SYNAPSE€¦ · their efficacy and the search for new antibiotics is more challenging, the widespread application of antibiotics has not waned. Without a cap on distribution, the

SPRING 2014 | SYNAPSE | 1

Your HealtH The Role of the Individual in Medicine Today

MappinG

SYNAPSEPENN’S UNDERGRADUATE MEDICAL CONNECTION

SPRING 2014

Vaccine RefusalAddresssing the recent opposition to vaccines

Organ DonationDispelling misconceptions

about the donation process

Personalized MedicineBreakthroughs in stem cell research

2 | SYNAPSE | SPRING 2014 SPRING 2014 | SYNAPSE | 3

The Role of the Individual in Medicine TodayExECUTIVE BOARD

GENERAL BOARDSAssociate EditorsKartik BhamidipatiIyassu BerhanuLucy ChenShan ChoudhriSarah DeVaroHannah FagenYusra GimieLeah GoldbergBusra Gungor

Design StaffJaicey BangSahil DoshiStephanie Fagbemi

Business StaffSamantha MannalaSonya Mannala

ADVISORY BOARDKent Bream, MD: Assistant Professor of Clinical Family Medicine and Community Health, Hospital of the University of PennsylvaniaPhyllis Dennery, MD: Chief of Neonatology and Newborn Service, Children’s Hospital of PhiladelphiaJohn Heon, PhD: Professor of English and Writing, College of Arts and Sciences Lisa Mitchell, PhD: Assistant Professor of South Asian Studies, College of Arts of Arts and SciencesBrendan Maher: Features Editor, NatureMark Pauly, PhD: Bendheim Professor of Healthcare Management, The Wharton SchoolPhilip Rea, PhD: Professor of Biology, College of Arts and SciencesHarvey Rubin, MD, PhD: Professor of Medicine, Penn School of MedicineMichael Topp, PhD: Professor of Chemistry, College of Arts of SciencesNicholas Wilcox: Founder of SYNAPSE

FEATURED SPEAKER SPRING 2014Laura Bessen, MD: Vice President, Head of U.S. Medical at Bristol-Myers Squibb

MANY ThANKS TO

ExEcutivE Board

BACK: Aman Singh, Leonard Chiu, Arjun Bashyam, Teja Alapati, Alex King, Osama Ahmed

FRONT: Sahil Doshi, Niharika Gupta, Vicky Ro, Fatoumata Diarra, Praneet Mylavarapu

Not pictured: Changhee Han, Chacha Wang

Sahil Doshi, Praneet MylavarapuAman SinghOsama Ahmed, Teja Alapati, Leonard Chiu, Niharika Gupta, Changhee Han, Chacha WangArjun Bashyam, Vicky RoFatoumata DiarraAlex King

Editors-in-ChiefVice President

Editorial

VP DesignVP Finance

VP Marketing

Kevin HuangSunny LuSiera MartinezAfrah MohammadNish PatelIndu SubbarajKevin YouJames Zhang

Dear Readers,

In today’s rapidly evolving healthcare landscape, the role of the individual as an advocate, a contributor, and an activist becomes increasingly evident. With increasing access to information and the advent of social media, the individual voice has the power to shape and define the future of healthcare delivery.

SYNAPSE takes a look at the driving forces of medicine and the voices behind them as our publication explores the theme of “Mapping Your Health: The Role of the Individual in Medicine Today.” A recent issue, driven by a few loud individual opinions, is the vaccine refusal movement in the United States. We question why certain people oppose necessary vaccinations, and probe what that means for the greater population. Along the same lines of medical misconceptions lie the myths revolving around organ donation. We rebut false beliefs and explore what people are doing to increase access to healthy organs for suffering patients. Furthermore, our issue discusses how the information revolution has transformed how physicians must practice in a clinical setting. Extending our discussion to the laboratory, we rethink the organization of clinical research with patients playing a more central role.

Delving into other topics aside from our theme, we analyze the rising bacterial resistance to antibiotics and the increasing use of cognitive enhancement drugs on college campuses. Hopefully, the diverse array of articles published in this issue will inspire you to engage in discourse over the role of the individual in medicine today.

In the ninth installment of SYNAPSE, we would like to sincerely thank every member of our team for their contribution this semester. We would especially like to thank Kathy Liu, Amy Le, Megan Falls, Ellen Kim, Mallika Marar, and Farrah Alkhaleel for their dedication to this organization over the years and wish them luck in their future endeavors.

Sahil Doshi and Praneet MylavarapuEditors-in-Chief

Jessica Fan Angela LiOlivia Rabe

Carl Wittig

Interested in writing for SYNAPSE?Go online to www.upennsynapse.com or email [email protected] for more information.

CONTENTS

covEr art BY arJuN BaSHYaM

The cover art was inspired by the ever expanding nature of healthcare in our lives today. The lungs

contrasted with a satellite image of the Earth highlights the integration of the individual with

the vast reach of the medical field.

THE ANTIBIoTIC CRISISExamining the rise in bacterial resistance

Alex King

4

oRGAN DoNATIoNDispelling misconceptions about the donation process

Michael Schatz

6

VACCINE REFuSAL Addressing the recent opposition to vaccines

Eileen Wang

9

PATIENT ACTIVISMCan laymen contribute to medical innovation?

Cameron Kiani

11

community health

RNAi THERAPEuTICSA novel approach to treating disease

Julian Pei

26

HIV AND THE HuMAN GENoME

Looking to gene therapy as a cure

Tuli Mitra-Majumdar

28

PERSoNALIzED MEDICINE

Breakthroughs in stem cell research

Iyassu Berhanu

31

TREATING PTSDErasing fear memories by mod-ifying the epigenome

Jenna Hebert

33

research

QuANTIFIED SELFThe role of self-tracking in healthcare

Sumun Khetpal

19

CLARITyA new brain imaging method

Afrah Mohammad

21

FECAL MICRoBIoTA TRANSPLANTATIoN

A unique solution for gut infections

Linda Wang

23

MoDELING INHEALTHCARE

The intersection of medicine and computer science

Tejas Narayan

25

technology

ADDERALL NATIoN Exploring its increase in popularity on college campuses

Tina Hsu

13

THE CHANGING PRoFESSIoNoF MEDICINE

How physicians are responding to challenges in autonomy

Seema Patel

16

medicine & society


biotics are used to stave off infections, the greater the incidence and strength of bacterial resistance.

OVERUSE IN PATIENT CARE

One of the main factors contributing to the rapid multiplication of superbugs is the almost unrestricted dispersal of antibiotics in hospitals. Both patient demand and doctor misdiagnosis drive this growing problem.

A report from Brigham and Women’s Hospital in Boston showed that prescriptions of antibi-otics for sore throat and acute bronchitis are far more common than they should be. While only 10% of adults with reported sore throat actually had strep, a condition requiring anti-biotic treatment, doctors prescribed antibiotics in 60% of the cases. The inability to accurately differentiate between bacterial and viral infec-tions has accelerated the spread of antibiotic resistance. Unnecessary antibiotics can de-stroy weak bacteria that live naturally in the body and permit resistant colonies to survive and potentially transfer their resistance genes to more dangerous forms of bacteria. In other words, if a patient is given an antibiotic with-out justifiable cause, that same antibiotic’s fu-ture function may be compromised when the patient really needs it.

The diseases that cause an irritated throat have some of the highest antibiotic misuse rates. As a result, the financial cost of unnecessary an-tibiotics for sore throat symptoms in the United States for the past thirteen years is conservatively $500 million. However, this number could be actually be 40 times higher if side effects like diarrhea were included in the cost calculation.6 Undoubtedly, attempts to break established habits of prescribing antibiotics in abundance are largely inconsequential.

ANTIBIOTICS IN INDUSTRIAL AGRICULTURE

When compared to the public healthcare sector, animal farming has a significant role in the upsurge of antibiotic resistance. Re-cent research reveals that antibiotic usage in animals is related to the risk of human infection. An analysis examining 30 antibiot-ics used in animal feed found that the majority of them are likely contributing to today’s growing problem of resistance. The top 63 resistance genes found in animal compost were recorded in concentrations between 192 and 28,000 times higher than con-trol samples of animals without antibiotic treatments.7

Because livestock receive more antibiotic treatments than hu-mans, optimal microenvironments for spreading superbugs arise in these animals. Thus, when farmers feed drugs to their animals in order to maintain their health in crowded living con-ditions, they indirectly cause bacteria to develop a resistance that is passed on to people through the environment and from con-sumption of meat from those animals.

After an antibiotic drug is discovered, a precarious race against time and biology begins. Within a period of a few years, the targeted bacteria can develop widespread resis-tance to the antibiotic. Due to the biological mechanisms driving the survival and evolution of organisms, antibiot-ics have capitulated to resistance for almost as long as peo-ple have been using them.

Despite this inextricable relationship between bacteria and resistance, antibiotics have a prodigious presence in the medical field. Although outcries concerning antibiotic overuse have surfaced in the media over the last decade, substantial gains in the fight against resistance are exig-uous. In 2010 alone, almost 260 million courses of anti-biotics were distributed to an American population of just over 300 million.1 That is, U.S. doctors are prescribing enough antibiotics to give them to four out of five Amer-icans every year. It is this unfettered prescription of anti-biotics that has resulted in the propagation of undesirable externalities.

Currently, 2 million Americans are infected with resistant bacteria every year. Furthermore, the annual death toll due to resistance-related illnesses has climbed to at least 23,000 patients.2 Although antibiotics are gradually losing their efficacy and the search for new antibiotics is more challenging, the widespread application of antibiotics has not waned. Without a cap on distribution, the continued overuse of antibiotics could pose a serious threat to the foundations of modern healthcare.

BY ALEx KING

The Antibiotic Crisis:

Why Superbugs are outpacing Healthcare

coMMuNitY HEaltH

References

1. Hicks, L. A., Taylor, T. H., & Hunkler, R. J. (2013). U.S.Outpatient Antibiotic Prescribing, 2010. New England Journal of Medicine, 368(15), 1461-1462.

2. United States Centers for Disease Control and Prevention. (2013). Antibiotic Resistance T hreats in the United States, 2013. Retrieved from http://www.cdc.gov/drugresistance/threat-report-2013/pdf/arthreats-2013-508.pdf

3. Sykes, R (2001). Penicillin: from discovery to product. Bull. World Health Organization, 79 (8): 778–9.

4. Amyes, SG. (2000). T he Rise in Bacterial Resistance. BMJ, 320(7229): 199–200.5. Mosher, D. (2012, December 29). What is a Superbug?. LiveScience. Retrieved from http://www.

livescience.com/32370-what-is-a-superbug.html6. Barnett ML, Linder JA. Antibiotic Prescribing to Adults With Sore T hroat in the United States,

1997-2010. JAMA Intern Med. 2014; 174(1):138-140.7. Z hu, Y.G, Johnson, T.A., Su, J.Q, Qiao, M., Guo, G.X., Stedtfeld, R.D., Hashsham, S.A., Tiedje, J.M.

(2013). Diverse and abundant antibiotic resistance genes in Chinese swine farms. Proceedings of the National Academy of Sciences, 110(9):3435-40.

8. Pfeifer, S. (2014). Plant closure over roach infestation latest setback for Foster Farms. Los Angeles Times. Retrieved from http://articles.latimes.com/2014/jan/09/business/la-fi-fosterfarms-cockroach-20140110

9. Roberts, R.R., Hota, B., Ahmad, I., Scott, R.D., Foster, S.D., Abbasi, F., Schabowski, S., Kampe, L.M., Ciavarella, G.G., Supino, M., Naples, J., Cordell, R., Levy, S.B., Weinstein, R.A. (2009). Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clinical Infectious Diseases, 49(8):1175-84.

ThE METEORIC RISE OF ThE ANTIBIOTIC

The origin of antibiotics can be traced back to a discovery made by Scottish biologist Sir Alexander Fleming. In 1928, he first ex-tracted penicillin from the fungus Penicillium notatum. With penicillin, he perfected the treatment of bacterial diseases like tuberculosis, syphilis and gangrene. Later, a formal manufac-turing process emerged in 1942, which incited an industrious search for new antibiotics within the scientific community.3

The usual method for unearthing antibiotics involves screenings of large libraries of compounds. For billions of years, microor-ganisms have waged an arms race for survival, continually evolv-ing adaptations to fend off foreign enemies. Their weapons exist in the form of secreted toxic compounds designed to destroy microbial combatants. These substances are often produced by a fungus or another microorganism, who use them to kill dis-ease-causing bacteria.

After the revolutionary discovery of penicillin, antibiotics be-came ingrained in the toolkit of medical professionals. Starting in the 1960s when antibiotics were first implemented on a mas-sive scale, the fight against bacterial ailments saw huge success-es.4 Many diseases thought to be fatal became treatable or pre-ventable. However, current hospital records tell a different story. New classes or modifications of previous classes of antibiotics have been matched with the proliferation of antibiotic resistant strains of bacteria, colloquially known as “superbugs”.5 The more anti-

In October of 2013, an outbreak of salmonella linked to Foster Farms affected more than 400 people. Within these strains of salmonella, several were resistant to one or more commonly pre-scribed antibiotics.8 This resistance incident in industrial agricul-ture exemplifies the snowball effect of recurrent antibiotic usage. As new studies trace the emergence of superbugs to agricultural origins, the indiscriminate incorporation of antibiotics in fodder is becoming linked to the antibiotic resistance dilemma.

A BOON OR BANE TO hEALThCARE?

While the benefits of antibiotics are irrefutable, the widening repercussions of antibiotic over-use and misuse require action. Already, anti-biotic-resistant infections cost Americans be-tween $16.6 billion and $26 billion a year.9 The spread of complex, deadly diseases resistant to multiple forms of medicine now sits at the fore-front of the United States’ health agenda.

Currently, the burgeoning incidence and se-verity of resistance-related illnesses reflect an unfavorable fate for medicine. We are ap-proaching a threshold of resistance that—if not assuaged by a higher rate of newly discovered antibiotic compounds or by policy changes—will destroy the age of the antibiotic. Contem-porary approaches for minimizing antibiotic usage are few and far between; they are usually solely practiced at the arbitrary level of an in-dividual hospital or doctor. Moreover, coordi-nated action, especially in the realm of politics, is practically absent. National and international

health standards that guide hospital stewardship, responsible agriculture use, and community education would carry the political weight needed to alter antibiotic attitudes.

Looking towards the future, it may be beneficial to invest in re-search for alternatives to antibiotic treatments, like those that utilize DNA instead of natural compounds. Such methods could pave the road to a new future where the current race against time for antibiotics turns into a state of medical longevity.

WIKIMEDIA/ GRAPHIC

WIKIMEDIA/ GRAPHIC


MYThS & ORGAN DONATION

The first and perhaps most tenacious myth is that an individual’s medical treatment will be compromised if a

physician is made aware that he or she is an organ donor. This is completely and unequivocally false. The quality of care that an individual receives is completely independent of his/her status as an organ donor, organ donation cannot be considered until the person is considered medically dead, and, finally, the treating physician and the transplant surgeon, are separate, as mandated by law.5,6 Another common misconception is that organ donation is against most religions. In reality, most branches of nearly all major religions permit organ donation.7 If someone is uncertain as to the stance of his/her religion on the issue of organ donation, then he/she should contact his/her local religious leader. Perhaps the next most common misconception is that some people are too old or in too poor of health to

did You kNow tHat MaNY StatE iSSuEd drivErS licENSES HavE

orgaN doNor SigNaturE liNES oN tHE Back of tHEM? SigNiNg

it iS a good firSt StEp, But tHE SurESt waY iS to alSo ExprESS

Your prEfErENcES witH Your faMilY aNd friENdS.2Visit the website of any major organ donation organization

and you will be bombarded with at least one of three things: statistics, inspirational stories, a call to action, and/or more statistics. According to DonateLife, there are approximately 120,000 American men, women, and children currently on the waiting list.1 OrganDonor.gov indicates that “18 people will die each day waiting for an organ” in the U.S. alone.2 Finally, according to the National Institutes of Health, a single organ donor can save or help up to 50 different lives.3 Clearly there is a huge demand for organs in this country. The question is then two-fold: why is there a supply shortage, and what can we, as a society, do to remedy the situation?

