Vertices by kimdoanpham

VER TICES 29

ISSUE//

VOL# 02

VERTICES* SPRING 2014

ER //

DUKE UNIVERSITY JOURNAL OF SCIENCE AND TECHONOLOGY

TI _

CES* }

VERTICES* DUKE UNIVERSITY JOURNAL OF SCIENCE AND TECHONOLOGY

SPRING//2014*

ISSUE#//029 Vol #//02 // Editors-in-Chief // Prachiti Dalvi Pranali Dalvi // List of Editors // Cindy Abello Abhishek Balakrishnan Yash Bhatnagar Elisa Berson Manoj Kanagaraj Komal Kinger Suyash Kumar Akhil Sharma Jenny Wang // Project Advisor // Denise Gonzalez Crisp // Designers // Kim Pham Yairon Martinez // List of Artists // Madison Dixon Lara Kozak Stephen Lindberg Michael Celedonia Yairon Martinez Copyright 2014 Duke University Undergraduate Publications Board Vertices is a franchised publication authorized by the Duke University Undergraduate Publications Board (UPB). No part of this publication may be reproduced, except for personal use, without prior written consent of the UPB. Any opinions expressed herein are those of the authors, who are solely responsible for the content. ##

Dearest reader,

Thank you for picking up a copy of the spring 2014 issue of Vertices! We are excited to present the

work of nine undergraduates who have taken their interest in learning outside of the classroom and explored interdisciplinary topics such as the morality of the brain, astromicrobiology, and numerical cognition. The undergraduates featured in this issue are prime examples of students who are using the various schools and institutes at Duke to cultivate their interests and craft their own educational paths. The research done by these undergraduates is just a subset of the exceptional research that happens in this powerhouse every day. We hope you can find something in this issue that will both inspire you and make you proud of the work of your peers.

Additionally, we present to you our third installment of our Graduate Student Spotlight Series. We

hope these interviews with graduate and medical school students will give you advice on how to make the most of your undergraduate experience and make you excited you about your future after Duke. As this is our final issue as editors-in-chief of Vertices, we would also like to leave you with an interview with our personal inspiration, Dr. Victor Dzau, the CEO and President of the Duke Health System. We have had a wonderful time creating the past 6 issues of Vertices as editors-in-chief and are so grateful to our readers for their feedback and committed readership. We would like to sincerely thank both our editors at Duke and our design team at NC State for their countless hours of hard work and dedication. Thank you for making Vertices such an integral part of our undergraduate experience and one we will cherish for years to come.

All our very best, Prachiti + Pranali

## 03

//TABLE OF CONTENTS//

AN INTERVIEW WITH VICTOR J. DZAU, MD. DNA OF THE DENISOVA MORALITY IN THE BRAIN

Prachiti Dalvi

Andrew Luo

Partha Chodavadia

UNDERSTANDING NUMERICAL COGNITION

Andrew Luo/Nick DeWind/Michael Platt

GRADUATE STUDENT SPOTLIGHT: STEPHANIE SANTISTEVEN VIIP SYNDROME:

Elisa Berson

Deepak Sathyanarayan

VISION DETERIORATION IN LONG-TERM SPACE TRAVEL

A CASE FOR DRUG RE-PURPOSING:

Eric Lakey

WHERE LESS IS MORE

THE THREATENING DECLINE OF JAPAN:

Gregory Moore

AS THE THINNEST AND LONGEST-LIVED COUNTRY

GRADUATE STUDENT SPOTLIGHT: LAUREN GROSKAUFMANIS ETIOLOGY OF THE BAD LSD TRIP

Elisa Berson

Shaq Junaid

MICROBIOLOGY AND THE FINAL FRONTIER:

Alissa Wall

REVIEWING THE IMPACT OF SPACE’S UNIQUE ENVIRONMENT ON MICROBIAL ECOLOGY AND HUMAN HEALTH

GRADUATE STUDENT SPOTLIGHT: JOE BARTER

Elisa Berson

EXERCISE AND THE CYTOKINE INDUCED KILLER CELLS EFFECTS OF RESVERATROL: USING A MODEL OF SENESCENCE IN ZEBRAFISH EMBRYOS

Michelle Wu

Aileen Bi

VERTICES//029.02

12 32 42

24 24

6 6

10 10

30 40 30

62 62

68 68

Victor J. Dzau, MD//

//INTERVIEW.00

[AN INTERVIEW* WITH// //VICTOR J. DZAU, MD] By: Prachiti Dalvi

// DIALOGUE // Prachiti Dalvi: What piqued your

interest in the sciences and medicine? Victor Dzau: During a part of my medical school education, I became quite intrigued by physiology. I remember studying about cardiovascular physiology and I thought it made so much sense and was so interestingâ&#x20AC;&#x201D;the fact that it could explain diseases.

//An Interview With //

I started out very interested in fundamen-

tal mechanisms and there were people around me who were doing research. I had some research experience as an undergraduate, more like a summer job. So, that renewed interest in understanding physiology plus my summer experiences working in a lab made me realize that this was something I wanted to do. I was intrigued by the work that was coming

VERTICES//029.02

PD: You have been at a variety of academic institutions, Stanford, Harvard,

and Duke to name a few. What have you

noted about the academic and research environments in each of these places?

VD: The right academic environments are all very similar. At the end of the day, any environment is made of people and an academic environment is made up of people who are seeking out knowledge. Everywhere I have been, I have encountered people who have a true inquisitiveness and real desire to do excellent research, to gain

I GUESS THAT FOCUS AND COMMITMENT TO RESEARCH GAVE ME A REAL APPRECIATION FOR IT. IT TOOK ME SEVERAL YEARS TO GET MY PROJECT DONE BUT WHEN I WAS DONE, IT WAS VERY SATISFYING.

more knowledge. That is very similar. I do not think there is a tremendous difference between these places in that context. Every place is different in the physical nature, the structure, and the specific people. That differs from place to place. I have been very lucky in all three places to meet people who were so dedicated, so passionate about their research, and so smart. For me it has been a tremendous pleasure to work in these different places.

out from articles that were published in

every fellow comes in wanting to do clinical

the New England Journal of Medicine,

work first and then research to hedge their

Circulation Research: research that takes

bets so that if research does not work,

evidence-based science towards patient

they already have their clinical skills in

VD: I really enjoyed the idea of collaborat-

care. I was at McGill at the time. I thought

their pocket. â&#x20AC;&#x2DC;If you are really committed to

ing, interacting, and, particularly, learning

I would like to go to the United States and

research, I want you to do it first and then

from people who are in different disciplines.

so I ended up at Harvard. My real engage-

do clinical work,â&#x20AC;&#x2122; he told me, which is what

What attracted me to Duke was the fact

ment with research did not happen until

I did. I guess that focus and commitment to

that as chancellor, I had the opportunity

I finished my residency and started my

PD: What brought you to Duke?

research gave me a real appreciation for it.

to, from a broader perspective, look at

fellowship. I wanted to be a cardiologist.

It took me several years to get my project

everything from medical practice to basic

Given my interest in cardiovascular physi-

done but when I was done, it was very

science research to even different areas

ology, disease, and therapy, I applied for a

satisfying. I was a little late in appreciating

such as engineering, economy, and law.

cardiology fellowship at Mass General. The

research. I was exposed a little bit as an

For me, it was really attractive because so

person who was the head of the Cardiolo-

undergraduate but when I was a fellow I

many of our problems are now interdis-

gy Department was named Ed Haber. He

truly started doing research. Before that,

ciplinary. To have a campus that is highly

was a very distinguished physician-sci-

I was always intrigued by mechanism of

interactive where everything is accessible

entist. He trained with Anfinsen, who was

disease, which emerges from research, but

was very appealing. As chancellor, I am

a Nobel Laureate, at the NIH. Haber was

I never put in enough time until then.

able to bring these opportunities together

very much using molecular techniques

to solve problems.

towards cardiovascular disease. Before he would accept me as a cardiac fellow, he wanted me to do research first because 07

//INTERVIEW.00 >>

PD: How do you a strike a balance

PD: The Duke University Health Sys-

hospital administrator?

chancellorship, from the new Duke Can-

between your roles as a researcher and

VD: Some people imagine that these roles compete with each other and that they are polar opposites of each other. I do not see it that way. I see this as a continuum

tem has made great strides during your cer Institute to the new Trent Semans

Center for Health Education. What has been the key to achieving these huge

successes in such a short time period?

because what we do in administration is to

try to make this place better—better for our

VD: That’s easy. The people. My entire

patients, better for our students, better for

life, I have been so lucky to have so many

our faculty. If you are not yourself having

good people around me. They are the

that experience, then you will be carrying

ones that make things happen. As I said

out your administrative duties from an in-

earlier, my job is to create the right environ-

sulated space; whereas, if you are like ev-

ment, to work with everyone to come up

erybody else (you continue to do research,

with a vision, and then being able to help

etc.), you understand the challenges a lot

people get there. If you look at everything

better. Secondly, I believe you learn so

that has happened, I give credit to every-

much more by being surrounded by stu-

one around me. I am very lucky to be part

dents and others and, therefore, in the lab

of an amazing team.

I can continue having interactions, which are very helpful in helping me do a better job. The first thing is relevance, credibility, and being able to learn at the same time. Research, for me, is the ability to think creatively, the ability to think about what the most innovative idea, and then to be able to work with my lab members to test it out.

PD: You are going to be going to the

Institute of Medicine this summer. What

about your new position excites you the

most and what will be the most pressing challenges you will have to face?

Thus, I see research as an expression of

VD: It is a very different job. Here, I have

my creativity and passion; whereas, with

25,000 people working at Duke Medicine

administration, you can do those things as

with a budget of 4 billion dollars. I will

well, but you have a little more balance in

be going to an organization that is much

thinking about many different issues, many

smaller—about 200 people working for

different people. Thus, these two are in a

me and a budget of 40 million. Here, I am

continuum—from expressing your creativity

responsible for running and managing the

to using that knowledge to modulate what

place. I have to look at every aspect of it

is best for the organization.

to assure quality and efficiency. There, my

I BELIEVE YOU LEARN SO MUCH MORE BY BEING SURROUNDED BY STUDENTS AND OTHERS AND, THEREFORE, IN THE LAB I CAN CONTINUE HAVING INTERACTIONS

main job is to advise and think about what is best for medicine and healthcare in this nation. It will give me more time to reflect and have intriguing conversations. What I would like to do is spend more time talking to people, getting out of the Institute and meeting people to figure out what is really going on and what should we spend our energy looking at, especially issues that affect healthcare and science in this nation.

//PRACHITI DALVI

We will be putting our heads together with

those qualities. When you work hard, new

some of the best people to craft some

opportunities come to you. Then, you can

ideas about the directions we should be

follow your gut and your passion. Whatever

going in. What IOM does is a fair amount

you do, you have to love what you do and

of study that influences government in

be good at what you do.

terms of policy decisions. Hopefully, we can actually put our best minds together to figure out what is in the future and how

we can get there together. We want to be able to rally the support of the public so that we can be a much better and stronger nation. What is exciting about this is that we will have the resources and the time to bring people together to determine how we can make a difference. At the end of the day, having made a difference is going to

THAT FUNDAMENTALLY COMES DOWN TO AN INDIVIDUAL’S VALUES. THAT IS PROBABLY THE MOST IMPORTANT. TOO MANY PEOPLE THINK THEY CAN PLAN OUT THEIR ENTIRE LIVES AND THAT IS JUST NOT SO.

be most important. In this new role, I will focus more on advising and policy to the government and to the public. PD: What is the most important trait in an aspiring physician and/or scientist? VD: That fundamentally comes down to an individual’s values. That is probably the most important. Too many people think

they can plan out their entire lives and that is just not so. As a young man from China, I never thought I would be doing this and if I had planned it out, it would have probably failed. The doors open as you do a good job. Thus, the value really matters: who you are, what you care about, and what you are passionate about. When you have high values—whether you do science to improve the knowledge to help society or you help patients to help the individual— you work with the community to do greater good. You may be creating knowledge, a better explaining disease, coming up with a discovery that can help patients, or being a compassionate doctor that not only gives patients the treatment but also the whole compassion. You should be able to come to a job with the passion and an enthusiasm to always do a good job no matter what you do. People recognize 09

//ARTICLE.01

[DNA OF THE// //DENISOVA ]

By: Andrew Luo

Roughly 1.9 million years ago, Homo

However, in a Nature report published in

erectus became first wave of hominins

April 2010, German researchers success-

of Neanderthal and human mtDNA, which

to migrate away from Africa. Since then,

fully extracted the complete mitochondrial

is estimated at 465,700 years ago. In

subsequent hominin groups also departed

DNA sequence of an ancient hominin finger

conclusion, researchers speculate that the

Africa, the Neanderthalâ&#x20AC;&#x2122;s ancestor leaving

bone found in the Denisova Cave of south-

Denisova specimen lived between 30,000

between 500,000 to 300,000 years ago

ern Siberia. The bone, originally thought

to 50,000 years ago, at a time when

and anatomically modern humans about

to be of Neanderthal origin, indicate a

multiple Late Pleistocene hominin lineages

50,000 years ago. Despite the expansion

previously unrecognized human species

coexisted in Eurasia. [A]

of hominin DNA around the globe and

that migrated out of Africa. [B] Data reveal

steady improvements in genetic retrieval

that the Denisova hominin mtDNA differed

technologies, the vast majority of ancient

from humans at roughly 385 nucleotide

hominin DNA are unknown. With the

positions. [A] This sharply contrasts with

exception of several DNA samples from

Neanderthal mtDNA results, which only

Neanderthal specimens, sequences for

differ with that of modern humans at an

Pleistocene hominins such as H. Erectus

average of 202 positions. [A] Based on the

or H. heidelbergensis still have not yet

assumption that the average divergence

been found. [A] The difficulty in finding

of human and chimpanzee mtDNAs is six

ancient DNA samples is largely attributed

million years ago, researchers conclude

to DNA degradation; it takes an extraordi-

that the most recent mtDNA ancestor of

nary set of conditions for DNA to survive

the Denisova hominin, Neanderthals and

through temperature and soil conditions

modern humans is around one million

over long periods of time.

years ago. This figure indicates that the divergence of the Denisova hominin

010

mtDNA is twice as old as the divergence

//ANDREW LUO

Two aspects of the Denisova mtDNA

ianâ&#x20AC;? selection, this low ratio value points

Denisova mtDNA and human mtDNA is

report were particularly noteworthy: the re-

convincingly at negative selection, in which

twice as deep as that of Neanderthal

searchersâ&#x20AC;&#x2122; methods of sequencing and the

there is an obvious sign of evolutionary

mtDNA, the divergence of the Denisova

explanation of the dN/dS ratio. To extract

constraint in the evolution of Denisova mi-

nuclear genome to human genomes is

DNA from the bone sample, researchers

tochondrial proteins. In other words, there

roughly the same to that of Neanderthals.

converted 30 mg of bone powder into an Il-

was a specific survival advantage with

[C] However, this is not to say that the Den-

lumina sequencing library to isolate mtDNA

these mitochondrial proteins in Denisova

isova is closely related to Neanderthals.

fragments from the entire mitochondrial

individuals, and all other changes were

Rather, the primitive traits of the Denisova

genome. These isolated fragments were

subsequently selected against.

tooth suggest that Denisovans separated

subsequently sequenced using the

Despite the mounting mtDNA evidence

from the Neanderthal lineage more than

Illumina platform, using 76 cycles per read.

on the relationship of the Denisova to

300,000 years ago [C], before Neanderthal

Fragments were used in more analyses

modern humans and Neanderthals, there

dental features were documented. This

and merged into single sequences, with

are still questions left unanswered. Nuclear

new evidence from the Denisova genome,

all fragments over ~134 bp removed from

DNA samples must be evaluated before

coupled with the previous study on mtD-

consideration. In total, 30,443 distinct

any claims can be made regarding the

NA, show that the Denisova hominin group

sequences were used to assemble the

discovery of a new species. On its own,

shares a common ancestor with Neander-

mtDNA sequence, and only bases with

mtDNA is maternally inherited as a single

thals but has its own distinct history.

the highest quality score were used. [A]

unit without any recombination. [B] This

The meticulous sequencing was crucial,

Though the general relationship between

factor makes mtDNA prone to events such

Denisovans, Neanderthals, and humans

especially for the ancient Denisova mtDNA.

as gene flow, genetic drift, and positive

has been determined, the question now

Older DNA samples are prone to degrada-

selection. [C] In contrast, nuclear DNA is

is to see where Denisovans inhabited. At

tion in terms of fragment length, cytosine

composed of thousands of unlinked and

present, the only DNA evidence has been

residue replacement, or overrepresentation

evolving loci, which is much less affected

found in Southern Siberia. The next step

of purines outside the fragments. [A] The

by any chance events such as genetic

now is to locate more samples of Deniso-

intensive coverage throughout the sam-

drift. [C] In a Nature article published in

va DNA and to perform genetic tests on

ple measured at an average of 156-fold

December 2010, researchers expanded on

present-day humans in the East Asia and

[A], high read depth and coverage of the

the previous study on Denisova mtDNA by

Southern Siberia. These new tests have

Denisova sample allowed for accurate

sequencing Denisova nuclear genome and

the potential to not only indicate how wide-

comparisons, especially since the Deniso-

using a recently uncovered Denisova tooth

spread the Denisova lived but also divulge

va mtDNA was aligned to 54 present-day

as a morphological reference. Following

their impact on ancient hominin genomes

human mtDNAs and a Late Pleistocene

sequencing of the Denisova genome, the

as well as our own.

mtDNA found in Kostenki, Russia. [A]

DNA results were compared to both the

Of the twelve proteins encoded in the Den-

human reference genome and the Vindija

isova hominin mtDNA, data showed that a

Neanderthal. The results varied sharply

low per-site rate of amino acid replacement

with previous mtDNA findings. Divergence

(dN) compared to the per-site rate of silent

of the Denisova genome to the human

substitutions (dS). The calculated dN/dS

genome was 11.7% while the divergence

ratio is marked at 0.056. [A] Whereas a >1

with the Vindija Neanderthal was 12.2%.

ratio would suggest a positive â&#x20AC;&#x153;Darwin-

[C] Thus, while the divergence between

Krause J, Fu Q, Good J et al. (2010). The complete mitochondrial DNA genome of an unknown hominin from southern Siberia. Nature 464 894-896.

Dalton R, (2010). Fossil finger points to new human species. Nature 464 472-473.

In conclusion, researchers speculate that the Denisova specimen lived between 30,000 to 50,000 years ago,

Reich D, Green R, Kircher M et al. (2010). Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature 468 1053-1060

011

//ARTICLE.02

By: Parth Chodavadia

[MORTALITY*_OF THE// //BRAIN] Imagine that you are driving along a country road when you hear a plea for help coming from among the bushes to your right. You stop the car and encounter a man whose legs are drenched in blood. The man explains that he had an accident while hiking and asks you to take him to a nearby hospital. You initially want to help the man, who will most likely need his leg amputated if you do not get him to the hospital soon. However, if you take this man to the hospital, his blood will leave irremovable bloodstains on your leather seating, essentially ruining your car. Is it appropriate for you to abandon the man in order to preserve your car seats?

012

//PARTH CHODAVADIA

RECENT STUDIES HAVE IMPLICATED THAT MULTIPLE BRAIN REGIONS CONTRIBUTE TO OUR IMPRESSION OF MORAL COGNITION.

Most people would say that it would be

The vmPFC is central to most discus-

seriously wrong to abandon this man out of

sions of moral salience in the brain. It plays

concern for one’s leather upholstery. Now

an important role not only in regulating

consider a different case. You receive a

subjective evaluation, reward, memory,

letter in the mail from a non-governmental

and decision-making but also in learning

organization asking you to donate two

to associate context, locations, events,

hundred dollars. The letter explains that the

and emotional responses [F]. Injury to

two hundred dollar donation will be utilized

the medial prefrontal cortex has been

to provide needed medical attention to

associated with emotional blunting, higher

orphans and vulnerable children in Mom-

impulsivity, loss of social emotions such as

basa, Kenya. Is it appropriate for you to not

empathy and guilt, and greater disconnect

make a donation to this organization?

between emotion and context [P;I ]. In the

Recent studies have implicated that

context of moral reasoning, damage to the

multiple brain regions contribute to our im-

vmPFC at early ages leads to “sociopathic”

pression of moral cognition [L;J;H], pointing

and “psychopathic” behavioral pheno-

to the involvement of cortical (ventromedial

types, suggesting that early impairments in

(vmPFC) prefrontal cortex, frontopolar

vmPFC development may explain immoral

(FPC) sectors of the prefrontal cortex,

behaviors that develop later in life [E].

and anterior temporal cortex) and limbic

Interestingly, vmPFC damage also abnor-

(ventral striatum, hypothalamus, amygdala,

mally increases the likelihood an individual

hippocampus) structures in supporting

will endorse “utilitarian” approaches in

moral cognition [L]. Contribution of these

judging moral dilemmas that pit “consider-

areas to moral thought and behavior differs

ations of aggregate welfare against highly

with internal emotional states of the deci-

emotionally aversive behaviours” such as

sion-maker. Lateral regions of the frontal

having to sacrifice one person’s life to save

lobes seem to regulate emotions associat-

a number of other lives [K]. Consider the

ed with punishment whereas medial frontal

two scenarios [O].

regions seems to regulate perceptions of moral character associated with reward [J]. As we will see, there also exists a similar neurological distinction between “personal” (man lying on the side of the road) and “impersonal” (donations to an international

A Blair, R., Jones, L., Clark, F. & Smith, M. (1997). The psychopathic indiviual: a lack of responsiveness to distress cues? Psychophysiology, 34(2): 192198.

Blair, R. (2007). The amygdala and ventromedial prefrontal cortex in morality and psychopathy. Trends In Cognitive Sciences, 11(9):387-392.

Buckholtz, J., Treadway, M., Cowan, R., Woodward, N., Benning, S., Li, R.… & Zald, D. (2010). Mesolimbic dopamine reward system hypersensitivity in individuals with psychopathic traits. Nature Neuroscience, 13: 419-421.

aid organization) moral decisions [H]. 013

//ARTICLE.02 >>

A B

“Switch Dilemma” - You are at the wheel of a runaway trolley that is approaching a fork in the tracks. On the left is a group of five students tied to the tracks. On the right is a single student. If you do nothing the trolley will proceed to the left and kill all five students. The only way to save those five students, however, is to press a switch on your dashboard that will change tracks and send the trolley towards the right, leading to the death of one student. Most people say that it is morally acceptable to divert the trolley, a judgment that coincides with the utilitarian perspective that emphasizes the greater good. “Footbridge Dilemma” - Now imagine that you are walking on a footbridge above the runaway trolley’s track. Next to you is a stranger who happens to be very large. The only way to save those five students is to push this stranger off the bridge to the tracks below, where his large body will stop the trolley. The stranger will die but the five students will be saved. In this case however, most people say that it is morally unacceptable to push the stranger, a judgment that coincides with the deontological perspective that individual rights are more important than the greater good.

Carlo, P. (2009). The Ice Man: Confessions of a Mafia Contract Killer. New York, NY, USA: St. Martin’s Press.

Eslinger, P., & Damasio, A. (1985). Severe disturbance of higher cognition after bilateral frontal lobe ablation: patient EVR. Neurology, 35(12): 1731-1741.

Euston, D., Gruber, A., & McNaughton, B. (2012). The role of medial prefrontal cortex in memory and decision-making. Neuron, 76: 1057-1070.

Greene, J., Sommerville, R., Nystrome, L., Darley, J., & Cohen, J. (2001). An fMRI investigation of emotional engagement in moral judgment. Science, 293: 2105-2108.

