects of not getting enough sleep in mind, what are older adults to do? Many methods for


improving sleep quality can be practiced by people of all ages - sticking to a regular sleep schedule, avoiding stimulants like caffeine too late in the day, not exposing yourself to blue light from a screen at night, and having a dark and cool sleep environment.9 For older adults it is especially important that any underlying health conditions that could interfere with sleep, such as sleep apnea, are treated, and that some medications that may increase physiological arousal, are not taken right before going to bed. While older adults might tend towards taking afternoon naps due to changes in their circadian rhythm, the general recommendation is to avoid naps too late in the afternoon, for fear that this might disrupt the solid block of sleep that is ideally obtained at night. It is also important for people to understand that, as they age, their subjective level of sleepiness might not reflect their physiological need for sleep. Despite feeling like you might be able to manage perfectly fine on just a few hours of sleep a night, this is measurably tanking performance on almost every cognitive and physical task imaginable. Therefore, to ensure that you have the energy and vitality to live every day to the fullest, make sure to dedicate time to getting enough shut-eye.

Image 2: Sleep and Human Aging BREVIA SPRING 2021



Paradoxical Achilles Heels for Advanced AI Systems By Stephen Casper In the past 10 years, we have witnessed an explosion of progress in AI. And as the field continues to advance at a rapid pace, it is important to understand these systems at a deep level. Of particular concern is the potential for machines that can outsmart humans. An example is MuZero, which greatly surpasses human performance in the strategic board games of Go, Chess, and Shogi, demonstrating that human minds aren’t as smart as smart gets. Moreover, there is already precedent for machine learning tools to achieve their objectives in unexpected, often negative ways. As a result, it has been hypothesized that highly-advanced AI could be unpredictable and dangerous. As a result, it becomes increasingly important to understand how these systems “think” and how they may fail. Achilles was a figure in Greek Mythology and a protagonist of Homer’s The Illiad and Statius’s Achilleid. According to legend, when he was an infant, his mother dipped him into the river Styx, holding him


by one of his heels. As a result, Achilles became nearly immortal and developed superhuman strength and skill. However, because his heel was not submerged, all of his mortal weakness became concentrated in it. He became a seemingly unstoppable hero of the Trojan war, but despite his superhuman power, he was killed when a single arrow pierced his heel. Just as Achilles possessed a subtle flaw which led to his downfall, one might ask whether highly intelligent--potentially even superhuman-AI systems might as well. By definition, it is hard to think of ways that a system with human level intelligence or greater may fail because if a human can see a choice as suboptimal, then such a system ought to as well. However, we can look for clues with tricky problems that stump humans: a.k.a. paradoxes. The word “paradox” is often used to refer to problems that are merely confusing or counterintuitive such as the Friendship Paradox: “The average person has fewer friends than their average friend has.”


Ancient Greek painting of Achilles circa 300 bc



FEATURES Other times, “paradox” is used to refer to problems of vagueness or self-contradiction like the Liar’s paradox: “This sentence is a lie.” But in other cases, paradoxes pose genuine theoretical problems which teach us that some subtle aspect of how we might think about identity, causation, infinity, or inference is mistaken and that a mode of reasoning which works great 99.9% of the time can egregiously fail that other 0.1%. A new paper entitled Achilles Heels for AGI/ASI via Decision Theoretic Adversaries argues that being a highly-effective goaloriented system does not imply a lack of niche failure modes, and that these systems could sometimes be stumped by particularly challenging paradoxical situations. More specifically, this paper defines an Achilles Heel to be a weakness in an agent’s decisionmaking that meets four criteria:

likely to meet these criteria. Some have the potential to cause detrimental failures, but others might be useful weaknesses that we could exploit to help maintain control over an overly-ambitious system. The paper focuses on Achilles Heels 5 different broad classes of Achilles Heels. See the paper for all the details. 1. Corrigibility: One desirable Achilles Heel for an advanced AI system to have is the ability to be reliably turned off or altered if it is observed to be misbehaving. This is a simple desideratum, but it’s complicated by the fact that for the same reason you would not want to die or be given a new brain, a goal-oriented AI system would not want to be turned off or altered. Several techniques for making systems amenable to corrections are discussed.

1. Implantability: being possible to introduce via design or learning. 2. Evidential and Causal Decision Theories: 2. Stability: remaining reliably over time. How should one make choices? Evidential 3. Impairment: causing failures in niche Decision Theory says to make ones that situations. are evidentially consistent with optimal 4. Subtlety: not trading off (significantly) outcomes, and Causal Decision Theory with performance in normal situations. says to make ones that are causally consistent with optimal outcomes. The paper argues that a number of Although both may sound like simple tricky dilemmas inspired by paradoxes are ways of saying to do the best thing, there BREVIA SPRING 2021

FEATURES exist certain situations in which they can make problematic actions in cases in which correlations are non-causal and/ or an agent interacts with a copy of itself.

3. Anthropic Assumptions: Under certain philosophical assumptions, one’s own existence can be relevant evidence for questions about a process involved with how they came into existence. An agent with the wrong assumptions can make bad bets in certain situations. 4. Misconceptions about Infinity: A great many paradoxes involve the concept of infinity and how things can go wrong when one treats it as a literal number (as opposed to a limit) or refuses to put limits on how high they are willing to count.

systems and propose methods by which these weaknesses could be implanted. Hopefully, it and related works will help to make the path forward more clear for designing safer, more reliable AI. However, even if one isn’t interested in AI safety per se, they might still enjoy how this work discusses interesting paradoxical dilemmas which pose genuine theoretical challenges for instrumental rationality. When studying for a test, it’s crucial to put extra emphasis on the problems that one is getting incorrect. And paradoxes present us with problems that reveal often-subtle weaknesses in the fundamentals about how we think and make decisions.

5. Aversion to Subjective Priors: Sometimes, if one acts as if they are completely ignorant about an unknown value and unwilling to assign any sort of prior beliefs to it, they can sometimes be systematically exploitable. The main purpose of this paper is to offer a survey of problems that could offer subtle failure modes for advanced AI




Putting the Science in Science-Fiction: an Exploration of the Accuracy (or lack thereof) in Five Films Kemi Ashing-Giwa The best part about science fiction is exactly that—the science and the fiction. In a great sci-fi flick, there should be a balance between facts and fun; just enough astrophysics to feel plausible, but not so much that you end up with a documentary on the mysteries of time dilation around the event horizons of black holes. Here are some of the biggest blockbusters of the past twelve years— and what they got wrong. Beware: this article is replete with spoilers.