ECONOMICS & ORGAN DONATION

The first thing to realize is that this isn’t Econ 001. The situation is not as simple as drawing supply and demand curves and locating the market equilibrium by finding their intersection. Moreover, shifting organ supply curves cannot, at least in theory, be accomplished by the same factors as traditional goods and services. This is due to the National Organ Transplant Act of 1984, which made it illegal to sell human organs.4 There are many justifications for this legislation, but perhaps the most salient is the argument that organ markets are morally reprehensible since they would prey upon existing inequalities, and would result in organs being disproportionately taken from destitute and disenfranchised minorities and given to wealthy benefactors.

The lack of an organ market, however, does not in itself explain the shortage of organ donations since there remains a strong ethical imperative to donate. It is easy to understand why a living donor would be hesitant to donate: a second kidney, for example, while perhaps not completely necessary, might be a comforting fail-safe for some people. Furthermore, no operation, no matter how mundane, is risk-free. However, many organs nowadays can be harvested posthumously. Still, some people personally object to posthumous organ donations on psychological or other grounds, while many others oppose it simply because of misinformation. Thus, one of the most important first steps that we, as informed members of society, can take in alleviating the organ shortage crisis—and it is a crisis—is to dispel misconceptions.

donate. According to the Mayo Clinic, there is no “defined cutoff age for organ donation” and “very few medical conditions automatically disqualify you from donating organs.”7 Even if you are disqualified for some reason, there is no risk to registering as an organ donor since transplant surgeons and other medical professionals will make that assessment if and when the time comes.You may be a little confused as to why you have just spent the last five minutes or so reading information that could have been easily discovered from even the most cursory glance at any organ donation website homepage. The truth is that pointing someone in the direction of source material isn’t always enough. Minor inconveniences, such as having to search the Internet to discover readily available information, or having to check an opt-in box, can have startling impacts on human behavior, with dire consequences. My point here isn’t to disparage readers, but rather to draw attention to the disquieting fact that minor obstacles can counter-intuitively cause major impacts on important decisions.

OPT-IN & OPT-OUT DEFAULTS: PSYChOLOGY AND CROSS-CULTURAL STUDIES

To bring the discussion back to organ donations, consider what happens to the organs of an individual when he or she suddenly dies? What if he or she had not previously established what can be done with his or her organs? What is the default procedure? The answer, as it turns out, depends on what country you live in. Some countries, like the United States, Denmark and Germany have an opt-in default, meaning that individuals need to actively give their expressed consent in order to be considered a potential

donor. Other countries like Austria, Belgium and France have a presumed consent, or opt-out, default, meaning that unless the individual had previously stated otherwise, it is assumed that after they die, their organs can be donated.8

Now, according to traditional economics, whether a nation has an opt-in or opt-out default shouldn’t make all that much of a difference, since rational human beings will align their decisions with their preferences assuming that the opportunity cost of the action isn’t too large. In fact, since we’re talking about a decision that can potentially affect many lives, one would expect such an inconvenience would have to be exceedingly large in order to prevent one from choosing a donation position in line with his/her preference.

As it turns out, there are several reasons why that isn’t the case:

1. People have a tendency to associate defaults with recommended courses of actions.8

2. People have a tendency to avoid making an active decision against the status quo because of what psychologists call “loss aversion”—the idea that losses

BY MIChAEL SChATZ

DISSECTING ORGAN DONATIONS

OLIVIA RABE/GRAPHIC

did You kNow tHat orgaN doNorS aNd faMiliES of

dEcEaSEd orgaN doNorS arE Not rESpoNSiBlE for aNY of

tHE coStS aSSociatEd witH tHE HarvEStiNg procEdurE?7

Dispelling Misconceptions and Searching for Solutions

Opt-InCheck this box if you WANT to

participate in the organ donor

program.

Opt-OutCheck this box if you DO NOT

WANT to participate in the organ donor program.

OLIVIA RABE/ GRAPHIC


In January 2014, India was declared polio-free—a histor-ic triumph that leaves polio to be eradicated in just three countries around the world. This success stems from wide-reaching efforts to vaccinate more than 170 million children across the country. Throughout history, similar vaccination efforts have proven to be effective in reduc-ing the incidence of vaccine-preventable disease; their use allowed for the global eradication of smallpox in 1980, as well as the elimination of measles, polio, and diphtheria in the United States in the 1970s. In the United States, experts estimate that child immunization schedules and school immunization requirements prevent 42,000 deaths and 20 million cases of disease for each annual birth cohort.1 De-spite the worldwide success and overwhelming benefits of vaccinations, more and more people in the United States have recently been refusing vaccines.

In recent years, the number of nonmedical exemptions from mandated school immunization requirements has steadily increased, rising from 0.99% in 1991 to 2.54% in 2005, reflecting the rise in vaccine hesitancy.2 Exemptions and vaccine refusals harmfully impact public health as evi-denced by several statistical studies. Individually, unvacci-nated children are 22 times more likely to contract measles and six times more likely to attract pertussis than vacci-nated ones.3 In two 2008 measles outbreaks in Washington and Illinois, 41 of the 44 infected children had not received the measles vaccine due to their parents’ beliefs.4 On a larg-er scale, the Center for Disease Control reports that 65% of measles cases from 2001-2011 were unvaccinated indi-viduals, and 20% had an unknown vaccination status. In 2008, which had the highest incidence of measles cases in recent years, 95% of all measles cases were of unvaccinated individuals or of those who had an unknown vaccination status.5

The implications are even larger on a community level. The continued eradication of disease requires that a certain threshold of the population be vaccinated; this is a concept known as herd immunity. With herd immunity, the larger the proportion of individuals receiving vaccines, the small-er the chance that an unvaccinated or vulnerable individu-al, such as someone who cannot receive vaccines for medi-cal reasons, will become infected. That being said, if a large majority of the population is vaccinated, and the disease is not prevalent, individual parents may decide to free-ride on the benefits of others’ vaccinations without incurring

References

1. Donate Life America. (October, 2013). Organ Donation. In Donate Life America. Retrieved February 20, 2014, from http://donatelife.net/understanding-donation/ organ-donation/.2. U.S. Department of Health and Human Services. (n.d.). Donate the Gift of Life. In organdonor.gov Retrieved February 22, 2014, from http://www.organdonor.gov/ index.html.3. National Institutes of Health. (February 12, 2014). Organ Donation. In MedlinePlus. Retrieved February 21, 2014, from http://www.nlm.nih.gov/medlineplus/ organdonation.html.4. National Organ Transplant Act of 1984, Title 42, Section 273.5. United Network for Organ Sharing. (2014). Common Myths. In UNOS. Retrieved February 19, 2014, from http://www.unos.org/donation/index.php?topic=fact_ sheet_7.6. Art Brownstein, The National Network of Organ Donors, personal communication, January 1, 2013.7. Mayo Clinic Staff. (May 3, 2013). Organ donation: Don’t let these myths confuse you. In Mayo Clinic. Retrieved February 15, 2014, from http://www.mayoclinic.org/ healthy-living/consumer-health/in-depth/organ-donation/art-20047529.8. Johnson, E. J., & Goldstein, D. (2003). Do Defaults Save Lives? Science, 302, 1338- 1339. doi: 10.1126/science.10917219. Dan Ariely. (May 5, 2008). 3 main lessons of Psychology. Retrieved March 17, 2014, from http://danariely.com/2008/05/05/3-main-lessons-of-psychology/. 10. Johns Hopkins Medicine: News and Publications. (November 29, 2011). Presumed Consent Not Answer to Solving Organ Shortage in U.S., Researchers Say. Retrieved March 17, 2014, from http://www.hopkinsmedicine.org/news/media/releases/ presumed_consent_not_answer_to_solving_organ_shortage_in_us_researchers_ say11. Abadie, A., & Gay, S. (2006). The impact of presumed consent legislation on cadaveric organ donation: A cross-country study. Journal of Health Economics, 25(4), 599-620, http://dx.doi.org/10.1016/j.jhealeco.2006.01.00312. Delmoinico, F. L., Arnold, R., Scheper-Hughes, N., Simnoff, L. A., Kahn, J., & Youngner, S. J. (2002). Ethical Incentives – Not Payment – For Organ Donation. The New England Journal of Medicine, 346(25), 2002-2005.13. Arnold, R., Bartlett, S., Bernat, J., Colonna, J., Dafoe, D., Dubler, N., … Delmonico, F. L. (2002). Financial Incentives for Cadaver Organ Donation: An Ethical Reappraisal. Transplantation, 73(8), 1361-1367. doi:10.1097/00007890-200204270-00034

are viewed more negatively than identical gains are viewed positively.8 3. Though the task of check-marking a box requires negligible physical exertion, the decision can be emotionally arduous as it requires thinking about death. Accepting the default is one way to avoid such emotional contemplation.9

In this light it is not at all surprising that nations with opt-out defaults have a much higher effective percentage of people who have consented to donate their organs after they die. Austria, with it’s opt-out default, for example, has an effective consent percentage of 99.98% whereas an ethnically similar Germany, with an opt-in default, has only a 12% effective consent rate.8

The final analysis, however, is slightly more nuanced. A high effective consent percentage does NOT always translate to a higher donation rate per million. A team led by Dr. Dorry Segev, of Johns Hopkins University School of Medicine, attempted to solve this enigma by conducting interviews with transplant experts in different European countries.

They found that regardless of prior consent, physicians in most cases will consult with and honor the desires of the deceased’s next of kin.10 One explanation for this is that it safeguards against bad press. Based on this study, a far better alternative to the opt-out default would be to have a team of dedicated surgeons “who are knowledgeable about transplant issues and who screen for potential donors, manage their care and approach families.”10

This objection notwithstanding, other comprehensive studies have found that a nation’s default policies do, in fact, have a large influence not only on consent rates but also donation rates. In a 2006 study in the Journal of Health Economics, Alberto Abadie and Sebastien Gay analyzed 22 different countries over 10 years. Though they found that disparity in organ donation rates could be explained to a considerable extent by other variables, they concluded that opt-out default legislation does in fact result in a “positive and sizeable effect on organ donation rates.”11 In a separate cross-cultural study, Eric Johnson and Daniel Goldstein, also controlling for other variables such as “transplant infrastructure, educational level, and religion,” used a multiple regression analysis and came to the same conclusion.8

OThER SOLUTIONS

There are other methods, outside policy shifts in default

rEgiStEr to participatE iN tHE orgaN doNatioN prograM BY

viSitiNg orgaNdoNor.gov

settings, that have been proposed to increase organ donation rates. Some physicians and health experts believe that ethical incentives can be effective in increasing donation rates. For example, bestowing a congressionally recognized donor medal of honor to living donors, or families of deceased donors, may go a long way in encouraging ethical behavior.12 It may also be possible to increase the number of donations by providing paid medical-leave of absence for organ donations, and by guaranteeing living donors that they will be a given a higher priority should they need an organ in the future.12 In 2000, a panel of ethicists convened by the American Society of Transplant Surgeons concluded that it was acceptable to offer at least partial funeral reimbursements to the families of deceased donors.13 Since partial funeral reimbursements avoid direct payments to a living person for organs, it effectively gets around the National Organ Transplant Act of 1984.

STITChING IT TOGEThER

We have reviewed some of the basic statistics behind organ donation, analyzed the ideas behind default policies, and explored a few basic ideas for increasing organ donation, but where does that leave us? What can we do to alleviate the problem? One thing we can all do is further educate ourselves and push back against the misinformation surrounding organ donation. And, of course, assuming that you have no personal objections to posthumous organ donations, you can register today. Why not?

Vaccine Hesitancy and Refusal in the United States:a “First World” Problem?

BY EILEEN WANG

the costs of vaccinating—for example, if they believe it is an inconvenience or will cause an adverse effect on their child. For this reason, every state in the United States man-dates school-entry immunization laws.6 By compromising herd immunity, clusters of unvaccinated and exempted children are likely to increase the risk of outbreak in that community, affecting both unvaccinated and vaccinated children.7 Depending on the population size, decreased vaccination coverage could also lead to a significant in-crease in the severity and duration of an outbreak.8

The severity of the consequences associated with vaccine refusal has made it necessary to evaluate the reasons be-hind such a decision. Contrary to public perception, par-ents with unvaccinated children are generally not poor, nor

do they lack access to healthcare services. Rather, they are usually white, college-educated individuals with relatively high incomes.9 The refusal to vaccinate may be due to a number of reasons, including religious beliefs against im-munizations or philosophical beliefs against government impositions. However, a larger proportion of non-vacci-nators refuse to do so not because of strong philosophi-cal or religious beliefs, but because of misinformation and skepticism. The 1998 MMR (measles-mumps-rubella) vac-cine controversy, in which Andrew Wakefield published a now-discredited study claiming that the MMR vaccine caused autism, is an example of this misinformation. In addition, skewed media reports covered the initial study without later reporting that multiple studies refuted that belief. Anti-vaccine campaigns by celebrities such as Jen-ny McCarthy also contribute to misconceptions about

WIKIMEDIA/ PHOTO


immunizations, such as the belief that vaccines harm the health of the child, contain dangerous chemicals or preservatives, and overload immune systems.10-12 As one parent who decided not to vaccinate her child put it, “I never really liked how many vaccinations a baby was getting … I just felt, if I could put some of those off until later, I would rather not overburden my child’s system with a bunch of toxic organisms.”13 However, scientists such as Dr. Paul Offit, the Chief of Infectious Diseases at the Children’s Hospital of Philadelphia, believe that these notions are not scientifically supported and are implanted by celebrities who can more easily convince viewers of their own beliefs than scientific literature can: “[I]t’s the same reason they use celebrities to sell prod-ucts. You see them on the screen, you think you know them, you’re comfortable with them. Jenny McCarthy is fun and upbeat and brash and speaks ‘truth to pow-er.’ So, at some level, you trust her.”14 Some parents also believe that vaccination is unnecessary because of the low incidence of many vaccine-preventable diseases in the U.S.15,16 More generally, individuals who refuse are more likely to follow an “alternative,” “natural” style of living, to be skeptical of the government, pharmaceu-tical industry, and medical community, and to distrust information coming from those sources.17-19 Further-more, while a vast majority of Americans still comply with the immunization schedule, studies have shown

In the past two decades, the paradigm of expert scientists being infallible and autonomous has been seriously challenged. Recent controversies, such as the NASA Challenger 17 landing failure, have shown that even groups of experts are susceptible to groupthink incompetence.1 As a result, self-aware experts have made great strides towards engendering a culture of “doing research with people, rather than on people.”2 Also, some hyperactive patient groups have outwardly rejected the stereotype of the voiceless human volunteer and have banded together to raise funds, affect policy and advance research. Enlisting human volunteers as equals, rather than subjects, has the potential to greatly improve the quality of research produced.

PATIENT INITIATIVES: ThE POWER OF EMERGENT CONCERNED GROUPS

Emergent concerned groups are most often the ones pressuring scientists to explore uncharted territories, especially in the case of groups representing sufferers of seemingly terminal illnesses like AIDS and muscular dystrophy. One of the most extraordinary fund raising feats by the Association française contre les myopathies (AFM) is the annual Le Téléthon, which has raised a total of 700 million Euros since 1987. Seventy percent of their funds are allocated towards groundbreaking research, leading to the identification of the genes responsible for muscular dystrophy and developments in genotherapies. The former development was

Guinea Pig No MoreThe New Age of Patient Activism

and Involvement in ResearchBY CAMERON KIANI

paramount in changing MD sufferers from marginalized “quasi-nonhuman beings” to affected people.3 This is an important shift in public opinion, as in tandem with the formation of an identity; MD sufferers were able to disprove the assertion that their diagnosis was a death sentence, allowing for advances in research for a cure.