Joshua Greene and colleagues were

systems that are in competition with each

among the first neuroscientists to examine

other when an individual is presented with

neural responses to moral dilemmas like

difficult moral decisions [G]. In the context

the trolley problem presented above.

of difficult moral choices such as those

Normal subjects were exposed to moral

presented in the “Footbridge Dilemma”

and nonmoral dilemmas. Moral dilemmas

above, the emotional system would fran-

were divided into moral-personal (agent

tically tell the decision-maker not to push

acts directly like in scenario two) and mor-

the man over the bridge while the cognitive

al-impersonal (agent acts indirectly like in

system would recommend the rational

scenario one). Greene found that personal

choice with maximum benefit. According

moral dilemmas elicited greater responses

to this “dual process” theory, choosing

in areas associated with emotion such as

to push the man over the bridge would

the medial frontal gyrus, posterior cingulate

imply that top-down processes from the

gyrus, and the angular gyrus when com-

prefrontal cortex favored judgments with

pared with neural responses elicited by

the least opportunity cost and suppressed

impersonal moral dilemmas – confirming

emotional responses in the limbic system

the hypothesis that emotional engagement

– which are thought to be automatic and

affects moral salience [G].

uncontrolled. Such a model for moral cog-

While it is no surprise that both emotion

Greene, J. (2003). From neural ‘is’ to moral ‘ought’: what are the moral implications of neuroscientific moral psychology. Nature Reviews Neuroscience, 4: 847-850.

014

nition privileges the vmPFC at the expense

and cognition play an important role in

of other brain regions that are involved in

regulating moral judgment, how reason

regulating moral behavior.

and emotion interact to process a decision remains a heated topic for discussion. According to one view, emotion and cognition are diametrically opposed neural

VERTICES//029.02

An alternative novel proposal empha-

Psychopaths are particularly useful in

normally prevents individuals from violating

sizes that emotion and cognition work in

dissecting this dichotomous notion of mo-

moral codes [A;B].

parallel to foster moral motivations and that

rality and understanding the neurobiologi-

such cooperation is represented within the

cal implications of corticolimbic dysfunction

Kuklinski (“The Iceman”) was a serial killer

corticolimbic circuit [L]. Conflicting moral

on moral decision-making. Psychopaths

who was notoriously known for freezing his

decisions would thus not entail competition

lack moral salience, making them perfect

victims to confuse times of death. Kuklinski

between cortical and limbic regions but

models to study neural dysfunctions that

resorted to guns, knives, explosives, fire,

emphasize competition between two sep-

lead to aberrant behavior. Although studies

cyanide, asphyxiation, and even barehand-

arate choices governed by their respective

have shown that psychopaths exhibit no

ed beatings to kill his victims, treating each

cortico-limbic circuitries. In this case, moral

general impairment in identifying the mental

murder as some sort of deluded exercise.

motivation and sentiments rather than

states of other people based on photo-

Kuklinski later recalled one of the few

opportunity costs of the decision outcome

graphs, they lack the ability to recognize

murders he later regretted:

would primarily influence what choice an

distress in their victims and are unable to

individual makes when presented with a

associate actions that harm others with

moral dilemma.

aversive reinforcement, an ability that

Consider the following example. Richard

“It was a man and he was begging, and pleading, I guess. And he was, “Please, God, no,” all over the place. So I told him he could have half an hour to pray to God and if God could come down and change the circumstances, he’d have that time. But God never showed up and he never changed the circumstances and that was that. It wasn’t too nice. That’s one thing, I shouldn’t have done that one. I shouldn’t have done it that way” [Kuklinski, 1991].

...EMOTION AND COGNITION ARE DIAMETRICALLY OPPOSED NEUTRAL SYSTEMS THAT ARE IN COMPETITION WITH EACH OTHER WHEN AN INDIVIDUAL IS PRESENTED WITH DIFFICUL MORAL DECISIONS [GREENE, 2001].

Hare, T., Camerer, C., & Rangel, A. (2009). Selfcontrol in decision-making involves modulation of the vmPFC valuation system. Science, 324 (5927): 646-648.

Harris, S. (2010). The Moral Landscape: How Science Can Determine Human Values. New York, New York, USA: Free Press.

Koenigs, M., Young, L., Adolphs, R., Tranel, D., Cushman, F., Hauser, M., & Damasio, A. (2007). Damage to the prefrontal cortex increases utilitarian moral judgments. Nature, 446: 908-911.

Moll, J., de Oliveira-Souza, R., & Zahn, R. (2008). The neural basis of moral cognition: sentiments, concepts, and values. Annals of the New York Academy of Sciences, 1124:161-180.

015

//ARTICLE.02 >>

Kuklinski’s lack of association between

regards for subsequent consequences.

action and consequence may be ex-

In fact, many researchers speculate that

plained by reduced connectivity between

elevated dopamine response to anticipated

corticolimbic circuit hubs in psychopathic

reward prevents a person from learning

patients. In a recent study examining

negative emotions from others. Anticipation

functional connectivity between vmPFC

of reward thus may not only outweigh

and amygdala in psychopathic criminals

recognition of emotion but also deeply influ-

relative to non-psychopathic criminals,

ences decision-making in psychopaths.

Motzkin and colleagues found reduced

Let’s take another look at Kuklinski’s

structural integrity in the white matter

psychopathy using this reward-oriented

connection between the vmPFC and the

model. In his memoir recorded by Carlo in

anterior temporal lobe [N]. Further examina-

2006, Kuklinski notes why he continued to

tion of the anterior temporal lobe implicated

kill his victims:

diminished connectivity between the vmPFC and the amygdala, suggesting that impaired moral decision-making in psychopaths might be a result of deficient integration of affective information in the prefrontal cortex and supporting the hypothesis that emotion and cognition work together to create moral judgments [N]. But support for parallel processing of emotion and cognition in moral salience

“What I liked most was the hunt, the challenge of what the thing was. The killing for me

is not unanimous with regards to psycho-

was secondary. I got no rise as such out of it…for the most part. But the figuring it out,

path research. Buckholtz and colleagues

the challenge – the stalking and doing it right, successfully – that excited me a lot.

recently showed that there might be a third component affecting processes involved in moral judgment other than emotion and cognition [C]. He found that impulsive-antisocial psychopathic traits predicted the amount of dopamine released in the ventral pallidum (specifically the nucleus accumbens) in response to amphetamine intake, suggesting that the mesolimbic dopamine reward circuitry may be hypersensitive in individuals who exhibit more psychopathic traits [C]. Hypersensitivity in the dopamine reward system has been linked to engaging in risky and predatory behavior such as drugs and sex – without

016

The greater the odds against me, the more juice I got out of it” [Carlo, 2006].

//PARTH CHODAVADIA

Moll, J., Zahn, R., de Oliveira-Souza, R., Krueger, F., & Grafman, J. (2005). The neural basis of human moral cognition. Nature Reviews Neuroscience, 6: 799-809.

Motzkin, J., Newman, J., Kiehl, K., & Koenigs, M. (2011). Reduced prefrontal connectivity in psychopathy. Journal of Neuroscience, 31(48): 17348-17357.

Thomas, J. (1985). The Trolley Problem. The Yale Law Journal, 94(6): 1395-1415.

Van den Bos, W. & Guroglu, B. (2009). The role of the ventral medial prefrontal cortex in social decision making. Journal of Neuroscience, 29(24): 7631-7632.

It is clearly evident in Kuklinski’s narrative

contemporary neuroscience research sug-

that the anticipation of reward – anticipating

gesting the opposite with increasing clarity,

abstractions in the brain and come to

the “high” that resulted from hunting his

however, our historically held notions of

understand ourselves better – who we are,

victims to death and formulating elabo-

morality are being seriously challenged.

what makes us human, and why we make

rate plans to murder – was an important

Morality was once considered to

As we delve deeper into understanding

judgments as we do – debates focusing on

motivator of his actions, detracting from his

be an extremely personal judgment, a

the maturation of human morality will only

ability to make moral judgments. Kuklinski’s

reflection of our past experiences and

grow more intense. In the engaging duel,

fascination with killing thus overpowered

cultural upbringings – the direct result of

some of our pre-conceived beliefs and

his capacity for emotional and cognitive

the massive convergence of many inputs

values will survive this process of reflection.

processing. Neurologically speaking, do-

to form a single decision outcome. But

Some will not. I cannot predict exactly how

pamine release triumphed recognition and

now morality is being attributed to neural

we will change. All I can state with certainty

reaction processed within the corticolimbic

projections and moral truths that might

is that neuroscience will undoubtedly force

circuit.

have been evolutionarily advantageous to

us to rethink our definition of being human

preserve, a product of natural selection

– maturing our worldviews, our intellect,

morality can even be reduced to neural

on our social brains. What does this imply

and our personalities in the process – to

signals – that moral cognition, moral

for our perception of morality? Was the

create a more aware human worthy of the

motivations, and moral knowledge can

world a happier and more peaceful place

twenty-first century.

be traced to activation of the vmPFC and

when we were ignorant of the objectivity

limbic forebrain structures and linked to the

our most subjective decisions? Or are we

dopaminergic system – presents a threat

now happier knowing that we are closer

to our notion that we are unique. Morality

than ever to solving a mystery that has

is societally considered a construct of the

plagued philosophers and psychologists

human mind, not the human brain. With

for centuries?

Regardless of the accurate model, that

017

//ARTICLE.03

By: ANDREW LOU Nick DeWind Michael Platt

[UNDER_ STANDING. NUMERICAL// //COGNITION] Introduction

Dehaene S.; “Origins of Mathematical Intuitions” The Year in Cognitive Neuroscience 2009, 2323-259 (2009)

Brannon E., Terrace H;, “Ordering of the Numerosities 1 to 9 in Monkeys”, Science 282, 746 23 October 1998

Nieder A., Miller E.; “A parieto-frontal network for visual numerical information in the monkey”, PNAS Vol. 101 no. 19 7457-7462 (2004)

Roitman J., Brannon E., Platt. M.; “Monotonic Coding of Numerosity in Macaque Lateral Intraparietal Area”, PLoS Biology Vol. 5 Issue 8. August 2007

Mathematical intuition, or the ability to

is known to be correlated with numerical

solve simple arithmetic problems quickly

cognition, we still do not know if the IPS

with little conscious control, is evident in

plays a causative role in that behavior.

humans at a young age. Over 30 years

This paper examines past studies that

ago, Rochel Gelman and Randy Gallis-

look into the neurological functions behind

tel published The Child’s Understanding

numerical cognition, starting with a general

of Number, showing that preschoolers

overview of number sense and followed by

could detect unexpected changes in small

several key studies that implicate the IPS

numbers or violations in a counting pattern

in numerical cognition. Additionally, there

[A]. More recent studies have also demon-

is a brief analysis a study using transcra-

strated that even non-human primates can

nial magnetic stimulation, a non-invasive

use number to discriminate between sets

method of stimulating nerve cells and its

of discrete quantities [B]. These studies

relation to IPS research. The purpose of

on arithmetic intuition have also prompted

these analyses is to address the current

neurological research. Brain imaging stud-

questions in numerical cognition research

ies showed that whenever human adults

and to justify the motivation behind an

perform calculations, the intraparietal

upcoming study involving IPS inhibition by

sulcus (IPS) is consistently activated [A]. In

muscimol injection.

fact, single cell recordings in rhesus macaques have found IPS activation linked to number-related tasks, including same-different judgments [C] and implicit number comparisons [D]. Although IPS activation

018

//ANDREW LUO

What is Number Sense?

Investigating ANS present numerous

overall accuracy was very high in both the

questions, such as whether or not honing

first and last sessions. However, there was

universal skill, even for those with little or

ANS at a young age could potentially have

no correlation in response time. Lastly,

no mathematical education. Cross-cultural

long-term effects on symbolic mathemat-

in line with the results of past studies,

studies have shown that arithmetic intuition

ics. A 2012 study examined the malleability

people with higher standardized test math

is a fundamental processing feature of

of ANS acuity by testing whether partic-

scores (SAT/GRE) tended to have lower w

the brain that extends past the restraints

ipants improved their accuracy over six

scores (r2 = 0.28, p <0.02), meaning that

of lexical barriers. In a 2004 study on the

training sessions [F]. Of the twenty adult

they were better at the ANS tasks. Verbal

Mundurucu, an Amazonian group who lan-

participants that participated in the study,

standardized test scores showed no such

guage only has words up to five, research-

each of them performed a numerosity

correlation. Overall, the results of this study

ers showed that the both the adults and

comparison task and a line length compar-

addressed the malleability of NS and that

children in the population were excellent at

ison with and without trial-by-trial feedback.

trial-by-trial feedback does provide a rapid

distinguishing numerosities based on their

Based on the results across the trials, there

number, as well approximate addition and

was a strong dependency in accuracy and

yet short improvement period [F].

subtraction [E]. In fact, their psychophys-

response time in the numerosity compar-

matical abilities have prompted researchers

ical behavior matched those of Western

ison task, though there was no change

to look at its potential in creating more

students; their arithmetic ability was deter-

in the Weber ratio despite the extended

effective methods to teach arithmetic in

mined by Weberâ&#x20AC;&#x2122;s law, which states that

training. However, when the trial-by-trial

minimal difference between two numbers

feedback was incorporated, there was

classroom [G]. In another Duke University

that leads to a fixed level of discrimination

a rapid improvement in ANS acuity and

experiments that gauged ANS training on

is proportional the size of the numbers [E].

overall performance, which was maintained

approximate addition and subtraction of

in the last session when the feedback

dot arrays. Throughout a combined sixteen

the principles of number sense, or the ap-

mechanism was taken away (b = -0.047,

trials in across the two experiments, the

proximate number system (ANS). By defini-

p <0.005)6. The trial-by-trial feedback did

participants showed tremendous improve-

tion, ANS is a cognitive system that allows

have its limits in ANS improvement; after

ment in the non-symbolic arithmetic task,

estimation and calculations of quantities

the initial session, the ANS acuity seemed

and the response rate for each participant

represented without symbols or language,

to plateau off despite extended change. On

decreased as well. This recent study sup-

and it is thought to be the foundation of

the other hand, response time (RT) showed

plements the earlier 2012 study (DeWind

higher level symbolic mathematics [G].

a continuous decrease across subsequent

& Brannon 2012), by showing, for the first

ANS play a crucial role in other numerical

training sessions, with the RT in session

time, an improvement in ANS performance

recognition skills, such as understanding

[F] being significantly lower than on the

exact numbers and simple math, and it

first training period. In comparison, the

across multiple trials [G]. These findings

may predict mathematical achievement in

line length test had much lower w scores,

teaching methods in mathematics. To date,

children. Adults and children with higher

indicating it was an easier task, and the

neuroscientists have proposed new tactics

Basic arithmetic intuition in humans is a

Similar studies such as this one reaffirm

The impacts of ANS in human mathe-

study this year, researchers created two

can perhaps provide a foundation for new

ANS is typically characterized by ratio dependence and improves significantly in its precision

such as simple board games or comput-

over development6. For example, in humans, 6-month old infants have been found

er-based number association games to

to discriminate large numerosities at 1:2 ratios, and by 9 months old, babies can then

enhance learning in schools.

distinguish more difficult numerosities that have a 2:3 ratio6. The accuracy of ANS continues to develop from age 3 and into adolescence, which are tested using explicit choice and number comparison tasks. ANS acuity or lower Weber ratios (w) oftentimes performed higher on standardized math tests and were more proficient at future math education6.

019

//ARTICLE.03 >>

Numerical Cognition in non-Human Primates

Apart from its practical applications in

with basic mathematical skills. The task

the intraparietal sulcus of the brain, which

measured factors such as spatial sensi-

is a main interest area for many current

tivity, attention, reward expectation, and

neuroscience studies on numerical cog-

motor preparation from neural coding of

nition. While humans are the most adept

number. In the trails, the monkeys were

at processing number, numerical abilities

shown several numerosities in which 8 was

extend to non-human primates such as

the standard while 2, 4, 16, and 32 are

macaque monkeys. Both humans and

deviants [D]. The monkeys’ task was the

animals show similar methods of recog-

shift their gaze to a visible target after the

nizing numerosity in visual and auditory

initial fixation point disappeared. Because

tasks. In monkeys, the numerosity-tuned

LIP neurons are spatially selective, the

neurons are concentrated in the depth of

neurons were mapped when the monkeys

the intraparietal sulcus and display visual

made delayed saccades (fast movement

flow-field responses, which coincide with

of both eyes in the same direction) to the

the location of the ventral intraparietal area

visible targets.

(VIP) [A]. Researchers have also found that

staggered modulation as the numerosity in

in macaques during numerical calculation

the task changed. 35 neurons (61%) were

may overlap with the human homolog of

sensitive to visual quantity, and the 97%

the VIP.

of the neurons, it was found that activity did not depend on which number served

experiment that examined monotonic

as the standard or the deviant numerosity.

coding of numerosity in the lateral IPS of

As the number of elements in the display

macaques [D]. It was discovered that a

changed between 2-32, the neurons

group of parietal neurons in the LIP actually

showed progressively increasing activity.

are correlated with ‘summing up’ individual

ANOVA analysis was used to determine

items in a group. These neurons, appro-

whether or not neurons were modulated by

priately named “accumulator neurons”,

numerosity, and the “preferred” numerosity

respond to increasing numbers of items in

was assigned to the neurons that gave the

a display with stronger activity. These find-

largest response. For example, the number

ings were recorded in the parietal cortex of

cue 2 and 32 garnered 16 and 12 neuron

monkeys [D].

responses, while 4, 8, and 16 received

The researchers looked at the activity

less than five each [D]. (ANOVA analysis

of single neurons in the LIP as monkeys

is a collection of statistical models used

performed implicit numerical discrimination

to analyze the differences between group

tasks. Previous studies have shown that

means and their associated procedures)

Pica P., Lemer C., Izard V.; et al. “Exact and Approximate Arithmetic in an Amazonian Indigene Group” Science Vol. 306 no. 5695 pp. 499-503 October 2004

DeWind N., Brannon E.; “Malleability of the approximate number system: effects of feedback and training” Front. Hum. Neorosci 6:68

020

The neuronal responses revealed

the horizontal segment of the IPS activation

One particularly notable study is a 2007

damage to the parietal cortex interfere

mathematical learning, ANS is linked to

VERTICES//029.02

35 neurons (61%) were sensitive to visual quantity, and the 97% of the neurons, it was found that activity did not depend on which number served as the standard or the deviant numerosity.

Park J., Brannon E.; “Training the approximate number system improves math proficiency” Psychol Sci. October 2013

Mazzocco M., Feigenson L., et al. “Preschooler’s precision of the approximate number system predicts later school mathematics

Sousa, David (2010) Mind, Brain, and Education Neuroscience Implications for the Classroom, Solution Tree Press

The findings from this study support the computer generated models that separate the processes of summing and numerical identification, and it may explain why people who suffer parietal cortex damage have difficulty doing mathematical calculations.

Homologies between Monkeys and Humans A second notable study examined

In the delayed match-to-numerosity task,

the role that the prefrontal cortex (PFC)

the subject held a lever and fixated on a

and posterior parietal cortex (PPC) plays

center point to initiate the trial. The monkey

during numerical judgment. From previous

shown a first display followed by a memory

experiments, it was thought that the PPC

delayed period of 200 milliseconds [C].

and anterior inferior temporal cortex (aITC)

Afterward, a test sample, which had 50%

provides the PFC with visual input, which

probability of having the same number

outputs feedback projections [J]. Another

of times as the sample, would appear.

hypothesis was that numerical information

If there was a match, the monkey would

is first taken from the PFC and transferred

release the lever to receive a reward. If the

to the PCC [J]. In order to test these

test display was a nonmatch, the monkey

hypotheses, the researchers examined the

would continue to hold the lever until a

brain activity in the PCC and aITC areas of

second test display appeared, which was

the brain while monkeys performed numer-

always a match. At the point, the monkey

osity judgment tasks. The results showed

would release the lever in order to receive

that in the PCC, the highest proportion of

an award. Observations were made across

numerosity-selective neurons were in the

four hemispheres of the PPC and three

fundus of the intraparietal sulcus. Addi-

hemispheres of the aITC in two adult

tionally, neurons in the fundus responded

rhesus monkeys. The neural response

and conveyed information earlier than PFC

latencies in the two subjects were found

neurons, which suggests that numerosity

through per stimulus time histograms.

information actually flows from the PPC to

In the PCC, neurons were sampled

the lateral PFC [C]. The data used in the studies was

from the superior parietal lobule (SPL) and inferior parietal lobule (IPL). It was found

collected by presenting monkeys with two

that the PPC neurons were encoded

displays that contained the same number

visual numerosity, showing maximum

of items (1 to 5). These dot arrays were

stimulation to a preferred numerosity and

randomized over 24 locations around the

had a progressive decline in activity with

monkey’s center point of fixation.

increasing numerical distance from the preferred. 021

//ARTICLE.03 >>

PCC neurons also had a significant

Current Experiment: Effect of Muscimol on IPS Throughout this academic year, I will be

decrease in activity during error trials, with

performing a pharmacology experiment

a reduction of 19% and 20% in sample and

that directly tests the causal role of IPS

delay period [C]. This suggests a direct

activation on the numerical cognition

relationship between PPC activity and task

of rhesus monkeys through intracranial

performance. Comparatively, in the ITC, the

muscimol injections. Muscimol is a GABAA

neurons only had 8% and 6% numerosity

direct agonist and acts to locally silence

selectivity during the sample and delay

neural activity. It is a psychoactive alkaloid

intervals. However, it is important to note

compound derived from mushrooms in

that 48% of the neurons that showed a

the Amanita genus [K]. In order to silence

significant effect of numerosity also had

brain activity, the drug will be injected into

a main effect in response to changes in

the ventral and lateral intraparietal areas

stimulus type [C]. It appears that aITC

in the intraparietal sulcus of two rhesus

neurons are mainly concerned with the

macaques. These sites have been linked

physical appearance of the displays, not

to numerical cognition in aforementioned

the number of items in the display.

studies. In order to test the effect of the

Overall, this study shows that number of

muscimol, two trained rhesus monkeys

neurons that are activated by small visual

will be shown two simultaneous dot arrays

stimulation from numbers. These findings

(numerosities) on a computer monitor. The

suggest the intraparietal sulcus is a primary

dot arrays will have different numbers of

source of numerosity processing, at least

dots, and the monkeys will be rewarded

relative to the lateral prefrontal cortex. Most

with juice for picking the dot array with the

importantly, visual numerosity-encoding

more red dots. In a control task, monkeys

neurons in the IPS of monkeys appear to

will be rewarded for discriminating color in

have close homologies to that of humans.

the dot arrays. We expect to see a drop

Petrides, M. & Pandya, D.N. (2002) Principles of Frontal Lobe Function, eds. Stuss, D. T. & Knight, R. T. (Oxford Univ. Press, Oxford)

Cappelletti M., Barth H., Fregni F., et al. “rTMS over the intraparietal sulcus disrupts numerosity processing”

National Institute of Mental Health (2009) “Brain Stimulation Therapies” nimh. Nih. Gov Dec 2013

022

in number task performance but not color task performance following muscimol injections. To test this hypothesis, I will be administering the drug and recording monkey’s behavior throughout the semester. After data collection, I will write custom MatLab scripts to analyze the data.

