penn bioethics journal vol viii, issue ii

7/22/2019 Penn Bioethics Journal Vol VIII, Issue ii

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Volume VIII Issu

Research Ethics and

Enhancement

Also insideConversations with David Perlman and Jennifer Walt

Gun Control and Mental Hea

Surrogate Motherhoo


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Archived editions of the Journal and information about the submission process can be found on our website:

http://bioethicsjournal.com

The editorial staff also promotes bioethics by hosting campus-wide events through formal lectures, case study presenta-

tions, public debates, debrieng of current bioethical issues and student-led conversations.

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Penn Bioethics Journal

Email [email protected] to get more information about bioethics at Penn.

The Penn Bioethics Journal(PBJ) is the nations premier peer-reviewed undergraduate bioethics journal. Established in 2004,

the Journal provides a venue for the contributions of undergraduates to bioethics. The PBJ, embracing the interdisciplinary

focus of bioethics, reviews and publishes reports of empirical research and analysis of previous work -- addressing debates

in medicine, technology, philosophy, public policy, law, theology and ethics, among other disciplines. The biannual Journal

also features news briefs and editorials reviewing current bioethical issues, as summarized by our undergraduate editorial

staff. Undergraduate editors and authors have a unique opportunity to get involved with the peer-review process through

the collaborative and rigorous review and preparation of the PBJ. With an audience ranging from scholars in the eld

to a broader public seeking unbiased information, the Penn Bioethics Journalscholastically involves all undergraduates

interested in the extensive eld of bioethics.

Te Penn Bioethics Journalis published twice a year by the University of Pennsylvania, Philadelphia, PA.

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Copyright 2013 Penn Bioethics Journal, Philadelphia, PA.

ISSN: 2150-5462

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EDITOR IN CHIEF

Anand Muthusamy

PUBLISHER

Kathleen Sun

MANAGING EDITORS

Klyde Breitton

Lucy Chen

Lili McKinley

Ruchita Pendse

Sudesh Raju

Aditi Verma

ASSOCIATE EDITORS

Osama Ahmed

Mohammad AlMagweshi

Christopher Ataksuka

Diana Blidarescu

Shayan Cheraghlou

Laura Cosgrove

Imran Cronk

Samantha Freedman

Elana Furman

Andy Guo

Audrey Harnagel

Jacquelyn Kemmer

Ellen Kim

Kurt Koehler

Georgio Legerme

Nicholas Lim

Robin Lo

Eileen Mayro

Loren Miller

Tim Shinn

Shashank Sirivolu

Hannah Victor

Andrew Wadley

Abby Worthen

Grace Wu

Garrett Young

Ahmed Yousef

Samir Zaman

Nikolai Zapertov

Timothy Zhou

FACULTY ADVISORJonathan Moreno, Ph.D.

Questions or Comments?

Please direct all inquiries to the

Editor in Chief at

[email protected]

Contents

Interviews

Letter from the Editor in ChiefAnand Muthusamy

PBJP e n n B i o e t h i c s J o u r n a l

Q&A with David Perlman

Adolescent Care and Health Policy A Conversationwith Jennifer K. Walter

Gun Control and Mental Illness

Bioethics in Brief

The Potential of Epigenetic Therapy and the Need for

Elucidation of RisksJosh Tycko, Danielle Fields, Daniel Cabrera, Mahamad Charawi, Bradley Kaptur,

University of Pennsylvania

Monetary Compensation of Research Subjects:

The Shortfalls of Research Standards in Preserving

AutonomyShivam Amin, University of South Alabama

Genetic Enhancement: Definitions, Methodologies, and

the Effect of Parental AttitudesSarah Mayes, University of Virginia

Denmarks Precautionary Approach to Antibiotic

Resistance

Surrogate Motherhood, Disability, and Abortion in theCase of Baby S

Adolescent Organ Donation at the Childrens Hospital of

Philadelphia

Environmental Applications of Synthetic Biology

Articles

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6

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Dear Readers,

Bioethics is a burgeoning field that has gained more attention with recentadvances in the life sciences and political movements shaping healthcare law.