Similarly, in the late 1980’s AIDS activists became disillusioned with the dearth of novel treatments from so-called “experts”, referring to this dependence on institutions for their well being as “a form of group suicide”. Generally starting from the initiatives of white, middle-class, and well-educated sufferers, activists learned the language of AIDS and were eventually granted precarious entry into medical research institutions. Once their credibility had been established, AIDS activists mobilized through demonstrations and protests; and researchers, in need of compliant participants, were forced to listen because AIDS activists had become an “obligatory passage point” towards realising their clinical trials. And though initially contentious in nature, the relationship between AIDS activists and researchers became a fruitful one, leading to the joint development of new technologies and an eventual symbiosis. Now, many activists are full voting members of AIDS-related NIH and FDA committees. AIDS activists helped convert AIDS research from neatly-controlled hypothesis testing to groundbreaking, open-ended translational research.4 Dr. Melinda Cooper of the University

References

1. Zhou, F. (2011). Updated economic evaluation of the routine childhood immunization schedule in the United States. Presented at the 45th National Immunization Conference, Washington, D.C.

2. Omer, S. B., & Pan, W. (2006). Nonmedical exemptions to school immunization requirements: Secular trends and association of state policies with pertussis incidence. JAMA: The Journal of the American Medical Association, 296(14), 1757–1763. doi:10.1001/jama.296.14.1757

3. Feikin, D. R., Lezotte, D. C., Hamman, R. F., Salmon, D. A., Chen, R. T., & Hoffman, R. E. (2000). Individual and community risks of measles and pertussis associated with personal exemptions to immunization. The Journal of the American Medical Association, 284(24), 3145–3150.

4. Centers for Disease Control and Prevention. (2008). Update: Measles --- United States, January--July 2008. Morbidity and Mortality Weekly Report, 57(33), 893–896.

5. Centers for Disease Control and Prevention. (2013). Chapter 7: Measles. Centers for Disease Control and Prevention. Retrieved from http://www.cdc.gov/vaccines/pubs/surv-manual/chpt07-measles.html

6. Horlick, G., Shaw, F. E., Gorji, M., & Fishbein, D. B. (2008). Delivering New Vaccines to Adolescents: The Role of School-Entry Laws. Pediatrics, 121(Supplement), S79–S84. doi:10.1542/peds.2007-1115I

7. Salmon DA, Haber M, Gangarosa EJ, Phillips L, Smith NJ, & Chen RT. (1999). Health consequences of religious and philosophical exemptions from immunization laws: Individual and societal risk of measles. JAMA, 282(1), 47–53. doi:10.1001/jama.282.1.47

8. Britten, N. (2009). Measles outbreaks in the face of decreasing herd immunity: The impact of vaccine exemptions (M.P.H.). Yale University, United States -- Connecticut. Retrieved from http://search.proquest.com/docview/305040041/abstract?accountid=14707

9. Luthy, K. E., Beckstrand, R. L., & Meyers, C. J. H. (2012). Common Perceptions of Parents Requesting Personal Exemption From Vaccination. The Journal of School Nursing. doi:10.1177/1059840512455365

10. Gust, D. A., Kennedy, A., Weber, D., Evans, G., Kong, Y., & Salmon, D. (2009). Parents

that the exemptions tend to cluster in certain geograph-ical regions, suggesting a sociocultural reason for this phenomenon.20

Some solutions have been suggested to help temper the rise in vaccine hesitancy and refusal. The first strategy, where most of the focus has been, is to prevent parents from exempting their children in the first place. States such as Oregon, Vermont, and California have passed policies in recent years that require parents to go to a healthcare provider before obtaining an exemption.21 Other preventative measures include educating par-ents about the risks of not vaccinating through trusted individuals such as health care providers and making parents aware of the proportion of exempted children in their school.22 Interventions can also be used to ac-commodate unvaccinated children by spreading them in multiple classrooms to diffuse risk.23 This may also provide social pressure for parents to vaccinate their children. However, there are currently few studies ex-amining the effectiveness of these various solutions, and it is unknown whether any have been implemented in communities with a large proportion of unvaccinated kids.

Ultimately, the rise of vaccine refusal in the United States is a “first world” problem, caused not by the lack of ac-cess to life-saving technology but instead by the entitle-ment to refuse it. Granted, that is not to say that vaccine refusal does not occur in other developing countries—it took many years and much effort to overcome resistance to polio vaccination in northern India—but just that Americans who have traditionally accepted vaccines are now changing their minds because of misinforma-tion brought forth by recent media attention. Further complicating the matter is that while vaccination is a public health issue that protects the entire community, America has a strong culture of protecting and respect-ing individual beliefs and rights, a reason why exemp-tions to immunization requirements are allowed. While issues of the law and what constitutes the right balance between protecting public interest and individual rights are moot, what is clear is that vaccinations save lives and that unvaccinated children are associated with disease outbreaks. As vaccine hesitancy and refusal continues to rise, we may try to expound upon this science and the beneficial effects of vaccines. However, human beings are not robots: decisions to vaccinate are tied to moral-ly complex individual beliefs and sociopolitical aspects of a culture, neither of which are easily swayed by the dictates of science. We should therefore note that while more education and knowledge may be a way to help people rationalize the decision to vaccinate, it is equally important to explore other ways to prevent parents from being swept up by their emotions and others’ opinions when making these decisions for their children.

Herd immunity will stop the spread of diseases, even when not every single person has been immunized.

WIKIMEDIA/ GRAPHIC

Questioning Immunization: Evaluation of an Intervention. American Journal of Health Behavior, 33(3), 287–298. doi:10.5993/AJHB.33.3.7

11. Luthy et al., 201212. Salmon DA, Moulton LH, Omer SB, deHart M, Stokley S, & Halsey NA. (2005). Factors associated with

refusal of childhood vaccines among parents of school-aged children: A case-control study. Archives of Pediatrics & Adolescent Medicine, 159(5), 470–476. doi:10.1001/archpedi.159.5.470

13. Brown, K. (2013, November 11). Parents refusing vaccines: Raising fears among the medical community of disease outbreaks. The Boston Globe. Retrieved from http://www.bostonglobe.com/lifestyle/health-wellness/2013/11/11/more-parents-are-refusing-immunizations-for-their-children-raising-fears-among-medical-community-disease-outbreaks/m3mGJgFhzrT7PUehai87tN/story.html

14. Koven, S. (2013, October 7). Q&A with Dr. Paul Offit. The Boston Globe. Retrieved from http://www.bostonglobe.com/lifestyle/health-wellness/2013/10/06/with-paul-offit/XZ36fLL23PRSUxtJzGe9sM/story.html

15. Gullion, J. S., Henry, L., & Gullion, G. (2008). Deciding to Opt Out of Childhood Vaccination Mandates. Public Health Nursing, 25(5), 401–408. doi:10.1111/j.1525-1446.2008.00724.x

16. Salmon et al., 2005.17. Gaudino, J. A., & Robison, S. (2012). Risk factors associated with parents claiming personal-belief

exemptions to school immunization requirements: Community and other influences on more skeptical parents in Oregon, 2006. Vaccine, 30(6), 1132–1142. doi:10.1016/j.vaccine.2011.12.006

18. Gullion et al., 200819. Salmon et al., 200520. Gaudino & Robison, 2012.21. Blank, N. R., Caplan, A. L., & Constable, C. (2013). Exempting Schoolchildren From Immunizations:

States With Few Barriers Had Highest Rates Of Nonmedical Exemptions. Health Affairs, 32(7), 1282–1290. doi:10.1377/hlthaff.2013.0239

22. Gust, D. A., Kennedy, A., Shui, I., Smith, P. J., Nowak, G., & Pickering, L. K. (2005). Parent Attitudes Toward Immunizations and Healthcare Providers: The Role of Information. American Journal of Preventive Medicine, 29(2), 105–112. doi:10.1016/j.amepre.2005.04.010

23. Britten, 2009.


AdderAll nAtion

America’s favorite amphetamine, Adderall, has been growing increasingly popular on college campuses. But how much will this addiction really cost us, and what are some alternatives?

References

1. Stilgoe, J., Irwin, A. and Jones, K. (2006). The received wisdom. London: Demos.2. Reason, P. and Bradbury, H. (2008). The SAGE handbook of action research. Los Angeles, Calif.: SAGE.3. Rabeharisoa, V. and Callon, M. (2004). Patients and scientists in French muscular dystrophy research.

States of knowledge: The co-production of science and social order, pp. 142--160.4. Epstein, S. (1995). The construction of lay expertise: AIDS activism and the forging of credibility in

the reform of clinical trials. Science, Technology & Human Values, 20 (4), pp. 408-437.5. Cooper, M. (2012). The pharmacology of distributed experiment--user-generated drug innovation.

Body & Society, 18 (3-4), pp. 18-43.6. Selikoff, I. and Robitzek, E. (1952). Tuberculosis Chemotherapy with Hydrazine Derivatives of

Isonicotinic Acid. CHEST Journal, 21 (4), pp. 385--438.7. Bradburn, J., Maher, J., Adewuyi-Dalton, R., Grunfeld, E., Lancaster, T. and Mant, D.

(1995). Developing clinical trial protocols: the use of patient focus groups. Psycho-oncology, 4 (2), pp. 107-112

8. Morris, N. & Schneider, M. (2010). Volunteer research subjects’ experience of participation in research on a novel diagnostic technology for breast cancer. Qualitative Health Research, 20 (1), pp. 81--92.

9. Goodare, H. and Lockwood, S. (1999). Involving patients in clinical research: improves the quality of research. BMJ: British Medical Journal, 319 (7212), p. 724.

10. Williamson, C. (2001). What does involving consumers in research mean?. QJM, 94 (12), pp. 661-664.

of Sydney, citing Epstein’s AIDS activism paper, contends that the aforementioned movement set the precedent for the burgeoning field of crowd-sourced drug innovation.

OPEN SOURCE COLLABORATION: INFORMING DRUG DISCOVERY

In fact, the AIDS activist movement set the foundation for a new age of patient collaboration in research initiatives. Although this was initially a patient-directed push towards gaining entry to the discussion table, researchers began to recognize the benefits of patient input and started to incorporate volunteer feedback in all stages of the research process.

By monitoring social networking sites like “PatientsLikeMe, where patient openly discuss their experience with illness and their response to prescribed, sometimes experimental, treatment regiments, researchers have access to a wealth of valuable information that can inform drug-innovation.5 This includes

information on under-the-radar off-label consumption of drugs and unexplored side effects of existing drugs that could serve as leads to new drug discovery. A notable example from history of this occurring is the discovery of antidepressants. In 1951, Irving Selikoff and Edward Robitzek, working on tuberculosis drugs isoniazid and iproniazid, noted patients exhibited “a subtle general stimulation” and “renewed vigor.”6 Max Lurie, a psychiatrist, picked up on this observation and tested out isoniazid as a treatment for his depressed patients. Other psychiatrists began to experiment with anti-tuberculosis drugs for psychostimulant effects, eventually leading to the first batch of antidepressants: Monoamine Oxidase Inhibitors. And so the simple monitoring of patient feedback, led to the off-label prescription of a drug, and, eventually, a multi-billion dollar industry.

RESEARChER INITIATIVES: IMPROVING RESEARCh PROTOCOL AND RESULTS

The dissonance between surmised concerns of researchers and real-life concerns of participants has been a well-documented phenomenon.7 Taking patients’ intuitive concerns into account during this hypothesized “Phase 0” could improve the quality and implementation of clinical trials. In one notable study, Jane Bradburn and colleagues from Mount Vernon hospital proposed shifting follow-ups for outpatient breast cancer survivors from hospitals to community general practitioners. Pre-clinical trial focus groups done by the researchers, though not dubbed “Phase 0”, fall in line with the thinking of adding a pre-clinical stage. These focus groups indicated that the confidence conferred by patients to hospital-follow ups outweighed any sort of inconvenience attributed to them. Furthermore, unconsidered variables, such as

the psychosocial support afforded by the subjects’ breast cancer nurses and ease of access to specialist opinion, were deemed as the most important concerns by patients and the final protocol was changed accordingly.

Not only can asking for volunteer feedback improve the implementation of medical bureaucracy, it can also improve the development of new medical technologies. Researchers at the University College London conducting a clinical trial on a novel optical mammography device collected qualitative patient feedback alongside their quantitative data.8 The results of these interviews were insightful practical suggestions towards device interface and sources of anxiety with regards to the procedure. Self-evident flaws in the most quantitatively important feature, maintaining contact between the breast and the circular fiber array used, pre-empted a redesign from the researchers’ point of view. Nonetheless, patient feedback led to previously unconsidered changes, mainly regarding accommodations to allow subjects to relax during the scan, and further reaffirmed the need to redesign the device. The interviews also allowed the researchers to identify important “Criterias for acceptance”, some of which were previously unconsidered psychosocial factors such as “invasiveness” and “isolation”. By using patient feedback as early as possible with regards to interface, unnecessary time and money need not be spent on superfluous prototypes. And by creating more patient-directed diagnostic procedures, patient adherence to getting tested can increase dramatically. Thus, patient feedback can improve the speed, quality and reach of new diagnostic procedures.

CONCLUDING REMARKS

Volunteers have qualitative information in regards to particular diseases and treatment regiments that can supplement impassive scientific data.9 Expert laymen can help highlight the problems with overly theoretical research, and help steer committees towards more applicable, translational projects. And of course, researchers have the technical and scientific knowledge base to address patient concerns with new technologies and treatments. The relationship between consumer and expert will always be both complex and fragile, as activists will always respect but be cautious of experts and vice versa.10 But by traversing these potentially muddied waters together, consumers and researchers can revitalize scientific discovery.

ENLISTING HUMAN VOLUNTEERS AS EQUALS, RATHER THAN SUBJECTS, HAS THE POTENTIAL TO GREATLY IMPROVE THE QUALITY OF RESEARCH PRODUCED.

From a young age, we have all been taught that drugs are bad for you. Meth makes you crazy. LSD causes hallucinations and delusions. Cocaine gives you a ton of energy, until you realize you can’t function without it. But what about prescription drugs?

Prescription drugs are just as frequently abused – usually by people you would never expect – and can be just as lethal as illegal drugs. The abuse of pre-scription drugs has specifically been proliferating on college campuses. Sure, there’s not much of a black market here at Penn for so-called “chill” drugs such as Xanax and oxycodone, but at a tough Ivy League schools like ours, there’s one drug that is sought after more than any other: Adderall. And it’s becoming an epidemic. hISTORY

In 1887, Romanian chemist Lazar Edeleanu synthe-sized amphetamine for the first time.1 Along with other stimulant drugs like methylphenidate, amphet-amines are currently legally used to treat symptoms of attention-deficit hyperactivity disorder (ADHD). Symptoms of ADHD include difficulty with paying attention or following directions, as well as a tenden-cy to get distracted easily.2 Adderall, by far the most well-known ADHD medication, is a 3:1 mixture of the right-handed and left-handed isomeric salts of amphetamine: levoamphetamine and dextroamphet-amine. Due to its potential for abuse, Adderall is clas-sified as a Schedule II narcotic – the same category as cocaine and oxycodone. Despite the government’s attempts to control the dis-tribution of Adderall, diagnoses of ADHD are steadi-

BY TINA hSUANGELA LI/ GRAPHIC

ly increasing, along with a proportional increase in Adderall prescriptions.3 A study recently published in Pharmacotherapy showed that the number of pre-scriptions, as well as the number of college students taking Adderall without prescription, has increased significantly within the past five years.4 The popular-ity of the drug is due to its effects on concentration, focus, and memory. The accessibility of the drug fur-ther serves to increase its popularity. Chris (name has been changed to protect identi-ty), a student at Penn, sells Adderall pills for $10 to $20, depending on the dosage. According to Chris, a full bottle of the pills from the pharmacy only costs around $30, and students with access to Adderall prescriptions can easily make a sizeable amount of pocket change. Chris says that Adderall is one of the easiest drugs to sell at Penn, especially during exam season. hOW IT WORKS

Scientists are not completely sure how prescription ADHD drugs actually affect the brain. Ritalin, which contains methylphenidate as its active ingredient, has been shown to increase energy and focus by inhibit-ing the reuptake of norepinephrine and dopamine in the brain.5 Adderall, however, works a bit differently. Although Adderall is also a central nervous stimulant that acts by inhibiting the reuptake of dopamine in the brain, scientists think that Adderall may actually increase levels of dopamine in the brain by triggering its release.5 Dopamine is a neurotransmitter in the catecholamine and phenethylamine families released by neurons in the brain. This particular neurotrans-mitter is involved in several different cognitive sys-tems, including reward-motivated behavior. In other

MEdiciNE & SociEtY


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words, receiving a reward increases the level of dopamine in the brain. This is why drugs that act on dopamine levels in the brain, including stimulants like Adderall, are often addictive; they amplify the effects of dopamine, tempo-rarily increasing pleasure and happiness.