//ANDREW LUO

The findings from these studies may

the forehead of the test subject, and short

shed light on how we humans under-

electromagnetic pulses are set through the

stand arithmetic. In a broader context, the

skull. These pulses have a short range (2

study hopes to address some questions

inches), so scientists can precisely pinpoint

that have yet to be answered in past IPS

which areas of the brain are affected. A re-

studies. Numerous studies to date discuss

cent study used rTMS on the left and right

a correlation between approximate number

IPS to investigate the effects of temporary

recognition in the brain (accumulator

deactivations of these regions on symbolic

neurons etc. in the parietal cortex etc.), but

and non-symbolic numerosity processing

this relationship does not imply a causal

[K]. Contrary to what was expected, the

relationship. By using muscimol, we will be

researchers found that the rTMS impaired

investigating whether the lateral intraparietal

function when used on the left IPS but

areas and the intraparietal sulcus actually

enhanced cognition when used to the

govern numerical cognition, or there is

right IPS. There was greatest impairment

another mechanism involved in number

when the participants were processing

processing.

numerosities of similar magnitude, which

Alternative Approach: TMS While muscimol is a direct method of

is a signature effect of numerical distance. The data from the study suggest that the left IPS is critical in number processing.

shutting down IPS function, there are other

Indeed, TMS does seem to be a promising

methods of that also disrupt numerosity

alternative, as it is currently being used to

processing. One known alternative method

treat illnesses such as depression and is

is repetitive transcranial magnetic stimu-

clinically used to evaluate damage from

lation, which is a noninvasive method that

stroke or multiple sclerosis.

causes depolarization of neurons in the brain. It effectively interferes with neural function and allows for studies to be conducted on the brainâ&#x20AC;&#x2122;s functioning and interconnections [L]. The process involves the use of a magnet instead of an electric current to activate the neurons in the brain. An electromagnetic coil is held against

023

//SPOTLIGHT.01

[GRADUATE. STUDENT_ SPOT_LIGHT// //STEPHANIE SANTISTEVAN*]

By: Elisa Berson

// BIOGRAPHY // I grew up in Salt Lake

master’s degree in psychology at Palo Alto

City, UT and attended Brigham Young Uni-

University, then applied for PhD programs. I

versity for my undergrad. After losing interest

accepted an offer in the Cognition/Cognitive

in my declared math major, I switched to

Neuroscience division of the Psychology

business management with an emphasis

and Neuroscience department at Duke.

in marketing. During my undergraduate

In the year between my master’s and PhD

courses, I became especially fascinated with

programs, I worked in the clinical trials de-

consumer behavior - how and why indi-

partment of a hospital in Mountain View, CA.

viduals make decisions about purchasing.

In this position, I became aware of the many

After graduating, I completed a marketing

cognitive challenges that exist within evolving

internship in Brussels, and took a permanent

medical technologies. This awareness has

marketing position in Northern Utah. While

guided my research interests, and I am

working in those positions, I quickly found

currently working on research in the field of

that my real passion wasn’t just how people

medical cognition.

thought about consumption - I wanted to know how and why people thought about everything. I decided to pursue graduate education in psychology. I completed a 024

//ELISA BERSON

My favorite class in undergrad was...

My favorite class in grad school was..

My advice to undergraduates is..

Entrepreneurial marketing. It was so useful

Ethics and policy in genomics. It is so

Find an area you are passionate about.

to learn how to sell my own ideas.

important that as scientists, we are also

Pay attention to those things that really

ethicists. There cannot be a separation of

get you fired up, that keep you up all night

science from ethics.

reading because you can’t get enough. Life

What experiences in undergrad began to cultivate your current interests? Throughout my marketing classes, I

Can you share more about your

is so pleasant when your work is also your passion.

learned that people don’t always make

research?

decisions the way you would expect, and

I am interested in how people understand

yourself. You have a lot of years ahead of

oftentimes emotion trumps rationality. This

and make decisions about medical

you, so attend to your mind, body, and

elucidated the need to conduct empirical

information, especially in regards to genetic

spirit. When you have health and balance,

research about how people behave in

testing. These types of situations present

you are capable of so much.

certain situations, rather than relying on

many cognitively challenging tasks, like

how we think they would behave or what

comprehending complex descriptions,

would be rational.

statistics, and probabilities. I want to learn

Did you pursue any research during undergrad?

My other advice is take good care of

I’m going to spend my next day off

(any hobbies, interests, etc. can also

about how people think about this infor-

be included here)..

mation so that we can develop methods

Traveling! My favorite weekend activity is

to help them make informed and beneficial

visiting my fiance in San Francisco. We

I worked as a research assistant for a mar-

decisions. I also want to conduct research

love to try a new hiking trail in the morning,

keting professor during my senior year. This

that will help to guide ethics and policy in

see a new movie in the afternoon, and try a

experience showed me that knowledge is

medical fields.

new restaurant in the evening. Life is more

not static - we always have the opportunity to dig deeper and learn more. I knew then

What is one of the best experiences

that I wanted to always be on the cutting

you’ve had as a PhD student? Just after

edge of new research.

I arrived at Duke, I came across the re-

Did you spend any time between un-

dergrad and the pursuit of your PhD?

And if so, what did you do during that time?

fun when you are always discovering new things! An interesting thing I’ve done since

search of a professor in the Fuqua School

coming to Duke... One word :

of Business. I was completely fascinated,

campout. I can’t wait to do it again... 4

and sent him an email to introduce myself.

more times.

The next thing I knew, we were meeting for lunch to discuss his work and my research

Something I’d like to do in Duke/

I took several years to work, read books,

interests. He invited me to work with his

Durham but maybe haven’t done yet..

discover new interests, and do a lot of

team on a study that I could have only

I’m trying to test out all the BBQ joints and

yoga :) These couple of years gave me the

dreamed about, and it has been a fantastic

complete an empirical analysis. I’ve tested

flexibility to really figure out my area of inter-

opportunity. This whole experience taught

3 so far, but I don’t yet have enough data

est before committing to a PhD program.

me early in my graduate experience that

to reach a clear conclusion :)

What brought you to Duke?

there are people all over Duke doing amaz-

My advisor works in the field of medical

ing research, and if you just get out and

cognition, and I knew that my research

talk about your interests and your work,

interests would be an excellent fit with

you will find great opportunities that can

hers. I also loved the emphasis that Duke

guide the course of your research.

puts on interdisciplinary collaboration. My

My other best experience has been at-

work crosses many department lines, and

tending the Duke basketball games. I have

I wanted to be at a school where I could

become completely obsessed :)

approach my research from many different perspectives. Lastly, I am in love with Durham!

025

//ARTICLE.04

[ VIIP SYN_ DROME:: VISIONDETERIORATION. IN // L O N G TERM SPACE TRAVEL//]

By: Deepak Sathyanarayan

Special Thanks To: Embry-Riddle Aeronautical University Team – Nancy Do, Gaurav Girish, Jashan Grewal, Nathalie Quintero, Dr. Sathya Gangadharan,

With population growth skyrocketing, and resource depletion becoming an ever-nearing threat, the world has begun to turn its sights to the stars in search of new

Dr. Birce Dikici

home. An emerging international movement of scientists

Duke University Undergraduates –

and engineers has brought about the formation of

Roman Kowalchuk, Darrin Lim, Carrina Dong, Dr. George Truskey

organizations, like Mars One, which aim to establish the

NASA’s Reduced Gravity Education

first human settlements on Mars by 2025 (Mars One,

Flight Program Engineering Alumni Council

2014). Although human settlement on Mars would be the next big leap for mankind, such a feat would not come without a price.

026

//DEEPAK SATHYANARAYAN

Since the establishment of the Inter-

changes have begun to emerge after 5 or

syndrome, now known as the visual impair-

national Space Station (ISS), astronauts

more months of space travel. As currently

ment/intracranial pressure (VIIP) syndrome,

gained the ability to truly live in the space

projected, the trip to Mars for the first crew

is still widely unknown, but the leading

environment. Longer durations in space

of settlers would take a total of 210 days,

hypothesis is that intracranial pressure

opened the door for great advancements

or about 7 months. In essence, the first

underlies the observed visual changes in

in the study of space-related phenomena,

crew of Mars settlers would potentially

crewmembers.

while also giving rise to several unantic-

arrive blind at their new Martian home.

ipated risks. Due to the lack of gravity

Anecdotes exist of these complaints

Developed in the early ‘90’s, the measurement of intraocular pressure

and increased radiation levels, astronauts

even 40 years ago, however recent

(IOP), the pressure within the eye, is still

have fallen victim to significant physiolog-

observations show that these changes can

the common practice by astronauts to

ical changes, including but not limited to

be permanent with many of these visual

determine if the environments inside their

bone demineralization, muscle atrophy,

symptoms persisting over 12 months after

eyes have changed during the mission.

cardiovascular deconditioning, vestibular

returning to Earth. Noting the extent of the

This measurement is done through a

and sensory imbalance, altered metabolic

observed vision loss, NASA and other re-

technique called tonometry. Tonometers

and nutritional status, and dysregulation

searchers around the nation began closely

are typically hand-held instruments that are

of the immune system [F]. These effects

studying astronauts who were returning

used to tap the cornea and measure the

on crewmembers are known collectively

after extended periods of time in space. At

deformation that occurs given an applied

as space adaptation syndrome. Scientists

this point NASA’s research has shown that

force. Using this technique, astronauts

around the world have been working since

the extent of vision loss has been correlat-

have observed an approximate 5 mmHg

the initial human space flights in 1961 to

ed with increases in intracranial pressure,

increase in intraocular pressure within

alleviate the detrimental health effects of

which are likely due to the observed cranial

the first 10 minutes of reduced gravity.

the reduced gravity environment. Emerging

shift of fluids in the absence of gravity.

Initially thought to be the cause of the

in the past 5 years have been reports of a

Loss of visual acuity puts a major block on

visual impairment observed in astronauts,

new negative effect of space travel – the

the future of long-term space travel and

this increased IOP is actually observed to

impairment of visual acuity. Studies have

has become the focus of ongoing research

return to normal levels within the first week

shown that ocular structural and functional

across the world. The etiology of this

of space travel.

Figure 1: Principle behind contact-based tonometry. Increases in applanation

Figure 2: MRI of visual changes that occurred after long-duration spaceflight,

(flattened) area in contact with the tonometer decreases signal received by

including kinking of the optic nerve, 30 days after returning to Earth (a). Flattening

detectors. Given force applied and signal returned, the intraocular pressure

of the posterior globe and optic disc edema indicated by the blue and red arrows,

can be determined. Source: Draeger et al., 1993

respectively (b). Distention (widening) of the optic nerve sheath is indicated by the yellow arrows (c).

027

//ARTICLE.04 >>

Otto, Christian A., David J. Alexander, C. Robert Gibson, Douglas R. Hamilton, Stuart M. C. Lee, Thomas H. Mader, Cherie M. Oubre, Anastas F. Pass, Steven H. Platts, Jessica M. Scott, Scott M. Smith, Michael B. Stenger, Christian M. Westby, Susana B. Zanello. “Evidence Report: Risk of Spaceflight-Induced Intracranial Hypertension and Vision Alterations.” Human Research Program, Human Health Countermeasures Element (2012). Print.

Liu, Jun, and Cynthia J. Roberts. “Influence of Corneal Biomechanical Properties on Intraocular Pressure Measurement.” Journal of Cataract & Refractive Surgery 31.1 (2005): 146-55. Print.

Chiquet, Christophe, Marc-Antoine Custaud, Anne Pavy Le Traon, Catherine Millet, Claude Gharib, and Philippe Denis. “Changes in Intraocular Pressure during Prolonged (7-Day) Head-Down Tilt Bedrest.” Journal of Glaucoma 12.3 (2003): 204-08. Print.

Draeger, J., R. Schwartz, S. Groenhoff, and C. Stern. “Self-tonometry under Microgravity Conditions.” The Clinical Investigator 71.9 (1993): n. pag. Print.

“Roadmap.” Mars One. N.p., n.d. Web. 27 Feb. 2014.

Taibbi, Giovanni, Ronita L. Cromwell, Kapil G. Kapoor, Bernard F. Godley, and Gianmarco Vizzeri. “The Effect of Microgravity on Ocular Structures and Visual Function: A Review.” Survey of Ophthalmology 58.2 (2013): 155-63. Print.

Wiener, Thomas C. “Space Obstructive Syndrome: Intracranial Hypertension, Intraocular Pressure, and Papilledema in Space.” Aviation, Space, and Environmental Medicine 83.1 (2012): 64-66. Print.

028

However, recent studies have shown that

Due to the difficulty of obtaining signifi-

this method for determining IOP may be

cantly large sample sizes of astronauts

significantly skewed by various properties

in space, researchers have opted to the

of the cornea. A paper written by Liu and

standard head-down tilt bedrest experi-

Roberts in 2005 showed that the corneal

mental setup. This technique, which calls

biomechanical properties greatly impact

for subjects reclining for extended periods

intraocular pressure measurements and

of time (up to 7 days), has been shown to

can make these measurements invalid

induce a similar cranial shift of bodily fluids

across multiple subjects [B]. Assuming

to that which has been observed in re-

that these variations are negligible, as

duced gravity environments. However, one

the practice is today, the increase of

drawback of this method is that subject

intraocular pressure observed in astronauts

movement and typical behaviors are sig-

during space missions is very similar to

nificantly altered, which may skew results

pathologies that we see on Earth, such as

from these studies. After the discovery of

the onset of glaucoma and hyperopic shifts

vision loss in space, NASA has been able

(decrease in near visual acuity). Since

to closely monitor 7 astronauts from the

these high-pressure peaks appear to be

time of launch throughout the mission and

transient, they are typically well tolerated

following their return to Earth. Through the

by the eye structures, given no prior

studies conducted with these individuals,

pathologies [D].

NASA has been able to identify several

VERTICES//029.02

key pathologies that are highly correlated

step closer to understanding the reasons

with the loss of visual acuity. These include

for vision loss in space. For this reason,

but are not limited to optic disk edema

I have brought together teams of under-

(widening of the optic nerve sheath), globe

graduate students from Duke University

flattening, and choroidal folds. On Earth,

and Embry-Riddle Aeronautical University,

these ocular changes typically are found in

the leading schools in biomedical and

patients with idiopathic intracranial hyper-

aerospace engineering, respectively, to

tension (IIH). However the crewmembers

help lay a foundation for understanding the

that express these symptoms do not

cornea’s potential role in visual acuity loss

feel the headaches and transient visual

in space. We have been selected to take

obscurations that are typical with IIH. The

part in NASA’s Reduced Gravity Education

knowledge we currently have on micro-

Flight Program through which our corneal

gravity-induced vision loss is very limited,

biomechanics experiment will be tested on

but we continue to funnel our efforts toward

Zero-G Corporation’s microgravity flights

developing solutions for alleviating this

this summer aboard their specially modified

problem.

Boeing-727, nicknamed the “Vomit Comet.”

Previous studies have primarily focused

With this information, there is potential for

on the posterior chamber of the eye, for

developing contact lens based solutions to

instance the choroidal dynamics and

prevent or reverse the symptoms experi-

optic disk deformations; however, the

enced by astronauts, thereby allowing for

current literature on the cornea’s behavior

the continuation of long-term space travel

in space is lacking, and investigating the

from the ISS to Mars and beyond.

corneal biomechanics can take us one

ISS CREW MEMBER

CASE 1

MISSION DURATION

6 MONTHS

REFRACTIVE CHANGE

PREFLIGHT: OD:-1.50 SPH OS:-2.25-0.25X135 POSTFLIGHT: OD:-1.25-0.25X005

INTRAOCULAR PRESSURE (mmHG)

PREFLIGHT: 15OU

FUNDOSCOPIC EXAM POSTFLIGHT

DISC EDEMA (FRISEN)

OCT POSTFLIGHT

EYE MRI POSTFLIGHT GLOBE FLATTENING

-CHLOROIDAL FOLDS OD -COTTON WOOL SPOT OD

POSTFLIGHT: 10OU

EDEMA: NO DISK EDEMA

-CHLOROIDAL FOLDS

-MRI NOT PERFORMED

STILL VISIBLE INFERIOR TO THE OD DISC (R+>5YRS)

CSF PRESSURE POSTFLIGHT (cnH20)

NOT MEASURED

-GLOBE FLATTENING: NOT ASSESSED

OS:-2.50-0.25X160

CASE 3

6 MONTHS

PREFLIGHT: OD:-0.5SPH OS:-.025SPH POSTFLIGHT: OD:PLANO

PREFLIGHT: 10OU

-SMALL HEMORRHAGE OD -BILATERAL DISC EDEMA OD>OS

POSTFLIGHT: 10OU

EDEMA: GRADE 3 OD GRADE 1 OS

-SEVERE NFL THICK-

-OPTIC NERVE SHEATH

ENING OD>OS C/W

DISTENTION OD

DISC EDEMA

-GLOVE FLATTENING:

ELEVATED 21 AT R+19 DAYS

NON OBSERVED

OS:PLANO

CASE 4

6 MONTHS

PREFLIGHT: OD:-0.75-0.50X100 OS:PLANO-0.5X090 POSTFLIGHT:

PREFLIGHT: 15/13

-DISC EDEMA OD -CHOROIDAL FOLDS OD

EDEMA: GRADE 1 OD

POSTFLIGHT: 11/10

OD:+0.75-0.5X105

-MILD NFL THICKEN-

-OPTIC NERVE

ING OD>OS C/W DISC

SHEATH DISTENTION

EDEMA

AND TORTUOUS OPTIC

-CHOROIDAL FOLDS OD

NERVE OD>OS

ELEVATED 28.5 AT R+57 DAYS

-GLOVE FLATTENING: OD>OS

OS:+0.75-0.75X090

Figure 3: Spaceflight Data: 3 of 15 confirmed cases of VIIP from NASA Longitudinal Spaceflight Astronaut Health Database. (OD=right, OS=left, OU=both eyes, sph=sphere, OCT=optical coherence tomography, MRI=magnetic resonance imaging, CSF=cerebral spinal fluid, NFL=retinal nerve fiber layer, R+=return to Earth; [presented by number of days, for example, R+19 is 19 days after return to Earth]). Source: Otto et al., 2012

029

//ARTICLE.05

[A CASE FOR //DRUG RE_ PURPOSING:// WHERE LESS IS M O R E*] By: Eric Lakey

Dhara A. Patel, A. C. P., William C. Nolan,

Guangming Huang, Arthur G. Romero, Nichole Charlton, Eugene Agapov, Yong Zhang, and Michael J. Holtzman, High-Throughput Screening Normalized to Biological Reponse: Application to Antiviral Drug Discovery. J. Biomol. Screen. 2013, 19 (1), 119-130.

Collins, F. S., Mining for therapeutic gold. 2011, 10..

Paul, S. M. e. a., How to improve R&D productivity: the pharmaceutical industryâ&#x20AC;&#x2122;s grand challenge. . Nature Rev. Drug Disco. 2010, (9), 203-214.

Donna L. Hoyert, P. D., Kenneth D. Kochanek, M.A., and Sherry L. Murphy, Deaths: Final Data for 1997. Natl. Vital Stat. Rep. 1999, 47 (19).

030

//ERIC LAKEY

The purpose of a drug is to enact some sort of positive change in the human body. This can involve inhibition of a negative pathway. Alternatively, this can involve the amplification of a positive process. Historical approaches to drug targeting have involved the screening of large libraries of chemical compounds for promising activity [A]. The idea is that this promising activity can be replicated within the human body in the form of a drug. But identifying a compound that shows promising biological activity is only the beginning in the long process of obtaining an FDA-approved drug. 95% of all promising targets will fail [B]. The few successful targets may take

CONVENTIONAL WISDOM STATES THAT THERE IS A TRADE-OFF BETWEEN INNOVATION AND SAFETY IN DRUG DEVELOPMENT. SHORTER APPROVAL PERIODS ERR ON THE SIDE OF MEDICAL INNOVATION. LONGER APPROVAL PERIODS, CONVERSELY, GIVE THE NOD TO SAFER DRUGS THAT HAVE BEEN MORE EXTENSIVELY TESTED.

upwards of 13 years and $1 billion USD

before they reach the healthcare marketplace [C]. This process is slow, expensive, and inefficient.

have been more extensively tested. Consequently, the 13 year FDA approval period

The healthcare needs and demands

represents a conscious choice by society

of a society can change markedly in this

to choose safety over innovation [F]. In my

13 year approval period. In 2000, chronic

opinion, there is often no need to choose.

liver disease and associated conditions

In drug development, you CAN have both.

accounted for 9.4% of all US deaths [D].

And, in a world where medical needs are

In 2013, it accounted for only 1.3% of all

constantly changing, we should strive to

US deaths [E]. With an 86% decrease in

have both.

prevalence over the typical time period

There are currently 1,082 FDA-approved

of drug discovery and approval, societal

prescription drugs [G]. With an approval

need for such a drug may have decreased

process of around 13 years per drug, this

dramatically. Pharmaceutical companies

amounts to around 14,000 drug-years of

may no longer profit from the $1 billion

research and development [B]. The work

investment to get the drug on the market.

has been done. There is a large library of

New clinical practices may have rendered

safe bioactive drugs. These drugs have

null the initial need the drug is designed to

often not yet been tested for alternative

target. Why, then, does such an arduous

purposes and are just as valuable drug

process even exist?

targets as completely novel compounds

There is a 13 year approval period for a reason. Conventional wisdom states that there is a trade-off between innovation and safety in drug development. Shorter

Sherry L. Murphy, B. S. J. X., M.D.; and Kenneth D. Kochanek, M.A., Deaths: Final Data for 2010. Natl. Vital Stat. Rep. 2013, 61 (4).

Hemphill, T. A., Policy debate: The US food and drug administration and new drug approvals: A safety vs. innovation paradox? Innovation: Management, Policy & Practice 2013, 15 (3), 364-367.

MedLexiconInternational Full FDA Prescription Drug List. http://www.medilexicon.com/drugsearch.php?z=true.

that have not yet received FDA approval. It is a far simpler, cheaper, and shorter process to adapt current FDA drugs for new treatments. A given drug can perform

approval periods err on the side of medical

more than one function. Why reinvent the

innovation. Longer approval periods,

wheel?

conversely, give the nod to safer drugs that 031

//ARTICLE.06

[THE THREAT_ ENING DECLINE. OF//JAPAN*// Introduction

When national wellbeing is compared on

AS THE THINNEST AND LONGEST-LIVED COUNTRY

and an efficient, nationalized, and universal

a global scale, GDP per capita is the most

healthcare system. Nonetheless, closer

commonly accepted standard. In the past,

inspection of these variables demonstrates

GDP per capita measured national wellbe-

that they are rapidly changing. Japan’s diet

ing on a global scale. However, in an effort

is becoming more westernized, resulting

headed by Nobel Laureate Robert Fogel,

in poor nutrition, increasing obesity, and

the singular importance of GDP per capita

incidence of disease. Significantly, current

as a proxy for wellbeing is being scrutinized

research suggests that Japanese genetics

and challenged. As a result, other mea-

actually worsens the effects of obesity.

sures that reflect the biological wellbeing

These circumstances become even more

of nations—such as height, incidence of

perilous when set in the context of Japan’s

obesity, and life expectancy–have become

healthcare system. As currently struc-

increasingly more popular and are thought

tured, the Japanese healthcare system is

to better incorporate the multidimensional

ill-equipped to face the intense and costly

aspect of a nation’s overall wellbeing. By

pressures from its changing demographic.

these new, more human-centered and

Japan has reached a tipping point. If Japan

non-economic metrics, one nation appears

continues in the direction it has taken for

anomalous: Japan. And yet, judged by

the last half-century, it will struggle to retain

these same measures, the wellbeing of

its reputation as the slimmest and lon-

Japan is changing…for the worse.

gest-lived country in the world, exhibiting

Japan has a life expectancy of 83.91 years, far greater than that of other developed countries, and an incidence of obesity impressively low compared to that of its industrialized peers [A]. This spectacular statistical display of superior na-

tional wellbeing is attributed to the benefits of the Japanese traditional diet, genetics, 032

the highest biological indicators of national wellbeing.

By: Gregory Moore

//GREGORY MOORE

Weiner, Miriam. “Top 10 Hotspots for Human Longevity.” US News. U.S.News & World Report, 09 Mar. 2012. Web. 26 Apr. 2013. <http://health.usnews. com/health-news/living-well-usn/ articles/2012/03/09/top-10-hotspots-forhuman-longevity?page=2>.

Paulson, Morten. “Sword of Starvation: How Agriculture Defines Japan.” CLSAU Blue Books (17 January, 2011): 1-54. Print.

Nagata, Kazuaki. “Japan Needs Imports to Keep Itself Fed - The Japan Times.”Japan Times RSS. Japan Times, 28 Feb. 2008. Web. 26 Apr. 2013

Komlos, John. “A Three-Decade History of the Antebellum Puzzle: Explaining the Shrinking of the U.S. Population at the Onset of Modern Economic Growth.”Journal of the Historical Society 12.4 (2012): 395-445. Wiley Online Library. Web. 26 Apr. 2013. <http://onlinelibrary.wiley.com/ doi/10.1111/j.1540-5923.2012.00376.x/full>.