Tis issue of the Penn Bioethics Journal focuses on the ethics of medicalresearch and human enhancement to address particular links between scienceand healthcare outcomes.

ypically, basic science addresses a range of interesting problems without astrict agenda or need to immediately prove its utility. However, recent budgetcuts have restricted the work of the National Institutes of Health, amongother scientific organizations. In this environment especially, pressing societalproblems raise questions about the priorities in scientific research. Recenttrends have emphasized clearly demonstrating the medical applications ofbasic life science research. Considerations for the safety of research subjectsand future patients impose additional constraints on research. wo piecesenclosed discuss the promise of synthetic biology while considering how thenew associated risks demand stringent clinical trials. Our first feature articlediscusses the limitations of the Belmont Report, the standard guidelines forconducting biomedical research, in informing institutional review boards.Furthermore, a newly adopted medical technology raises questions of how

various agents will adapt their behavior. Our second feature article analyzesthe parent-child relationship in different cases of genetic enhancement.

Tis issue also addresses current bioethical issues outside medical research,such as surrogate motherhood, adolescent organ transplantation, the fightagainst antibiotic resistance, and the role of mental health in gun controlmeasures. Tese topics are notable not only for their timeliness, but also fortheir implications for other practices including but not limited to scientificresearch and clinical practice.

I thank our editors and authors for their work in compiling this issue. I

am also grateful for the strength of the bioethics community across manydepartments at the University of Pennsylvania. Te turnout at the NationalUndergraduate Bioethics Conference last April at Georgetown University

demonstrated a strong interest in an undergraduate bioethics communityacross the country. Looking forward to the next conference, we are continuingto develop and share practices to promote undergraduate bioethics. Te PennBioethics Journal will continue to serve as an open, international forum forundergraduates across all disciplines to discuss bioethics.

Letter from the Editor Anand MuthusamyEditor in Chief

Anand MuthusamyEditor in Chief

University of Pennsylvania C14


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Gun Control and Mental Illness

Te results of the Newtown shooting sparked a debateabout gun control and mental illness that catalyzed significantpolitical activity. Te ethics of gun control and mental healthprovisions strain a balance between individual privacy andsocietal safety. Of special concern is the degree to whichinformation about mentally ill patients should be disclosedto prevent dangerous individuals from obtaining firearms.On one hand, patient confidentiality is critical for treatment;however, others argue that a national database is especiallyuseful for firearm regulation. Te information required for thedatabase is readily accessible and the number of individualsthe system can screen is high (Mowbray 2002). In a world

with complete information symmetry, this solution appearsto be ideal as suspect individuals can be monitored whileothers can more freely purchase firearms.

However, before the symmetry of information is evenconsidered, the effectiveness of the information must beassessed. First, many individuals already illegally purchase

weapons and may be further encouraged to turn to the illegaldealers (Mowbray 2002). Second, increased backgroundchecks may only serve to penalize law-abiding gun owners

while increasing the cost to the government for perhaps amarginally effective system (Kapur 2013). Tird, those who

voluntarily seek treatment are most likely not the onesinterested in purchasing firearms for an ulterior motive(Swanson 2013). Tese three points not only question themeaningfulness of a database but also warrant a discussion ofunintended side effects in collecting information.