Though both amphetamine salts found in Adderall play a role in maintaining high levels of dopamine in the brain, dextroamphetamine in Adderall binds to the D1 and D4 reward pathways more tightly.6 On the other hand, levo-amphetamine tends to release dopamine through the D2 reward pathway, creating more cardiovascular and peripheral sensations in the body.6 Therefore, dextro-amphetamine creates less of an initial “high” but causes longer increases in focus and intelligence, while levo-amphetamine gives a sudden and intense euphoric rush. Together, Adderall’s patented mixture of salts causes the drug to have different and often more excitatory ef-fects than other ADHD drugs – another reason why it is abused so frequently. EFFECTS OF USAGE

An increased flow of dopamine to the prefrontal cortex allows the brain to process information more efficient-ly than it normally does. The prefrontal cortex is re-sponsible for executive function (e.g. decision-making, problem-solving, and moderating social behavior), and stimulating this region of the brain predictably causes in-creased alertness, wakefulness, and concentration. For most people living with ADHD, these drugs do ex-actly what they’re supposed to: create a sense of calm and allow life to go on without distractions. For others who don’t actually suffer from ADHD, Adderall over-stimu-lates the body and creates a “euphoric high.” In essence, Adderall is a form of “legal” speed, an illegal street drug

containing varying mixtures of amphetamine, caffeine, and sometimes cocaine.Drug-use, gambling, and even sex stimulate the same dopamine reward pathways as amphetamines, and like these vices, amphetamines are also extremely addictive. The same properties that make amphetamines addictive help increase concentration and productivity. The extra dopamine in the brain helps with focus, while the norepi-nephrine increases retention and learning.7 Because these chemicals also play a role in the body’s stress response, increased concentrations can lead to feelings of invinci-bility. Unfortunately, the positive effects of Adderall don’t last. There are plenty of negative physiological side effects of prescription stimulants such as increased blood pressure, heart rate, and body temperature.8 Short-term side effects

include stress, malnutrition, insomnia, and an inability to focus after coming off the drug. Other reported side effects include headaches, dry mouth, and nausea. Those who mix Adderall with alcohol are more susceptible to alcohol poisoning, since Adderall hides some of the common signs of inebriation. Both substances are dehy-drating, and the potential for migraines and chronic dry mouth is a possibility. In addition, long-term use of pre-

scription stimulants can also lead to insomnia and anorex-ia. In children, prolonged use of amphetamines can stunt growth and weaken bone development. Rare cases of Ad-derall abuse have led to a development of trichotillomania, an excessive skin- and hair-picking addiction.9 Adderall has also been shown to cause many cardiovascular complica-tions such as stroke when taken in unreasonably high doses. That’s not all, though. Those who abuse amphetamines also report a development of psychological problems, including depression, paranoia, and hostility.10 Chronic abuse may lead to a constant, schizophrenia-like psychosis, which includes daily hallucinations and visions. On top of that, the chance of addiction is very high, and dependence may be psychological or physical. From a physical standpoint, because Adderall causes long-term changes in the dopa-mine-controlled reward system in the brain, when the use of Adderall stops, dopamine levels in the brain drop sud-denly, triggering many withdrawal symptoms.11 Psycholog-ical dependence is also common; if drug-use becomes rou-tine, it may become a habit that is extremely hard to break, because users will begin to believe that they need the drug to function.

Although Adderall can improve learning and memory tem-porarily, it is unclear whether or not long-term Adderall use in students without ADHD actually increases memory and learning. Since students who take Adderall without a pre-scription obtain it illegally, all of the information regarding Adderall usage must be self-reported. This would require students to implicate themselves of illegal activity. Thus, the efficacy of Adderall in college students is almost impossible to measure, and it is hard to tell if Adderall has long-term benefits.

ALTERNATIVES

We all have those off-days, and alternatives for those look-ing for a boost in brainpower do exist. One option is taking a nootropic, a general class of drugs and supplements that have been reported to increase memory, intelligence, cog-nition, and concentration. They are also legal, inexpensive, and can be tolerated when taken long-term.12 A popular nootropic is piracetam, a derivative of the neurotransmitter gamma-aminobutyric acid, which has been shown to mod-ulate neurotransmission in cholinergic and glutamatergic systems, as well as increase neuroplasticity.13 In simpler

terms, piracetam has many physiological effects, which in-clude increased cognitive processing

If pills are out of the question, there’s always music. Focus@Will is an online website that streams “neuroscience-based music” to improve concentration. Listening to music at 60 beats per minute can increase neural activity by creating a relaxed, awake state in the brain known as the alpha state.14 Although there is not much scientific evidence for the ben-efits of music on concentration, it’s a start. Better yet, unlike Adderall, there are no side effects.

References

1. Donate Life America. (October, 2013). Organ Donation. In Donate Life America. Retrieved February 20, 2014, from http://donatelife.net/understanding-donation/organ-donation/.

2. U.S. Department of Health and Human Services. (n.d.). Donate the Gift of Life. In organdonor.gov. Retrieved February 22, 2014, fromhttp://www.organdonor.gov/index.html.

3. National Institutes of Health. (February 12, 2014). Organ Donation. In MedlinePlus. Retrieved February 21, 2014, fromhttp://www.nlm.nih.gov/medlineplus/organdonation.html.

4. National Organ Transplant Act of 1984, Title 42, Section 273.5. United Network for Organ Sharing. (2014). Common Myths. In UNOS. Retrieved February 19,

2014, fromhttp://www.unos.org/donation/index.php?topic=fact_sheet_7.6. Art Brownstein, The National Network of Organ Donors, personal communication, January

1, 2013.7. Mayo Clinic Staff. (May 3, 2013). Organ donation: Don’t let these myths confuse you. In

Mayo Clinic. Retrieved February 15, 2014, from http://www.mayoclinic.org/healthy-living/consumer-health/in-depth/organ-donation/art-20047529.

8. Johnson, E. J., & Goldstein, D. (2003). Do Defaults Save Lives? Science, 302, 1338-1339. doi: 10.1126/science.1091721

9. Dan Ariely. (May 5, 2008). 3 main lessons of Psychology. Retrieved March 17, 2014, from http://danariely.com/2008/05/05/3-main-lessons-of-psychology/.

10. Johns Hopkins Medicine: News and Publications. (November 29, 2011). Presumed Consent Not Answer to Solving Organ Shortage in U.S., Researchers Say. Retrieved March 17, 2014, from http://www.hopkinsmedicine.org/news/media/releases/presumed_consent_not_answer_to_solving_organ_shortage_in_us_researchers_say

11. Abadie, A., & Gay, S. (2006). The impact of presumed consent legislation on cadaveric organ donation: A cross-country study. Journal of Health Economics, 25(4), 599-620,http://dx.doi.org/10.1016/j.jhealeco.2006.01.003

12. Delmoinico, F. L., Arnold, R., Scheper-Hughes, N., Simnoff, L. A., Kahn, J., & Youngner, S. J. (2002). Ethical Incentives – Not Payment – For Organ Donation. The New England Journal of Medicine, 346(25), 2002-2005.

13. Arnold, R., Bartlett, S., Bernat, J., Colonna, J., Dafoe, D., Dubler, N., … Delmonico, F. L. (2002). Financial Incentives for Cadaver Organ Donation: An Ethical Reappraisal. Transplantation, 73(8), 1361-1367. doi:10.1097/00007890-200204270-00034

altHougH addErall caN iMprovE lEarNiNg aNd MEMorY

tEMporarilY, it iS uNclEar wHEtHEr or Not loNg-tErM addErall uSE iN StudENtS

witHout adHd actuallY iNcrEaSES MEMorY aNd lEarNiNg.

oNE optioN iS takiNg a Nootropic, wHicH HaS BEEN rEportEd to

iNcrEaSE MEMorY, iNtElligENcE, cogNitioN, aNd coNcENtratioN.

it iS alSo lEgal, iNExpENSivE, aNd caN BE tolEratEd wHEN takEN

loNg-tErM.


At the 2009 annual American Medical Association con-ference, President Obama extended a welcoming hand to physicians across the nation: “I need your help, doc-tors. To most Americans, you are the healthcare system. Americans—me included—just do what you recom-mend. That is why I will listen to you and work with you to pursue reform that works for you.”1 In other words, the public invests a great deal of confidence in medicine. As a matter of fact, physicians have more support from Americans than our president does in terms of recom-mendations for healthcare reform. From an anthropo-logical perspective, physicians possess all the qualities of a preeminent profession: autonomy, authority, prestige, and deference.2 For pre-medical students, medical stu-dents, residents in training, and attending physicians, the bedrock of all medical training is an appreciation of scientific knowledge, coupled with a collective orienta-tion toward societal needs.3 However, capitalistic and technological changes in our nation have largely caused

medicine’s de-professionalization. Further changes may have significant impact on the autonomy of the profes-sion. Thus, a sociological approach is useful to under-stand how physicians will react to changes in medicine that may challenge their position. ThE MEDICAL MARKETPLACE

A major premise of the field of medicine is “profession-al dominance.” A dominant profession is one that has achieved autonomy due to its distinct role and favorable results.3 Advances in healthcare after World War II in-creased dependence on doctors, a trend that continued throughout the nineteenth and twentieth centuries.4 During this “golden age of doctoring,” physicians held the reins of the entire healthcare system.5 However, “the golden age” soon became a literal adage; money started to bolster the healthcare industry. Revolutionary chang-es in pregnancy and birth control, the success of penicil-

Doctor Who: The Changing Profession of Medicine

lin, improvements in transplant surgery, and other medical advances—all results of increased medical spending—caused much excitement in the field of healthcare. On the other hand, this sparked the first backlash of medical capitalism. For example, trust in physicians decreased with the increase in medical expenditures from $250 to $650 billion between 1980 and 1990.6 Medical advancement and the emerging medical marketplace had introduced a new population of healthcare consumers; but with patient consumerism on the rise, people are starting to pay more attention to their spend-ing preferences than they have had in the past. This tendency remains true today. While citizens are able to pay for more health-related services, they are skeptical of the quality of care they are receiving.2

The prerogatives of capitalism and the medical marketplace have also introduced a means-end calculus thinking to phy-sicians by means of managed care, specifically health main-tenance organizations (HMOs). Physicians under HMO guidelines can no longer control the pricing of their medical services and instead work under the HMO’s guidelines.7 Driv-en by profits, physicians are forced to make decisions relative to quantity rather than quality. As a result, there is a gener-al societal belief that physicians are compromising the best interest of the patient for profits. Patients are losing sight of their physicians’ altruistic nature and developing distrust in healthcare.

A new reliance on technological diagnostic instruments is a byproduct of the medical marketplace. For example, an in-dividual no longer has to go to the doctor’s office to have his or her blood pressure checked; blood pressure can easily be monitored at home with simple blood-pressure cuffs. Phy-sicians are losing their autonomy and ability to self-regulate as technology begins to replace many of their skills. Loss of autonomy is a key characteristic of a profession headed to de-professionalize.

Moreover, an informational revolution has transformed the healthcare system by changing how much patients rely on doctors for treatment information. With the emergence of new communication parties, such as HMOs, medical inter-net databases, and online patient forums, patients have more access to information regarding the status of their health than they did when doctors were their sole trustees. In this sense, the information revolution gives the impression that the med-ical profession is headed for a diminished position. Patients generally rely on physicians to tell them how to get better, but this patient-physician dynamic is lost when patients can seek information and treatment elsewhere.8 When patients hold the same information as physicians, there is a decrease in the competence gap between patient and physician and “less mys-tique” surrounding the physician, as described by Professor of Sociology, Jason Schnittker, from the University of Pennsyl-vania. However, aspiring doctors of today are the voice of the technology generation, internet included. We have grown up in a capitalistic environment since birth, so the question we must ask ourselves is, will we use the medical marketplace to our advantage or disadvantage?

Physicians respond to medical capitalism and technology

BY SEEMA PATEL

SAHIL DOSHI/ GRAPHICSOURCE: GALLUP

VICKY RO/ GRAPHICSOURCE: 1976 AMCUS & 1988 GSS


My experiences with the quantified self

Is self-tracking the future of healthcare?

BY SUMUN KhETPAL

I woke up this morning at 7:13AM, and given that it was midterm week, I had gotten a mere five hours and six minutes of sleep. Plus, according to Ari (my trusty Siri-like coach on the OptimizeMe iPhone app), my quality of sleep plummeted to a value of 40%. A seven-day data collection revealed my average heart rate to be 72 beats per minute, and my blood pressure, 116/73. I had spent an average of 33 minutes per day on exercise and took an average of 6608 steps—a total of 3 miles--daily.1 Each time I logged an activity, the black pixelated oval-shaped face and yellow dotted eyes would come to life on my iPhone screen. My digital doctor, Ari, would greet me and prescribe suggestions like, “Go for a run today” and also would ask questions like, “How many glasses of water have you had today?” or “What are you doing next?”

Started in 2007 by Gary Wolf and Kevin Kelly at Wired Magazine, the quantified self (QS) is a movement that aims to connect health data technology to self-improvement in hopes of bolstering preventative care and healthy life behaviors among Americans. An extension of running logs, travel journals and personal diaries, the movement lies on the premise of turning the quest for data information inward and into our own bodies. Imagine a world where we rarely visit the doctor’s office. Instead, we would track health behaviors and measurements via smartphone apps, accelerometers and pedometers. We would listen to the recommendations of a remote source, and we would possibly even self-treat. The system operates through a feedback loop—data is pooled among many individuals, analyzed by the comp-bio aficionados, and returned to us in the form of recommendations and risk alerts. Consider the progress we have already made: in a mere fifteen years we sequenced the entire human genome through the Human Genome Project. We now analyze trends quickly. We can pinpoint sources of disease. We can take preventative measures. More recently, at this past January’s Consumer Electronics Show in Las Vegas, there was a huge buzz about smart watches and their role as health-monitoring devices. Analysts were most excited about FitBit and Samsung’s recent Gear2 not only as 2014’s most fashionable hand accessories, but also as convenient health monitors.2 Clearly, the quantification of our genetic information has the ability to revolutionize the world’s health.

Is self-tracking the future of healthcare?Given its potential, it might be. But we are not quite ready yet.

References 1. News. (n.d.). Text: Obama’s AMA Speech On Health Care - CBS News. Breaking News

Headlines: Business, Entertainment & World News - CBS News. Retrieved October 13, 2013, from http://www.cbsnews.com/stories/2009/06/15/politics/main5090277.shtml

2. Wolinsky, F. (1993). The Professional Dominance, Deprofessionalization, Proletarianization and Corporatization Perspectives: An Overview and Synthesis. London: Oxford University Press.

3. Timmermans, S., & Oh, H. (2010). The Continued Social Transformation of the Medical Profession. Journal of Health and Social Behavior, 51, S94-S102. Retrieved September 28, 2013, from http://hsb.sagepub.com/content/51/1_suppl/S94

4. Quadagno, J. (2004). Physician Sovereignty and the Purchasers’ Revolt. Journal of Health Politics, Policy, and Law, 29, 822–834. Retrieved September 28, 2013, from http://jhppl.dukejournals.org/content/29/4-5/815.citation

5. McKinlay, J., & Marceau, L. (2002). The End of the Golden Age of Doctoring. International Journal of Health Services, 32, 379-416. Retrieved September 28, 2013, from the PubMed database.