The Westernization of the Japanese Diet Agriculture in Japan faces intrinsic

growing season and reduces crop yields,

topographical and climatic strains, pre-

making Hokkaido the land with the highest

disposing it to a precarious dependence

marginal product of agricultural labor but

on imports. Food imports are essential

also the lowest marginal crop yield per acre

as Japan’s topography consists primarily

[B]. This topographical and climatic curse

of forests and mountains making farming

places severe strain on Japan’s self-suffi-

very difficult [B]. Only 12.6% of land is

ciency, driving the importation of over 60%

dedicated to agriculture compared to 51%

of Japanese caloric intake, which in turn,

of land in the U.S. [B] Hokkaido, Japan’s

has reinforced the trend towards Westerni-

northernmost island, has large swaths of flat land without significant foliage, lending

zation of the Japanese diet [C].

itself to agricultural economies of scale [B]. Unfortunately, Hokkaido is classified

as having a sub-Antarctic climate, and the island experiences long and harsh winters. The severe weather significantly curtails the 033

//ARTICLE.06 >>

Makita, Hajika. “Present State and Prospect of Soybean Production and Soybean Breeding in Japan.” National Institue of Crop Science (2008): 49-52. Web. 26 Apr. 2013. <http://www.gene.affrc.go.jp/pdf/misc/ international-WS_14_49.pdf>

Tetsuji, Tanaka, and Hosoe Nobuhiro. “Productivity Shocks and National Food Security for Japan.” RIETI Discussion Paper Series 4.9 (2008): 1-62. Web.

“FAO Fisheries & Aquaculture - Tuna Fisheries.” FAO Fisheries & Aquaculture Tuna Fisheries. Fisheries and Aquaculture Department, n.d. Web. 26 Apr. 2013.

Paulson, Morten. “Sword of Starvation: How Agriculture Defines Japan.” CLSA Blue Books (17 January, 2011): 1-54. Print.

“Success of Japanese School Lunch Program Could Teach U.S. Schools a Lesson.”Success of Japanese School Lunch Program Could Teach U.S. Schools a Lesson. The Children’s Obesity Fund, 26 Mar. 2013. Web. 26 Apr. 2013.

Yamagishi, K., H. Iso, C. Date, M. Fukui, K. Wakai, S. Kikuchi, Y. Inaba, N. Tanabe, and A. Tamakoshi. “Fish, ω-3 Polyunsaturated Fatty Acids, and Mortality From Cardiovascular Diseases in a Nationwide Community-Based Cohort of Japanese Men and WomenThe JACC (Japan Collaborative Cohort Study for Evaluation of Cancer Risk) Study.” Journal of the American College of Cardiology 52.12 (2008): 988-96. Web.

“The IDF Consensus Worldwide Definition of Metabolic Syndrome.” International Diabetes Federation, 2006. Web. 26 Apr. 2013. <http://www.idf.org/webdata/docs/ IDF_Meta_def_final.pdf>.

As seen during the Antebellum Period in the United States, agricultural self-suffi-

tuted for the traditional Japanese stress on

ciency is protective of health-compromising

vegetables, rice, and seafood [H]. Thus,

phenomena [D]. Following WWII, Japan’s

while caloric intake of Japanese children

self-sufficiency rate reached 80%; howev-

grew significantly, it changed significantly

er, by 2012 that number was more than

also. Over the subsequent half-century,

halved [C]. Japan is increasingly reliant

Japan experienced a dietary transgenera-

on imports from China, the United States,

tional ripple effect as the post-WWII gener-

and Indonesia. While Japan is not unique

ation raised on a Westernized diet, passed

in its dependence on imported foodstuffs,

down unhealthy dietary preferences to the

Japan’s reliance on imported proteins

next generation. Additionally, thousands

and essential micronutrients is cause for

of tons of imported wheat seed were

concern. The main sources of protein for

planted throughout the country to ensure

the country, namely meat and soybeans,

that wheat would become an integral part

have self-sufficiency rates of only 50% and

of the Japanese diet [H]. While the school

5% respectively [E]. A diet so contingent

lunches have largely returned to more

on the vicissitudes of the global economy

traditional, lower-calorie standards, outside

and political climate is not a sustainable

of schools, a high calorie, low nutrition

solution to maintaining the population’s

Westernized diet continues to inflate the

high nutritional needs [F]. At this low level

waistlines of the Japanese [I].

of self-sufficiency, Japan would suffer

tremendously from the lack of protein in its diet as the result of an embargo or international or civil war involving its major exporters. Historically, Japan has relied on locally caught fish and whale meats, both of which confront increasingly more restrictive international regulation. Whale harvesting has been banned almost entirely, and global fish stocks are experiencing precipitous declines. In fact, the tuna, the icon of Japanese aquatic gastronomy, has suffered population declines of over 90% [G]. By contrast to its vulnerability to

external sources of protein, Japan is highly self-sufficient when it comes to unhealthy foods that are high in carbohydrates and cholesterol such as wheat and eggs. As a result, any decrease in food imports will be counteracted by an increase in production of local food of little nutritive value and food that is detrimental to long-term health. In the late 1940’s and early 1950’s, the United States and its allies created a student lunch program to alleviate malnutrition stemming from the social and political strife in post-WWII Japan. Imported wheat, dairy,

034

poultry, and meat foodstuffs were substi-

VERTICES//029.02

In addition to the increase in daily caloric intake, there are detrimental health consequences in the adoption of a Westernized

acids, and so does not contain protective

and 22% of the population smokes

factors against cardiovascular disease.

as a whole. Moreover, an even larger

The decreased consumption of

amount of the population is affected by

diet. These adverse effects are most

seafood in Japan likely also has the

a culture of smoking, especially children,

apparent in the substitution of terrestrial

effect of decreasing life expectancy

for whom exposure to tobacco smoke

meat in place of seafood and the substi-

through increased incidence of metabolic

is particularly harmful. Cardiovascular

tution of wheat for rice. While meat and

syndrome and cancer. Metabolic

disease risk increases from exposure

seafood have comparable protein content,

syndrome, colloquially abbreviated as

to second-hand smoke. Nevertheless,

micronutrient composition differs between

“metabo” in Japan, broadly encompasses

despite the abundance of smoking,

the two and therefore has varied nutritional

the onslaught of ailments that accompany

cardiovascular disease is not among the

impact. Fish contains omega-3 fatty acids

obesity, mainly heart disease, high blood

leading causes of death in Japan due to

that are amino acid chains that the human

pressure, and diabetes [K]. The decrease

the protective nature of regular omega-3

in fish consumption will increase the

fatty acids consumption. Consumption of

that regular consumption of omega-3 fatty

prevalence of these serious diseases as

omega-3 fatty acids is a significant factor

acids has a protective effect on cardiovas-

the micronutrients in fish also mitigate

shielding non-smoking Japanese from

cular disease and can halt the maturation

many of the negative effects of smoking.

the deleterious cardiovascular effects of

of early-stage cancers [J]. Furthermore,

Tobacco smoke has long been known

chronic second-hand smoke.

like terrestrial meats, fish contain iron, zinc,

to increase incidence of heart attack

and vitamin B12, The critical difference is

and arterial plaque build-up [L]. In

body is unable to synthesize. Studies show

that terrestrial mean lacks omega-3 fatty

Japan, 45.8% of adult men are smokers,

Glantz, Stanton A., and William W. Parmley. “Passive Smoking and Heart Disease.” The Journal of the American Medical Association 273.13 (1995): 1047-053. Print.

Bracey, Alexi. “Tag Archives: Whole Wheat.” Stoveless Cuisine. N.p., 30 Jan. 2013. Web. 26 Apr. 2013.

IN ADDITION TO THE INCREASE IN DAILY CALORIC INTAKE, THERE ARE DETRIMENTAL HEALTH CONSEQUENCES IN THE ADOPTION OF A WESTERNIZED DIET.

Takimoto, Hidemi. “Thinness Among Young Japanese Women.” American Journal of Public Health 94.9 (2004): 1592-595. PubMed. Web. 26 Apr. 2013. <http://www.ncbi.nlm.nih. gov/pmc/articles/PMC1448499/>.

Nishida, Tomoko, and Hisataka Sakakibara. “Low Lymphocyte Count in Underweight Japanese Women.” Environmental Health and Preventive Medicine 13.6 (2008): 345-48. Web.

Han, Z., S. Mulla, J. Beyene, G. Liao, and S. D. McDonald. “Maternal Underweight and the Risk of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-analyses.” International Journal of Epidemiology 40.1 (2011): 65-101. Web.

035

//ARTICLE.06 >>

Since the post-WWII school lunch pro-

Shiwaku, K., E. Anuurad, B. Enkhmaa, A. Nogi, K. Kitajima, K. Shimono, Y. Yamane, and T. Oyunsuren. “Overweight Japanese with Body Mass Indexes of 23.0–24.9 Have Higher Risks for Obesity-associated Disorders: A Comparison of Japanese and Mongolians.” International Journal of Obesity 28.1 (2003): 152-58. Web.

“International Health Systems.” Physicians for a National Health Program. N.p., n.d. Web. 26 Apr. 2013. <http://www.pnhp.org/facts/international_health_systems.php?page=all>.

“Comparing International Health Care Systems.” PBS. PBS, 6 Oct. 2009. Web. 26 Apr. 2013. <http://www.pbs.org/newshour/updates/health/ july-dec09/insurance_10-06.html>.

Harden, Blaine. “Healthcare in Japan: Low-cost, for Now.” Washington Post. N.p., 07 Sept. 2009. Web. 26 Apr. 2013. <http://articles.washingtonpost.com/2009-09-07/world/36813795_1_medical-care-health-care-health-care>.

Henke, Nicolaus, Sonosuke Kadonaga, and Ludwig Kanzler. “Improving Japan’s Healthcare System.” Improving Japan’s Health Care System. McKinsey and Company, 3 Mar. 2009. Web. 26 Apr. 2013. <http://www.mckinsey.com/ insights/health_systems/improving_japans_ health_care_system>.

Yuji, Koichiro, Seiya Imoto, Rui Yamaguchi, Tomoko Matsumura, Naoko Murashige, Yuko Kodama, Satoru Minayo, Kozho Imai, and Masahiro Kami. “Forecasting Japan’s Physician Shortage in 2035 as the First Full-Fledged Aged Society.”PLOS One 7.11 (2012): n. pag. Web.

Hiyama, T., and M. Yoshihara. “New Occupational Threats to Japanese Physicians: Karoshi (death Due to Overwork) and Karojisatsu (suicide Due to Overwork).”Occupational and Environmental Medicine 65.6 (2008): 428-29. Web.

036

are far from equals at a biochemical level.

gram, the Japanese diet has experienced

Baked whole-wheat products contain

a shift away from the consumption of rice

amylopectin-A, a compound that has

towards the consumption of wheat. This

been shown to accelerate aging and have

trend has generally been overlooked as

carcinogenic effects [M]. As the amount of

a source of dietary concern because rice

omega-3 declines in in the Japanese diet

and wheat have long been thought to be

along with a substitution of rice for wheat,

perfect substitutes, both occupying a sim-

the negative repercussions of smoking will

ilar role as a nutritional core and culinary

emerge as increased incidence of heart

foundation to most meals. On the contrary,

disease paired with increased cancer risk

however, as compared with wheat, rice has

will threaten Japan’s future longevity.

the physical property of expansion upon arrival in the acidic environment of the stomach, thus inducing a sense of satiety sooner than an equivalent of wheat. This feeling of fullness has prevented overeating for generations, but as wheat continues to invade the Japanese diet, overeating might become an issue. Moreover, recent research has revealed that rice and wheat

UNDERWEIGHT FEMALES HAVE SIGNIFICANT EFFECTS ON THE FUTURE POPULATION. ALL OF THE STUDIES REFERENCED ABOVE SAMPLED FEMALES IN THE AGE RANGE OF MAXIMAL FERTILITY, ALLOWING FOR REFLECTIONS ON THE HEALTH IMPLICATIONS FOR THE NEXT GENERATION.

//GREGORY MOORE

The Disguised Japanese Obesity Issue Japan’s low levels of obesity, as indi-

cated by BMI, 22.9 kg/m2 compared to 28.7 kg/m2 in the U.S., are perceived as

BMIs and shorter lifespans [O].

Underweight females have significant

indicative of an overall national high level

effects on the future population. All of the

of health. However, when scrutinized at

studies referenced above sampled females

a closer level, there are two factors that

in the age range of maximal fertility, allow-

create a disconnect in using average BMI

ing for reflections on the health implications

values to infer the overall health of the cur-

for the next generation. Most underweight

rent and future population: 1) the increasing

mothers have underweight infants. An

prevalence of underweight and extreme

anomaly among developed nations, Japan

underweight BMIs in Japanese young

has experienced a 7-ounce decrease in

women and 2) as reported in the Interna-

the average birth weight of infants since

tional Journal of Obesity, the Japanese

1980 [O]. A review in the International Jour-

genetic predisposition for diabetes and

nal of Epidemiology analyzed the growing

cardiovascular disease even at lower BMI

body of scientific literature on underweight

values than other ethnicities.

mothers, concluding increased long-term

A large study published in the American

incidence of Type II diabetes, coronary

Journal of Public Health (2004) analyzed

heart disease, stroke, psychological

data from 30,903 women from 1976-2000

disorders, and obesity in underweight

from ages 15-29. The study concluded

infants [P]. Therefore, while Japan’s low

that female BMI’s have decreased by an

national average BMI might initially viewed

average of one kg/m2, and the percentage

positively, it disguises significant underlying

of females who are extremely underweight

heath concerns. Clearly, Japan’s national

has increased by 2% [N]. These changes

average does not necessarily reflect good

might appear small, but these marginal

health, as a growing cohort of low BMIs in

increases take place in the outliers in the

underweight females artificially depresses

data, so the effect on the overall mean BMI

the average.

of the population is significant. Popular

In this paper and the studies referenced

media is a likely culprit in driving this

herein, the conventional BMI cutoffs of

decreasing trend in BMIs as evidenced

18.5 for underweight, 25 for overweight,

by a study demonstrating that females in

and 30 for obese as established by the

large cities with the most intimate exposure

International Diabetes Federation have

to Western fashion model culture had the

been assumed. However, the enhanced

largest decrease in BMI. A BMI below 18.5

Japanese genetic pre-disposition to

defines an underweight woman. In a survey

metabolic syndrome also demonstrates the

performed in 2010, young Japanese

problems with interpreting BMI based on

women indicated they found 18.59 to be

conventional standards. It has been shown

an ideal BMI, It is not surprising; therefore,

that at BMIs of 23-24.9kg/m2, the Japa-

that 25.2% of young women in Japan are

nese are susceptible to the same degree

underweight [N]. While being underweight

of detrimental health effects as other

results in mild malnourishment, it has great-

exists between underweight individual’s

er implications through increased disease

ethnicities at BMIs of 25-30kg/m2 [Q].

susceptibility. Underweight conditions bring on a decrease in disease resilience from a decline in lymphocytes or white blood cells; there is a strong correlation 037

//ARTICLE.01

A Healthcare System on the Verge of Trouble

healthcare also fall heavily on physicians.

physicians is not sustainable and Japan

in place since 1961, is often praised

Japan has three-fourths the number of

has made efforts to alleviate the pressures

as being part of the reason why Japan

physicians per capita as the average

on physicians by increasing medical school

has both the lowest obesity rate of any

of developed countries [V]. Healthcare

nation-wide enrollment from 8,000 to 9,000

providers are extremely overworked, often

students. However, by the time those

lived population. Economic efficacy

having to work 36 hours straight and

students become practicing physicians,

is also a high point of the Japanese

take on 100-hour workweeks. In fact, the

various other pressures will greatly diminish

national healthcare system, only totaling

astronomical pressures on physicians has

to 9.5% of GDP while that in the U.S. is

created a new set of medical conditions

the effect of the increased enrollment [W].

approaching 20% of GDP [R]. The system

and terminology according to the Journal

on the healthcare system is the country’s

covers all Japanese through one of two

of Occupational and Environmental

aging population. The current aging

plans: Employee’s Insurance or National

Medicine: karoshi and karojisatsu [W].

demographic “devolution” in Japan is

the employee paying a low yearly premium

to overwork, and took the lives of 328

compounded by very long lifespans. In

and 10%-30% of medical fees (depending

Japanese physicians in 2005 [W]

Japan, the total fertility rate, the number of

Overworked physicians are more prone

children a woman will bear in her lifetime,

the remainder. The National Insurance plan

to make mistakes in the operating room

is roughly 1.31, significantly below the

is similar to Medicare and Medicaid in the

and in diagnosing patients due to mental

U.S., covering the unemployed, the elderly,

fatigue and reduced amount of time

level of replacement number of 2 [X]. This

the self-employed, and those who have

spent per patient. The severity of the

establish themselves in the workplace, a

agricultural vocations [S].

problem of overworked physicians is

corporate culture dominated by men. This

Emerging issues in the Japanese

even more apparent in the emergence of

male-centered cultural dynamic results in

healthcare system are long patient wait

karojisatsu, a term meaning suicide due

appalling maternal leave allowances, as

times, physician overworking, diminishing

to the stresses of being overworked. In

well as the increasing cost of raising a child

quality of care, and an overall decline in

2005, 42 physicians in Japan took their

physician wellbeing. Because of the low

lives [W]. The system’s poor treatment of

in Japan [X].

Japan’s healthcare system or kaihoken,

developed country as well as the longest-

Insurance. Employee’s Insurance involves

on income), with the company paying for

cost of healthcare, Japanese hospitals are facing a tragedy of the commons where there is no incentive to reduce the number of unnecessary hospital visits. The average number of hospital visits per annum is fourteen in Japan compared to seven in the U.S., and the Japanese hospital stays are on average three times longer than those in the U.S. [T] The cramped

waiting rooms and occupied hospital beds create a crowding out effect, where those patients who are most in need cannot get care in a timely fashion [T]. Therefore, the quality of care is significantly below that

of comparable developed countries. The Japanese are one-fourth as likely to suffer a heart attack as a European or American; however, they are twice as likely to die following the occurrence of a heart attack. [U] The negative effects of open access to 038

Karoshi means sudden death related

One of the largest imminent pressures

characterized by declining birthrates

largely stems from more women striving to

Wilson, Jessie. “Women on Strike: The Tide Is Turning but it is a Waiting Game.”CLSAU Blue Books (2008): 1-51. Web. 26 Apr. 2013.

“A Nation’s Bouncers; Japanese Immigration Policy.” The Economist (US) 15 May 2010: n. pag. Print.

Z “Healthcare in Japan: Not All Smiles.” The Economist. The Economist, 10 Sept. 2011. Web. 26 Apr. 2013. <http://www.economist. com/node/21528660>.1124:161-180.

AA USA vs. Japan: Top 10 Causes of Death.” USA vs. Japan: Top Ten Causes of Death. N.p., n.d. Web. 26 Apr. 2013.

VERTICES//029.02

: Japan’s population is aging at a blistering

A DECLINING POPULATION MEANS LESS PEOPLE IN THE WORKFORCE AND LOWER TAX REVENUE GOING TOWARDS SUPPORTING THE HEALTHCARE SYSTEM.

It is evident that health care costs are

shifts below the surface. For the past few

pace, with 40% of the population set to

already being negatively affected. Japan

decades, Japan has consistently fared far

be above 60 by 2050 [X]. In addition, the

invests only one third as much in cancer

better than any other country in the world

population is declining so rapidly that it is

research as the U.S. on a per capita

with regard to health. However, Japan

projected that the last Japanese person will

basis. Among the top ten leading causes

should proceed with caution; a history of

be born in 955 years [X].

of death in Japan, five are cancer-related

thriving success can breed a dangerous

[AA]. Some of those cancers, such as

complacency. In reality, Japan is in a

people in the workforce and lower tax

stomach and colon cancers, are treatable

precarious situation. The overall effect of

revenue going towards supporting the

in the U.S. and elsewhere, and therefore

an increasingly Western diet on Japan is

healthcare system. This loss of labor

do not cause high mortality. Japan, under

decreasing nutritional status, increasing

could be easily ameliorated by regular

its universal healthcare system, is unable

obesity, and raising incidence of disease,

infusions of immigrant workers. To Japan’s

to put sufficient funding towards the more

threatening the nation’s overall longevity.

detriment, it is one of the most strict

expensive cancer drugs and diagnostics

Concurrently, metabolic syndrome,

nations with regards to immigration, with

that could prevent a large fraction of

cancer, and an overdependence on food

only 1.7% of the population being foreign-

cancer-related deaths. The limitations on

imports are all on the rise. An expanding

born compared to 13% of the population

spending for patients with costly diseases

underweight female cohort threatens

in the United States [Y]. McKinsey and Co.

may only worsen with the increased strain

both the health of these women and the

on the system.

futures of their babies –if they choose to

A declining population means less

estimates that national healthcare costs

will triple in the next 25 years [Z]. Japan’s

In most of the world, Japan is viewed

have them at all. A declining, malnourished

healthcare system is a time bomb, trapped

as a paragon of public health. Japan

population, impervious to new immigration

between (a) future tax revenue decreases,

has many unique initiatives in place to

and increasingly unable to afford quality

as Japanese leave the workforce and

encourage a healthy lifestyle within its

care, will eventually propel Japan towards

their tax payments decrease, and are not

population and has much to teach the rest

the backwaters of healthcare and have a

replaced by the younger generation and

of the developed world about creating a

long-term effect on national wellbeing

(b) and rising medical costs to support

culture that is conducive to creating and

the aging and increasingly unhealthy

sustaining a healthy population. But as

population.

the evidence shows, there are tectonic 039

//SPOTLIGHT.02

[GRADUATE. STUDENT_ SPOT_LIGHT// //LAUREN GROSKAUFMANIS*]

By: Elisa Berson

// BIOGRAPHY // Lauren is a MS1

How did you become interested in

and the Secretary of American Medical

medicine?

Womenâ&#x20AC;&#x2122;s Association. She is interested

I went to a high school that was a magnet

for me because I enjoyed that experience

in Emergency Medicine, Internal Medicine

school for science and math, and I was

a lot. After working in that role for a while, I

or Family Med. Lauren is from Virginia and

really involved in scientific inquiry and

decided I wanted to go to medical school.

studied Neuroscience at the University of

research during that time. I came into

What was your favorite class as an

Virginia before coming to Duke. She really

undergrad thinking that I did not want to

undergraduate?

enjoys spending time outdoors hiking,

focus on science, so I initially majored

I was a Neuroscience major, and through

snowboarding, running, kayaking and

in political science, and I took some of

the major, I took some really cool classes

camping.

those classes. However, I kept the option

on topics, including the cellular basis of

of medical school open and started

the sensory systems. I also took a really

taking chemistry. By the end of the year

great seminar on public health. During

I discovered that I really did not like my

my undergraduate years I enjoyed both

political science classes, and I was really

ends of the spectrum: the really hard core

enjoying the science classes a lot more. I

basic science material and the public

began working in a hospital, but I was not

health aspects of how society plays into

able to interact with patients in a useful or

healthcare.

meaningful way. This experience did not give me a sense of what it is like to be a 040

medical professional. I then started working as an EMT, which was a big deciding factor

//ELISA BERSON

Are you continuing to explore public health in medical school?

While I don’t know exactly what I plan to do for my third year project, I am definitely interested in health systems and how

week. I don’t have any doctors in my family,

and patient safety. I am trying to set up

so I really wanted some place where there

a research program for first year medical

were people who could guide you.

students to get them more familiar with

Can you describe those supports in

quality improvement projects and quality improvement skills. I am also working with

they are designed. I am interested in

place?

not just figuring out the basic sciences

A lot of the supports revolve around

students go into Durham School of the

of what cellular molecules do and drug

community building. Deans invite us to

Arts, and we help the teachers teach sex

development, but more so how we can get

their houses for dinner, and I have been

education and health education topics.

patients to use the drug effectively and on

to dinner at professors’ houses already.

time.

Professors want to work with students

Did you pursue any research as an undergrad?