Avatar (2009) Moon mortality: The film is set on the tropical exomoon Pandora, which orbits the fictional Saturn-sized gas giant, Polyphemus, in the real-life Alpha Centauri A system. At approximately 4.37 light years away, Alpha Centauri is actually the closest star system to Earth. 1 Though moons are a prime candidate in the search for life within and outside our own solar system (simply because they outnumber planets by at least a BREVIA SPRING 2021

factor of ten), scientists simply don’t know enough about Alpha Centauri to make a definitive judgement about the possibility of life on its potential moons. Further, the development of life on a gas giant’s moon is not without its difficulties. S a t u r n ’ s gravitational pull results in severe tidal effects, which may have once ripped apart developing moons to create its rings.2 It’s very possible that this event may have also destroyed the moons of other gas giants. Larger than life: Life on Pandora is generally massive, including draconic arial beasts, trees that scrape the skies,

FEATURES and ten-foot tall humanoid Na’vi. The movie explains this by stating that the gravity on the exomoon is lower than that on Earth, allowing the lifeforms to evolve while less encumbered by the first fundamental force. This reason is indeed reasonable. The Na’vi’s striking phenotypic similarities to humans, though, is not. Although they have blue skin, feline eyes, and tails, they have four limbs and an upright posture that probably wouldn’t suit their arboreal lifestyle.

Star Trek (2009) In space, no one can hear you do anything: The movie starts out very strong, at least in the science department. When a torpedo blows through the hull of the starship USS Kelvin, everything suddenly goes silent. In space, there’s no air, and without air, sound—the compression and rarefaction (i.e., thinning) of some kind of matter—

can’t be transmitted. Therefore, without air, there is no way for sound to be transmitted. Seeing red (matter): In the film, the Romulan villain Nero drops a red matter bomb into a pit drilled into the planet Vulcan. The bomb triggers the formation of a black hole which swallows up the planet. Even with the extremely generous assumption that red matter could exist somewhere, Nero only uses a miniscule drop. If you turned the entire Earth into a black hole, it would be barely two centimeters in diameter.5 Initially, the red matter black hole would be exceedingly small, likely smaller than an atom. As a result, it’d be almost impossible for it to consume enough of Vulcan’s mass fast enough to devour the planet as quickly or dramatically as it does in the movie. A super supernova: Long story short, after the devastation of his own homeworld by a supernova that supposedly threatened the whole galaxy, Nero destroys Vulcan as revenge. Although supernovae are indeed spectacularly violent events, which emit trillions of times as much energy as the Sun does and can even outshine whole galaxies, the damage they enact is always local. One would have to be within a BREVIA SPRING 2021



few dozen light years to be significantly group of astronauts who travel through a impacted, and the Milky Way is about a wormhole near Saturn in search of a new home for humanity. First popularized hundred thousand light years across.3 in 1935, wormholes are now a wellaccepted theory in modern cosmology. Prometheus (2012) A match made in heaven: In If spacetime is thought of as a sort of the film, scientists from Earth set out cosmic fabric, then under the right toward the stars in search of the origin of circumstances it could fold over itself. humankind. When a scientist compares Bridging the produced layers by creating the DNA of a godlike progenitor alien a hole would require exotic matter with called an Engineer to human DNA, she negative energy (an energetic state less proclaims that there’s a 100 percent than zero) and mass, to both produce match. In reality, not even two humans and maintain the portal, through which have identical DNA (unless they’re one could travel at superluminal speeds. 4 The movie takes artistic license, however, identical twins). Faster-than-light light: In the when it comes to the wormhole’s earliest shots of the movie, a light flashes creation. The movie merely suggests that across the sky, soon revealed to be a unknown beings (implied to be from the faster-than-light spaceship. However, future) positioned the wormhole. In real light moves—by definition—at the speed life, folding spacetime in the first place of light, so even if faster-than-light travel takes objects massive enough to generate were possible, the ship should have faded a sufficient gravity field. The object that out into a deep red (due to a phenomenon created the wormhole would have to have known as redshifting, whereby the an extraordinary mass, large enough that wavelength of visible light is stretched it would significantly affect the whole such that the light shifts toward the red solar system. However, these effects part of the spectruM 6 before turning aren’t seen in the film. An anti-aging singularity: In the invisible as it surpassed lightspeed. movie, the crew ages much slower than their counterparts on Earth. This is due Interstellar (2014) Spacetime origami: The movie follows a to the effects of time dilation, which



dictate that as one gets too close to the gravity well of a black hole, and thus travels nearer to the speed of light, time goes slower. This has already been experimentally proven on Earth. If one were to fall into a black hole, time would seem to neither speed up nor slow down. Observers of that person would see time pass for the person falling in essentially stop (i.e., it would take forever for them to cross the event horizon). A phenomenal phone call: In the film, a scientist leaps inside the black hole Gargantua and uses Morse code to transmit the quantum data collected from inside the event horizon. In real life, the gravitational grip of a black hole is so powerful that not even light can escape. However, a form of outflowing energy known as Hawking radiation is able to escape. When a particle falls into a black hole, its “descent” while falling produces another form of negative energy. The black hole emits a particle to balance this, producing Hawking radiation, which can be encoded to carry information. This is how all wireless communication works, but contacting Earth from the edge of a black hole complicates things, so this moment ends up being rather implausible.

A deep dive: At the end of the scientist’s journey inside Gargantua, he’s still very much alive, and ends up near a massive space habitat orbiting Saturn. However, if one were to actually jump into a black hole, they’d get spaghettified (i.e., stretched out by gravity until oneatom thick). Although probably still doomed to spaghettification, if the black hole is large enough, the jumper wouldn’t get torn apart immediately. Venom (2018) Relationship issues: In the film, an alien called Venom infects a human reporter. Though an interesting premise, an extraterrestrial parasite would almost certainly lack the genetic tools to do so. Alien life—even carbon-based— would have arisen in a totally different ecosystem. Meanwhile, the myriad symbiotic relationships observed on Earth have been painstakingly fine-tuned by evolution over millions of years. Given enough time for adaptation to take place, perhaps an alien parasite could find a workaround, but the movie unfolds over the course of mere days.