6. Cutler, D., & McClellan M. (2001). Is Technological Change in Medicine Worth It? Health Affairs, 20, 11-29. Retrieved September 28, 2013, from http://content.healthaffairs.org/content/20/5/11.full

7. Scott, W., Ruef, R., Mendel, P., & Caronna, C. (2001). Institutional Change and Healthcare Organizations: From Professional Dominance to Managed Care. Chicago, IL: University of Chicago Press.

8. Blumenthal, D. (2002). Doctors in a Wired World: Can Professionalism Survive Connectivity? The Milbank Quarterly, 80, 525-530. Retrieved September 28, 2013, from the American Medical Association database.

9. Henwood, F., Wyatt, S., Hart, A., & Smith, J. ‘Ignorance is Bliss Sometimes’: Constraints on the Emergence of the ‘Informed Patient’ in the Changing Landscapes of Health Information. Sociology of Health and Illness, 25, 589–607. Retrieved September 28, 2013, from http://onlinelibrary.wiley.com/store/10.1111/1467-9566.00360/asset/1467-9566.00360.pdf?v=1&t=hm7a54v5&s=1f5a88f429d8495c55aa5127f2dc07c68b35c5d6:

RE-PROFESSIONALIZATION

Despite what has been presented about the changing profession of medicine, re-professionalization is possi-ble. Reliance on the Internet for support does not indi-cate a complete turn away from medical care but rather reveals a desire for up-to-date information.9 Professor Schnittker comments that, “Americans want informa-tion related to their health and seek it online, but they also get a lot from old sources like family and friends, and at the end of day they go to a doctor. Patients won’t even talk about the information they have gathered and instead listen to what their physician has to say. They rely on the expertise and wisdom of physicians.” That is, data is not knowledge; despite all the information pa-tients have at their disposal, they still do not understand how their bodies work. Physicians will remain the sole decision analysts, but to remain relevant, doctors should respond to patients’ desire for updated information and thus use new sources of information, like web-data sites and technological devices. This is beneficial to the gen-eration of doctors who will likely emerge with the infor-mation revolution. For those aspiring doctors who may now feel uneasy about their future careers, rest assured because there is still a lot to say about individuals’ beliefs regarding their own doctor. Virtually everyone has faith in his or her personal physician. In places where the presence of the medical marketplace is heavy (i.e. HMOs), physicians might be more driven by practice guidelines rather than by altruistic care. For that reason, HMO enrollees trust their physicians a little less than the patients of tradi-

VICKY RO/ GRAPHIC

tEcHNologYtional doctors do. However, this number is still under half of all HMO enrollees.

A fair argument is that physicians are assimilating new and additional roles in medicine, but the profession still stands. For young scholarsin the fields of medicine and healthcare, it is important to separate one’s ideas about the institution of medicine as a whole from what one believes makes a great physician, because more often than not, patients are willing subscribers to what their physician has to say.

WIKIMEDIA/ PHOTO


References

1. Wolf, G. (2009, June 22). Know Thyself: Tracking Every Facet of Life, from Sleep to Mood to Pain, 24/7/365. Wired.com. Retrieved March 8, 2014, from http://www.wired.com/medtech/health/magazine/17-07/lbnp_knowthyself?currentPage=all

2. Blakeway, L. (2014, January 20). A Growing Role in Health Care for Smartwatches. The New York Times. Retrieved March 8, 2014, from http://www.nytimes.com/2014/01/21/fashion/a-growing-role-in-health-care-for-smartwatches.html

3. Khetpal, V. (2014, January 31). The Rise of Homo Auxilium?. The Huffington Post. Retrieved March 8, 2014, from http://www.huffingtonpost.com/vishal-khetpal/the-rise-of-homo-auxilium_b_4697927.html

4. Rekhi, R. (2013, December 4). A government ban on 23andMe’s genetic testing ignores reality. theguardian.com. Retrieved March 8, 2014, from http://www.theguardian.com/commentisfree/2013/dec/04/23andme-consumer-genomics-fda-ban-regulation

5. Dockterman, E. (2013, November 18). Experts Warn New Cholesterol Calculator Doesn’t Add Up | TIME.com. Time. Retrieved March 8, 2014, from http://healthland.time.com/2013/11/18/experts-warn-new-cholesterol-calculator-doesnt-add-up/

6. Counting every moment.. (2012, March 3). The Economist, Q1 2012. Retrieved March 8, 2014, from http://www.economist.com/node/2154849

VICKY RO/ GRAPHIC

Over two hundred QS iPhone applications have surfaced from the movement. Perhaps the most promising is the Zurich, Switzerland-based OptimizeMe, a life logging application that helps users assess their health behaviors. The app was recently launched in mid-January of 2014 and allows users to log their daily activities from four main categories---pleasure, routine, health, and creativity—and further select from multiple subcategories, including gym, personal care, and special event. OptimizeMe provides the services of multiple QS apps and even integrates Moves, an automatic activity tracker. Thus, it would seem that usability and favorability towards the app is high among users. Perhaps the QS movement is the reality of 2014. Maybe OptimizeMe is the app that we will all be using, sooner or later. So I decided to try out OptimizeMe and see for myself.

The app setup was quite straightforward, but that’s where the ease of use ended. Firstly, I realized the process of quantifying oneself is time-consuming, inconvenient, and quite daunting of a task. Imagine recording each and every activity of your day, whether eating, sleeping, showering, or studying. But are the results even worth the time? Here are my results after my seven-day data collection, my personal week-long quantification of self: “your time spent on routine correlates positively with your time spent of health. To improve one of these parameters, try to increase the other one. But be cautious--the cause may be neither of the two.” The results seem expected and somewhat uninteresting, but it is too early to judge the value of in-app analyses. Within a few months, we can hopefully expect complex analyses with more extensive logs and more developed algorithms to advise OptimizeMe users and instill better health behaviors.

Second, the problem exists in our growing dependence on technology, and particularly, technology’s disruption of today. In order to attain accurate and useful results, I found myself bound to my smart-phone, perpetually reminding myself to log every minute and hour of the day. The robot-like Ari was a virtual mentor that instilled positive health behaviors in my daily routine, but contributed to my isolation from my classmates and professors. The application viewed me as a specimen, defined by numbers, frequencies and time-frames. My identity was data-driven, so was my life for that week. One Huffington Post article, titled “The Rise of Homo-Auxilium (the aided man),” articulates that QS has an astounding potential to improve humanity’s health, but notes that we must remember humanity itself. Our society has developed an addiction to data, such as defining its members with test scores, IQs, take-home salaries and hometown zip codes.3

Third, a problem resides in assuring the accuracy of the data itself. For the QS movement to take off, companies must avoid inaccuracies in the collection of the data information. Consider 23andme, a startup that used to run complete DNA sequences for individuals and generate their disease risk profile. With this information the patient can alter his or her health behaviors and perhaps even evade the proposed imminent diagnosis. Imagine how much money the American government would save if people prioritized preventative care. Unfortunately, this past November, 23andme was shut down due to potential false positives and negatives that mislead consumers and ultimately

caused them to allocate more money to unnecessary tests and procedures.4 Moreover, in a recent article in Time Magazine, American cardiologists were quite overwhelmed when they learned that a recently-designed heart risk calculator over-predicted risk by 75 to 150 percent. Specifically, physicians do not treat patients with 4% risk or less, consider treatment for 5% risk level and advise treatment for those with at least 7.5% risk for heart disease.5 Patients who used the calculator were overwhelmingly placed in the high-risk category--a misrepresentation that, if relied upon, would lead to an over-prescription of statins. In that case, the QS movement would be doing exactly what it aspired not to do: increase spending.

Glitches aside, The Economist article “Counting thyself ” contends that the quantified self will proceed through 2014 and shape the future of healthcare. Today, self-tracking may seem geeky, but soon, the rest of us will do what the geeks are doing.6 Of course, QS needs to address the usability and practicality of apps like OptimizeMe and account for the inaccuracies in the 23andme and risk calculators. Then, maybe, Ari and 23andme will be my doctors, OptimizeMe will be my go-to app, FitBit will be my most fashionable hand accessory, and the quantified self will record my reality.

Despite the rapid popularization of the field of neuroscience, there is very little known about the brain’s physiological properties. Most information about the brain has been obtained by invasive technology that requires dividing the organ into smaller tissue samples.1 Beyond this knowledge, the brain as a holistic organ and cognitive model has lain beyond our reach—until now. Luckily, in April 2013, researchers at Stanford University in Palo Alto, Ca. developed a neuroimaging technology, CLARITY, which facilitates brain observation by rendering the entire organ see-through. The team of diverse specialists, led by bioengineer and psychiatrist Dr. Karl Deisseroth, “clarified” a mouse brain by selectively removing its lipid molecules, which block the entrance of light in microscopy.2

The operation takes place in three main steps. First, experimenters must petrify the molecules they want to observe. This is accomplished by infusing the specimen with a hydrogel (gel-like substance with water molecules); when heated, gel particles bond covalently with the target molecules, including neurotransmitters, proteins, and nucleic acids. Then, the brain is immersed in a detergent solution containing ionic molecules that cluster around each lipid molecule. Finally, an electric current is passed through the organ. Because these ions have a net charge, they will move in the direction of the terminal with opposite charge, dragging the lipid molecules with them as they exit the brain.1

CLARITY has an advantage over previously used imaging methods in that by studying the brain in its entirety, we can discover important nuances that are undoubtedly overlooked when breaking it down into sections.3To understand this logic, imagine being faced with the task of analyzing how a car works. You would need to piece together how its different components, such as the engine, cooling system and fuel supply, work together. However, you cannot divide the car into its functional parts without initially knowing the delineations of each component. Analogously, neuroscientists cannot break the brain down into specialized regions of tissue when they do not truly know which clusters of cells participate in any given task.3,4 Researchers have historically tried to avert this obstacle through employment of more advanced microscopy or

BY AFRAh MOhAMMAD

Reimaging the BRain

with CLARITY

finer sectioning tools. Still, CLARITY’s precision, achieved through targeting of specific types of molecules, is unmatched by any other imaging system.

CLARITY has unique medical potential in the area of “molecular phenotyping,” or investigating the relationship between form and function of brain cells—particularly in the area of disease mechanisms. For one, it could enable access to a treasury of morphological attributes of tissue cells themselves (size, shape, span, and so on). In another approach, molecular markers (dyes) could be injected into the

brain to highlight neural circuits. This has clinical relevance because researchers can study brain circulation to understand how diseases proliferate or develop a strategy of where to insert certain antibodies. For example, a species of virus prepared with green fluorescent protein (GFP) will label the set of neurons that participate in exhibiting the sickness.1

Naturally, being a recent development, CLARITY

claritY HaS aN advaNtagE ovEr prEviouSlY uSEd iMagiNg MEtHodS iN tHat BY StudYiNg tHE BraiN iN itS ENtirEtY, wE caN diScovEr iMportaNt NuaNcES tHat arE uNdouBtEdlY ovErlookEd wHEN BrEakiNg it dowN iNto SEctioNS.

WIKIMEDIA / GRAPHIC

http://www.bibme.org./



























Scientists infuse the specimen with hydrogel monomers (simple organic molecules that, along with water, constitute a swollen gel). When researchers heat and add formaldehyde to the sample, these particles bond covalently with the molecules in the brain that we want to preserve: neurotransmitters, proteins and nucleic acids.

References

1. Chung, K. & Deisseroth, K. (2013, May 30). CLARITY for mapping the nervous system. Nature Publishing Group. Retrieved October 1, 2013, from http://www.nature.com/nmeth/journal/v10/n6/full/nmeth.2481.htmlhttp:///h

2. Myers, A. (2013, April 10). Getting CLARITY: Hydrogel process discovered at Stanford creates transparent brain. Stanford University School of Medicine. Retrieved October 1, 2013, from http://med.stanford.edu/ism/2013/april/clarity.html

3. Ward, J. The Student’s Guide to Cognitive Neuroscience (2nd ed.). United Kingdom: Psychology Press.

4. Bear, M. F., Connors, B. W., & Paradiso, M. A. (2007). Neuroscience: Exploring the Brain (3rd ed.). Philadelphia, PA: Lippincott Williams & Wilkins.

5. Caprette, D. (2012, November 18). Introduction to SDS-PAGE. Rice University—Web Services. Retrieved October 1, 2013, from http://www.ruf.rice.edu/~bioslabs/studies/sds-page/gellab2.html

6. Freeman, S., & Hamilton, H. (2011). Biological Science (4th ed.). Upper Saddle River, N.J.: Pearson Prentice Hall.

tHE BiocHEMiStrY of How CLARITY workS:

Via this mechanism, researchers can now selectively evacuate lipids from the sample while leaving the rest of the tissue intact. When exposed to an electric current in a process called electrophoresis, the charged heads exposed in each micelle will flow in the direction of the region with opposite charge. The detergent used in CLARITY is anionic, meaning it exhibits a net negative charge; consequently, it is attracted to the positive terminal. As these molecules exit the brain, they carry the rest of their micelles–including the lipid molecules–with them.1

The brain is then immersed in an ionic detergent.5 The structure of ionic detergents directly enables their function. Each detergent molecule consists of a hydrophilic (charged, or polar) “head” and a hydrophobic (uncharged, or nonpolar) “tail.” Lipids are hydrophobic; thus, when exposed to the solution, the detergent’s tails cluster around each lipid molecule, forming a sphere that exposes the heads to a surface in a structure known as a micelle.5,6

StEp1:

StEp3:

StEp2:

What Can Poop Do For You?

BY LINDA WANG

The notorious poop transplant has gotten a makeover with the advent of poop pills. Packaging bacteria derived from human stool into neat little capsules allows for much tidier consumption than do the enemas, feeding tubes, and colo-noscopies used in traditional fecal microbiota transplanta-tion (FMT). However, the mission remains the same - to transfer beneficial human gut bacteria from one person to another. FMT emerged as a promising therapy for diseas-es that involve imbalances in the gut microbiome, which consists of the natural flora of the intestines, and is best known for an astonishing success rate in treating infec-tions from the bacterium Clostridium difficile.1 Now that the first poop pills have been administered with success to C. difficile patients, testing fecal microbiota transplan-tion’s effects on inflammatory bowel disease (IBD) could become easier.2 For as many as 1.4 million sufferers, FMT provides the hope of a cure from IBD, and it’s treatment potential makes it paramount to further identify the in-teractions between the intestinal microbiota and the host immune system.3,4

LINKING IBD AND GUT BACTERIA

Inflammatory bowel disease affects about 0.5% of the adult population in the U.S. and is considered an autoimmune disease because of how the body’s immune system attacks its own healthy tissue.3 This lifelong disorder is marked by chronic inflammation of the intestine and, depending on the location and manner of inflammation, is usually diag-nosed as either ulcerative colitis or Crohn’s disease. Both types of IBD are associated with an increased risk of colon cancer. There is currently no cure for IBD, and it is hy-pothesized that the chronic inflammation partially stems from unbalanced microbe populations in genetically sus-ceptible individuals.5 One line of evidence is the decreased diversity in the intestinal microbiota of IBD patients com-pared to that of healthy individuals. Furthermore, most of the genes associated with IBD involve microbe recogni-tion and barrier function in the intestinal mucosa. Cur-rent treatments are used to suppress patients’ inflamma-tory response, which unfortunately often opens the door to opportunistic infections that a healthy immune system would normally fight off.4

WIKIMEDIA/ GRAPHIC

is still a diamond in the rough. While about 92 percent of the mass we want to study remains in the brain after the operation, researchers are looking for ways to conserve the remaining eight percent. Furthermore, several species of proteins do not adhere to the hydrogel mesh. It is widely acknowledged, however, that this technology is a quantum leap in the direction of crystal-clear neuroimaging, or clarifying the brain’s most densely obscured mysteries.