“Hey Durham” which is where medical

Have you explored anything in Durham

and provide support. Also, my Dean’s

that you have really enjoyed?

knowledge is invaluable in explaining the

I haven’t spent nearly as much time

ins and outs of residency, describing the

exploring Durham as I would like. However

I worked in a lab that did peripheral nerve

impact of the research year, and how we

I have had the chance to check out some

development in zebra fish. While basic

should be proactive about pursuing a

of the restaurants downtown, and even go

science research is not something I am

specialty.

to a Durham Bulls game. Hopefully I will

interested in pursuing for a career, I had an awesome mentor and a great experience.

Are there any classes that you have

What brought you to Duke?

at this point?

particularly enjoyed in medical school

have opportunities to explore Durham more extensively. Any advice that you have for

undergraduates looking to pursue

I really liked the idea of getting into the

It goes really fast. It feels faster in segments

wards during the second year and

where I don’t have as much background

medicine?

then having a break before applying to

knowledge. We are lucky in that we have

Do something where you have to do work

residency. It’s been really appealing to me

professors that are good lecturers in

with patients before coming to medical

to be able to have more time to explore

addition to being very knowledgeable,

school and do real work that isn’t always

things before jumping into residency

which when you are churning through a lot

necessarily pleasant to make sure it is

applications. The research year was a

of material, really helps. For example, our

something that you really want. I know a lot

really big factor because I know I want to

anatomy professor gave us 20-30 hours of

of people have worked in nursing homes

do some type of research. During my third

lecture time when we were doing anatomy,

or as an EMT or something similar, but

year, I am thinking about getting a second

and he was a great engaging speaker.

something where you see what a doctor

degree or working on a project so I can

The same thing occurred in Brain and

does on a day-to-day basis was really

figure out what second degree I would

Behavior, our condensed neuroscience

important to me. Just because I really

want to pursue later on.

course. I’m kind of biased because I am

enjoyed it helped me because it served as

a neuroscience major, but Dr. White is

a great break from just doing coursework.

a really great speaker, and the course is

I think it’s important to like the work that

very well designed. It is a course where

doctors do before you go to medical

There are a lot of different types of public

you watch all of the recorded lectures at

school.

health degrees that you can get and some

home and then each day in class there

are a lot more anthropology based and

are specific activities, lab experiences, or

others are biostatistics/epidemiology. So I

patients coming in.

If you were to do a second degree, what are you considering?

am thinking for my third year that I will work on a project and do some coursework so

Are there any activities that you are

then I can figure out what I want to do. I

involved in?

really appreciate the faculty support for

I am involved in the Duke Chapter of

students at Duke. We have deans’ lunches,

the Institute for Health Improvement that

and the deans meet with us about every

tries to promote quality improvement 041

//ARTICLE.07

[ETIOLOGY OF THE //BAD L S D* TRIP//] BY: SHAQ JUNAID

Aghajanian, G. K., Haigler, H. J., & Bloom, F. E. (1972). Lysergic acid diethylamide and serotonin: direct actions on serotonin-containing neurons in rat brain. Life Sciences, 11(13), 615-622.

Battaglia, G., Shannon, M., Glennon, R.A. and Titeler, M., (1983). Hallucinogenic drug interactions with S-I and S-2 cortical serotonin receptors, Soc. Neurosci. Abstr. 9. 1157.

Farde, L., Hall, H., Ehrin, E., & Sedvall, G. (1986). Quantitative Analysis Of D2 Dopamine Receptor Binding In The Living Human Brain By PET. Science, 231(4735), 258-261.

Fiorella, D., Rabin, R. A., & Winter, J. C. (1995). The Role Of The 5-HT2A And 5-HT2C Receptors In The Stimulus Effects Of Hallucinogenic Drugs I: Antagonist Correlation Analysis. Psychopharmacology, 121(3), 347-356.

042

//SHAQ JUNAID

Introduction

Drugs have been a fascination of the

human race as long as history has been

control for both psychological and environ-

recorded. Their mind-altering properties

mental influences while administering LSD

have long made them useful in rituals and

to subjects, adverse reactions to the drug

ceremonies, as well as being utilized recre-

still occur [R]. To this day, there seems to

ationally. Recently, drugs have been stud-

However, in experiments conducted that

be no infallible method of preventing these

ied intensively to uncover the mechanisms

adverse reactions, or “bad trips.” In addi-

in the brain that account for their psycho-

tion, LSD binds to multiple receptors in the

active properties. For example, researchers

brain, which attributes to the unpredictabili-

have found that for most drugs of abuse,

ty of its effects. Thus, it’s difficult to account

binding to receptors in the synapses of the

for what constitutes a “bad trip” that some

nucleus accumbens triggers the release of

users of LSD report having.

dopamine, which then provides euphoric feelings to the user. However, the effects of lysergic acid

In order to uncover several possibilities that contribute to an adverse reaction to LSD, I first explore LSD’s binding patterns

diethylamide (LSD) cannot be explained

in the brain, namely with the serotonin

as simply. In contrast to most other drugs,

(5-HT) and dopamine receptors of the D-2

LSD produces almost entirely unpredict-

subtype. Then, I examine other potential

able symptoms. A user’s reaction to LSD

factors that contribute to a bad trip and

on a single dose can range from pleasant,

relate them to the physiological properties

profound hallucinations to full-blown, inex-

of LSD. Through investigation of all of these

plicable psychosis. In the past, the cause

factors, with both selective and holistic

of adverse reactions was attributed entirely

analysis, I discuss the influence of each of

to either a detrimental psychological state

these respective factors in the determina-

or unfavorable environmental conditions during the ingestion of the drug.

Hartig, P., Kadan, M., Krohn, A., Evans, M., &

RESEARCHERS HAVE FOUND THAT FOR MOST DRUGS OF ABUSE, BINDING TO RECEPTORS IN THE SYNAPSES OF THE NUCLEUS ACCUMBENS TRIGGERS THE RELEASE OF DOPAMINE, WHICH THEN PROVIDES EUPHORIC FEELINGS TO THE USER.

Waltz, R. (1983). LSD: a selective, high sensitivity ligand for serotonin 5HT 2 receptors. In Soc. Neurosci. Abstr. 9. 334.

Hemsley, D., & Ward, E. (1985). Individual Differences In Reaction To The Abuse Of LSD. Personality and Individual Differences, 6(4), 515-517.

Lucki, I., Nobler, M. S., & Frazer, A. (1984). Differential actions of serotonin antagonists on two behavioral models of serotonin receptor activation in the rat.Journal of Pharmacology and Experimental Therapeutics, 228(1), 133-139.

043

//ARTICLE.07 >>

What is a “Bad” LSD Trip? A “bad trip” is the colloquial term for an

THE SEVERITY OF A BAD TRIP CAN VARY GREATLY DEPENDING ON THE INDIVIDUAL. OFTEN, A BAD TRIP ONLY CONSISTS OF MILDLY ANXIOUS FEELINGS, WHICH ARE NOT PARTICULARLY THREATENING OR DANGEROUS TO THE INDIVIDUAL OR OTHERS.

becomes aware of the altered state of

was driving me into a living hell. The doctor

adverse reaction to a psychedelic drug,

consciousness, becomes anxious in

looked like the devil to me. He had tricked

more properly referred to as “drug induced

thinking that the effects are permanent,

me. I didn’t think either of us was sane

psychosis.” While a bad trip can occur after

and fears that they cannot return to their

now. As a matter of fact, I thought everyone

the ingestion of any psychedelic drug, it is

original mental state. In the culmination of

was inhuman, and I would go through life in

most often associated with the use of LSD.

these feelings triggered from the effects of

this situation and this would go on forever.

Bad trips are usually constituted of fear,

the drug, the user can become depressed

There never even existed something

confusion, and/or anxious feelings that are

or violent, doing drastic things they would

as wonderful as death that could get

vague in nature and have no clear source

not do if not under the influence of the

me—body and mind—out of this horrible,

or explanation [R].

drug. When losing sense of time or space,

unnatural life. [Q]

depending on the individual. Often, a bad

in the psychotic state. Written here is a

investigation, the definition of the bad trip

trip only consists of mildly anxious feelings,

description of this psychosis experienced

will be limited to severe cases similar to

which are not particularly threatening or

by a test subject administered LSD in a

this. Since the boundary between a good

dangerous to the individual or others.

clinical setting:

trip and a bad trip in mild cases can be

The severity of a bad trip can vary greatly

Some users even report that a bad trip

the user becomes especially dangerous

For the purpose of this

It seemed as if I had three minds, two

subjective and trivial, the focus will instead

can be psychologically therapeutic,

that were insane and one perfectly normal.

be on instances when the users become

allowing them to face personal issues

In other words, I was having the experience

a danger to themselves or society directly

they’d otherwise ignore and release

of having a front row seat watching myself

because of the effects of LSD. Making this

built up emotional tension [F]. In some

who was insane. Faces now looked

distinction assists in providing a consistent

cases however, the user can go into a

distorted, eyes were of a cruel expression,

base from which the etiology of the

psychotic rage, becoming a danger both

and they seemed to have the power of

adverse effects can be studied.

to him or herself and others. The rage is

looking through me and my very thoughts.

usually a consequence of a dissociative

The least amount of noise sounded one

psychological state in which the user

hundred times louder. Everything I heard

044

VERTICES//029.02

LSD and the Brain

5-HT Serotonin Receptors

Coincidentally, the original discovery of

LSD’s complex psychological effects

After establishing the importance of the

are very much a product of its varied

serotonin (5-HT) as a neurotransmitter and

5-HT2 receptor in the LSD interaction,

synaptic interactions in the brain. LSD acts

the first synthesis of LSD occurred only a

the next step was to identify the receptor

on both dopaminergic and serotonergic

year apart, with the former being in 1937

subtypes that are most influential in

signaling systems, and the wide array

and the latter being in 1938. The finding

of receptor binding is the basis for the

that LSD acted primarily on the 5-HT2

producing LSD’s hallucinogenic effects. [E],

physiological effects of the drug. In addition,

receptor did not come until later, at which

and 5-HT2C receptors as being the most

serotonin also modifies the transmission

point scientists intensively researched

involved with LSD. Originally, the 5-HT2C

of dopamine, which further complicates

LSD’s binding to the receptor and its

receptor was thought to be the most

LSD’s pharmacodynamics. LSD is rather

subsequent effects. In 1984, Nakada,

important receptor in the interaction, since

distinctive in this regard. It is one of the

Wieczorek, and Rainbow characterized

LSD and other hallucinogens actually bind

very few psychedelics that are able to

the activity of LSD in a rat brain using

more potently to the 5-HT2C receptor than

act substantially upon receptors of both

quantitative autoradiography. Through

the 5-HT2A. However, in studies that utilize

neurotransmitters, making its psychoactivity

this method, they confirmed the results of

a 5-HT antagonist, such as ketanserin,

relatively intense and unpredictable.

prior scientists [B], [E], and [G], who had

the antagonist is about 2000 times more

observed LSD’s high affinity to the 5-HT2

selective for the 5-HT2A receptors than

receptor.

the 5-HT2C receptors, yet they still reverse

There is substantial research that has

many of the behavioral effects of the

elucidated the importance of the 5-HT2

hallucinogen (Nichols 2004). Therefore,

receptor in interactions with a number

the binding of LSD to the 5-HT2A receptor

of other hallucinogens, as well as LSD.

accounts for far more of the psychoactive

David Nichols (2004) conducted a

effects. [D] Fiorella, Rabin and Winter

study on the effects of hallucinogens on

(1995) gave further evidence that 5-HT2A

specific receptors and parts of the brain,

receptor activity is more decisive in

highlighting the 5-HT2A receptor subtype

hallucinogenic effects than 5-HT2C

on pyramidal neurons. The activation

receptors through an antagonist correlation

of these neurons leads to release of

analysis. In the analysis, there was a

cortical glutamate caused by the trigger of

correlation between the blockage of the

signals in the thalamus through the locus

stimulus properties of LSD and antagonist

coeruleus. As the thalamus and other parts

affinity to 5-HT2A but not 5-HT2C, meaning

of the locus coeruleus are functionally

that only the binding of LSD to the 5-HT2A

associated with consciousness and

subtype had a direct influence on the

alertness, it is rational that hallucinogens

manifestation of its psychoactive effects.

have a significant impact on this area.

as mentioned earlier, identified the 5-HT2A

THERE IS SUBSTANTIAL RESEARCH THAT HAS ELUCIDATED THE IMPORTANCE OF THE 5-HT2 RECEPTOR IN INTERACTIONS WITH A NUMBER OF OTHER HALLUCINOGENS 045

//ARTICLE.07 >>

While the actual manifestation of the symptoms are dependent on LSD’s binding

when applying 5-HT studies on rats to

to the 5-HT2A subtype, its differential

humans in the long-term, as there are

effects may be due to its binding with other

functional differences of the receptors

5-HT receptors. As shown by Rosecrans,

between different species. For example,

Lovell, and Freedman (1967), LSD can have

tolerance to LSD and other hallucinogens

either an excitatory or an inhibitory effect

in both species develops through the

on serotonin signaling [P]. In their study,

down-regulation of the 5-HT2A receptor.

the overall serotonin levels in the rat brain

However, the rate at which the tolerance

fluctuated at inconsistent rates as time

occurs in rats and monkeys (and probably

elapsed after the LSD injection. In some

humans) differs, and the substitution

cases, the overall amount of serotonin in

of LSD with another 5-HT2 agonist

the brain would decrease, while in others, it

hallucinogen in discriminatory studies

would increase. This was also exhibited in

sometimes fails in monkeys. It’s possible

Peroutka and Snyder’s study (1979) on the

that after monkeys develop a tolerance to

differential binding of LSD [O]. Interestingly,

a hallucinogen, the cue for distinguishing

when Aghajanian, Heighler, and Bloom

between that hallucinogen and another

(1972) measured the action of serotonin-

substance may transfer to the binding of a

containing neurons in the raphe nuclei (part

different 5-HT serotonin receptor.

of the brain stem responsible for releasing

Important to note, an issue arises

Even though tolerance mechanisms in

serotonin to the rest of the brain), they

the species are different, Sadzot et. al.

found that LSD consistently inhibited the

(1989) found in his research that human

action of those neurons [A]. This could

brains and rat brains have a very high

mean that LSD only interacts with the

correlation of LSD agonist activity to the

serotonin that has already been released to

5-HT2 receptor. Thus, while long-term

the brain’s pathways prior to its ingestion,

studies in cannot be compared directly,

since the raphe nuclei neurons are unable

brain activity in the short term can be

to effectively release serotonin to the rest of

compared between rats and humans

the brain after that point. Then, a possible

with relatively high confidence, and so

explanation for the fluctuating serotonin

only studies examining the short-term are

levels could be the binding activity of LSD and its effect on serotonin metabolite levels (Rosencrans. Lovell, and Freedman 1967), but exactly how LSD binding affects serotonin and its metabolite levels is still unknown [P]. However, since increased serotonin levels are known to be the

cause of many psychiatric disorders, such as depression and phobias (also similar to symptoms in a bad trip), it could be hypothesized that adverse reactions are more likely to occur in the instances when LSD increases overall serotonin levels in the brain.

046

AS LSD IS A D-2 AGONIST, IT IS POSSIBLE THAT THE PSYCHOTIC BEHAVIORS THAT CAN ARISE AFTER THE INGESTION OF A LARGE DOSE ARE ASSOCIATED WITH THE ACTIVITY OF THE D-2 RECEPTORS.

//SHAQ JUNAID

THIS COULD MEAN THAT LSD ONLY INTERACTS WITH THE SEROTONIN THAT HAS ALREADY BEEN RELEASED TO THE BRAIN’S PATHWAYS PRIOR TO ITS INGESTION, SINCE THE RAPHE NUCLEI NEURONS ARE UNABLE TO EFFECTIVELY RELEASE SEROTONIN TO THE REST OF THE BRAIN AFTER THAT POINT.

Marona-Lewicka, D., Thisted, R. A., & Nichols, D. E. (2005). Distinct Temporal Phases In The Behavioral Pharmacology of LSD: Dopamine D2 Receptor-mediated Effects In The Rat And Implications For Psychosis. Psychopharmacology, 180(3), 427-435.

Minuzzi, L., Nomikos, G. G., Wade, M. R., Jensen, S. B., Olsen, A. K., & Cumming, P. (2005). Interaction Between LSD And Dopamine D2/3 Binding Sites In Pig Brain. Synapse, 56(4), 198-204.

Mittman, S. M., & Geyer, M. A. (1991). Dissociation Of Multiple Effects Of Acute LSD On Exploratory Behavior In Rats By Ritanserin And Propranolol. Psychopharmacology, 105(1), 69-76.

D-2 Dopamine Receptors Although the central importance of serotonin receptors in hallucinogenic

As LSD is a D-2 agonist, it is possible that the psychotic behaviors that can arise after the ingestion of a large dose

noted the evident modulation of serotonin receptors in the process [I]. Furthermore, a study observing both the behavioral

effects has been shown, the dopaminergic

are associated with the activity of the D-2

changes and the neuropharmacological

properties of LSD also play an important

receptors. In essence, the adverse reaction

changes of seven healthy males after

role.

could be homologous to a schizophrenic

administration of psilocybin, which has

In order to evaluate the role of the D-2

symptom, similar to the comparison

hallucinogenic properties very similar to

receptors in an LSD trip, it is necessary to

made earlier with hyperserotonergic

LSD, revealed the presence of a serotonin-

compare its functions in other contexts.

symptoms, in which the overstimulation

dopamine balance system that regulated

Notably, the D-2 receptor is the primary

of the D-2 receptors induces a psychotic

the characteristics of the experimentally

receptor that many anti-psychotic

state. Though this is valuable as a partial

medications antagonize. Farde, Ehrin,

explanation, it is not wholly sufficient in

induced psychosis [T]. Relating back to

and Sedvall (1986), using PET scans

explaining the psychotic behavior. If it

serotonin-dopamine interactions have a key

of the brains of schizophrenic patients

were, “bad trip” symptoms would be nearly

role in many psychological diseases, such

taking these D-2 antagonist medications,

identical to schizophrenic symptoms,

as schizophrenia, and are also relevant in

found the drugs blockaded 85-90% of

which is not usually the case. Thus, the

the drug-induced psychoses of LSD and

the D-2 receptors in the putamen, and

explanation most likely more complicated

other drugs.

that these drugs were reported to be

than an isolated interaction with D-2

clinically effective [C]. Three chemically

receptors would portray.

their principal shared characteristic being

positron emission tomography (PET) scans

their D-2 receptor antagonism. Thus, this

confirms the suspected complexity of the

suggests that the blockade of the D-2

D-2 receptor interactions. Examinations

receptors is the primary factor in reducing

of pig brains under the influence of LSD

the patients’ psychotic behavior [C].

reinforced the partial activity of the drug

different treatment drugs were used, with

the earlier theory, it may be the case that

In fact, more recent research with

D-2 and D-3 dopamine receptors, but also 047

//ARTICLE.07 >>

5-HT and D-2 Interactions

Stimulation of the 5-HT2 receptor is

propranolol to block the 5-HT1 receptors

correlations by conducting a study with

essential to the hallucinogenic properties

actually increased late-phase locomotor

PET scans of users experiencing a bad

of many drugs, as explained earlier. Thus,

activity. This is seemingly contradictory

trip, though it would be difficult to create

there is little surprise at the present day

to Marona-Lewicka et. al.’s (2005) and

the experimental conditions. Even with this

that LSD’s primary effects are due to its

Nakada et. al.’s (1984) findings, suggesting

data however, it would still be apparent that

high affinity to this receptor. However, in

that differential serotonin receptors are what

the psychopharmacology alone cannot

the Minuzzi et. al. (2005) study concerning

modulate the two-phase phenomenon.

account for all of the etiology of an adverse

the D-2 receptors, when their activity was

However, after synthesizing the results of

reaction, and that other general factors

blocked with the antagonist sulpiride, there

these studies, it seems that 5-HT2 receptor

must be examined.

was an evenly distributed decrease in the

activity has some interactive impact on

amount of specific LSD binding across the

D-2 receptor activity. Residual D-2 activity

brain [I]. However, after utilizing ketanserin

increased in the Nakada, Wieczorek, and

to block binding to the 5-HT2 receptors,

Rainbow study when ketanserin (5-HT2

there was still residual binding to D-2

antagonist) was not used, compared to

receptors in many of the brain structures

when it was used [K]. If there were no

that encircle the reward pathway, including

interaction between the activity of the two

the nucleus accumbens and the putamen

receptors, one would expect the binding

[K]. This suggests that while LSD has an

of the 5-HT2 receptor to have no effect on

affinity for both receptors, it binds to D-2

the activity of the D-2 receptors. Thus, it

receptors in the reward pathway structures

seems that an increase of binding to 5-HT2

several hours late, but binds to 5-HT2

produces a subsequent increase in binding

receptors immediately across all regions

to D-2 receptor, effectively amplifying the

of the brain, which indicates that the drug

probability of an adverse reaction.

acts in two phases. The significance of D-2

This interaction can also address

receptors in this two-phase reaction was

how many other chemically similar

supported Marona-Lewicka et.al. (2005),

psychoactive drugs, such as tryptamines

who stated that the interactions between

and phenethylamines, also interact with the

LSD and the D-2 receptors occur largely in

5-HT2 receptors but do not exhibit the two-

the second half of the drug’s later phase:

phase characteristic of LSD. It is possible

the phase hypothesized to be associated

that there are fewer interactions between

with the initiation of a bad trip [H] .

the 5-HT2 serotonin and D-2 dopamine

the two-phase characteristic of LSD

the brain that regulates the release of one

effects through testing in rats [J]. The first

of these neurotransmitters. One hypothesis

behavioral responding” while the second

nuclei remain uninhibited in tryptamine

Mittman and Geyer (1991) described

half of the trip induced “suppression of half induced “increased locomotor

receptors, or that there is a mechanism in

could be that neurons in the raphe and phenethylamine interactions, and

activity that was not observed with other

so the serotonin levels are kept more

serotoninergic hallucinogens”. In their

constant. However, the conclusions in

study, they manipulated the administration

many of the above studies are drawn

5-HT1 and 5-HT2 antagonists ritanserin

mostly from correlational deductions,

and propranolol in rats that were treated

and without any studies to affirm the

with two different dose levels of LSD.

psychopharmacology of an adverse

While the utilization of ritanserin to block

reaction, precise explanations for these

5-HT2 receptors resulted in a substantial

phenomena cannot be established. The

decrease in locomotor activity, use of

next step, perhaps, is to elucidate these

048

VERTICES//029.02

THE FIRST HALF OF THE TRIP INDUCED “SUPPRESSION OF BEHAVIORAL RESPONDING” WHILE THE SECOND HALF INDUCED “INCREASED LOCOMOTOR ACTIVITY THAT WAS NOT OBSERVED WITH OTHER SEROTONINERGIC HALLUCINOGENS”.

Nakada, M., Wieczorek, C., & Rainbow, T. (1984). Localization And Characterization By Quantitative Autoradiography Of [125I]LSD Binding Sites In Rat Brain. Neuroscience Letters, 49(1-2), 13-18.

Nichols, D. (2004). Hallucinogens. Pharmacology & Therapeutics, 101(2), 131-181.

Pahnke, W. N., & Richards, W. A. (1966). Implications of LSD and experimental mysticism. Journal of Religion and Health, 5(3), 175-208.

Pantelis, C., Velakoulis, D., McGorry, P. D., Wood, S. J., Suckling, J., Phillips, L. J., ... & McGuire, P. K. (2003). Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. The Lancet, 361(9354), 281-288.s

Peroutka, Steven J., and Solomon H. Snyder. “Multiple Serotonin Receptors: Differential Binding of Hydroxytryptamine and Lysergic Acid

THUS, IT SEEMS THAT AN INCREASE OF BINDING TO 5-HT2 PRODUCES A SUBSEQUENT INCREASE IN BINDING TO D-2 RECEPTOR, EFFECTIVELY AMPLIFYING THE PROBABILITY OF AN ADVERSE REACTION.

Diethylamide.” Molecular Pharmacology 16 (1979): 687-99. Print.

Rosecrans, J. A., Lovell, R. A., & Freedman, D. X. (1967). Effects of lysergic acid diethylamide on the metabolism of brain 5-hydroxytryptamine. Biochemical pharmacology, 16(10), 2011-2021.