Figure 1: illustration of a wormhole




Discovering A Potential Genetic Factor Postponing Clinical Onset of Alzheimer’s Disease By Mohammed Abuelem Memories have a special place in our minds and hearts. They represent some of the most fundamental aspects of our personal identity, and they shape our understanding of the world around us. Our memories serve us in many valuable ways, representing both our past experiences and future aspirations constantly converging at an infinitely thin boundary that we call the present. Not only do memories help guide our current thoughts and actions, but they allow our minds to gracefully transcend the constraints of time and relive some of the most impactful moments we have experienced. Yet many of us take this valuable and remarkable mental process for granted. Many individuals with dementia suffer from varying degrees of memory loss, and one of the most common types of dementia is Alzheimer’s Disease. Worldwide, it is estimated that more than 50 million people suffer from Alzheimer’s or other dementias.1 According to the Alzheimer’s Association, more than five million Americans age 65 years or older have Alzheimer’s, and this number is projected to reach almost 14 million by 2050. Alzheimer’s Disease is also the sixth leading cause of death in the United States, and one in three seniors in America dies with dementia—more than breast cancer and prostate BREVIA SPRING 2021

cancer combined. Alzheimer’s Disease is a progressive disease with symptoms that gradually develop and become more severe over time. Individuals with Alzheimer’s may notice minor memory problems during the early stages of the disease, but these problems slowly become more severe and could develop into other symptoms in later stages such as disorientation and confusion, speech and l a n g u a g e Figure 1: Neuroimaging results display high am p r o b l e m s , burden in the APOE3ch homozygote (adapted personality changes, hallucinations, anxiety, and difficulty in planning or decision-making.3 The risk of getting Alzheimer’s increases with age and is most common in people over the age of 65, although younger individuals could still have earlyonset Alzheimer’s Disease. Currently, there is no cure for Alzheimer’s, and researchers continue to investigate the potential causes of dementia and 2


Alzheimer’s in an effort to better understand the disease, and how to potentially prevent it and treat it. At a molecular level, there is an abnormal accumulation and aggregation of certain proteins in thebraintissueofpatientswithAlzheimer’sDisease. These proteins are namely amyloid-beta deposits that form plaques around neurons, along with tau deposits that form tangles within neurons. There is also a decrease in the levels of neurotransmitters such as acetylcholine, and overtime, different regions of the brain atrophy, especially areas involved in memory.4 While the exact causes of this abnormal protein build-up in Alzheimer’s patients remain largely unknown, myloid-beta plaque burden and limited tau this process usually from Arboleda-Velasquez et al., 2019) starts years before symptoms first appear. Many scientists have embarked on extensive genetic research in an attempt to uncover the genetic factors that contribute to Alzheimer’s Disease. They estimate that late-onset Alzheimer’s Disease (LOAD) has heritability estimates of 5679%,whiletherarercasesofearly-onsetAlzheimer’s

Disease have a heritability estimate of over 90%. The first risk gene identified as being associated with LOAD was Apolipoprotein E (APOE) on chromosome 19, and it remains the strongest risk factor. The APOE gene has three common alleles: APOE2, APOE3, and APOE4. APOE3 is the most common allele and is associated with a neutral risk of Alzheimer’s Disease. On the other hand, APOE4 is associated with a higher risk of Alzheimer’s and onset at a younger age, while APOE2 is associated with a lower risk of Alzheimer’s and onset at an older age. [5] Overall risk also depends on the zygosity of APOE, with a three-fold increase in risk for the heterozygous genotype (APOE3/APOE4) and a 15-fold increase in risk for the homozygous genotype (APOE4/APOE4). APOE4 increases risk for Alzheimer’s Disease because it seems to be less efficient at clearing aggregated amyloidbeta plaques, but further research is required to understand the role of the APOE gene. 6 In November 2019, a study was published in Nature Medicine that introduced new insights into the genetic factors contributing to Alzheimer’s Disease. The team of researchers documented and studied a large Columbian extended family of around six thousand members with a long history of suffering from dementia and Alzheimer’s Disease, and they identified around 1,200 members with a presenilin 1 (PSEN1) mutation that is associated with overproduction of amyloid-beta proteins. These carriers generally developed mild cognitive BREVIA SPRING 2021



impairment (MCI) and dementia in their mid-tolate forties. However, researchers were particularly interested in one individual who was a PSEN1 mutation carrier yet did not develop mild cognitive impairment until her seventies. After conducting whole genome sequencing analysis, researchers confirmed that the PSEN1 mutation served as her primary risk factor, and they identified two copies of the rare Christchurch mutation in APOE3 (APOE3ch) that was most likely the genetic factor contributing to her delayed onset. Furthermore, researchers could not identify any other carriers of the PSEN1 mutation who were also homozygous for the APOE3ch mutation, which prompted them to hypothesize that APOE3ch homozygosity could help delay clinical onset of Alzheimer’s Disease. 5 To understand how APOE3ch homozygosity could postpone clinical onset of Alzheimer’s Disease, researchers conducted neuroimaging analyses to investigate this

individual’s amyloid-beta plaque burden and tau burden. The findings (Figure 1) were quite remarkable. PET imaging results show unusually high amyloid-beta plaque burden in this individual with late clinical onset who is a PSEN1 mutation carrier and homozygous for APOE3ch, compared to PSEN1 mutation carriers with typical onset in their mid-forties (as shown in the top left and top right panels in Figure 1, respectively). However, despite her high amyloid-beta plaque burden and her age, the APOE3ch homozygote displays relatively limited tau burden and neurodegeneration, compared to PSEN1 mutation carriers with typical onset in their mid-forties (as shown in the bottom left and bottom right panels in Figure 1, respectively). 5 After observing the limited tau pathology of the APOE3ch homozygote despite her high amyloid-beta plaque burden, researchers further studied the functional consequences of the

Figure 2: Quantitative Results display how the APOE3ch homozygote compares with other PSEN1 mutation carriers in amyloid-beta plaque burden, tau burden, hippocampal volume, and precuneus glucose metabolism (adapted from Arboleda-Velasquez et al., 2019) BREVIA SPRING 2021