Pill-based fecal transplant as a cure for gut infections

WIKIMEDIA/ GRAPHIC

INTERACTING hOST IMMUNE SYSTEM AND GUT BACTERIA

Suppressing the immune system only addresses a branch of the issue, while the roots of IBD development remain entangled in a cyclical question: does the disease cause imbalances in the microbiome or do these imbalances drive the disease? Proper development of the immune system itself requires the presence of the microorganisms that have co-evolved with us. More than 100 trillion mi-croorganisms dwell in the human gastrointestinal tract, and the majority of these species belong to the bacterial phyla Firmicutes and Bacteroidetes.5 Complex interac-tions take place between the microbiota, the intestinal epithelium, and the host immune system. For instance, Bacteria make products that bind to receptors on the in-testinal epithelial cells to promote homeostasis and tissue repair. In turn, the host has to recognize these bacteria, distinguishing the good ones from the bad.6 In one fas-cinating interchange, Bacteroides fragilis and some sub-groups of Firmicutes induce cells of the human immune


to simulate real life.8 Thus, development of ABMs require understanding the model’s mathematical mechanisms and reliance on experimental data for calibration before achieving further understanding.

Many of these applications, especially the larger projects, require massive processing power. Through the advents

of cloud computing and parallel processing, thousands of computers over the world can collaboratively simulate and parse through much more massive datasets than were ever previously possible, even with the most powerful supercomputers. This advancement is particularly relevant to areas of bioinformatics that involve application of statistical analysis to millions of data values to extract new information.9 This process has become increasingly parallelized, which facilitates understanding of much larger datasets.

Computer science and medicine should no longer be treated as separate subjects. The intersection of these two fields opens access to unexplored territory for designers of and participants in healthcare.

system to reduce inflammation of the colon.6,7 IBD pa-tients were found to have reduced levels of Firmicutes and Bacteroidetes, which means they lose the anti-inflamma-tory benefits of these bacteria.8 Simultaneously, inflam-mation allows pro-inflammatory bacteria to invade, cre-ating a cycle where cause and effect are hard to study..5 But knowledge continues to grow, since most of the studies in this field have only been made possible during the last ten years by advances in genetic sequencing.

PROMISING EFFECTS OF FMT

Testing fecal microbiota transplantation in inflammatory bowel disease is a bold leap over the intricacies of these relationships. Although still in the early stages of research, FMT has shown promising effects on IBD. In 17 differ-ent studies, the most recent of which was conducted in 2012, 76% of IBD patients studied had partial or complete reduction of symptoms. These patients were taken off of their IBD medications. Interestingly, 86% of patients who had been unresponsive to IBD medications prior to receiving FMT responded to IBD medication after the treatment.9 A review summarizing the results of nine IBD patients treated with fecal enemas reported that all nine patients were subsequently symptom-free for anywhere from three months to 13 years.4 With limited knowledge of the mechanisms behind these successes, FMT operates as a sort of magic mix. It might be called an admission of ignorance, founded on a need to restore balance by some-how manipulating the multitude of tiny creatures living within the gut.

LOOKING TO ThE FUTURE

Understanding the interactions between the gut microbi-ome and the host immune system becomes increasingly

References:

1. Roach, J. (2013, September 24). Teens face down flu viruses, energy crises in winning Google Science Fair entries. NBC News Science. Retrieved September 25, 2013, from http://www.nbcnews.com/science/teens-face-down-flu-viruses-energy-crises-winning-google-science-4B11246371

2. Computer & Information Science. (n.d.).Computer & Information Science. Retrieved September 25, 2013, from http://www.cis.upenn.edu/ugrad/Computational_Biology.shtml

3. Computer Modela May Give Longer Life To Joint Replacements. (n.d.). Medical News Today: Health News. Retrieved September 25, 2013, from http://www.medicalnewstoday.com/articles/263025.php

4. Rosenfeld, L., Fox, C., Kerr, D., Marziale, E., Cullum, A., Lota, K., et al. (2009). Use of computer modeling for emergency preparedness functions by local and state health officials: a needs assessment.. Journal of Public Health Management and Practice, 15(2), 96-104. Retrieved September 25, 2013, from http://www.ncbi.nlm.nih.gov/pubmed/19202407

5. Kirkpatrick, S., Gelatt, C. D., & Vecchi, M. P. (1983). Optimization By Simulated Annealing. Science, 220(4598), 671-680.

6. Forrest, S. (1993). Genetic Algorithms: Principles Of Natural Selection Applied To Computation. Science, 261(5123), 872-878.

7. Poli, R., Kennedy, J., & Blackwell, T. (2007). Particle Swarm Optimization.Swarm Intelligence, 1(1), 33-57.

8. Ausk, B., Gross, T., & Srinivasan, S. (2006). An Agent Based Model For Real-time Signaling Induced In Osteocytic Networks By Mechanical Stimuli. Journal of Biomechanics, 39(14), 2638-2646. Retrieved September 25, 2013, from http://dx.doi.org/10.1016/j.jbiomech.2005

9. Olman, V., Fenglou Mao, Hongwei Wu, and Ying Xu. “Parallel Clustering Algorithm For Large Data Sets With Applications In Bioinformatics.” IEEE/ACM Transactions on Computational Biology and Bioinformatics 6.2 (2009): 344-352.

cHEN’S proJEct iS But oNE potENtial applicatioN of

coMputEr-ModEliNg to iMprovE patiENt HEaltHcarE.

References

1. Aleccia, JoNel. (2013, Oct 3). Poop pills are latest way to cure dangerous C. diff. infections, new study shows. NBC News. Retrieved from http://www.nbcnews.com/health/poop-pills-are-latest-way-cure-dangerous-c-diff-infections-8C11300066.

2. Brandt L. & Aroniadis, O. (2013, Aug). An overview of fecal microbiota transplantation, tech-niques, indications, and outcomes. Gastrointestinal Endoscopy, 78, 2, 240-249. Retrieved from http://dx.doi.org/10.1016/j.gie.2013.03.1329http://dx.doi.org/10.1016/j.gie.2013.03.1329

3. “What are Crohn’s & Colitis?” Crohn’s & Colitis Foundation of America. Retrieved from http://www.ccfa.org/what-are-crohns-and-colitis/.

4. Damman, C, Miller, S, Surawicz, C, & Zisman, T. (2012).The microbiome and Inflammatory bowel disease: Is there a therapeutic role for fecal microbiota transplantation? American Journal of Gastroenterology 107, 1452–1459. doi:10.1038/ajg.2012.93

5. Kaser, A, Zeissig, S, & Blumberg, R. (2009). Inflammatory bowel disease. Annual Review of Immunology. 28, 573-621. DOI: 10.1146/annurev-immunol-030409-101225.

6. Abreu, M. (2010, Feb). Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nature Reviews: Immunology. 10, 2, 131-44. doi: 10.1038/nri2707.

7. Round JL, Lee SM, Li J et al. (2011). The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–7.

8. Sokol H, Seksik P, Furet JP et al. (2009). Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflammatory Bowel Disease. 15, 1183–9.

9. Anderson, JL, Edney, RJ, & Whelan, K. (2012). Systematic review: faecal microbiota transplan-tation in the management of inflammatory bowel disease. Aliment Pharmacological Therapy, 36, 503–516.

10. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, Benchimol EI, Panaccione R, Ghosh S, Barkema HW, Kaplan GG. (2012, Jan). Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 142, 1, 46-54. doi: 10.1053/j.gastro.2011.10.001.

11. Wu, G. (July 2013). Personal interview.

Several projects submitted to this year’s Google Science Fair, an international competition to discover some of the most robust research by teenagers, manifest the increasingly important role that computer modeling plays in the field of healthcare. The winner, Eric Chen, developed a computational model to facilitate development of medicine to treat the flu virus, a disease with several strains that have the potential to evolve into a global pandemic.1 His paradigm includes a three-dimensional computer model of the influenza virus, along with information about five hundred thousand chemicals to determine which substance would be most effective in countering the flu, according to the biochemistry and structure of the virus. The resulting model dramatically cut the number of chemicals to be tested from half a million to two hundred and thirty-seven. From this point, it is relatively easy to conduct further testing of this final list of chemicals to arrive at the best possible antivirals, a process that Chen has also undertaken.

Chen’s project is but one potential application of computer-modeling to improve patient healthcare, ease the lives of physicians, and accelerate the development of new medicines by chemists, biochemists, and other research scientists. This growing importance is also demonstrated within the Penn community itself by the offering of the computational biology major through the School of Engineering and the College of Arts and Sciences, a confluence of the computer science and biology departments.2

Modeling’s uses extend to not only enhancing medicine but also surgical applications. For instance, researchers at the University of Southampton have invented an XML computer model that uses patient information to design artificial joints and also includes new surgical options for surgeons to better fit these joints, which could increase their lifespan and performance and reduce recovery time.3 Additionally, public healthcare officials can capitalize on other computational models to understand and prepare for various scenarios.4

These models take different forms, including dynamic models that change in response to input, stochastic (probability) models, and agent-based models (ABMs) that simulate individual components (agents) within a larger system. An ABM is based on known mathematical models of important interactions among the agents to form a preliminary model. These results are then compared to experimental data, which can lead to reparametrization of the model should it fail

Computer Modelingin Healthcare

BY TEjAS NARAYAN

urgent as IBD prevalence increases across the globe.10 Dr. Gary Wu, who conducts research on the gut microbiota at the Perelman School of Medicine, touched upon the hygiene hypothesis by pointing out that “we live in a dif-ferent world compared to several decades ago. We have a sanitized environment, we use food additives, even refrig-erating food can make a difference.” He agreed that stool is currently being used because there is “no better way,” but the goal is to engineer a “defined consortia” of mi-croorganisms that can be administered to patients.11 Poop pills allow for easier delivery of the gut microbes with less of the nonessential poop components, but the price tag and number of pills required per treatment, two to three dozen, are still high.1 Perhaps one day, natural probiotics such as this will be as recognized and accepted as synthet-ic vitamins are now. In the meantime, poop pills should make testing fecal bacterial therapy more feasible.

There is currently no cure for iBD, and it is hypothesized that the chronic inflammation partially stems from unbalanced microbe populations in genetically susceptible individuals.

76% of IBD patients studied had partial or complete reduction of symptoms.

86% of patients who had been unresponsive to IBD medications prior to receiving FMT responded to IBD medication after thetreatment.

VICKY RO/ GRAPHIC


References:

1. FIRE, A., XU, S., MONTGOMERY, M. K., KOSTAS, S. A., DRIVER, S. E., & MELLO, C. C. (1998). Potent and specific genetic interference by double- stranded RNA in Caenorhabditis elegans.

2. Coelho, T., Adams, D., Silva, A., Lozeron, P., Hawkins, P. N., Mant, T., … Suhr, O. B. (2013). Safety and Efficacy of RNAi Therapy for Transthyretin Amy-loidosis. New England Journal of Medicine, 369(9), 819–829. doi:10.1056/NEJMoa1208760

3. Cheng, K. (2011, November 07). The future of rnai-based drugs: antisense therapy or nonsense?. Retrieved from http://www.oxbridgebiotech.com/review/research-and-policy/the-future-of-rnai-based-drugs-antisense-therapy-or-nonsense/

4. Paul et al, NRDD, March 2010; Eichler, EMA

The final distinct advantages of RNAi over traditional drugs are opportunities to treat many new and/or poorly treated current drug targets. Because it is easier to design a unique short siR-NA molecule to silence mRNA than to design a unique mole-cule to act on each unique protein, almost any protein becomes a “druggable” target. This property gives RNAi the ability to target many “undruggable” proteins with inaccessible binding sites that traditional drugs cannot target. Since RNAi is a nat-ural defense against viruses, a treatment strategy against virus-es such as HBV, HCV, and HIV could be helping to activate the RNAi process against the viruses by introducing siRNAs against key viral RNAs. ALN-RSV01, a potential treatment for respiratory syncytial virus, is an example of a prospective treatment utilizing this strategy. Cancer, in which many genes are abnormally overexpressed and with current treatments having high toxicity and off-target effects, is another potential application of these processes. Many genetic diseases such as Duchenne muscular dystrophy are actively being targeted as well. In summary, RNAi treatments are potentially more effi-cacious, durable, safe, and bear higher development potential than conventional small molecule therapies.

ChALLENGES AND ThE FUTURE OF RNAi ThERAPY

The biggest challenge for converting our knowledge of RNAi into a safe therapy for humans has been delivery. siRNA mole-cules are negatively charged and cannot cross into the cell’s lip-id bilayer by themselves. In the past few years, vastly improved siRNA delivery technology that has significantly increased the uptake of siRNA into cells. The two primary methods in-volve the use of lipid nanoparticles (LNPs) and conjugation. LNPs enclose the charged siRNAs, enabling them to cross the cell membrane to subsequently induce RNAi. Conjugates are siRNAs attached to another molecule with properties that pro-mote uptake by cells. For example, the GalNAc-siRNA conju-gate developed by Alnylam Pharmaceuticals is a novel way to deliver siRNAs specifically to the liver. GalNAc, a derivative of the sugar galactose, is specifically favored for uptake by the liver, so a molecule attached to it (such as an siRNA) tend to follow along with it into the cell.

Though RNAi therapy continues to have many challenges, its future in treating human disease is bright. RNAi companies have progressively become more focused on targeting specific organs and disease groups, a sign that the field is confident the technology is ready.3 Alnylam’s GalNAc platform targeting the liver has enormous potential because of the large number of known diseases associated with liver function. In 2011, Alnyl-am expressed confidence in this platform, announcing goals to have 5 drugs in the clinic by 2015, most of which are based on GalNAc-siRNA conjugates targeting the liver. In September 2013, Alnylam announced Phase I results for its TTRsc treat-ment based on the GalNAc platform, demonstrating robust, consistent, and statistically significant knockdown of the TTR protein up to an impressive 94%. The treatment was well tol-erated with no major adverse side effects. If approved, TTRsc would be a landmark in the battle against a rare and fatal genet-ic disease called familial amyloidotic cardiomyopathy (FAC)

Welcoming the Age of Gene

With many of the low hanging fruits in the small molecule drugs space (chemical entities with molecular weights under 900 dal-tons) picked clean, there is a dire need for new types of drugs to fill the innovation gap. With potential to follow the same path of biologics in the 1990s and 2000s, RNAi (Ribonucleic Acid interference) is a promising therapeutic drug class poised to meet some of the most chal-lenging problems in medicine. Most diseases are caused by too much or too little of a protein. Unlike small molecules that target proteins after cells produce them, RNAi targets mRNA, the genetic messenger which instructs protein produc-tion. By interfering with the production of proteins, RNAi directly addresses the underlying cause of certain diseases. Prom-ising RNAi treatments have made considerable progress in clinical de-velopment, with thousands of patients awaiting their results. Many of these pa-tients are at the end stages of life-threatening dis-eases, and have no treatment options left. The success-ful treatment of these patients would represent an important milestone in validating of the power of RNAi.

WhY IS RNAi SO ExCITING?

Andrew Fire and Craig Mello first observed the RNAi mechanism in animals, and pub-lished their findings in 1998. Fire and Mello found that introduction of dou-ble stranded RNA into C. elegans worms caused “potent and specif-ic interference” of gene expression at the RNA level.1 In the context of the Central Dogma of Molecular Biolo-gy where DNA is transcribed into RNA and then translated into protein, the mechanism was dubbed “RNA interference” because it interfered with the RNA to protein translation process.

BY jULIAN PEI

RNAi was later found to be a natural defense mechanism against viral attacks in many organisms, including humans. Viruses hijack cellular machinery to make copies of themselves by us-ing their own DNA as instructions for making proteins. RNAi defends against this attack when the host cell produces “short

interfering RNA” (siRNAs) that recognize and interfere the viral RNA after it is transcribed, effectively sup-

pressing production of the virus by the cell.