Unger, S. M. (1964, May). The current scientific status of psychedelic drug research. Unpublished paper read to the Conference on Method in Philosophy and the Sciences in New York City (Vol. 3).

049

//ARTICLE.07 >>

Other Factors that Cause a Bad Trip Though LSD’s interactions with receptors

in the brain go far in explaining the possible causes of a bad trip, biological explanations are rarely sufficient in providing comprehensive explanations for psychological phenomena. Environmental circumstances and other holistic factors must also be considered, including the user’s “set,” “setting,” and socioeconomic circumstances, as Nichols (2004) elaborates: Dr. Stanislov Grof, who supervised more clinical LSD sessions than any other individual, wrote, ‘‘I consider LSD to be a powerful unspecific amplifier or catalyst of bio-chemical and physiological processes in the brain’’ (Grof, 1975). These thoughts were echoed by Barr et al. (1972) who stated, “ . . .the phenomena induced by LSD (and probably by any similar drug) cannot be predicted or understood in purely pharmacological terms; the personality of the drug taker plays an enormous and critical role in determining how much effect there will be and of what particular type.” To complicate matters further, an individual subject’s response to repeated administration of the same drug and dose may also vary. (p. 137) [L]

As stated, these general factors result in variable effects on different users, so it is important to analyze each of them. Set and Setting

The most common cited cause of

LSD based on users’ “sets.” In his book

the subjects interviewed were all current

a bad trip, both by users and medical

Drug, Set, and Setting (1984), Norman

users of the drug, it is evident that the

professionals, is the user’s thoughts

Zinberg surveyed 26 LSD users and

high rates of bad trips among first-timers

before taking the drug, or their “set”.

transcribed interviews with three of them to

are still present even when the users are

Under an anxious, angry, or depressed

gauge their perceptions of the influence of

willing to take the drug (willing enough that

mindset, taking a psychedelic drug often

set and setting on their trips [U].

they continued using it). Because of this, it

consistently expressed that first-time

has a higher influence than actual thoughts

Discomfort or unwillingness to take a drug

users were far more likely to suffer a bad

of the drug. Still, the two often go hand in

is the usual cause for these mindsets,

trip than more experienced users. In their

hand. Comfort with the drug increases with

as well as mood from recent life events.

explanation, they cited factors such as

experience, and multiple users reported

Still, users sometimes underestimate “set”

comfort with the drug, knowledge of ideal

that after continued use, they learned

as a factor in the outcome of their trips

dosage, purpose of use and experience of

to manipulate their “setting” to optimize

because they are not mentally aware of

their accompanying users. Though some

their reaction to the drug, as explained by

their actual psychological state. Since the

researchers speculate that higher rates of

Zinberg:

drug removes regular filters from the brain,

adverse reactions among first-time users

the user sometimes faces inner terrors

are due to their predisposed unwillingness

that they are not completely aware of or

to take the drug, Zinberg’s findings

prepared for in a regular state of mind [L].

suggest that this is not the case. 50% of

logical states of LSD users is difficult to

at one time or another, and 22% of those

acquire, anecdotal studies are the best

subjects claimed that they had one the first

demonstrators of the differential effects of

time they used LSD (p.69) [U]. However, as

intensifies these emotions, taking them to unpleasant or even dangerous levels [S].

As scientific data comparing psycho-

050

The subjects of his interviews

the subjects reported having a bad trip

would seem that experience with the drug

//SHAQ JUNAID

THE SUBJECTS OF HIS INTERVIEWS CONSISTENTLY EXPRESSED THAT FIRSTTIME USERS WERE FAR MORE LIKELY TO SUFFER A BAD TRIP THAN MORE EXPERIENCED USERS.

From discoveries about place and time another sanction emerged among experienced users: “Only use at a good time, in a good place, with good people.” Originally this sanction was offered as advice from one friend to another, but soon users far removed from the initial advisor accepted it as an important and valid way to avoid trouble. (p. 70)

051

//ARTICLE.07 >>

The “good time, good place, and good people” relates back to several of the key

28% of respondents from the sample of

aspects of set and setting. “Good time”

users in Zinberg’s research claimed to

and “good place” are rather multifaceted;

strictly use LSD for spiritual purposes in

time can refer to both a pleasant instan-

order to avoid bad experiences. Pahnke

taneous psychological state, as well as

and Richards (1966) attribute the increase

a period with no impending tasks that

in pleasant experiences during religiously

have to be completed. For example, one

or spiritually motivated LSD trips to the

interviewee stated, “I wouldn’t want to

nature of the actual trips [M]. They re-

trip on a Sunday if I had three classes on

religious and spiritual purposes. In addition,

port that these users’ trips have specific

Monday” (p. 72). Place can refer to the

characteristics, such as increased “unity,

user’s emotional state, as well as openness

transcendence, sense of sacredness,

and comfort of the environment, with good

ineffability, and persisting positivity.” While

examples being an open field or one’s own

this suggests that user’s with religious or

backyard. “Good people,” though also

spiritual motives have different LSD experi-

relatable to comfort, refers more to the

ences altogether, this is difficult to validate

experience of those around the user. Inter-

since the trips are so subjective and inde-

viewees were quick to note the importance

scribable. It may just be that associations

of having a guide, or “babysitter,” someone

with specific purposes contribute to a more

who “knew what they were going through”

positive overall “set,” which consistently

and could “help them if they needed help

leads to improved experiences.

[during a bad trip]” (p. 73). This decreases

In synthesizing the influence of set and

the chances of the first-time user ingesting

setting and the mechanisms of receptors in

an excessive dose and having a bad trip

the brain, research has yet to determine if

that develops into a dangerous psychosis.

the two aspects are independent influenc-

A user’s purpose for using LSD is also

es on the LSD trip, or whether they have

a significant part of the “set.” Though the

a causal relationship. Since there are pat-

general purpose of “wanting to use LSD”

terns in both aspects that are indicative of

versus “not wanting to use LSD” makes

a bad trip, the two do appear to have some

a difference, specific intents before using

association. The next step in research is

LSD tend to be just as influential. Perhaps

to identify the nature of the association by

in connection to the previously discussed

comparing correlational data of outcomes

aspects of the user’s “set,” those that use

based on set and setting and their corre-

for religious or spiritual purposes report

sponding mechanisms in the brain.

fewer adverse reactions to the drug. Ungerleider et. al. (1968) conducted a study comparing twenty-five non-problematic users of LSD with twenty-five hospitalized inpatients for adverse reactions to LSD [R]. In the comparison of religion, they

found that 32% of users in the hospitalized group reported never using LSD for any religious or spiritual purpose, while 96% of the non-problematic group reported either consistently or occasionally using LSD for

052

VERTICES//029.02

Socioeconomic and Other Circumstantial Factors

to be more reckless with their LSD use, re-

example, employment and education rates

include factors that are relatively vague, the

sulting in higher doses, frequent ingestion,

could reflect family history of drug use,

Ungerleider et. al. (1968) study mentioned

and unsafe practices that amplify recur-

self-esteem due to social success, and/or

earlier that compared twenty-five regular

rence of bad trips. Marital status could also

free time to experiment with drugs. Thus,

non-problematic users of LSD with twen-

simply be a consequential statistic rather

it is difficult to analyze each to incorpo-

ty-five hospitalized users found several tan-

than an explanatory one, as their person-

rate them into the etiology of an adverse

gible, highly significant differences between

ality traits that have predisposed them to

reaction. Still, it is notable that these

the two groups that could have contributed

drug use have also prevented them from

correlations exist, as they can be used

to the susceptibility to a bad trip [R]. These

getting married in one way or another. Even

as predictors in combination with other

factors included marital status, employ-

without a clear deduction of the origin of

circumstances.

ment, education, criminal history, drug

the highly significant difference in marriage

Though set and setting can often

Of the factors examined in Ungerleider

rates between the two groups, it seems

et. al.’s study (1968), psychiatric diagnosis

Interestingly, none of the inpatient users

clear that marriage is a relatively powerful

history was arguably the most substantial.

were married at the time of their admission

indicator of the likelihood of experiencing

While 40% of the inpatient group was diag-

to the hospital, compared to 60% of the

an adverse LSD reaction.

nosed or had previously been diagnosed

history, and psychiatric diagnosis history.

non-problematic users. In addition, 84% of

Employment, education, and criminal

with a psychological disorder, no members

the inpatients had never been married, and

history, in being socioeconomic mea-

of the comparison group had any history of

the median ages of the two groups were

sures, were also similar indicators. Of the

psychiatric diagnosis. This suggests that

not significantly different. Without any anec-

inpatients, only 20% were employed to the

neuroanatomical abnormalities causing

dotal data elaborating on these drastically

point of self-sufficiency, 64% had crime

the psychiatric disorders could be altering

differing rates, it is hard to explain what

records, and none of them had attended

LSD-receptor interactions that contribute

predispositions being single has on the

college. The comparison (non-problematic)

to the causation of an adverse reaction.

likelihood of suffering an adverse reaction

group had a 70% rate of employment, 8%

Considering recent research linking

to LSD. One could argue that being single

crime record rate, and 72% high school

psychiatric disorders with neuroanatomical

makes a person less likely to be happy,

graduation rate, with 16% having attended

deficiencies, this seems even more likely.

therefore negatively affecting their “set” and

college. These three statistics are straight-

Pantelis et. al. (2003) utilized MRI machines

leading to inflated chances of having an ad-

forward socioeconomic indicators that

to discover an association with lower gray

verse reaction. The lack of marital support

would be expected in the use of any drug.

matter densities in several brain regions

and responsibility could also prompt a user

Their implications are very far reaching, for

and the development of psychosis after drug ingestion or traumatic experience [N]. In addition, Hemsley and Ward (1984)

found strong positive correlations between

INTERVIEWEES WERE QUICK TO NOTE THE IMPORTANCE OF HAVING A GUIDE, OR “BABYSITTER,” SOMEONE WHO “KNEW WHAT THEY WERE GOING THROUGH” AND COULD “HELP THEM IF THEY NEEDED HELP [DURING A BAD TRIP]” (P. 73).

high scores on the Minnesota Multiphasic Personality Inventory (MMPI) schizophrenic personality tests, “recurrence of psychedelic drug symptoms” or “flashbacks,” and the frequency of bad trips. If research continues to pinpoint anatomical abnormalities and the detrimental changes they cause, their findings could be compared to the symptoms of drug psychosis [F].

Then, these comparisons could uncover anatomical consistencies in a drug psychosis, bringing us closer to having a comprehensive explanation of the etiology of a bad trip. 053

//ARTICLE.07 >>

Conclusion

Mentioned in the Ungerleider’s

in current knowledge. As most productive

discussion, there have been remarkable

LSD research took place during the 1960s,

instances in which medical professionals

probing further into the same research

have experienced adverse reactions to

with modern technology and methods

LSD even with favorable mental and social

could unearth similarly productive findings.

circumstances [R]. Also, 8% of those

Even with academic interest in LSD

hospitalized claimed to have taken extra

decreasing due to increase stigmatization

precaution to avoid the occurrence of an

of research on illicit drugs, it is important to

adverse reaction. Taking these statements

assert the intellectual value in their study.

within the context of the other findings

LSD and similar hallucinogens provide

of the causes of bad LSD trips, it seems

a unique manner of inquisition into the

that the interaction is still too complex to

human brain; they reveal an element of

rule with a definitive answer. Even with

human psychology that is not otherwise

the observance of physiological and

observable. Though agreeably unsafe to

circumstantial patterns that either increase

use, the study of these drugs allows for the

or decrease the probability of a bad trip,

potential of augmenting the understanding

there are still a multitude of exceptions that

of humans, our brains, and our psychology

defy the patterns.

to a level that was not possible before.

Still, the patterns and explanations

of LSD’s psychoactive effects that have been uncovered so far leave much to be learned about the drug in the future. As understanding of its psychopharmacological interactions with 5-HT2 and D-2 receptors improves and new tools develop that allow for more efficient experimentation, new discoveries will be available to be made that will hopefully account for the voids that exist

Ungerleider, J. T., Fisher, D. D., & Fuller, M. (1966). The Dangers of LSD Analysis of Seven Months’ Experience in a University Hospital’s Psychiatric Service. JAMA: The Journal of the American Medical Association, 197(6), 389-392.

Ungerleider, J. T., Fisher, D. D., Fuller, M., & Caldwell, A. (1968). The “Bad Trip” - The Etiology of the Adverse LSD Reaction. American Journal of Psychiatry, 124(11), 1483-1490.

Vollenweider, F. X., Vontobel, P., Hell, D., & Leenders, K. L. (1999). 5-HT Modulation of Dopamine Release in Basal Ganglia in PsilocybinInduced Psychosis in Man—A PET Study with [11C]ralcopride. Neuropsychopharmacology, 20, 424-433.

Zinberg, N. E. (1984). Drug, Set, and Setting. New Haven: Yale University Press.

054

//ARTICLE.08

[MICRO. BIOLOGY AND THE //FINAL_FRONTIER://] REVIEWING THE IMPACT OF SPACE’S UNIQUE ENVIRONMENT ON MICROBIAL ECOLOGY By: Alissa Wall AND HUMAN HEALTH Abstract The rise of the space age in the 1960’s

variation in ontogeny between Earth and

saw man shooting himself into the final

space populations. These studies have

frontier, and with him traveled some of

contributed to the critical understanding of

Earth’s microbial organisms. For both man

how space impacts human/microbial inter-

and microbe, space offered novel evolu-

actions in astronauts, and the identification

tionary forces within a previously unknown

of key genetic and morphological adapta-

ecological niche: one defined by micro-

tions to microgravity and radiation. Here,

gravity and extreme-relative-to-Earth levels

I survey advances in the field of astromi-

of radiation. Accordingly, the space age

crobiology and the resulting characteriza-

ushered in a myriad of questions regarding

tions of microbial populations subjected to

the impact of space on microbial diversity

microgravity environments and increased

and virulence. Originally, research was

radiation exposure. I investigate the syner-

focused on sterilization techniques for NA-

gy between the impact of microgravity and

SA’s expeditions to the moon, but expand-

radiation on the ontogeny of microbial spe-

ed to evaluate microgravity’s impact on

cies in closed-system space environments,

microbial development, proliferation, gene

the resulting changes to the genetic ar-

expression, and physiology. Developments

chitecture of microbial space populations,

in molecular techniques have enabled

and the adaptive physiological processes

researchers to identify both the genetic

identified in these populations. Finally, I

and morphological changes in bacterial

assess the impact of these variations on

populations subjected to microgravity and

the health of human space populations.

radiation-rich environments, and to identify 055

//ARTICLE.08 >>

Castro, V.A., Thrasher, A.N., Healy, M., Ott,

Introduction : Overview of astromicrobiology The field of astromicrobiology is

precise conditions experienced in space,

concerned with the origin, evolution, and

the data garnered from such experiments

distribution of life in space. There are two

are generally corroborated by in-space

particular lenses through which to study

analogues [O].

astromicrobiology: (1) exchange from

planet to planet, and (2) exchange between

from space back to Earth. Although the

[N]. Galactic cosmic radiation describes

from Earth to space, then b) exchange

geomagnetically trapped particle radiation

first lens is of intellectual and academic

radiation that originates outside our

interest because of its implications for

solar system, and notably contains high

extraterrestrial life, the second is being

energy heavy ions (HZE), which are of

actively examined and researched

particular hazard to astronaut health

by NASA because of the immediate,

because of their ability to penetrate

potentially dangerous consequences of

through 1 mm of spacecraft or spacesuit

microbial evolution in space.

shielding [N - P] . Solar particle radiation

Microbes travel into space because

and geomagnetically trapped particle

of unintentional pre-launch spacecraft

radiation generally consist of large clouds

contamination [A,B,C], astronaut microflora

of protons from the sun and pose fewer

human-directed microbial experiments

particles comprise the most-studied

[C;D;E], payloads [C], and intentional

known risks to human health [N]. HZE

[C;F;G]. Numerous studies have

radiation in astroradiology. Radiobiological

demonstrated that the unique selective

experiments with the most extrapolative

pressures in space alter bacterial virulence

ability are those conducted directly in

and proliferation, and antimicrobial efficacy

space. Those conducted in particle

[E;F;G;H], while simultaneously affecting

accelerators on the ground are only able to

crewmember immune function [I;J;K].

analyze a narrow range of energies, which

Two key driving selection factors thought

do not encapsulate the spectrum of HZE

to be implicated in these changing traits

particle energies. Coronal mass ejections,

are spaceâ&#x20AC;&#x2122;s microgravity [F- M] and levels

in which large quantities of electromagnetic

of radiation [I;L- M]. Due to the difficult

material such as gamma rays are released

nature of planning and executing in-

into the solar system from the sun, are

space experiments, researchers have

of concern to spaceflight as well, but

developed techniques to replicate space

little research is available on their impact

environments on the ground.

on space-bound humans, much less

Microgravity acts on bodies in orbit in space, and denotes a nonzero, but small,

microbes. A summary of current research

gravitational force. The International Space

in astromicrobiology relevant to the

Station (ISS) experiences microgravity,

diversity and evolution of Earth-originated

and it is this force that keeps it in orbit

microorganisms is provided in this review.

around the Earth. Studies of microgravityâ&#x20AC;&#x2122;s

Much of this research is observational

effect on microbial populations include

and focuses on describing, rather than

both in-space experiments, such as

explaining, the resulting physiological,

experiments conducted on the ISS and

metabolic, genetic, and regulational

simulated microgravity (SMG) experiments

changes microbial organisms undergo in

conducted on the ground. Although

space.

SMG experiments cannot replicate the 056

ecology 47, 119-126.

Ott, C.M., Bruce, R.J., and Pierson, D.L. (2004).

Earth is composed of galactic cosmic radiation, solar particle radiation, and

of the International Space Station. Microbial

The radiation environment near

Earth and space, involving a) exchange

C.M., and Pierson, D.L. (2004). Microbial characterization during the early habitation

Microbial characterization of free floating condensate aboard the Mir space station. Microbial ecology 47, 133-136.

Pierson, D.L. (2001). Microbial contamination of spacecraft. Gravitational and Space Biology Bulletin 14, 1-6.

Roberts, M.S., Garland, J.L., and Mills, A.L. (2004). Microbial astronauts: assembling microbial communities for advanced life support systems. Microbial ecology 47, 137-149.

Klaus, D.M., and Howard, H.N. (2006). Antibiotic efficacy and microbial virulence during space flight. Trends in biotechnology 24, 131-136.

Wilson, J.W., Ott, C.M., Honer zu Bentrup, K., Ramamurthy, R., Quick, L., Porwollik, S., Cheng, P., McClelland, M., Tsaprailis, G., Radabaugh, T., et al. (2007). Space flight alters bacterial gene expression and virulence and reveals a role for global regulator Hfq. Proceedings of the National Academy of Sciences of the United States of America 104, 16299-16304.

Foster, J.S., Khodadad, C.L., Ahrendt, S.R., and Parrish, M.L. (2013). Impact of simulated microgravity on the normal developmental time line of an animal-bacteria symbiosis. Scientific reports 3, 1340.

CiftĂ§ioglu, N., Haddad, R., Golden, D., Morrison, D., and McKay, D. (2005). A potential cause for kidney stone formation during space flights: enhanced growth of nanobacteria in microgravity. Kidney International 67, 483-491.

Mermel, L.A. (2013). Infection prevention and control during prolonged human space travel. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 56, 123-130.

//ALISSA WALL

SOLAR PARTICLE RADIATION AND GEOMAGNETICALLY TRAPPED PARTICLE RADIATION GENERALLY CONSIST OF LARGE CLOUDS OF PROTONS FROM THE SUN AND POSE FEWER KNOWN RISKS TO HUMAN HEALTH

Current microbial diversity in space Studies have aimed to identify the unintentional microorganisms brought into space via contamination.

Sonnenfeld, G., and Shearer, W.T. (2002). Immune function during space flight. Nutrition 18, 899-903.

Borchers, A.T., Keen, C.L., and Gershwin, M.E. (2002). Microgravity and immune responsiveness. Nutrition 18, 889-898.

Reitz, G., B端cker, H., Facius, R., Horneck, G., Graul, E., Berger, H., R端ther, W., Heinrich, W., Beaujean, R., Enge, W., et al. (1989). Influence of cosmic radiation and/or microgravity on development of carausius morosus. Advances in Space Research 9, 161-173.

Horneck, G. (1999). Impact of microgravity on radiobiological processes and efficiency of DNA repair. Mutation Research 430, 221-228.

Horneck, G. (1992). Radiobiological experiments in space: A review. Special Issue Space Radiation 20, 185-205.

Crewmembers are the dominant source of bacterial contamination in spacecrafts, with pre-flight construction

water were largely gram negative and had comparable fingerprints across species. These isolates collected from the

contaminants and in-flight contaminants

ISS in-space experiments did not

from delivered payloads also acting as

cause researchers to worry about

contributing sources [C]. A study in 2003

environmental hazards or health risks.

sought to describe the initial changes

However, a comparable study done

from ISS pre-flight microbiota to in-flight

in the older Russian Mir space station

microbiota from ground to space to better

demonstrates that the risk of dangerous

understand what contaminants are being

microbial contamination grows over time

transmitted to space [A]. After standard

[2]. Mir, launched in 1986 and studied in

antimicrobial sterilization techniques

1998, contained higher fungal species

were applied to the module, researchers

than the ISS when studied, and had a

took pre-flight bacterial samples from

more diverse set of microbes including

spacecraft surfaces, water sources, and

dust mites, ciliated protozoa, and

air and compared these to in-flight samples

spirochetes. Additionally, opportunistic

collected up to one year later when the ISS

pathogens such as Stenotrophomonas

was in orbit. 16S sequence identification

maltophilia, Ralstonia paucula, Candida

was used to identify isolates. Pre- and

guilliermondii, and Candida krusei were

in-flight bacterial samples from surfaces

isolated and identified using the Biolog

were largely gram positive and had similar

Automated Identification System or a

fingerprints; samples from air were largely

VITEK Identification System. Researchers

gram positive and had some similar

studying the microbial diversity of the

fingerprints, although M. leteus strains

ISS worry that over many years the ISS

all had different fingerprints; and from

microbiota profile will look like that of Mir [A]. 057

//ARTICLE.08 >>

Increase of Microbial Virulence and Growth in Microgravity Conditions Bacterial virulence increases in conditions of microgravity in both simulated microgravity and in-space experiments.

In a 2007 study conducted by Wilson

chamber in the vertical plane such that

A luminescent bacteria, Vibrio fischeri,

et al., Salmonella typhimurium, an enteric

the rotating fluid cancels the gravitational

and its host, the Hawaiian squid Euprymna

mouse pathogen, was grown both in

force in selected “sampling ports”

scolopes, were used as a model system in

the ISS and on the ground [F]. Other

across the chamber. This results in the

HARVs to simulate microgravity conditions.

than uniquely space-related factors (e.g.

loaded sample to be in free-fall, or to

Compared to controls subjected to

microgravity and potentially increased

experience microgravity (comparable to

horizontal (not vertical) rotation in the

exposure to radiation) , conditions (e.g.

that experienced on the ISS). The system

HARV, squids grown in SMG showed

humidity and temperature) were kept

is designed to be “low-shear”, meaning

higher sensitivity to chemicals causing

identical between the sites. Mice infected

that the stress coplanar to the material is

the initiation of cellular apoptosis, higher

with in-flight cultures had lower percent

minimized. Although shear forces are not

concentrations of bacteria, and perturbed

survival, and died faster than mice

present in space environments such as

hematocyte trafficking (indicative of immune

infected with ground cultures. Particular

the ISS, “low-shear” SMG experiments

suppression).

inoculum-size of in-flight S. typhimurium

have high extrapolative potential when

resulted in higher mortality than of the

cross-compared to analogous in-

bacterial virulence in space, in conjunction

same sized ground S tymphimurium

space experiments [G;O]. To check the

with suppression of astronaut immune

background noise of the minimal shear

systems, might contribute to astronaut

of the different cultures using scanning

forces present in a vertically-rotating HARV,

health problems. A 2005 study implicated

electron microscopy (SEM), they noticed

an HARV that rotates in the horizontal

increased nanobacterial growth due to

the novel formation of an extracellular

plane, and therefore does not offset Earth’s

decreased lag-phase in the abnormally

matrix in the in-flight cultures. Extracellular

gravitational force and allows samples

high prevalence of kidney stones in

matrices have been linked to increased

to growth under regular gravitational

bacterial virulence in previous studies

conditions, is used as a control experiment

returning astronauts [H]. A 2010 study

[Q]. The regulator that likely responded

[O].