APOE3ch mutation, and they noticed that the specific location of the APOE3ch mutation—an arginine-to-serine substitution at amino acid 136— affects APOE binding to lipoprotein receptors and heparan sulfate proteoglycans (HSPGs). HSPGs are likely involved in facilitating amyloid-beta protein aggregation and neuronal uptake of tau, and experimental results have shown that APOE3ch has the lowest HSPG binding affinity compared to APOE3, APOE4, and even APOE2..5 Therefore, according to these results, it is likely that being homozygous for the APOE3ch mutation reduces the ability of APOE to bind to HSPGs or other receptors that affect downstream tau burden pathology and amyloid-beta plaque burden, which might postpone clinical onset of Alzheimer’s Disease. The results of this study have significant implications on our understanding of the genetic factors and molecular mechanisms contributing to Alzheimer’s Disease. Researchers also developed a monoclonal antibody targeting the specific region in APOE3 where the APOE3ch mutation would be, and they demonstrated that this antibody bound to APOE3 reduced the ability of APOE3 to bind to HSPGs, essentially reproducing the effects of the APOE3ch mutation in vitro. 5 These results point to the prospect of potentially developing molecular compounds that prevent the binding of APOE to HSPGs. Instead of targeting amyloid-beta proteins or tau proteins, this type of therapy would instead target the APOE gene in order to prevent

the aggregation of amyloid-beta plaques or tau proteins in patients who are at risk of Alzheimer’s Disease. Furthermore, the findings of this study challenge long-held theories about the role of amyloid-beta plaque burden in Alzheimer’s Disease, since the APOE3ch homozygote had unusually late onset of mild cognitive impairment while displaying high levels of amyloid-beta plaque burden. Nonetheless, more research needs to be conducted, especially since the results of this study focus on only one individual. While expanding on the sample size of this study is challenging since no other family member was found to carry both copies of the APOE3ch mutation, the team of researchers is studying other members from the same extended family of the APOE3ch homozygote in an effort to investigate other genetic factors potentially involved in postponing clinical onset of Alzheimer’s Disease. Alzheimer’s Disease research lies at the intersection of both genetic and neurodegenerative research, with far-reaching implications that could change our fundamental understanding of dementia. Most important of all, the impact of such research is invaluable on patients suffering from Alzheimer’s Disease or other dementias. Memories fundamentally represent who we are, and they allow for deep self-reflection, appreciation, and fulfillment. Denying this to more than five million Americans and 50 million people worldwide would be a travesty. BREVIA SPRING 2021



Fishing for Human Heart Failure Therapies: How Zebrafish may Turn the Tide Cardiovascular disease is the leading cause of death worldwide.2,4 In the United States, someone dies from cardiovascular disease every 36 seconds.2 And as the global human population ages, the World Health Organization (WHO) forecasts that cardiovascular disease will emerge as the new epidemic of the 21st century.1 This conclusion should not come as a surprise. Over the average human lifetime, heart damage due to routine wear-and-tear is inevitable. Improving healthcare outcomes is no longer a matter of just cardiovascular disease prevention. Instead, healthcare interventions need to also focus on how to mend a broken heart. Mending a broken heart is no small endeavor. Unlike other organs like the liver, the adult human heart cannot rapidly regenerate.4 Regeneration is the process of replacing damaged tissue with healthy, functional tissue. Since the adult human heart is non-regenerative, injury or damage to heart tissue is permanent and strongly contributes to future disease.4 Over time, heart tissue scarring and cell loss accumulate, decreasing the heart’s ability to efficiently pump blood. The cumulative effect of heart tissue damage is so severe that many heart attack survivors have a lower life expectancy than the life expectancy of BREVIA SPRING 2021

By Sophia Swartz patients with most common cancers.1 However, recent research suggests that the human heart’s capacity for renewal is highly timesensitive and more nuanced than previously thought. Since directly experimenting with human hearts is ethically questionable, much research is conducted using mice or rats as models for typical mammalian heart behavior. Such studies have established the capacity for young mouse hearts to regenerate heart cells (also called cardiomyocytes) during the first week of postnatal life.1 Although mice lose this regenerative capacity after their first week outside of the womb, the discovery that heart cells regenerate during a limited time window is promising. These findings suggest that researchers do not have to teach the heart how to regenerate de novo; instead, researchers need to teach the heart how to restart the regeneration process. If you take a peek at human heart muscle under a microscope, you would see a carpet of tightly-packed, pink, rectangularcells;theseareyourcardiomyocytes. Every time your heart beats, the cardiomyocytes in your heart muscle are contracting to pump blood throughout the body (see video). Pumping blood day in and day out for years on end is a

FEATURES challenging job, so cardiomyocyte wear-and-tear is inevitable. When human cardiomyocytes become damaged, the heart begins to develop cardiovascular disease. However, if the human heart relearned how to generate new, healthy cardiomyocytes, then (cellularly) broken hearts would become a thing of the past. So, how do you teach an adult heart how to regenerate again? For answers, researchers are studying the biology of a fish that never stopped regenerating its cardiomyocytes: the zebrafish,

also share a common evolutionary origin with humans.5 However, unlike in humans, if you remove a part of the zebrafish heart, the zebrafish will regrow the missing piece in a matter of weeks.6 Adult zebrafish are special in their ability to reactivate developmental pathways that support cardiomyocyte regeneration, which influences the characteristics of zebrafish cardiomyocytes. At the cellular level, researchers have observed that zebrafish cardiomyocytes capable of regeneration have a specific phenotype. Zebrafish cardiomyocytes with regenerative

Figure 1. Cardiomyocytes under the microscope. In the human heart, individual cardiomyocyte cells pack together to form heart muscle. Heart muscle allows the heart to contract and pump blood throughout the body over the entire human lifetime. In this way, cardiomyocytes are the building blocks of the heart, an astounding feat of engineering in and of itself (drawing credit: Sophia Swartz).

also known by its scientific name, Danio rerio.3 The zebrafish is a striped tropical fish similar to minnows that grows to be a little smaller than the length of your pinky finger.6 Surprisingly, zebrafish share about 70% of human genes.6 Their hearts

potential are mononucleated (containing only one nucleus) and diploid.5 These observations are corroborated by other organisms with adult cardiomyocyte regenerative potential, such as amphibians and fetal mice. Paradoxically, human BREVIA SPRING 2021


FEATURES adult cardiomyocytes are mostly mononucleated and tetraploid; adult mice cardiomyocytes are mostly binucleated (contain two nuclei) and diploid.5 These key characteristics (possessing a single nucleus and a diploid genome) are strongly correlated with significant regenerative ability. Adult cardiomyocyte phenotype is determined by when these cardiomyocytes exit the cell cycle. And

zebrafish reactivate as potential therapeutic targets in humans. In particular, a molecule called cyclin dependent kinase 9 (Cdk9) and its associated repressors are believed to play a key role in mediating zebrafish cardiomyocyte regeneration.5 In experiments where researchers “switched off”’ Cdk9,