RNAi therapy takes advantage of this innate mechanism in the body. Scientists realized that if they could deliver artificial siRNAs into cells, they could silence specific genes of their choosing. Studies confirmed that in primates and humans that the mechanism

not only works, but also has extraordi-nary efficacy, with target RNA levels

knocked down as much as 85 to 95%.2 Because RNAi destroys the specific

RNA before it can be used to pro-duce protein, it directly reduc-es the target protein levels. This mechanism of action is potential-ly more effective than traditional therapies that act on proteins after they have already been produced, which must be constantly removed as to avoid dangerous accumulation. What makes RNAi an even more unique therapy is that since the drug itself is an siRNA mole-cule, which are naturally found within cells, the cell does not

immediately attempt to destroy the drug. This property gives RNAi

therapy advantages in being fairly safe and long lasting. The knockdown in

protein expression after one injection of RNAi treatment can last up to weeks, which

saves trips to the hospital. A few known dan-gers of RNAi are simply irritation at the site of

injection and possible off target effects, which are small concerns when compared with the dangers of

fatal illnesses.

WIKIMEDIA/ GRAPHIC

that affects at least 40,000 people worldwide and has no effective treatments. For diseases like FAC, so long as we know its gene tar-get in the liver, GalNAc based RNAi theoretically can treat it. With the recent advances in delivery technology, Alnylam believes that the only major bottleneck right now is finding these targets.

Confidence in RNAi technology has also recently been supported by investments by large pharmaceutical corporations, potentially accelerating the process of bringing the treatments to market. In January 2014, Sanofi invested $700 million for a 12% stake in the Alnylam, giving Alnylam the resources to progress its lead drug candidates through their remaining clinical trials. RNAi compa-nies like Isis and Tekmira have also garnered partnerships with the likes of Merck, Biogen Idec, and Bristol Myers Squibb. To qualify the optimism surrounding RNAi, failure rates of drugs in Phase I and Phase II are historically treacherously high. As much as 45% of drugs fail in Phase I, 65% in Phase II, and 50% in Phase III (4). However, the robust efficacy and safety data emerging from early trials allow for cautious optimism about the future of RNAi ther-apy.

RNAi promises to treat challenging diseases with astonishing efficacy

While plants and animals have slightly different methods of RNA interference, both are able to use RNAi to silence genes.

WIKIMEDIA/ GRAPHIC

rESEarcH


Genetic Foundations of Susceptibility and Resistance to HIV

Looking Toward Gene Therapy as a Cure

A large fraction of research on HIV (human immunodeficiency virus) focuses on its ret-roviral nature, characterized by the use of reverse transcription within host cells to

reproduce and propagate. While this mechanism of in-fection and the viral proteins involved do account for a good deal of HIV’s potency, other Wdiscourse empha-sizes the importance of human genes to HIV infection. The host cell’s machinery is integral to the reproduc-tive success of HIV; it follows that variations in human genes that facilitate or inhibit HIV function are crucial to our understanding of how to control the HIV epidemic. Much of the research on this topic focuses on alleles of the host cell surface receptor and coreceptor – CD4 and CCR5, respectively – that HIV binds to. However, these receptors are only two of several genes in the human genome that have the ability to promote resistance or susceptibility to HIV. How do these different alleles of certain human genes affect HIV mechanisms? And if human genes influence HIV infection, how feasible is gene therapy as an alternative to current multi-drug therapies? These questions are at the forefront of HIV and public health research.

hUMAN GENES AND ANTI-RETROVIRAL PROTECTION

Recent research has looked at how certain human genes impact HIV’s infectious capa-bility. For example, observing that a small number of indi-viduals remained HIV-neg-

ative despite multiple exposures, Liu et al. found that many of these individuals were homozygous for a mutant allele of the CCR5 host cell surface coreceptor, named Δ32 for its characteristic 32 base-pair deletion.1 HIV has a much lower affinity for CCR5-Δ32 and cannot bind to it to fuse with the host cell membrane. Because HIV can still enter a cell via other cell surface receptors, albeit much less commonly, Δ32 provides strong, but not per-fect, protection against HIV infection.2 Multiple other studies have found that the Δ32 allele is more common among HIV-negative individuals than among the infect-

ed population, supporting Δ32’s protective nature.3-5 The variant allele for the CD4 receptor, however, actually in-creases susceptibility to HIV infection. This mutation, called C868T, results from the substitution of the thy-mine nucleotide for cytosine at position 868, causing the translation of the amino acid tryptophan in place of arginine. Julius Oyugi and colleagues followed a cohort of female Kenyan sex workers – the Kenyan population harbors a high C868T allele frequency of 15 percent – and found that the women who had a double copy of the C868T allele contracted HIV at a significantly higher rate than those with a single copy.6,7

On the other hand, intriguing loss-of-function genes increase human susceptibility to HIV infection. Certain genes code for proteins that block retroviruses. While most other non-human primates can produce function-al proteins from these genes, humans cannot. For ex-ample, retrocyclin, the human counterpart of the theta defensin gene found in closely related primates, should block stages of the retroviral life cycle.8 However, due to a premature stop codon that ends protein translation abruptly, humans cannot make the functional protein product. Another antiretroviral protein, TRIM5α, was discovered by Matthew Stremlau and colleagues in 2004. They found that HeLa cells (an immortal cell line used in research) transduced to express the version of TRIM5α found in rhesus monkeys suffered significantly lower rates of HIV infection than did control HeLa cells.9 Fur-ther investigation identified TRIM5α as a cytoplasmic protein that targets motifs within viral capsid proteins. Because TRIM5α prevents viruses from shedding their protein capsids, reverse transcription and integration into the host cell genome do not occur.10 The reduction in human TRIM5α antiretroviral capability is due to a single, non-synonymous base change in its SPRY do-main.11-13 Like retrocyclin, other non-human primates can make functional copies of TRIM5α, which leads current researchers to hypothesize that these non-func-tional genes were selected for against an extinct retrovi-rus that human ancestors faced, but leave modern hu-mans vulnerable to HIV.14-15

GENE ThERAPY: LOOKING BEYOND MULTI-DRUG TREATMENTS

Current HIV therapy relies on multidrug therapy or HAART (highly active antiretroviral therapy) – a cock-tail of drugs that target several points of HIV’s life cy-cle simultaneously. These drugs can inhibit co-receptor binding by targeting either the host cell receptors or the HIV binding proteins (gp120 and gp40, among others),

or they can interfere with functionality of the viral pro-teins reverse transcriptase, integrase, and protease.16 Al-though the introduction of multi-drug therapy correlat-ed with a significant decrease in HIV-related mortality, there are major disadvantages associated with it, such as serious side effects, high costs, and the evolution of HIV strains that, due to HIV’s high mutation rate, become resistant to one or more drugs. Since gene manipulation has become more feasible with the advent of modern molecular biology techniques, and given that the differ-ence between resistance and vulnerability is only that of a few nucleotides, the potential for gene therapy to re-place multidrug treatments is being seriously explored. The concept of gene therapy as a panacea to HIV arose in the mid-1990s. Numerous studies have used genet-ic engineering to study the differences between human and non-human antiretroviral proteins in vitro. For in-stance, researchers have shown that a simple back mu-tation would restore the functionality of retrocyclin.8,11 In another case, Melvin Yap and colleagues greatly in-

creased the functionality of human TRIM5α by substi-tuting the amino acid proline for arginine at position 332.13 This idea of exploiting the existence of protective human genes in vivo came to the forefront in 2008 with the case of the “Berlin Man.” German hematologist Gero Hütter and his team transplanted bone marrow into the Berlin Man, an HIV-positive American cancer patient. The donor was homozygous for the CCR-Δ32 allele. As a result, the patient began producing T cells – immune cells targeted by HIV – that were also homozygous for the antiretroviral Δ32 allele. The patient was gradually taken off of HAART, and two and a half years after the transplant, still had an undetectable viral load (levels of HIV in the bloodstream). In short, Hütter and col-leagues cured the Berlin Man of HIV.17

Hütter et al. were fortunate in that possible obstacles to curing the patient of HIV – such as an increase in frequency of HIV strains which use coreceptor CXCR4 instead of CCR5 – did not arise. Nonetheless, the case of the Berlin Man indicates that there are ways to stave off the 30-year ongoing HIV epidemic. In a recent break-through, researchers at the University of Pennsylvania

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Multi-drug tHErapY caN HavE SEriouS SidE EffEctS, HigH coStS, aNd rESult iN drug-rESiStaNt Hiv StraiNS.


“Mr. Smith, your new kidney is almost fully formed and will be ready for the surgery by next month.” “I wouldn’t be worried about your first mammogram re-sult; your genome data suggests a four percent chance of breast cancer.” Can phrases like this become part of regular discourse in medicine, where each patient can be quantified by their genetic profile and be treated with their own cells? Medi-cine is an imperfect science, historically having developed and advanced through trial-and-error learning, clinical experimentation, and, more recently, biomedical research. In the modern age, we increasingly look to make more foundational changes in medical treatment through ex-perimentation at the cellular level, the basis of translation-al medicine. The answers that we find at the basic level are transferred to real medical problems. Today, modern medicine looks toward a future of treatment based on re-search at the individual patient level. PERSONALIZED MEDICINE IN ThE FUTURE In attempts to develop more effective treatment methods, modern medicine is investigating the possibility of providing treatment that takes into

account patients’ individual conditions. This concept is called personalized medicine, and it is receiving increasing attention as successive research discoveries make it a more affordable and executable reality. Currently, the main ob-stacles of patient-specific treatments involve the cost and efficiency of maintaining accessible databases of patient in-formation as well as tailoring medical treatments to each patient. Our healthcare systems are not built around this style of medicine, and regulatory systems are not yet pres-ent.1 However, personalized medicine appears to be a viable option at the institutional level; studies indicate that it not only leads to better health on average, but it is also more cost-effective.2

Several advancements have led to the increasing belief in a future that involves personalized medicine. The completion of the Human Genome Project led to a complete sequencing of the entire human genome. Beyond that, new technology has allowed for faster and cheaper sequencing and analysis of an individual’s genome. Examining the genomes of indi-vidual patients allows doctors to identify patients’ genetic

predispositions to certain conditions and diseases, re-sulting in more effective treatments.3 With the more recent discovery of induced pluripotent stem (iPS) cells, the stem-cell craze drew much attention to the possibility of tailored treatment in the near future.

TreaTed in The hospiTal and in The lab

BY IYASSU BERhANU

References

1. Liu, R., Paxton, W. A., Choe, S., Ceradini, D., Martin, S. R., Horuk, R., ... & Landau, N. R. (1996). Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell, 86(3), 367-377.

2. Winkler, C. A., Hendel, H., Carrington, M., Smith, M. W., Nelson, G. W., O’Brien, S. J., ... & Zagury, J. F. (2004). Dominant effects of CCR2-CCR5 haplotypes in HIV-1 disease progression. JAIDS Journal of Acquired Immune Deficiency Syndromes, 37(4), 1534-1538.

3. Samson, M., Libert, F., Doranz, B. J., Rucker, J., Liesnard, C., Farber, C. M., ... & Parmentier, M. (1996). Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene.Nature, 382(6593), 722-725.

4. Gonzalez, E., Bamshad, M., Sato, N., Mummidi, S., Dhanda, R., Catano, G., ... & Ahuja, S. K. (1999). Race-specific HIV-1 disease-modifying effects associated with CCR5 haplotypes. Proceedings of the National Academy of Sciences, 96(21), 12004-12009.

5. Galvani, A. P., & Novembre, J. (2005). The evolutionary history of the CCR5-Δ32 HIV-resistance mutation. Microbes and Infection, 7(2), 302-309.6. Oyugi, J. O., Vouriot, F. C., Alimonti, J., Wayne, S., Luo, M., Land, A. M., ... & Fowke, K. R. (2009). A common CD4 gene variant is associated with an increased risk of HIV-1 infection in Kenyan

female commercial sex workers.Journal of Infectious Diseases, 199(9), 1327-1334.7. Nagelkerke, N. J., de Vlas, S. J., Jha, P., Luo, M., Plummer, F. A., & Kaul, R. (2009). Heterogeneity in host HIV susceptibility as a potential contributor to recent HIV prevalence declines in Africa.

AIDS (London, England), 23(1), 125.8. Venkataraman, N., Cole, A. L., Ruchala, P., Waring, A. J., Lehrer, R. I., Stuchlik, O., ... & Cole, A. M. (2009). Reawakening retrocyclins: ancestral human defensins active against HIV-1. PLoS biology,

7(4), e1000095.9. Stremlau, M., Owens, C. M., Perron, M. J., Kiessling, M., Autissier, P., & Sodroski, J. (2004).The cytoplasmic body component TRIM5α restricts HIV-1 infection in Old World monkeys. Nature,

427(6977), 848-853.10. Sebastian, S., & Luban, J. (2005). TRIM5α selectively binds a restriction-sensitive retroviral capsid. Retrovirology, 2(1), 40.11. Cole, A. M., Hong, T., Boo, L. M., Nguyen, T., Zhao, C., Bristol, G., ... & Lehrer, R. I. (2002). Retrocyclin: a primate peptide that protects cells from infection by T-and M-tropic strains of HIV-1.

Proceedings of the National Academy of Sciences, 99(4), 1813-1818.12. Sawyer, S. L., Wu, L. I., Emerman, M., & Malik, H. S. (2005). Positive selection of primate TRIM5α identifies a critical species-specific retroviral restriction domain. Proceedings of the National

Academy of Sciences of the United States of America, 102(8), 2832-2837.13. Yap, M. W., Nisole, S., & Stoye, J. P. (2005). A single amino acid change in the SPRY domain of human Trim5α leads to HIV-1 restriction. Current Biology,15(1), 73-78.14. Kaiser, S. M., Malik, H. S., & Emerman, M. (2007). Restriction of an extinct retrovirus by the human TRIM5α antiviral protein. Science, 316(5832), 1756-1758.15. Johnson, W. E., & Sawyer, S. L. (2009). Molecular evolution of the antiretroviral TRIM5 gene. Immunogenetics, 61(3), 163-176.16. Arts, E. J., & Hazuda, D. J. (2012). HIV-1 antiretroviral drug therapy. Cold Spring Harbor perspectives in medicine, 2(4), a007161.17. Hütter, G., Nowak, D., Mossner, M., Ganepola, S., Müßig, A., Allers, K., ... & Thiel, E. (2009). Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. New England Journal of

Medicine, 360(7), 692-698.18. Tebas, P., Stein, D., Tang, W. W., Frank, I., Wang, S. Q., Lee, G., ... & June, C. H. (2014). Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV. New England Journal of

Medicine, 370(10), 901-910.19. Didigu, Chuka A., et al. “Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection.” Blood123.1 (2014): 61-69.20. Penn Medicine (2014, March 05). Personalized gene therapy locks out hiv, paving the way to control virus without antiretroviral drugs. Retrieved from http://www.uphs.upenn.edu/news/

News_Releases/2014/03/june/

used zinc finger nuclease editing (ZFN) to genetically en-gineer the T-cells of twelve HIV-positive patients to re-sist infection.18 Zinc finger nucleases are highly specific, artificial restriction enzymes that induce double-stranded breaks in unique DNA sequences. This allows for precise alteration of organism genomes.19 Tebas et al. used ZFN technology to modify T-cells to express the CCR5-Δ32 allele. These modified T cells were then infused into the patients. The researchers found that, of the six patients who were taken off HAART for twelve weeks (the other six, who remained on HAART, constituted a comparison

group), four had significant decreases in viral load. Dr. Carl H. June, senior author of the Tebas et al. study, asserted that these results, “reinforce our belief that mod-ified T cells are the key that could eliminate the need for lifelong [antiretroviral drug therapy] and potentially lead to functionally curative approaches for HIV/AIDS.”20 The transition from HAART to gene therapy may be gradual,

but the necessary knowledge, technology, and experimen-tal foundations exist to make gene therapy entirely feasi-ble. Recent breakthroughs heavily rely on the CCR5-Δ32 allele. One entirely possible scenario to consider is the evolution of HIV in response to its inability to bind to the CCR5 coreceptor containing the Δ32 mutation. HIV strains that primarily utilize coreceptor CXCR4 could achieve higher rates of reproductive success, making gene therapy that only focuses on CCR5 ineffective. In this situ-ation, it is important to note that Δ32, C868T, retrocyclin, and TRIM5α are just four of several genes and proteins that can facilitate or inhibit HIV infection. These alter-native targets for genetic engineering could enable gene therapy to evolve with the potential evolution of HIV. In the end, the question remains: is there a way to perma-nently eradicate HIV? If current research provides any indication, the answer may come not too far in the future.