Disclosure of personal information further exposespatients to stigma, which may hinder them from seekingmental healthcare. Te increase in untreated mental illnessesnot only adversely affects patients, but also may result inincreased criminal activity. Jeffrey Swanson, a professorof psychiatry and behavioral sciences at Duke University,studied the correlation between policy action and subsequentcriminal behavior of the mentally ill (Webster 2013). Swanson

considered two groups: the mentally ill with a criminalhistory and the mentally ill without one. When aggregatingboth of these groups, policy appeared to have no significanteffect on decreasing violent crimes by the mentally ill as a

whole (Webster 2013). However, analyzing the two separategroups individually yielded more decisive results. Regulationdid decrease the risk of future violence for patients withoutcriminal records. However, for those with criminal records, themore restrictive gun control policy, surprisingly, increased thelikelihood of future violent crimes by a staggering 60 percent(Webster 2013). Swanson suggests that increased stigma andstronger regulations affect the individuals desire to reach

out for medical attention when under scrutiny. Specifically,patients with criminal history especially feel judged andpersecuted, thinking that they have more to lose or hide.

Without that patient-doctor confidentiality, these patientsare less likely to trust in a medical institution that appears tohave not just their interest but also societys interest at heart(Mowbray 2002). Terefore, while it is critical to have someform of background check or regulation in society, the intentshould be on helping and reducing the number of mentallyill, rather than solely focusing on preventing people fromobtaining weapons (Webster 2013).

Te Obama administrations recent proposals regardinggun control and mental health care represent societys nextsteps. Specifically, the administration seeks 23 stipulationsthat converge in two specific executive orders: the first closesloopholes in the current background check system and the

second keeps surplus military weapons off the streets (WhiteHouse 2013). Te Obama administration plans to targetmental illness by allocating $235 million in the 2014 fiscalbudget proposal to three distinct areas: training for teachersin public schools, education for medical physicians, andalleviation for schools with violent history (Kliff 2013). Teoverlap of the two proposals provides a focus and sense ofpriority in the nation to address mental health concerns.

However, while the gun control proposals and mentalhealth budget are steps forward, the most critical componentof all these stipulations remains understated: the need forenforcement, which brings with it the power of suspicion

Bioethics in Brief

Bioethics in Brief

Dean Rohrer


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Denmarks Precautionary Approach to Antibiotic Resistance

In 1928, when Sir Alexander Fleming discoveredpenicillin for use as an antibiotic, the medical field changedradically. Patients no longer had to fear scarlet fever ordeath from infected wounds. Since then, many antibioticshave been developed and are now highly available. However,

with the growing use of antibiotics, bacteria have become

increasingly resistant to such drugs. Pathogens buildresistance to antibiotics by evolving their genomes, a processthat can outpace drug development. Antibiotic resistancethreatens global health by increasing the possibility thatbacterial genes will confer resistance to medicine used astreatment against disease.

Responding to this concern in the 1990s, Denmarkinitiated the ban of antibiotic use for promoting growth inlivestock. Te ban was critical because at the time antibiotics

were used so prevalently that bacteria were almost completelyimmune to the drugs. For example, in 1995 when the banof Avoparcin was implemented,72.7% of broilers chickens hadglycopeptide-resistant E. faecium(GRE), a bacterium found inthe broilers fecal collection(Aarestrup 2001). Following theban in 2000, that figure fell to5.8% (Aarestrup 2001). Similarresults were found after the ban of other antibiotics, such asVirginiamycin and Erthomycin (Aarestrup 2001).

Additionally, the European Molecular BiologyLaboratory recently released a study that investigated252 metagenomes and found that resistance is highest forantibiotics that are highly available and used in animals,

suggesting that exposure to prevalent antibiotics is a catalystfor developing antibiotic resistance (Forslund 2013). Teseand other studies support Denmarks findings that lowerantibiotic use may result in lower antibiotic resistance, even

when considering off-target effects.Despite these findings, many individuals in the

agricultural industry have expressed concern regardingbans on antibiotics. Withholding certain banned antibiotictreatments may unintentionally cause withdrawal symptomsin the animals. Tese symptoms would then need to betreated with other unbanned antibiotics. Tis situationmight lead to no appreciable change in overall antibioticresistance, since antibiotics would just be given later ratherthan earlier (Casewell 2003).