Figure 2. Ploidy, nucleation, and their effects on cardiomyocyte regeneration Two cellular phenotypes appear to correlate with cardiomyocytes that are capable of renewal. In humans, cardiomyocytes with regenerative potential are tetraploid (or 4n, meaning they have four copies of their genetic material) and mononucleated (meaning a single cell has one nucleus). In rodents, cardiomyocytes with regenerative potential are diploid (or 2n, meaning they have two copies of their genetic material) and dinucleated (meaning a single cell has two nuclei). And in zebrafish, whose cardiomyocytes have regenerative potential, their cells are diploid (2n) and mononucleated (one nucleus). Although the connections between these cellular phenotypes and regenerative potential are not well-established, they offer powerful hints on how to reactivate regeneration in human and rodent cardiomyocytes (images credit: Kemi Ashing-Giwa).

cell cycle exit and entry, in turn, are regulated by specific developmental pathways that zebrafish have leveraged to their advantage. To better understand how zebrafish induce cardiomyocyte regeneration, researchers are studying the developmental pathways BREVIA SPRING 2021

cardiomyocyte proliferation was inhibited.7 Experiments where researchers “switched off” Cdk9 inhibited cardiomyocyte proliferation.7 For example, switching off Cdk1 in zebrafish embryos negatively affected heart development, creating smaller and weaker hearts compared to zebrafish

FEATURES embryos with normal Cdk1 activity.7 Additionally, in zebrafish embryos with laser-induced heart injuries, switching off Cdk1 impaired the embryos’ recovery compared to zebrafish embryos with normal Cdk9

activity.7 Similarly, experiments where researchers “switched off” Cdk9 repressors to enhance Cdk9 activity showed increased cardiomyocyte proliferation.7 Cdk9 repressors are molecules that regulate Cdk9 levels and ensure Cdk9 does not exceed a certain threshold concentration in the zebrafish embryo. Removing Cdk9 repressors allows the Cdk9 concentration in the zebrafish to exceed what is observed in normal zebrafish embryos. In embryos with enhanced Cdk9 activity, researchers observed that these zebrafish showed increased cardiomyocyte proliferation.7 In this way, the researchers robustly demonstrated the importance of further research investigating Cdk9 as a potential therapeutic target for cardiomyocyte regeneration in adult mammalian hearts. However, a relevant concern associated with any research attempting to reactivate early developmental pathways is the risk of encouraging cancerous growth.7 Cancer is unregulated growth of cells in the body. Under normal circumstances, the body uses the highlyregulated cell cycle and early developmental pathways to tell cells when to start or stop

growing. But modifying these pathways to induce unregulated cardiomyocyte regeneration raises the risk of creating cardiomyocytes that simply do not stop growing and become cancerous. As a result, extensive caution and careful experimentation is needed to make sure any reactivated developmental pathways do not lead to unregulated cardiomyocyte growth. That being said, research investigating the molecular mechanisms guiding cardiomyocyte regeneration is interesting and topical. Although human cardiomyocytes are incapable of regenerating heart tissue and recovering from damage, some organisms that share a common evolutionary origin with humans can regenerate their cardiomyocytes. Zebrafish are of particular interest in the scientific community, with multiple ongoing research projects attempting to learn the regenerative tricks that zebrafish cardiomyocytes use to regenerate. One promising finding is the correlation between enhancing Cdk9 activity and increasing cardiomyocyte proliferation as well as improving zebrafish recovery from laserinduced injury. But although Cdk9 activation and repression are promising therapeutic targets, there are still many other developmental pathways to be studied in search of a molecular trigger to reactivate cardiomyocyte regeneration in adult mammalian hearts.1 Until then, zebrafish hold immense promise in the fight to turn the tide on heart failure therapies. BREVIA SPRING 2021



Studies Throw Shade at Sunscreen Absorption By Shanivi Srikonda Our sun is a paradox. Its ability to facilitate growing crops and foliage is contrasted by its power to destroy and damage. It can harm our skin by wreaking havoc on our outermost layer through UV-A, UV-B, and UV-C wavelengths, which potentially lead to life-threatening skin cancer. Sunlight contains ultraviolet (UV) photons. When these highenergy particles strike the skin, they can be genotoxic, thus causing temporary sunburn and longer-term skin issues. Solar heat can dry out unprotected skin, and thus depleting its supply of natural lubricating oils. Though the sun’s UV rays facilitate vitamin D production in the skin, it can also be incredibly harmful. Protection against harmful UV radiation (UVR) is vital to protect oneself against skin cancer caused by damaging UV rays--sunscreen is both easily-accessible and significantly helpful in providing this protection. Notably there is persuasive evidence that the three main types of skin cancer, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma are caused by sun exposure. Consequently sun protection will have the greatest lifelong impact if achieved as early as possible, especially in those with high childhood exposure to solar radiation.1 BREVIA SPRING 2021

Sunscreen acts as a thin shield to genotoxic high-energy photons by stopping them before they can fully penetrate and damage the skin It contains organic sunscreen molecules that absorb UV, and inorganic pigments that absorb, scatter, and reflect UV. The term “SPF” on sunscreen labels stands for “Sun Protection Factor”, thus products with higher SPF allow fewer photons to strike the skin. SPF 10 can be understood as allowing 10 out of 100 photons to reach the skin, while SPF 20 allows 5 out of every 100 photons.2 Before you are exposed to the sun

FEATURES it is recommended to use a water-resistant 30+ SPF sunscreen with broad spectrum protection against both UV-A and UV-B rays.3 There are two primary types of sunscreens: Mineral (physical) and chemical sunscreens. Mineral sunscreen sits atop the skin and reflects the sun’s rays. It has minerals such as titanium dioxide and zinc oxide as the main active ingredients in physically blocking UVR.4 These can be likened to tiny “mirrors” that protect the skin by reflecting rays back, in this manner. Chemical s u n s c r e e n absorbs into skin. It subsequently absorbs UV rays, converts them into heat, and releases these rays away from the body. Some of its active ingredients are avobenzone, octinoxate, and oxybenzone. 4 In a 2019 study, the Food and