Stem Cell BreakthroughS and the growing ViaBility of PerSonalized mediCine

SOURCE: WIKIMEDIA IYASSU BERHANU / GRAPHIC

The process of differentiation: A cell at a pluripotent (undifferentiated) state is in its developmental infancy. From this stage, it can be induced to transform into any type of specialized cell in the body, in the typically irreversible process of differentiation.

uNivErSitY of pENNSYlvaNia rESEarcHErS gENEticallY ENgiNEErEd t-cEllS to rESiSt iNfEctioN.

WIKIMEDIA/ GRAPHIC


References 1. “About the Personalized Medicine Coalition.” Personalized Medicine Coalition.

Retrieved February 4, 2014 from http://www.personalizedmedicinecoalition.org/about

2. Philips, K. A., Sakowski, J., Trosman, J., Douglas, M., Liang, S., & Neumann, P. (2013). The economic value of personalized medicine tests: what we know and what we need to know. Genetics in Medicine, 122.

3. “What is Personalized Medicine?” Harvard School of Medicine Center for Personalized Genetic Medicine. Retrieved Febrary 4, 2014 from http://pcpgm.partners.org/about-us/PM.

4. Takahashi, K. & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126 (4), 663-676.

5. Richter, R. (2010). “Stanford to open nation’s largest stem cell research building.” Stanford School of Medicine. Retrieved February 6, 2014 from http://med.stanford.edu/ism/2010/october/lokey-advisory.html.

6. Bilic, J. & Belmonte, J.C.I. (2012). Concise review: Induced pluripotent stem cell versus embryonic stem cells: Close enough or yet too far apart? Stem Cells 30, 33-41.

7. Cyranoski, D. (2014). “Acid bath offers easy path to stem cells.” Nature: News. 29 January 2014.

8. Obokata, H., Sasai, Y., Niwa, H., Kadota, M. Andrabi, M., Takata, N., Tokoro, M., Terashita, Y., Yonemura, S., Vacanti, C. & Wakayama, T. (2014). Bidirectional developmental potential in reprogrammed cells with acquired pluripotency. Nature 505, 676-680.

9. Obokata, H., Wakayama, T., Sasai, Y., Kojima, K., Vacanti, M. P., Niwa, H., Yamato M. & Vacanti, C. (2014). Stimulus-triggered fate conversion of somatic cells into pluripotency. Nature 505, 641-647

10. Cyranoski, D. (2014). “Acid-bath stem-cell study under investigation.” Nature: News. 17 February 2014.

11. Kelland, K. (2014). “‘Grow your own’ stem cells a game changer, say scientists.” The Sydney Morning Herald: Technology. 30 January 2014.

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BY jENNA hEBERT

Could a Drug thatEliminates Traumatic

Memories be in the Works?Neuroscientists at MIT successfully erase fear memories in mice by modifying the epigenome

In January of this year, headlines in Nature, National Geographic, and Forbes magazines were buzzing with hopes of a new drug that may eliminate traumatic memories. They referenced a paper published in Cell that discusses Dr. Li-Hieu Tsai and her colleagues’ recent study at Massachusetts Institute of Technology (MIT): they discovered that the use of a chemical that modifies neuronal DNA and increases neural plasticity in mice, allowing them to forget fearful memories weeks after the event. This is normally an impossible feat given the salience of fear memories.1

Considering that 50-60% of Americans experience “extreme stress” due to traumatic events at some point in their lives, of whom thousands develop Post-Traumatic Stress Disorder (PTSD), a successful pharmacological treatment would be monumental.2 Currently, Cognitive Behavioral Therapy (CBT) is the most common treatment for those who develop PTSD after undergoing particularly traumatic stresses, such as watching a close friend die in crossfire in Afghanistan or experiencing the Twin Towers fall first-hand on September 11. In fact, CBT was actually developed here at Penn in the 1960’s by Dr. Aaron Beck, a psychiatrist and current professor emeritus. Exposure therapy is the specific aspect of CBT that is used to treat anxiety disorders; patients

are prompted to imagine, face in real life, or use virtual reality-based simulations to confront the object or cue that causes them anxiety until they dissociate it from the fearful response.3 While this therapy can be effective, about half of PTSD patients continue to show symptoms even after treatment.2

Types of anxiety other than PTSD, such as extreme fear of heights, have already been successfully treated in a clinical setting with a combination of cognitive therapy and pharmacological intervention. Therefore, scientists believe that the most promising route for alleviating PTSD symptoms will likely involve a similar blend of treatments, an impetus for Tsai and others to investigate the neurobiological mechanisms that underlie fear memories.4

WIKIMEDIA/ GRAPHIC

STEM CELL RESEARCh - ThE KEY TO PERSONALIZED MEDICINE Stem cell research has been hailed as the key to the future of medicine since Shinya Yamanaka’s discovery of iPS cells in 2006, which earned him a Nobel Prize.4 This break-through shattered the scientific community’s conception of differentiating cells. Yamanaka demonstrated that fully differentiated cells can be reprogrammed into pluripo-tency which is an embryonic undifferentiated state. From pluripotency, undifferentiated cells can develop into any kind of cell based on the instructions they receive. Before Yamanaka’s discovery, differentiation into a specialized cell was believed to be an irreversible change in the cell. Additionally, stem cells were extracted from embryos, hence the familiar pro-life opposition to the destruction of embryos. Since the discovery, cell therapy through stem cell research has become an integral piece of the image of personalized medicine in the future. Although met with mixed amounts of enthusiasm and skepticism among the scientific community, stem cell research remains a major talking point in the advancement of medicine, with in-creasing attention and investment.5

It is uncertain if iPS cells are the key to developing an effective method of personalized medicine. Currently, there is only about a 1% conversion rate to iPS cells when treated, and the conversion to pluripotency takes several weeks. Furthermore, the cells are not entirely as pluripo-tent as embryonic stem (ES) cells are.6 These conditions, along with the need to develop detailed patient databases, decrease the viability of a cost-effective change in health-care to personalized medicine.7

ThE STAP CELL DISCOVERY In recent months, scientists in Japan have discovered a revolutionary method to reduce fully specialized cells to pluripotency. In what could be a major breakthrough for the efficiency question of stem cell research, scientists found that simple treatment with environmental stress can trigger the reversal of an animal cell to pluripotency. The phenomenon, stimulus-triggered acquisition of plu-ripotency (STAP), was achieved through simply treating differentiated mouse cells with acid for half an hour.7,8 Unlike other ways of reaching pluripotency, STAP does not require any genetic treatment.9 Furthermore, STAP cells have been reported to have a 30% conversion rate to pluripotency and are more versatile than ES or iPS cells.8,9 However, this reported discovery is still under scrutiny as other scientists claim to encounter difficul-ties when attempting to replicate the procedure.10

The discovery of STAP cells may likely answer some of the questions surrounding the viability of personalized medicine in the future. A cost-effective method is much more likely to develop with the increased efficiency and speed of producing stem cells for an individual. If the STAP phenomenon can be observed equally in human cells, it can make a wide range of individual cell treat-ments available.11 Regenerative medicine would be high-ly effective, and patients could receive transplants from their own programmed cells at every level, including full organs grown from their own somatic cells. Although there is still quite some time before the STAP cell procedures can be tested in humans, personalized medicine based on stem cell research appears to be prominent in the future of medicine. With the increas-ing ease of stem cell creation and genome sequencing and increasing evidence supporting the effectiveness of personalized treatment, many doctors and scientists are considering the need to restructure health care to sup-port personalized medicine. However, considering the extent of this restructuring, there is certainly much work to be done before the healthcare industry can accommo-date personalized medicine.

IYASSU BERHANU/ GRAPHIC


tHiS iS tHE firSt tiME tHat a fEar rESpoNSE HaS BEEN

rEvErSEd for loNg-tErM MEMoriES.2 “it’S rEMarkaBlE.

if wE iNJEct a SiNglE doSE of tHiS drug it actuallY iS

SufficiENt to rEactivatE NEuroplaSticitY,” Said tSai,

ExplaiNiNg How tHE drug waS SuccESSful iN rEwiriNg

NEuroNS iN HEr MicE’S BraiNS.

WIKIMEDIA/ GRAPHIC

WIKIPEDIA/ GRAPHIC

References

1 Gräff, J., Joseph, N.F., Horn, M.E., Samiei, A., Meng, J., Seo, J…Tsai, L. (2014). Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories. Cell, 156, 261–276.

2 Hughes, V. (January 22, 2014). Drug Tweaks Epigenome to Erase Fear Memories. National Geographic. Retrieved from: http://phenomena.nationalgeographic.com/.

3 Reardon, S. (January 17, 2014). Drug Helps to Clear Traumatic Memories. Nature. DOI:10.1038/nature.2014.14534.

4 Zovkic, I.B. & Sweatt, D.J. (2013). Epigenetic mechanisms in learned fear: implications for PTSD. Neuropsychopharmacology Reviews, 38, 77-93.

5 Graff J. & Tsai L. (2013). The potential of HDAC inhibitors as cognitive enhancers. Annual Review of Pharmacology and Toxicology. 53: 311-30.

6 Bahari-Javan S, et al. (2012). HDAC1 regulates fear extinction in mice. The Journal of Neuroscience. 32(15): 5062-5073.

7 Maren S., Phan K.L., & Liberzon, I. (2013). The contextual brain: implications for fear conditioning, extinction, and psychopathology. Nature Reviews. 14:417-428.

8 Radowitz, J. (January 17, 2014). Scientists a step closer to erasing traumatic memories. Irish Independent. Retrieved from: http://www.independent.ie/lifestyle/health/.

9 Berezin, R. (January 27, 2014). A New Drug to Erase Traumatic Memory is Not a Good Thing. Psychology Today. Retrieved from: http://www.psychologytoday.com/blog/the-theater-the-brain/.

PREVIOUS RESEARCh IN EPIGENETICS AND MEMORY

In the last twenty years, neuroscientists have made exciting discoveries in how experiences can change the way the brain is wired and make long-term behavioral changes. Of particular interest to PTSD research is how the dynamic regulation of gene activity is involved in the formation and fading of fear memories.4 Molecular markers such as acetyl or methyl groups act as “on/off switches” for genes that regulate the changes in neuronal connectivity that cause memory formation when they are attached to or removed from DNA. These types of changes are called epigenetic modifications.4 Scientists have found that inducing or inhibiting DNA methylation or acetylation of histones (proteins around which the DNA winds that also help to regulate gene expression) can either make recent fear memories more salient or facilitate their elimination in rodents, depending on what epigenetic modifications the researchers make.5,6

TSAI’S BREAKThROUGh

To further understand how fear memory formation and elimination work, Tsai and her associates modeled this process in mice by using “contextual fear conditioning” to evaluate how well the mice remembered a traumatic event. Fear conditioning is a classical behavioral paradigm in which an animal learns to link an aversive stimulus, such as a shock to the foot, to an ordinarily neutral “context,” typically a chamber with distinguishing features that allow the mouse to recognize the chamber again. When placed in the same setting, conditioned mice will become paralyzed and freeze, a behavior that is used to quantify fear in rodents. By recording the amount of time the mouse is paralyzed with fear, researchers are able to see the extent to which it associates the setting with the traumatic event.7

Within twenty-four hours after the mouse learns to associate the shock with the context, scientists can easily undo the association through a “fear extinction” paradigm, which is analogous to exposure therapy in humans. Fear extinction involves exposure to a context without the aversive stimulus until the mouse no longer connects the two. Tsai and her colleagues were able to successfully

decrease freezing behavior in mice undergoing extinction within twenty-four hours of the shock, which is indicative of successful disassociation of the context from the stimulus. In other words, the mouse is no longer afraid when it is placed in the same chamber.

A more realistic model of PTSD in animals would involve “remote” (very old) fear memories as opposed to recent ones.1 When the extinction procedure was performed one month after conditioning, however, freezing behavior remained, showing that the memory was not successfully modified and that the mice were still afraid of the chamber. It appeared that these remote memories could not be unwritten. These results drove Tsai to investigate why old fear memories are more stable than recent ones.1 Finding the answer could help explain why exposure therapy is often not effective for PTSD patients. Tsai and her lab took a closer look, investigating the brain at the level of neuronal DNA. They discovered that one of the epigenetic modifiers that regulates genes implicated in fear memory formation, the on/off switch mentioned earlier, is an enzyme called histone deacetylase 2 (HDAC2). Tsai’s lab had already found that the degree of histone acetylation is a factor in regulating memory genes, and other scientists had made fear extinction more effective with HDAC inhibitors for recent 24 hour-old memories, suggesting that this class of enzymes would be a promising target for rewriting older fear memories.5 HDAC2 removes acetyl groups from DNA and inactivates

genes related to memory formation. Tsai noticed that this protein is normally inactive during fear conditioning, making the neurons plastic and allowing the mice to learn the context-stimulus association. However, it is active 30 days later, decreasing neuroplasticity and making it difficult to modify the memory.1

The lab found that inhibition of HDAC2 in conjunction with extinction therapy for remote fear memories was effective in causing mice to forget the shock-context association. This is the first time that a fear response has been reversed for long-term memories.1 “It’s remarkable. If we inject a single dose of this drug it actually is sufficient to reactivate neuroplasticity,” said Tsai, explaining how the drug was successful in rewiring neurons in her mice’s brains. “We did a lot of control experiments to show that this mechanism doesn’t wipe out other memories. It really is very specific to the training condition.”2

WhAT ABOUT hUMANS?

While these results are exciting, there is some uncertainty about the use of this chemical as a drug for human treatment. Dr. Ted Abel, a biology professor at Penn who studies the molecular mechanisms of long-term memory, thinks the successful enhancement of extinction of remote fear memories is exciting. As for the use of an HDAC2 inhibitor in humans, however, “Who knows what it’s going to do?” He questions the validity of context-dependent fear conditioning as a model for PTSD, arguing that PTSD is a “disorder of generalization” in that the aversive stimulus becomes “unglued” from the context in victims’ minds and generalized to other situations. He explains that if a helicopter blows up in Afghanistan, a veteran with PTSD may feel jumpy whenever he hears any loud noise, regardless of his location. Meanwhile, mice that undergo fear conditioning associate the traumatic event with one specific context and feel anxiety only when

placed in that same context. He thinks that researchers will “need to look at other measures of anxiety to see how generalizable this drug can be.”

Moreover, to some, the idea of this chemical turning into a medication for use in humans seems comparable to something out of a science fiction movie gone awry. In fact, some news organizations compared Tsai’s results to just that. For example, the Irish Independent, a popular daily newspaper in Ireland, included with its article about Tsai’s study an image from the 2012 Colin Farrell film Total Recall, where life goes awry when memories are erased or otherwise tampered with.8 Some are truly concerned about the ethical implications of being able to

tamper with memories. Dr. Robert A. Berezin, psychiatrist and writer for Psychology Today, writes, “This amounts to a chemical lobotomy to erase memories.” He sees the idea of any kind of thought control as “truly frightening.”9

A STEP IN ThE RIGhT DIRECTION

Despite the skepticism, the response from the scientific community is overwhelmingly positive. To Dr. Abel, the results are promising and he looks forward to seeing where the research will go next. It will certainly be some time before we see HDAC inhibition make it to a clinical setting for this purpose, and it is still uncertain whether this drug will be effective in humans. But the prospect of dramatically improving the quality of life of those suffering from anxiety disorders certainly makes it worthy of further investigation.

36 | SYNAPSE | SPRING 2014

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