SMG result in increased survival of

stresses from Earth to space was identified

change in relationship between symbiotic

unclear if this is because of host immune

to be Hfq, a conserved RNA-binding

bacteria and host organisms when

suppression, increased bacterial fitness, or

protein [F]. The change in this regulator

subjected to microgravity [G].

a combination of the two.

inoculum. When researchers took images

to the change in environments and

altered the transcriptome and proteome

Another study in 2013 analyzed the

Researchers worry that increased

determined that both spaceflight and

bacteria in macrophages [R], although it is

of the in-space S. typhimurium strain. Furthermore, the lag-phase of the bacteria was decreased, consistent with other researchers’ findings that microgravity stimulates bacterial proliferation [H;I;O]. The above 2007 study utilized both

in-space and simulated microgravity (SMG) experiments. SMG involves a High Alpha Research Vehicle (HARV) bioreactor that offsets the gravitational force experienced on earth with a hydrodynamic force [O]. This hydrodynamic force is generated by rapidly rotating a circular, fluid-filled

058

Nickerson, C.A., Ott, C.M., Wilson, J.W., Ramamurthy, R., and Pierson, D.L. (2004). Microbial responses to microgravity and other low-shear environments. Microbiology and molecular biology reviews : MMBR 68, 345-361.

Grahn, D.E. (1973). HZE Particle Effects in Manned Spaceflight, (Washington DC: Radiobiological Advisory Panel, Committee on Space Medicine, National Academy of Sciences, National Academy Press).

VERTICES//029.02

IN ADDITION TO BIOFILM FORMATION, HORIZONTAL GENE TRANSFER (HGT) IS THOUGHT TO BE A CONTRIBUTING FACTOR TO INCREASED TOLERANCE TO ANTIMICROBIAL AGENTS.

Increased Tolerance to Antimicrobial Agents in Microgravity Conditions Microbial tolerance to antimicrobial agents increases in both simulated microgravity and in-

Biofilms describe dynamic groups of

application of potent, broad-spectrum

microorganisms that adhere to themselves

antibiotics, although better technologies

and a solid surface, and can be comprised

are being developed, and may include the

of multiple species. Bacterial biofilms

use of powerful noxious chemical agents

are thought to increase resistance to

when dealing with potentially dangerous

antibiotic agents by filtering them through

pathogens [I].

layers of functionally-diverse species, often including stress-resistant strains with

In addition to biofilm formation, horizontal

gene transfer (HGT) is thought to be a

pre-existing antimicrobial tolerance that act

contributing factor to increased tolerance

to physically separate other, less tolerant

to antimicrobial agents. HGT is the

strains from the stimulus. Additionally,

process by which genes are transferred

the extracellular matrix often secreted by

from one bacterium to another. A 2013

biofilms forms another physical barrier

study comparing bacterial isolates from the

to protect the underlying bacteria. This

ISS and the Concordia Research Station

disrupts the efficacy of antimicrobial

in Antarctica saw ISS isolates exhibit

agents, which are modern medicineâ&#x20AC;&#x2122;s

more antibiotic resistance and increased

first line of defense against bacterial

plasmid-containing strains [T]. Comparing

infection. Over the years, researchers have

the strains that contained plasmids from

demonstrated that SMG and in-space

both locations, relaxase and other transfer

conditions might potentiate, increase, or

genes that induce bacterial conjugation

precipitate bacterial production of biofilms

were present at higher numbers in

and bacterial attachment [E;F;S;T].

the bacterial ISS isolates than the

health, biofilms pose serious concerns for

horizontal gene transfer was not found

spacecraft physical integrity. They can

to be statistically different between the

disrupt air-tight rubber seals that maintain

two sites. This follows a contradictory

spacecraft internal pressure, contaminate

cohort of previous research [U-X] in

Beyond the impact on crewmember

the potable water supply, and corrode

bacterial Antarctic isolates. Surprisingly,

which researchers studying the effects of

electric conductivity [T]. Multi-species

microgravity on E. coli in 1986, 1995, and

that perform a variety of intra-group

Research is being currently being carried

biofilms form dynamic communities

2007 generated conflicting results [U-X].

functions, and are even more resistant to

out to further the understanding of HGTâ&#x20AC;&#x2122;s

antimicrobial agents than single-species

role in antimicrobial tolerance.

biofilms. Currently, the best defense against these biofilms in space is heat and 059

//ARTICLE.08 >>

Impact of HZE Particles on Cellular and Organismal Development Although high energy heavy ion (HZE) particles are detrimental to cellular development, HZE particles have been shown to work synergistically with microgravity in experiments on multicellular organisms at the DNA-repair level.

High energy heavy ion—termed “HZE”

has of yet been conducted on microbes. A

for high charge, “Z”, and high energy,

review done by Horneck et. Al published

“E”—particles pose serious threats to life in

in 1999 surveyed a multitude of research

space [M;N;P]. They belong to a class of

on this matter, and organisms from Dro-

radiation called galactic cosmic radiation,

sophila melanogaster to stick bugs grown

which describes radiation that originates

in conditions of combined HZE particle

outside our solar system, and are capa-

radiation and simulated microgravity saw

ble of penetrating up to one millimeter of

increased mortality as compared to controls,

protective space suits and radiation shields

HZE particle-only conditions, and SMG-only

[O]. The effects of ionization radiation

conditions [M]. Furthermore, in multicellular

DNA repair processes, increased DNA

disrupted and DNA breakage increased.

mutation rates, and increased single- and

Based on these studies, the combined effect

double-stranded DNA breakage [Y].

of HZE particle radiation and microgravity

When the stress-resistant endospores of

was determined to be synergistic, and

Bacteria subtillis were bombarded with

Horneck et al. recommends further studies

HZE particles, germination (the process

into the physiological, metabolic, genetic,

by which the spore grows into viable cells)

and structural changes on both eukaryotic

was not affected, but outgrowth (the act of

and prokaryotic organisms. Microgravity’s

projecting outwards from the original spore)

effects seem to be exacerbated in eukary-

was inhibited [N].

otic, multicellular organisms as compared

have attempted to determine the com-

microorganisms a pathogenic advantage in

on biological systems include disrupted

Experiments on multicellular organisms

binatorial effect of microgravity and HZE

organisms, DNA repair mechanisms were

to prokaryotic organisms [D;E;I;R], and give immuno-compromised hosts.

particle bombardment, but no research

Koo, H., Xiao, J., and Klein, M.I. (2009). Extracellular polysaccharides matrix--an often forgotten virulence factor in oral biofilm research. International journal of oral science 1, 229-234.

Rosenzweig, J.A., Abogunde, O., Thomas, K., Lawal, A., Nguyen, Y.U., Sodipe, A., and Jejelowo, O. (2010). Spaceflight and modeled microgravity effects on microbial growth and virulence. Applied microbiology and biotechnology 85, 885-891.

060

AS LONG-TERM MISSIONS BECOME MORE PREVALENT AND POSSIBLE DISTANCE OF SPACE TRAVEL INCREASES, SUCH FURTHER STUDIES WILL UNDOUBTEDLY SHAPE THE STILL-DEVELOPING LANDSCAPE OF ASTROMICROBIOLOGY

//ALISSA WALL

Summary

The field of astromicrobiology is con-

disrupts cellular function, more studies are

cerned with the interaction of microbes and

required to investigate the synergistic effects

space. Researchers are currently focused

of microgravity and radiation on host immune

on the direct exchange between Earth

systems, as well as microbial development,

and space facilitated by space exploration.

to better understand the implications for long-

Space offers a unique environment for

term space travel on microbiota/crewmember

both humans and microbes, with unique

symbiotic relationships. Additionally, research

selective forces such as microgravity and

into the poorly elucidated mechanisms behind

high radiation levels. Microgravity and

the physiological, regulational, genetic, and

HZE particle radiation can be simulated

metabolic changes in space-bound microbial

on the ground with SMG and particle accelerators, respectively, although SMG experiments have higher extrapolative

organisms is needed. As long-term missions become more prevalent and possible distance of space travel increases, such further studies

ability compared to particle accelerator

will undoubtedly shape the still-developing

experiments. Astomicrobiology is aided

landscape of astromicrobiology and prove

by molecular techniques such as 16S

themselves invaluable to the development of

bacterial identification, which provides

proper sterilization practices and crewmember

information on the classification of in-space

health-risk evaluation.

microbial samples and informs researchers of differences in composition between inspace and grounded populations. Among other factors, the increased virulence, antimicrobial tolerance, biofilm formation, and proliferation rate of microbes in space pose serious threats to both human health and spacecraft structural integrity and require the serious attention of astromicrobiologists. Although radiation from HZE particles damages cellular structure and

Mauclaire, L., and Egli, M. (2010). Effect of simulated microgravity on growth and production of exopolymeric substances of Micrococcus luteus space and earth isolates. FEMS immunology and medical microbiology 59, 350-356.

Schiwon, K., Arends, K., Rogowski, K.M., Furch, S., Prescha, K., Sakinc, T., Van Houdt, R., Werner, G., and Grohmann, E. (2013). Comparison of Antibiotic Resistance, Biofilm Formation and Conjugative Transfer of Staphylococcus and Enterococcus Isolates from International Space Station and Antarctic Research Station Concordia. Microbial ecology.

Beuls, E., Van Houdt, R., Leys, N., Dijkstra, C., Larkin, O., and Mahillon, J. (2009). Bacillus thuringiensis conjugation in simulated microgravity. Astrobiology 9, 797-805.

Ciferi, O., Tiboni, O., Di Pasquale, G., Orlandoni, A.M., and Marchesi, M.L. (1986). Effects of microgravity on genetic recombination in Escheria coli. Naturwissenschaften 73, 418-421.

Boever, P., Mergeay, M., Ilyin, V., Forget-Hanus, D., Auwera, G., and Mahillon, J. (2007). Conjugation-mediated plasmid exchange between bacteria grown under space flight conditions. Microgravity Science and Technology 19, 138-144.

Juergensmeyer, M.A., Juergensmeyer, E.A., and Guikema, J.A. (1995). Plasmid acquisition in microgravity. Journal of Gravitational Physiology 2, 161-162.

Moeller, R., Setlow, P., Horneck, G., Berger, T., Reitz, G., Rettberg, P., Doherty, A.J., Okayasu, R., and Nicholson, W.L. (2008). Roles of the major, small, acid-soluble spore proteins and spore-specific and universal DNA repair mechanisms in resistance of Bacillus subtilis spores to ionizing radiation from X rays and high-energy charged-particle bombardment. Journal of bacteriology 190, 1134-1140.

061

//SPOTLIGHT.03

[GRADUATE. STUDENT_ SPOT_ LIGHT// //JOE BARTER*] By: Elisa Berson

// BIOGRAPHY //

I grew up in Mount Desert Island, Maine. This place is really beautiful--it’s home to Acadia National Park--so I spent a lot of my childhood wandering around in the woods; running, kayaking, rock climbing and that sort of thing. I always had a lot of reverence for nature because I could always see how smart it was. Pretty much everything in nature is good at what it does at every level. I’ve actually never seen an awkward wild animal, or a depressed one. By contrast, people are pretty clumsy and conflicted. We screw up a lot, and there is a lot of suffering. I think this basic contrast between the harmony of nature and the ineptitude of people (including myself!) is what initially

062

got me interested in understanding how we work. I don’t think there is any way to really fix something unless you know how it works. I graduated from Macalester College in 2008 with a double major in cognitive/neuroscience studies and biology, and I am currently a 4th year PhD candidate in Psychology and Neuroscience through CNAP and an NSF Graduate Research Fellow.

//ELISA BERSON

What experiences in undergrad began to cultivate your current interests?

rewards and reward-predicting cues were

you know that a toaster is a machine for

also perfectly correlated with movement. So

heating up slices of bread, then you run the

I was taking a philosophy class. I was writing

I’m starting to think that dopamine has a lot

risk of collecting a lot of silly data. You might

an essay on the nature of ‘right and wrong’

more to do with movement than with reward.

measure the melting point of the toaster, or

and I realized that the concepts make

When you think about it though, this actually

the chemical composition of the paint, or its

zero sense except in relation to goals. For

makes a lot of sense. Parkinson’s disease, a

reflective properties. Or you might measure

example, if your goal is to take a nap in ten

disease in which dopamine neurons die, is

the temperature of a hundred different

minutes then you would be wrong to drink

characterized primarily by deficits in move-

toasters right after you plug them in and then

a lot of coffee right now. Or if your goal is to

ment. And the concept of reward is really

generate some sort of elaborate statistical

not piss people off then you would be wrong

not the most scientific concept in the first

model. You could write a thousand books

to throw rocks at everyone.

place--technically you can bend it to define

on toaster data and they would all be 100%

The cool thing about goals is that goal-seek-

anything you want as a reward. For example,

correct--and also completely useless. This

ing is a defining characteristic of all biological

if you’re hungry we could define food as a

might sound weird, but I think it’s actually a

systems. All living things need to continu-

reward, or if you’re bored we could define TV

pretty big problem. There is a lot of pressure

ously meet all of the goals that add up to not

as a reward, or if you wanted me to yell at

in academia to specialize and claim your

dying on a moment-by-moment basis, or

you then we could define that as a reward,

own little bit of intellectual territory, while

else they would be dead. They need to seek

etc.

development of a good theoretical worldview

food when they’re hungry, and sleep when

is usually an afterthought. But if you give

they’re tired, and warmer temperatures when

But movement is actually an extremely deep

in to this then you run the risk of studying

they’re cold, etc. So I got really interested in

problem. It’s not boring at all; it’s absolutely

something trivial or even made-up.

evolutionary biology and neuroscience.

essential. Our capacity for movement is the

Did you spend any time between undergrad and the pursuit of your PhD?

reason we have a nervous system in the first

I’m going to spend my next day off..

place. Plants don’t have nervous systems

I’m trying to build a robot in my apartment.

because plants don’t need to move; they

I need to dedicate some time to that. It still

Yes, I did a fellowship at the NIMH. I studied

just sit there and get their energy from the

doesn’t have a head.

the neural basis of ‘value’. Basically people

sun. I want to understand consciousness

would come and play games for money

and economic behavior as much as anyone,

while we scanned their brains. While I was

but I’m pretty sure that’s not going to happen

Durham but maybe haven’t done yet..

there we made a discovery that challenged a

until we can first understand how it is that we

Climb the lucky strike water tower.

lot of the literature, which was fun. Basically,

don’t fall over when we walk.

by manipulating task difficulty we found that

Specifically, I use wireless neural recording

activity in the ventral striatum correlates with

in combination with various behavioral tasks

how hard the subject is working for money.

and motion tracking to study the role of

Previously everyone thought that this pattern

dopamine circuitry in free movement. I do

of brain activity correlated with the ‘expected

this in mice. I also spend a lot of time trying

value’ of the money itself. The reason for this

to come up with computational models of

confusion is that the apparent value of a goal

movement/behavior that might actually work

and your level of engagement in pursuing it

in the real world if I built them.

are typically very well correlated. Can you share more about your research?

Something I’d like to do in Duke/

My advice to undergraduates is. Be careful about what you study. Most knowledge is useless if you’re actually trying

Currently I study dopamine and its role in

to understand something. You always need

movement. Initially I thought I was studying

to start with the right perspective so that you

the role of dopamine in reward, but all of

can evaluate whether a particular fact is even

the changes in dopamine neural activity I

worth learning. For example, imagine you

could find in response to presentation of

were trying to understand a toaster. Unless 063

//ARTICLE.09

[EXERCISE AND //CYTOKINEINDUCED KILL.ER CELLS*//] A

Pedersen BK, Hoffman-Goetz L. Exercise and the immune system: regulation, integration, and adaptation. Physiological Reviews 2000; 80(3): 1055-1081.

Delves PJ, Roitt IM. The immune system. The New England Journal of Medicine 2000; 343: 108-117.

Pedersen BK, Ullum H. NK cell response to physical activity: possible mechanisms of action. Medicine and Science in Sports and Exercise 1994; 26(2): 140-146.

Sangiolo, D. Cytokine induced killer cells as promising immunotherapy for solid tumors. Journal of Cancer 2011; 2: 363-368.

064

AS IMMUNO THERAPY TREATMENT FOR CANCER

BY: MICHELLE WU

//MICHELLE WU

Aerobic exercise is known to play a key

immunotherapy including (i) expansion of

role in immune system function, induc-

immune effector cells to sufficient amounts

ing the release of pro-inflammatory and

in vitro, (ii) overcoming tolerance, (iii) the

anti-inflammatory cytokines, growth factors,

specificity of the treatment, and (iv) limita-

and other soluble factors [A]. Normally, an

tions of the HLA system [D].

infectious pathogens and diseases by

therapeutic strategies involves the use of

recognizing and responding to antigens

cytokine-induced killer (CIK) cells. CIK cells

present on foreign bacteria, viruses, and

are cytotoxic T lymphocytes that express

cells. B lymphocyte cells differentiate into

CD3+ CD56+ cell surface markers [E].

immune response protects the host from

antibody producing plasma cells that

One of the most promising immuno-

They are functionally similar to classic cy-

recognize specific antigens and mark them

totoxic T lymphocytes (CTL) and NK cells.

for removal (opsonization) by phagocytes.

Although functionally similar to CTL and NK

Cytotoxic T lymphocyte cells target cells

cells, CIK cells possess additional mech-

that express non-self antigens presented

anisms of anti-tumor activity that remains

through HLA (Human Leukocyte Antigen)

poorly understood [D]. An advantage to

molecules expressed on the surface of

CIK cells is their highly selective and potent

Antigen Presenting Cells (APC) e.g. B cells,

pro-apoptotic effect on tumor cells. One in

dendritic cells, and even non-APCs. Im-

vitro study showed that CIK cells were able

mune effector cells e.g. macrophages and

to destroy up to 98% of NCI-H460 cells, a

natural killer (NK) cells therefore serve as a

human non-small cell lung cancer cell line

defense against foreign pathogens involved

[F]. Similar CIK-cell potency results have

in a variety of infectious and non-infectious diseases. The immune system recognizes foreign antigens, attacking them in a highly specific manner [B]. Mutated proteins expressed

been shown in other cancers, including

leukemia [E], melanoma [G], and stomach cancer [H].

CIK cells are naturally found in popu-

lations of peripheral blood mononuclear

in tumor cells represent potential non-self

cells (PBMC) but only in small amounts

antigens that can be targeted by immuno-

that are insufficient to exhibit anti-tumor

therapeutic strategies.

effects [F]. They must be extracted from

The earliest studies investigating the

PBMCs collected from cancer patients and

immune system as a potential approach to

expanded in number ex vivo. They can be

the treatment of cancer took place in the

cultured with interferon-gamma (IFN-Îł) to

early 1990s [C]. The idea that autologous

activate monocytes, and with CD3 and IL-2

immune cells could be programmed to recognize and attack cancer cells has

Lymphoma 2003; 44(9): 1457-1562.

Kim HM, et. al. Antitumor activity of cytokine-induced killer cells against human lung cancer. International Immunopharmacology 2007; 7: 1802-1807.

Gammaitoni L, et. al. Effective activity of cytokine-induced killer cells against autologous metastatic melanoma including cells with stemness features. Clinical Cancer Research 2013; 19(16): 4347-4358.

As previously published, CIK cells can be expanded over 1000 fold while remaining

tolerated alternative to highly toxic che-

85%-95% viable [F]. Once grown in vitro to

challenges to the development of effective

killer cells: NK-like T cells with cytotolytic specificity against leukemia. Leukemia and

antibodies to activate T lymphocytes [D].

become an attractive potentially better motherapies. However, there are several

Linn YC, Hui KM. Cytokine-induced

a sufficiently high quantity, autologous CIK cells can be injected intravenously back

065

//ARTICLE.09 >>

Na YM, Kim MY, et. al. Exercise therapy effect on natural killer cell cytotoxic activity in stomach cancer patients after curative surgery. Archives of Physical Medicine and Rehabilitation 2000; 81: 777-779.

Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Circulation 2007; 116: 1081–93.

Irwin ML, Smith AW, McTiernan A, Ballard-Barbash R, Cronin K, Gilliland FD, Baumgartner RN, Baumgartner KB, Bernstein L: Influence of pre- and post-diagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study. J Clin Oncol 2008; 26(24): 3958-3964.

Woods JA, Vieira VJ, Keylock KT. Exercise, inflammation, and innate immunity. Immunology and Allergy Clinics of North America 2009; 29: 381-393.

into the cancer patient, where they will rec-

mechanism [F]. Thus, even if tumor cells

ligands on the tumor cells4. NKG2D re-

are not recognized as being foreign, they

ceptors regulate activation of NK cells. The

is most effective when the CIK cells are

may still be susceptible to targeting by

ligands that bind to the NKG2D receptors

derived from the patient’s own autologous

CIK cells. Studies also suggest that the

include MHC class I related molecules MIC

PBMC as opposed to another individual’s,

production of IFN-γ protects CIK cells from

A/B as well as proteins ULBP 1, 2, and

paving the way for personalized cancer

GVHD [D]. If a patient is receiving CIK cells

34,7. Interestingly, immunotherapy often is

from a donor, the reduced risk of GHVD

not effective when administered in con-

protects the transfused CIK cells from

junction with existing chemotherapy drug

the use of CIK in the treatment of cancer

being attacked by the patient’s immune

is the reduced risk of graft-versus-host

system. This results in a higher efficacy of

treatments [H]. For example, resistance to

disease (GVHD) due to their reduced

the immunotherapy treatment. Additionally,

be due to the increased expression of MIC

alloreactivity in response to HLA incom-

the reduced risk of GHVD facilitates in vitro

A/B proteins on tumor cells, which would

patibility [D]. HLA are molecules that are

studies in which immunocompromised

increase the effectiveness of immune

present on almost every nucleated cell.

mice receive transfusions of CIK cells from

They display proteins from the cells for

human donors.

system-mediated killing by CIK cells [D].

ognize and attack tumor cells. This therapy

therapies [E].

An additional advantage associated with

T cells to recognize as either healthy or

The exact mechanism through which

the chemotherapy drug Trastuzumab may

Many epidemiologic studies have

reported evidence of the beneficial effects

foreign1. The immune systems of cancer

CIK cells induce apoptosis in tumor cells

patients are often compromised, so tumor

is not well established [D]. It has been

cancer when performed in conjunction with

foreign. CIK cells are advantageous to use

pressed on the surface of CIK cells play a

show that moderate and regular aerobic

in immunotherapies because they attack

significant role in MHC signaling pathways

exercise can strengthen the immune

tumor cells through an HLA-independent

through interaction with MHC-unrestricted

system. However, over-exercising may

cells may not be recognized by T cells as

066

thought that the NKG2D receptors ex-

of aerobic exercise in the treatment of chemotherapy treatments [I,J]. Studies

VERTICES//029.02

MANY EPIDEMIOLOGIC STUDIES HAVE REPORTED EVIDENCE OF THE BENEFICIAL EFFECTS OF AEROBIC EXERCISE IN THE TREATMENT OF CANCER WHEN PERFORMED IN CONJUNCTION WITH CHEMOTHERAPY TREATMENTS.

lead to the opposite effects, weakening

that the effects of CIK cells are specific.

the immune system through the release of

The role of aerobic exercise in the acti-

stress hormones and other soluble factors

vation and proliferation of CIK cells has yet

[K]. The release of systemic inflammatory

to be investigated. Since NK and CIK cells

markers is an integral component of the

share similar functional characteristics,

bodyâ&#x20AC;&#x2122;s immune response. Acute exercise,

and in light of the fact that CIK cells have

or short-term exercise of high intensity,

membrane receptors that regulate NK cell

induces release of systemic inflammatory

activation, it is intriguing to speculate that

markers whereas regular exercise does

CIK cells, similar to NK cells, are also acti-

not lead to an inflammatory response.

vated in response to inflammatory stimuli.