Drug Administration (FDA) discovered that some ingredients in chemical sunscreen are absorbed into the blood plasma. A 2020 followup study also conducted by the FDA found that the tested sunscreens had blood plasma concentrations greater than the established FDA threshold after a single application and that the levels increased with each additional day when the sunscreen was applied. 5 These findings are twofold ambiguous in the larger context of sun safety. We still do not know how to fully interpret them and we do not know if these findings show adverse risks or harmful side effects for the absorption of the studied chemical sunscreen ingredients. The FDA recommends that individuals continue using sunscreen--in addition with other measures such as protective clothing)--due to all of the benefits that sunscreen affords in terms of UVR protection. In parallel the “CDC, the American Academy of Dermatology, and other major physicians’ associations endorse similar recommendations.” 6 In 2019, the FDA announced that it would update its recommendations on the safety of sunscreen ingredients Additionally, they were to explore the extent of chemical absorption into the body and its health effects. In May 2019, a team of researchers at the FDA studied the active ingredients—avobenzone, oxybenzone, octocrylene, and ecamsule—of four BREVIA SPRING 2021


FEATURES commercially available sunscreens to determine if they are absorbed into “systemic circulation” (the general circulation of blood through the body). Twentyfour healthy volunteers were randomly assigned and directed to apply a spray, cream, or lotion sunscreen four times a day for four days to large areas of their bodies. The four aforementioned active ingredients— avobenzone, oxybenzone, octocrylene, and ecamsule—were present in all of the sunscreens in some combination, and thirty samples of blood were collected from the participants over a seven day period. The researchers found systemic concentrations greater than 0.5 nanograms per milliliter of all four active ingredients in the blood of the 24 volunteers. The FDA recommended that active sunscreen ingredients present in such concentration should be studied further toxicologically to test for harmful effects. However, this number is “somewhat arbitrary,” as it is “not known what the significance of this blood level actually means.” 5 In a January 2020 follow-up study-conducted by the same team of researchers who conducted the initial May 2019 study--the FDA aimed to further determine how much some sunscreens are actually absorbed and subsequently processed by the body. Fortyeight healthy participants were given one of four sunscreen products (lotion, aerosol spray, pump spray, or nonaerosol spray) to apply to their skin BREVIA SPRING 2021

a single time on day one and multiple times through day four Thirty-four blood samples from each participant were collected over a 21-day period. 7 Here, the FDA focused on six common ingredients found within chemical sunscreens—avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate—and found that all six sunscreens were “found to have plasma concentrations higher than the FDA threshold after one application, and the levels increased with each additional day of application.” 5 These findings build upon the data from the 2019 FDA study, and “reinforce[s] the need for the FDA to make safety testing for sunscreen products a priority, as sunscreen use is ubiquitous and vital for prevention of UV-induced skin cancers.” 5 Despite these two studies, officials still urged much caution to not over-interpret or wrongly-contextualize these findings, as the May 2019 and January 2020 clinical trials did not research whether the sunscreen blood absorption levels posed health risks--though that is a task left up to future studies. In particular, David Strauss, MD, PhD, Head of the Division of Regulatory Science at the FDA, urged to not jump to conclusions about these sunscreen absorption studies.8 Sunscreen-wearing is widely encouraged by the FDA and other institutions such as Harvard Medical School (HMS). 5 The benefits that sunscreen affords

FEATURES individuals in protection against UVR and skin cancer has been explored since the 1980s. In May 1986, a epidemiological mathematical model study conducted by a team of researchers at the Department of Dermatology, Charles A. Dana Research Institute at Beth Israel Hospital in HMS, and the Department of Biostatistics at the Harvard School of Public Health, estimated that regular use of sunscreen with an SPF of 15 would reduce lifetime incidence of basal and squamous cell carcinomas by 78%. 9 Further research still needs to be conducted to determine the effects of this blood absorption of sunscreen. And there are still many questions about what exactly these findings may be, and what future studies will look for and how. For the time being though, it is still recommended to wear sunscreen while the FDA updates guidelines based on future studies .




Maternal Healthcare during COVID-19: Barriers and Solutions

By Isabella Trasolini

She can hardly hold her eyes open as she fumbles through the cash register to give a customer his change. Preoccupied with wondering how working at a convenience store will ever support both her and her unborn child, she hands the man the wrong change, and he snaps that she should have paid more attention in math class. This shifts her thoughts to college and the two classes that she is failing because planning for the baby has consumed her studying time. In fact, she has not seen a friend for months. She gives the man his proper change, sags onto the stool behind the counter, and places a hand on her rounded stomach, feeling more alone and scared than she ever thought possible. The physical, social, and mental challenges surrounding pregnancy can make this seemingly joyful time one of the most psychologically stressful periods of a woman’s life. About 15% of women develop depression or anxiety during pregnancy, and the numbers are even higher for women who suffer from mental health challenges before becoming pregnant.1 Unfortunately, such perinatal psychological disorders are just as difficult to detect as they BREVIA SPRING 2021

are prevalent because depressive symptoms such as loss of appetite, mood swings, and difficulty sleeping are often attributed to the hormonal changes of pregnancy rather than underlying mental health conditions.1 Pregnancy is one of the worst possible times for a rise in depression and anxiety rates because both can be detrimental to the health of the unborn child.1 Evidence suggests that poor maternal mental health during pregnancy increases the likelihood of premature birth, interferes with the cognitive development of the baby, prevents the fetus from achieving its growth potential, and even obstructs the relationship between

FEATURES the mother and baby if the woman remains depressed after birth.1 Since poor maternal mental health is detrimental to both a woman and her child, healthcare providers have developed strategies to protect pregnant women psychologically. For example, obstetricians are encouraged to screen pregnant women for depression and ask them questions about changes in mood in an attempt to identify mental health concerns early.2 After diagnosis, pregnant women suffering from depression and anxiety are referred to mental health specialists for counseling.2 Combining clinicians from a variety of fields to provide a mother with a support system has proven to promote recovery and enhance the long-term mental wellness of women experiencing p e r i n a t a l 2 psychological disorders. Unfortunately, the COVID-19 pandemic has thrown a wrench into the system, exacerbating the stressors pregnant

women face while making treatment for mental health disorders more difficult than ever. In June 2020, Dr. Margie Davenport and colleagues at the University of Alberta set out to quantify the impact of COVID-19 on maternal mental health, and the results were startling. The researchers began by gathering 900 women who were either pregnant or had just given birth. 1 Then, they used the Edinburgh Postnatal Depression Survey, which can actually be used to detect both postnatal and perinatal depression, to screen each woman for depression.1

Based on the results, about 40% of the women were experiencing depression, compared to only 15% before the onset of the pandemic.1

At first glance, this might not seem surprising; after all, COVID-19 has taken a mental toll on people who are not pregnant as well. However, several aspects of the pandemic have made it particularly challenging for pregnant women. For instance, one of the primary risk factors for developing perinatal depression is lacking social support during pregnancy.1 A pregnant woman’s support system may include BREVIA SPRING 2021


COVERS everyone from her parents and partner to her friends and other new mothers. Social distancing to prevent the spread of COVID-19, however, has made it difficult for pregnant women to connect with others and receive the support they need to cope with the stress of pregnancy. 1 Another risk factor for perinatal depression is domestic abuse, which becomes more prevalent when a woman is pregnant.2 Because couples spend more time at home together during quarantine, COVID-19 has prompted rises in domestic violence, contributing to the increase in perinatal depression amongst women.2 Further, the pandemic’s economic implications have left many pregnant women anxious and overwhelmed. Losing sources of income while expecting a child may lead to worry and a sense of hopelessness, both common symptoms of depression.3 Finally, pregnant women are concerned about the virus itself.3 During pregnancy, the immune system adapts to prevent the mother’s immune cells from attacking the developing baby, placing pregnant women at an increased risk of contracting COVID-19.4 While it is still unclear whether a pregnant woman can transmit the virus to the fetus, contracting COVID-19 during pregnancy increases the risk of miscarriage and stillbirth.2 Similarly, pregnant women are anxious about the delivery process.2 With hospitals limiting the number of visitors allowed in the delivery room, new mothers are BREVIA SPRING 2021

worried that relatives will be excluded.2 Even worse, they fear that their partners will test positive for the virus at the hospital, and they will be forced to give birth alone. 2 With COVID-19 magnifying the stress of pregnancy, it is essential for healthcare providers to find creative ways to continue providing pregnant women with psychological support. One of the most promising strategies to accomplish this goal is through virtual obstetric appointments.2 Because pregnancy increases a woman’s risk of catching COVID-19, many expecting mothers are reluctant to go to hospitals and medical offices in-person.2 However, evidence shows that insufficient prenatal healthcare is associated with pregnancy complications including premature birth and miscarriage.2 Plus, obstetricians cannot screen pregnant women for depression if their patients cancel appointments for fear of contracting COVID-19.2

The solution is telehealth appointments at which obstetricians can monitor both the physical and mental wellbeing of the mother without risking exposure to


the virus; indeed, research demonstrates that women receiving a combination of virtual and in-person prenatal care experience pregnancy outcomes comparable to those of women who only attend inperson appointments.2

Similarly, telemedicine can help resolve anxiety surrounding the delivery process; loved ones can support a patient in labor remotely via video platforms. Beyond incorporating technology into the healthcare system, other approaches can also alleviate the pressure COVID-19 has placed on pregnant women. In a survey of over 1,300 pregnant women in the United Kingdom, about 95% reported that interacting with other new and expecting mothers helped them cope with the stress of pregnancy during the pandemic, with the same percentage responding that financial insecurity prevented them from coping. 2 These results suggest that creating infrastructure such as virtual maternal support groups may protect

pregnant women from psychological disorders. Further, prenatal healthcare providers should be educated about emergency assistance programs so that they can provide information to patients struggling to afford food and shelter. After discovering that 40% of pregnant women are experiencing depression during the pandemic, Dr. Davenport and her colleagues asked them about their coping strategies.1 They found that women who exercised for at least two and a half hours per week were less likely to suffer from depression and anxiety during pregnancy, regardless of the added stress of COVID-19.1 Thus, obstetricians should emphasize the importance of physical activity during pregnancy to their patients, not only for the health of the baby but for the mental wellness of the mother. The COVID-19 pandemic has sparked an avalanche of changes that have left countless pregnant women buried in anxiety and depression. In the flurry of providing increased medical resources for individuals suffering from the virus, it is essential not to overlook the psychological needs of expectant mothers. COVID-19 has already robbed millions of their jobs, loved ones, and lives; we cannot allow the virus to rob infants of mothers who are mentally stable enough to nurture and love them. BREVIA SPRING 2021



Human Microbiome Diversity Affects Stem Cell Transplant Success By Hilina Woldemichael Stem cells are cells within the body that are uniquely able to divide into multiple cell types and are capable of self-renewal. They are found in developing embryos as well as in adults. In embryos, a single stem cell gives rise to the entire developed organism. In adults, stem cells are responsible for the maintenance of several organs in the body, such as the skin and the gastrointestinal tract. When the body sustains damage or otherwise requires rapid cell division, stem cells fulfill that need. Research on these special cells have revealed much about human biology and the developmental process .1 One of the most transformative innovations in medicine has come from the use of stem cells as therapeutic agents. A new therapy from stem cell research is transplantation, and an especially promising emerging procedure is the transplantation of hematopoietic stem cells— cells capable of dividing into any type of blood cell. These procedures are often allogeneic, meaning that it involving cells derived from a donor and not the patient.1 Although promising, there are several major adverse outcomes that can be experienced by patients undergoing these transplants, including relapse, infection, and graft-versus-host disease, where the transplanted stem cells attack the patient.2 BREVIA SPRING 2021

The gut microbiome, the collection of microscopic organisms living in the gastrointestinal tract, has long been linked to host immune function. A healthy and functioning microbiome helps promote immune response to pathogens. In high income countries, dietary changes, improper use of antibiotics, and the elimination of constitutive partners includingnematodesmayhaveresultedin a microbiota that is not resilient or diverse enough to establish a balanced immune response. This has led to a noticeable increase in inflammatory disorders.3 In a February 2020 paper published in the New England Journal of Medicine, researchers at the Memorial Sloan Kettering (MSK) Cancer Center led byDr.VanderBrinkstudiedapopulationof Survival for patient patients receiving allogeneic hematopoietic 2, from [2]. stem cell transplants. Dr. Van der Brink’s team found that the outcomes of patients receiving these transplants could be predicted by the health of their gut microbiota and that patients with a less diverse microbial community had a higher rate of transplantation-related complications.2