Studies have shown that the release of

This may provide one potential mechanism

pro-inflammatory cytokines in the tumor

underlying the antitumor immune effects

microenvironment can promote the growth

of aerobic exercise. So far, there have

and proliferation of tumor cells. Moderate

been no studies examining a potential link

and acute aerobic exercise also induces

between aerobic exercise and CIK cell

NK cell activity, which is known to inhibit

activation, particularly in the context of

tumor cell growth [C]. NK cells are immune

cancer therapy.

effector cells that act through a non-specific, MHC-independent mechanism to

prevent the progression of infections and other diseases [C]. They function in a similar manner to CIK cells with the exception

067

//ARTICLE.10

[EXAMINING THE EFFECT OF //RESVERATROL//] USING A MODEL OF SENESCENCE IN ZEBRAFISH EMBRYOS BY: AILEEN BI A

Cellerino, D. R. V. and A. (2006). Resveratrol and the Pharmacology of Aging: A New Vertebrate Model to Validate an Old Molecule. Cell Cycle, 5(10), 1027–1032. doi:10.4161/cc.5.10.2739

Valenzano, D. R., Terzibasi, E., Genade, T., Cattaneo, A., Domenici, L., & Cellerino, A. (2006). Resveratrol Prolongs Lifespan and Retards the Onset of Age-Related Markers in a Short-Lived Vertebrate. Current Biology, 16(3), 296–300. doi:10.1016/j.cub.2005.12.038

Kishi, S., Bayliss, P. E., Uchiyama, J., Koshimizu, E., Qi, J., Nanjappa, P., … Roberts, T. M. (2008). The Identification of Zebrafish Mutants Showing Alterations in Senescence-Associated Biomarkers. PLoS Genet, 4(8), e1000152. doi:10.1371/journal.pgen.1000152

068

VERTICES//029.02

Abstract Resveratrol (3, 5, 4’-trihydroxyl-trans-stilbene) is a natural polyphenol compound most commonly accessed by humans through consumption of red wine [1]. What has particularly drawn attention from the scientific community is resveratrol’s potential efficacy as an anti-aging agent, as research has shown that resveratrol increases longevity in short-lived invertebrates [2]. This experiment utilized the embryos of zebrafish (Danio rerio) to study the efficacy of resveratrol on senescence. Zebrafish embryos were exposed to sub-lethal levels of oxidative stress, which served to effectively accelerate the aging process of the embryos. Resveratrol was then added to the water surrounding the embryos, thus exposing the embryos to the drug through absorption. The efficacy of resveratrol was determined by comparing the levels of senescence-associated β-galactosidase (SA β-gal) found in embryos exposed to different amounts of resveratrol with control embryos, which were merely exposed to oxidative stress and the drug vehicle. It was hypothesized that resveratrol would effectively reduce the signs of aging among all embryos exposed to the drug, with higher dosages being associated with more dramatic

Introduction

Resveratrol (3, 5, 4’-trihydroxyl-trans-stil-

bene) is a natural polyphenol compound found in many plants, such as in the grape (Vitis vinifera) and in the weed Polygonum

results. The major findings of this experiment supported the notion

cuspidatum. Red wine is considered

that resveratrol would effectively reduce the signs of aging among the

humans, due to resveratrol’s relatively high

the principal source of this compound in

embryos exposed to the drug, but no effect was detected between

concentration in this beverage (5mg/L in

resveratrol concentration level and amount of SA-β-gal present in the

been shown to have a wide spectrum of

embryos, implying that the optimal dosage treatment had already been reached. Not only did this experiment support the notion that a senescence model could be produced, it also demonstrated the effectiveness of resveratrol as an anti-aging agent.

average) [A]. As a drug, resveratrol has

biological effects. In laboratory studies with mammals, resveratrol has been shown to have many beneficial health effects, such as having anticancer, anti-inflammatory, and antioxidant effects. In addition, resveratrol is believed to play a very important action in the conversion of pro-carcinogens into carcinogens, the inhibition of platelet aggregation in vivo and in vitro, the protection the brain and kidney from ischemic damage [A], the regulation of the cell cycle, and the production of mitochondrial energy [G]. 069

//ARTICLE.10 >>

What has particularly drawn attention

tive stress is known as the stress the body

from the scientific community is resver-

experiences when there are more reactive

atrol’s potential efficacy as an anti-aging

oxygen species (ROS)—reactive molecules

agent, as research has shown that

containing oxygen—than the body is

resveratrol increases longevity in short-

able to readily detoxify. ROS are gener-

lived invertebrates [B]. In fact, up to recent

ated during normal cellular metabolism,

years, this polyphenol is the only molecule

particularly during mitochondrial respiration

that has been shown to consistently

in the presence of an inefficient electron

prolong lifespans across species and

transport chain. While optimally localized

laboratories [A]. While the precise mecha-

levels of ROS can facilitate the activation of

nism of the drug is not yet clear, research

some signal transduction pathways, having

has shown that micromolar concentrations

too much ROS in the body can damage

of resveratrol block NF-ĸb (Nuclear Factor

macromolecules—such as proteins, lipids,

Kappa-light-chain-enhancer of activated B

and DNA—which can in turn contribute to

cells) activation and suppress most of TNF

the progression of neuromuscular disor-

(tumor necrosis factor) – mediated cellular

ders and neurological diseases. Chronic

responses in human cells. Resveratrol

oxidative stress has been shown to reduce

also inhibits production of free radicals

lifespan in many species and accelerate

in the mitochondria by multiple pathways

aging [C]. Hence, it was appropriate to

[A]. Past studies on mice have suggested

expose the zebrafish embryos to oxidative

that resveratrol achieves its health benefits

stress in order to develop an accelerated

through the activation of the enzyme SIRT-

model of the typical aging process.

1, which is believed to activate a number

Senescence-associated β-galactosidase

of intracellular pathways that lead to the

(SA-β-gal) was then used as a marker

deacetylation of PGC-1 (a transcriptional

of biological aging in the embryos. This

coactivator) and ultimately improve mito-

biomarker was chosen due to its ease of

chondrial function and energy balance [G].

detection and reliability in indicating the

on resveratrol’s effect on vertebrates, due

onic development [C]. Performing a SA-β-

There has been a general lack of studies

to the challenges associated with conduct-

presence of oxidative stress during embrygal assay would stain cells in senescence

ing aging studies on organisms with rela-

with a blue dye, resulting from a cleavage

tively long lifespans [B]. This experiment

of the X-gal substrate. Research suggests

undertook this challenge by utilizing the

that the SA-β-gal assay relies on identifying

embryos of zebrafish (Danio rerio) to study

the accumulation of lysosomal β-galacto-

the efficacy of resveratrol on senescence.

sidase enzyme in aging cells [D], which is

Zebrafish are often used as vertebrate

caused by the amassing of non-degrad-

models in laboratories due to their high

able intracellular macromolecules and or-

degree of genetic similarity to humans.

ganelles in autophagic vacuoles, promoting

Other favorable characteristics of zebrafish

cell death [C]. Thus, performing a SA-β-gal

include rapid external development, embry-

assay would provide a measurement of the

onic translucence, and ease of genetic

amount of aging the embryo of interest has

manipulation [C]. A model of senescence,

endured by marking the presence of the

or biological aging, had to be developed in order to analyze resveratrol’s effects. To create this senescence model, the

SA β-galactosidase enzyme. In this experiment, zebrafish embryos were exposed to sub-lethal levels of oxida-

zebrafish embryos were first exposed to

tive stress, which served to effectively ac-

sub-lethal levels of oxidative stress. Oxida-

celerate the aging process of the embryos.

070

VERTICES//029.02

Resveratrol was then added to the water

Oxidative Stress

The ROS selected for this experiment

surrounding the embryos, thus exposing

was hydrogen peroxide (H2O2), due to its

the embryos to the drug through absorp-

availability and reliability in laboratory stud-

tion. The efficacy of resveratrol was de-

ies [C]. To apply oxidative stress, embryos

termined by comparing the aging process

were exposed to 100µM of H2O2. This

of embryos exposed to different amounts

concentration was selected because it

of resveratrol with control embryos, which

was slightly below 150µM, the maximum

were merely exposed to oxidative stress

tolerated dosage of H2O2 as determined

and the drug vehicle. It was hypothesized

by a previous study [C].

that resveratrol would effectively reduce the signs of aging among all embryos exposed to the drug, with higher dosages being associated with more dramatic results. The conclusions of this experiment could provide valuable insight into the drug’s potential effect on humans and whether taking this drug could be a viable method to increase one’s lifespan.

Materials and Methods

resveratrol, dimethyl sulfoxide (DMSO), and tank water—until staining.

02 H2 NO Ou M,

composed of various combinations of

0u M

were kept in their respective solutions—

treatment. After treatment, all embryos

1000

75 uM

methylene blue before embryos received

50 uM

26ºC in tank water, which was treated with

2000

University. All embryos were incubated at

25 uM

specialized zebrafish breeding lab at Duke

3000

(dpf) embryos that were obtained from a

Each trial used 3 days post fertilization

4000

Ou M,

according to institutional guidelines.

AVERAGE PIXEL PER FISH

Zebrafish Embryos Zebrafish embryos were maintained

SA B-GAL IN ZEBRAFISH EMBRYOS AFTER TREATHMENT

RESVERATROL TREATMENT Figure 1. Mean (± standard deviation) pixel to fish ratios for the six different treatment groups (left to right: 0µM with no H2O2 added, 0µM resveratrol, 25µM resveratrol, 50µM resveratrol, 75µM resveratrol, and 100µM resveratrol). Between the two control groups, coloration increased with the addition of H2O2. Between the groups that received oxidative stress, a drop in pixel to fish ratios was observed with the presence of resveratrol treatment versus the control group.

071

//ARTICLE.10 >>

Drug Treatment

SA-β-gal Assay

Resveratrol was sequentially added in

Seven days following drug treatment,

the following three concentrations from

a SA-β-gal assay was performed on the

a 50mM stock solution in DMSO: 25µM,

embryos using the SA-β-gal staining kit

50µM, 75µM, and 100µM. Dosages

purchased from Cell Signaling Technology

were selected based on what had been

(Danvers, MA). The staining kit included

reported in literature to produce results in

the following ingredients: 20% formalde-

zebrafish embryos [F]. The concentration

hyde and 2% glutaraldehyde in PBS, X-gal

of stock solution was selected out of

(5-bromo-4-chloro-3-indolyl-βD-galacto-

concern of damaging the embryos with

pyranoside powder), 20mM magnesium

potentially toxic levels of DMSO, taking

chloride, 1.5M sodium chloride, 400mM

into account the 7-day-period in which the

citric acid/sodium phosphate (pH 6.0),

embryos would stay in treatment solution

500mM potassium ferrocyanide, and

[E]. A negative control group was used, in

500mM potassium ferricyanide. Phos-

which the embryos were merely exposed

phate buffered solution (PBS), which was

to oxidative stress and the drug vehicle

required for staining but was not included

DMSO. Another control group was added

in the kit, was purchased from Sigma-Al-

that contained embryos that were neither

drich Co (St. Louis, MO). The staining

exposed to oxidative stress nor treated

process was conducted according to kit

with resveratrol, so the two control groups

instructions, but DMSO was used in place

could be compared to determine whether

of DMF. The embryos were then incubated

or not a senescence had been successful-

in a six-well plate overnight at 37ºC in a dry

ly created. All chemicals were purchased

incubator.

from Sigma-Aldrich Co (St. Louis, MO). The embryos were kept in a 26ºC incubator for the duration of the week.

Lee, B. Y., Han, J. A., Im, J. S., Morrone, A., Johung, K., Goodwin, E. C., … Hwang, E. S. (2006). Senescence-associated β-galactosidase is lysosomal β-galactosidase. Aging Cell, 5(2), 187–195. doi:10.1111/j.14749726.2006.00199.x

Maes, J., Verlooy, L., Buenafe, O. E., de Witte, P. A. M., Esguerra, C. V., & Crawford, A. D. (2012). Evaluation of 14 Organic Solvents and Carriers for Screening Applications in Zebrafish Embryos and Larvae. PLoS ONE, 7(10), e43850. doi:10.1371/journal.pone.0043850

Jones, K. S., Alimov, A. P., Rilo, H. L., Jandacek, R. J., Woollett, L. A., & Penberthy, W. T. (2008). A high throughput live transparent animal bioassay to identify non-toxic small molecules or genes that regulate vertebrate fat metabolism for obesity drug development. Nutrition & Metabolism, 5(1), 23. doi:10.1186/1743-7075-5-23

Markus, M. A., & Morris, B. J. (2008). Resveratrol in prevention and treatment of common clinical conditions of aging. Clinical Interventions in Aging, 3(2), 331–339.

072

VERTICES//029.02

SUMMARY GROUPS

COUNT

SUM

AVERAGE

VARIANCE

0µM, No H2O2

17067

1003.941

299523.7

0µM

27783

2137.154

1481163

25µM

16286

958

410856.1

50µM

14609

1217.417

371707.5

75µM

9092

1136.5

742959.7

100µM

18140

1133.75

568181.9

Table 1. // Summary of data // The summary of data provides information on the counts, sums, averages, and variances of all treatment groups, which were further subjugated to statistical tests.

ANOVA SUMMARY F

4.275

P VALUE

0.0017

P VALUE SUMMARY

*****

ARE THERE DIFFERENCES AMONG MEANS

YES

STATISTICALLY SIGNIFICANT (P < 0.05) R SQUARE

0.2173

Table 2. // One-Way ANOVA Test // The p-value (0.0017<0.05) indicated that there was statistical significance to conclude that the mean pixel to fish ratios were statistically different. The r2 value (0.2173) indicated that there was a modest correlation between resveratrol treatment and pixel to fish ratios. The assumption of equal variance was not met.

073

//ARTICLE.10 >>

Quantitation Quantitation first required using the

Resveratrol Groups

The control group that received H2O2

Evos XL Core digital inverted microscope

treatment had the highest apparent pixel to

(Advanced Microscopy Group, Mill Creek,

fish ratio, while the lowest ratio belonged

WA) to photograph the embryos with a

to the 25µM treatment group (Table 1).

plate reader. SA-β-gal activity was then

Overall, all resveratrol treatment led to a

quantitated using a selection tool in Adobe

decrease in pixel to fish ratios compared to

Photoshop for a color range of various

the control group with H2O2 to levels simi-

shades of light blue in regions that showed

lar to that of the control that did not receive

visually positive SA-β-gal staining. The

H2O2 treatment (Figure 1). The results of

color range was selected in the embryo

the one-way ANOVA test and Dunnett’s

body and not in the yolk, since the yolk has

multiple comparisons post-hoc test run

been shown to stain much more intensely

on the data rejected the null hypothesis,

at all stages of development, regardless

meaning that the average pixel to fish ratio

of the presence of oxidative stress [C]. A

was significantly different for all groups

fuzziness setting of 14 was used, and the

compared to the control group with H2O2

chosen pixel number was calculated using

treatment (Table 3). These findings mostly

the image histogram calculation. The level

supported the hypothesis, which stated

of SA-β-gal in each experimental group

that resveratrol would effectively reduce

was then determined by comparing the

the signs of aging among all embryos

amount of blue pixels displayed by each

exposed to the drug, with higher dosages

group to the other experimental groups.

being associated with more dramatic

Once outliers were identified and removed

results. However, when a Tukey’s multiple

from the data, one-way ANOVA tests were

comparison test was run on the treatment

run for the overall data, along with post-hoc

groups, no significant differences in means

multiple comparison tests. All figures and

were detected, meaning that increasing

statistical analyses were generated using

resveratrol concentrations did not produce

Microsoft Excel (Microsoft, Redmond, WA)

statistically different results (Table 4).

and GraphPad Prism (GraphPad, La Jolla, CA).

Results

Senescence Model

The results of an ANOVA test run be-

tween the two control groups showed that a senescence model had been successfully produced, as there was a significant difference in means between the two groups’ pixel to fish ratios (Table 3). There was sufficient evidence to conclude that the addition of 100µM hydrogen peroxide significantly increased the levels of oxidative stress found in zebrafish embryos, creating a sound model of senescence through which this experiment could be conducted.

074

THERE WAS SUFFICIENT EVIDENCE TO CONCLUDE THAT THE ADDITION OF 100ΜM HYDROGEN PEROXIDE SIGNIFICANTLY INCREASED THE LEVELS OF OXIDATIVE STRESS FOUND IN ZEBRAFISH EMBRYOS

VERTICES//029.02

Discussion

The purpose of this experiment was to

study the effect of resveratrol treatment on aging, measured by the amount of

SA β-galactosidase enzyme present in zebrafish embryos. The major findings of this experiment supported the notion that resveratrol would effectively reduce the signs of aging among the embryos exposed to the drug, but no effect was detected between resveratrol concentration level and amount of SA-β-gal present in the embryos. Thus, while it was concluded that resveratrol treatment would reduce the signs of aging, the hypothesis that stated

THE MAJOR FINDINGS OF THIS EXPERIMENT SUPPORTED THE NOTION THAT RESVERATROL WOULD EFFECTIVELY REDUCE THE SIGNS OF AGING AMONG THE EMBRYOS EXPOSED TO THE DRUG

that higher concentrations of resveratrol would produce more extreme results was unsupported. Additionally, while the results yielded from the treatment groups were not significantly different from those from the control that did not receive H2O2 treatment, a blanketed statement that resveratrol reverses all effects of aging should not yet be made due to the many confounds associated with such a statement and the ambiguities in quantitation of resveratrol and aging. This experiment merely suggested that 25µM of resveratrol was enough to protect the zebrafish embryos from the effects of aging produced by 100µM of H2O2. In this experiment, there were some notable possible sources of error. First, there were two occasions in which the SA β-gal assay failed to stain the embryos. Although this may have been attributed to the staining solution being kept in suboptimal pH levels or other environmental factors, it may also indicate that this assay might not be completely reliable. There were also many fish that were damaged in the process of collecting data, as the protocol for this experiment required that the embryos be transported multiple times. Although the majority of these damaged fish were removed from their groups, any unaccounted for damage done to the embryos may still have affected the results. 075

//ARTICLE.10 >>

In one trial, it was discovered that the dry incubator had been turned off over-

resveratrol. This study suffered from low

night. Thus, some of the fish received

group sizes, as several data points had to

approximately 14 less hours to stain in their

be removed from the final data set due to

solutions at the appropriate temperature.

various issues that arose during experi-

It was decided that there was no way to

mentation. Increasing the group sizes of

adjust these embryos’ data to account

this experiment could help draw a more

for this error, so these data points were

accurate picture of the effects and trends

eventually removed from the final data set.

of resveratrol treatment.

Finally, due to the nature of the quantitation

Additionally, further measures could

method, there existed some potential for

have been taken to better control the

variability when selecting shades of blue

quantitation methods used in this study.

pixels to count, which could have impacted

For instance, the arrangement of embryos

the results.

prior to taking photos could have also been

Kishi et al. conducted a study that

standardized by finding a means to arrange

showed that a senescence model could

all embryos so that photos provided either

be produced in zebrafish embryos by

side or dorsal views of the bodies. The

using hydrogen peroxide as an oxidative

lighting settings of the microscope should

stressor and an SA β-gal assay to measure

have been controlled to minimize variation

the amassing of oxidative stress in the fish

in photos. Calibration steps could have

over time [C]. This experiment supported

been added into the procedure to ensure

the notion that such a senescence model

greater control of extraneous variables.

could be produced, and it applied these

This quality control method could have

findings to determine whether a senes-

been achieved by using the microscope

cence model could be used to study

to take a photo of a standard slip of paper

the effects of resveratrol as an anti-aging

containing the light blue shade that would

agent. Just as resveratrol has successfully

be later tracked by the Photoshop software

produced results in other laboratories

program before each set of photos was

with other animal models [A], this was

taken. However, this would require having

also found to be the case with zebrafish

the software program installed in a portable

embryos. This study also suggested that

laptop that could be accessed in near

protection from 100µM of oxidative stress

proximity to the microscope, which was

from hydrogen peroxide could be achieved

not available at the time of experimentation.

with 25µM of resveratrol.

Other possible future experiments include

Further studies could improve on this

experimenting with older embryos—such

experiment in many different ways. There

as 6dpf embryos instead of 3dpf embry-

did not appear to be a trend in the data as

os—to study the effects of resveratrol on

resveratrol concentrations increased, so

aging when taken later in life, and experi-

adjusting the concentrations of resveratrol

menting with different dosage methods. It

used in this study and tightening treatment

would be interesting to investigate if giving

range could help determine whether a

multiple treatments throughout the week,

trend truly exists. It is possible that a

instead of giving the embryos a one-time

downward trend in SA β-gal could be

dose, would yield different results and

observed between 0µM and 25µM of res-

provide insight into how resveratrol should

veratrol. In other words, the lack of a trend

be taken to achieve optimal outcomes.

among the treatment groups could be because the embryo had already received 076

full protection from oxidative stress at 25µM

VERTICES//029.02

DUNNETT’S MULTIPLE COMPARISONS TEST

MEAN DIFF.

95% CI OF DIFF.

SIGNIFICANT?

0ΜM VS. 0ΜM, NO H2O2

1133

394.8 TO 1872

YES

0ΜM VS. 25ΜM

1179

440.7 TO 1918

YES

0ΜM VS. 50ΜM

919.7

117.4 TO 1722

YES

0ΜM VS. 75ΜM

1001

100.0 TO 1901

YES

0ΜM VS. 100ΜM

1003

255.0 TO 1752

YES

Table 3. // Dunnett’s Multiple Comparisons Test // All groups rejected the null hypothesis that under a 5% significance level, there was no difference in the mean of the control group that received H2O2 and the means of the other groups. Thus, for all groups, there was significant evidence that there was a difference in means between all groups and the control group that received H2O2.

TUKEY’S MULTIPLE COMPARISONS TEST

MEAN DIFF.

95% CI OF DIFF.

SIGNIFICANT?

SUMMARY

0ΜM, NO H2O2 VS. 25ΜM

45.94

-736.9 TO 828.8

0ΜM, NO H2O2 VS. 50ΜM

-213.5

-1074 TO 647.0

0ΜM, NO H2O2 VS. 75ΜM

-132.6

-1111 TO 846.0

0ΜM, NO H2O2 VS. 100ΜM

-129.8

-924.8 TO 665.1

25ΜM VS. 50ΜM

-259.4

-1120 TO 601.1

25ΜM VS. 75ΜM

-178.5

-1157 TO 800.0

NS NS

25ΜM VS. 100ΜM

-178.8

-970.7 TO 619.2

50ΜM VS. 75ΜM

80.92

-960.8 TO 1123

NS NS NS

50ΜM VS. 100ΜM

83.67

-787.9 TO 955.2

75ΜM VS. 100ΜM

2.750

-985.5 TO 991.0

Table 4. // Tukey’s Multiple Comparisons Test // Further tests were conducted to determine whether differences in means existed between the treatment groups under a 5% alpha level. There was no significant evidence to conclude that a change in resveratrol treatment concentrations yielded statistically different means.

077

//CREATORS_IDENTITY

NC STATE UNIVERSITY* COLLEGE OF DESIGN//

//IMAGE_CREDIT//

078

KIM PHAM:

YAIRON MARTINEZ:

RESVERATROL

DENISOVA DRUG REPURPOSING JAPAN MICROBIOLOGY KILLER CELLS RESVERATROL

LARA KOZAK:

MICHAEL

NUMERICAL COGNITION

CELEDONIA:

STEPHEN LINBERG:

MADISON DIXON:

MORALITY IN THE BRAIN

BAD LSD TRIP

LONG TERM SPACE TRAVEL

VERTICES//029.02

DESIGNER//01

DESIGNER//02

ARTIST//01

ARTIST//02

ARTIST//03

ARTIST//04

079

080