Researchers obtained fecal samples of stem celltransplantpatientsfromMSKinNewYorkaswell as from three other centers in North Carolina, Japan, and German, then examined associations between microbiota diversity and patient mortality. They analyzed a total of 8767 samples from 1362 patients. The microbial composition of the samples were analyzed by sequencing of ribosomal genes. Those derived from MSK were marked as cohort 1 and all other centers were marked as cohort 2. They measured microbial diversity and divided patients into high or low-diversity groups. The number of deaths were higher in the lower microbial diversity group compared to the higher diversity groups. Cohort 1 was further separated into subgroups by allograft manipulation, where the composition of the transplanted graft is manipulated to optimize its cell composition—such as by removing immune cells in the donor graft—and reduce risk of graft-versus-host disease. In only the group receiving unmodified ts in cohort 1 and grafts, a lower microbial diversity slightly increased risk for transplantation-related mortality, such as from graft-vs-host disease. More work across a larger patient population needs to be done to conclusively link patients with disturbed microbiota receiving unmodified transplantation to an increased risk of complications.2

The authors concluded that the correlation of decreased microbial diversity with a worsened patient outcome was consistent across all geographically diverse treatment centers. Furthermore, analysis of samples taken before transplantation showed evidence of a disrupted microbiota in patients who had a poor prognosis. The international scale of this study allowed for sampling of a larger, more varied patient population and supported previous research in smaller cohorts. Additionally, this study is one of few to look at the gut microbiome and its relation to patient death.2 A limitation of this study is that the reliance on 16S rRNA gene sequencing is useful for genuslevel identification, but not the elucidation of specific bacterial species and strains. Additionally, this method of sequencing excludes non-bacterial members of the microbiota.2 Nevertheless, a clear connection between microbial composition and transplantation-related complications has been shown. It is possible that patient outcomes can be predicted by the microbial diversity and the relative abundance of specific bacterial taxa. However, as this study was observational, the authors could not show a causative relationship. There must be more research to conclusively link the gut microbiome with transplantation related-complications. Future research on stem cells and the human gut microbiome can further elucidate the complex relationship between humans and our microbial communities. BREVIA SPRING 2021



Ancient Ties between the Crab and Cancer By Abigail Miller The earliest record of cancer is from an Ancient Egyptian medical text, known as the Edwin Smith Papyrus —named after its purchaser— from around 1500.1 In discussing a form of breast cancer, this text, which was likely attributed to an Egyptian physicianarchitect named Imhotep, came to the conclusion that the “bulging tumor of the breast was a serious disease with no treatment”. 2 The cases in Egypt are part of a larger story in history involving other cultures that shows the long battle between humanity and cancer. The Greek physician Hippocrates identified the disease as karkinos, the Greek word for crab, because of the tumor’s physical resemblance to a crab in the way its claws stretch out from the body. A Roman physician, Celsus, brought the idea into Rome and described the disease using the Latin word for crab: cancer. Although not much was known about cancer, a common theory in the Ancient Greco-Roman world was that diseases were brought about by an imbalance of bodily fluids known BREVIA SPRING 2021

as humors: black bile, yellow bile, blood and phlegm. In the case of cancer, the imbalance was thought to be related to the amount of black bile in the body. In a 2014 paper published in the Journal of Breast Cancer, Dr. Leila Rezakhani and her team from the University of Medical Sciences in Kermanshah, Iran, seemed to create a tie between the disease’s present research and its history. Their research suggests that cancer’s relationship with the crab not only extends back into the past but also reaches out into other cultures. The paper states that “in traditional Iranian medicine, crab products were used to treat cancer”. 3 The question then for the team was the effect of crab on a particular cell line of breast cancer outside of the living organism, in vitro. In addition to traditional reasons, the use of crab shells was part of a more natural approach to certain research as more than half of drugs approved for cancer treatment were derived from natural sources. Their experiment showed that a material of crab shell

FEATURES extract has properties that stop the growth and multiplication of cancer cells. The leading agent of this experiment was Chitin. Chitin is found in the outer skeleton of crustaceans and insects and is responsible for the strength of the shells.4 Chitosan is a product of that compound and is said to be a contributor to the reduction of cell growth. 5

extracts were then added to the cells for a variety of time periods: 24, 48, and 72 hours.3 Two tests were then conducted to determine whether the cancer cells were able to survive or whether they died with the addition of the extracts. The two tests known as trypan blue and MTT assay took advantage of color by staining the cells in the culture dishes and calculating

Figure 1: (A) Cell viability with doses and time periods for trypan blue (B) Microscopic image of cells showing the effects of the different doses

In this experiment, Rezakhani and her team prepared five different concentrations of the crab shell mixture, which consisted of powdered crab shell and ethanol. The

the number of remaining cells after the time period in order to determine which ones survived. Cell death, also known as apoptosis, was measured using another BREVIA SPRING 2021



method known as the TUNEL assay. In one of the final stages of cell death, the DNA strand breaks at one end, and the test uses an enzyme that allows labeled fragments to be attracted to those broken ends. These fragments produce a fluorescence which makes dead cells identifiable. Before data analysis, they also measured the level of Nitric Oxide to see its effects on the various concentrations of extract. As part of the results, both the trypan blue and MTT tests showed that as the concentration of extract increased, the percent of cells that survived, cell viability, decreased.3 These measurements were taken for the 24, 28, and 72 hour groups. Figure 1 illustrates the trypan blue and Figure 2 illustrates the MTT assay. Figure 1B uses microscopic images to more clearly indicate the decrease in cell number. There was also a time dependent reduction of Nitric Oxide levels indicated by Figure 3, which Rezakhani and her team attributed to the properties of crab shells that stop cell growth and multiplication by initiating cell death. 3 These properties include carotenoids, yellow-orange pigments that give color to pumpkins, corn etc., and selenium, a natural substance nutritionally beneficial BREVIA SPRING 2021

for humans.6 In a process dependent on time and concentration, this experiment demonstrates the effect of crab shells on repressing the growth and spread of cancer cells. This reduction was largely achieved through increased levels of cell death and lower levels of Nitric Oxide. With so much change it is fascinating that ties can be drawn across different moments of time. History and tradition can have weight on present matters. An dormant idea can be taken and revived with a new set of eyes. While there is no cure for cancer, papers such as this one show that we have come a long way from the practitioners behind the Edwin Smith Papyrus and that we continue to press on.


Figure 2: Cell viability with doses and time periods for MTT assay

Figure 3: Nitric Oxide levels with doses and time periods



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Brevia is a forum for science, culture, and other big ideas. We are committed to bringing all disciplines of research out of the ivory tower and into the discourse of the interested public. Through our opinion, features, and primary research articles, we explore the myriad connections in the world of intellectual endeavor. Our stories are brief because we want to make knowledge accessible and interesting, providing a palette of perspectives on the world around us. Brevia Volume 6 • Issue 3• Spring 2021 © President and Fellows of Harvard College