Such concerns may ultimately be unfounded. Te WorldHealth Organization found that the ban on antibiotics inDenmark did not significantly harm farmers income or

increase animals health risk.Rather, the ban reducedhuman health risk (Chan2012). As a result, othercountries have followedDenmarks ban on antibioticsand agricultural model.Denmark is a remarkable

example for efficiently banning antibiotics in agriculturesince the agricultural industry across the country is set up ina uniform manner (Aarestrup 2001).

All over the world, countries are pushing for legislationagainst antibiotic resistance. In Australia, there is a currentpush to fight antibiotic resistance by actively working to stay

Bioethics in Brief

Tis situation might lead to noappreciable change in overall antibioticresistance, since antibiotics would just be

given later rather than earlier.

(Devers 2013). Implementing policy necessitates training andheightened awareness, which reinforces strong stereotypes(Link 1999). Te stigma of the mentally ill and the stigmaof criminals permeate through society as individuals attemptto carry out the very laws that try to resolve this ingrainedstereotype. Ultimately, people need to bring the best interestsof others to the forefront and communicate a desire to

genuinely help. By demonstrating this true interest in thesuccess of the involved individuals, the issue of gun controland mental illness in society may finally begin to resolveitself (Corrigan 2002).

-Aditi Verma, University of Pennsylvania

Corrigan, P. W., Rowan, D., Green, A., Lundin, R., River, P., Uphoff-Wasowski, K., et al. 2002. Challenging two mental illness stigmas:personal responsibility and dangerousness. Schizophrenia Bulletin. 28(2),293309.

Devers, C. E., . Dewett, Y. Mishina, and C. A. Belsito. 2013. A GeneralTeory of Organizational Stigma. Organization Science20(1): 154-171.

Kliff, Sarah. 2013. Obamas Proposed Budget to Seek $235 Million for

New Mental Health Programs. Washington Post. N.p.

Link, B. G., J. C. Phelan, M. Bresnahan, A. Stueve, and B. A. Pescosolido.1999. Public Conceptions of Mental Illness: Labels, Causes,Dangerousness, and Social Distance.American Journal of Public Health89(9): 1328-1333.

Mohney, Gillian. 2013. Obama Budget Includes $235 Million For MentalHealth Care.ABC News. ABC News Network,

Moorhead, Molly. 2013. A Summary of the Manchin-oomey GunProposal. PolitiFact.ampa Bay imes.

Mowbray, Carol . 2002 Mental Health and Mental Illness: Out of theCloset? Social Service Review75.1 135-79. Print.

Obama Announces 23 Executive Actions, Asks Congress to Pass GunLaws. 2013. Web log post. CNN. CNN News.

Swanson, Jeffrey, PhD. 2013. Mental Illness and New Gun Law Reforms:Te Promise and Peril of Crisis-Driven Policy. Te Journal of AmericanMedical Association309(12): 1233-1234.

Te White House, Office of Press Secretary 2013. FAC SHEE: NewExecutive Actions to Reduce Gun Violence. Te White House.

Te White House. 2013. Now Is the ime. Rep. Te White House.Webster, Daniel W., and Jon S. Vernick. 2013. Reducing Gun Violence

in America Informing Policy with Evidence and Analysis. Baltimore:Johns Hopkins UP.

Wilkie, Christina. 2013. NRA: Background Check Deal A PositiveDevelopment, But Still Oppose Compromise Plan. Te HuffingtonPost. TeHuffingtonPost.com.


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ahead of the evolution of antibiotic strains. Te Office ofthe Chief Scientists of Australia released a paper that urgedscientists to develop more effective antibiotics and vaccinesto fight growing antibiotic resistance in bacteria (Prasadand Smith 2013). In the United States, there are also newmovements. U.S. Representative Louise Slaughter (D-NY )

wrote to Nature in August 2013 that she has been striving topass legislation to ban the use of eight medically importantclasses of antibiotics currently used in agriculture. Her piece

was in response to several articles published in Nature:MRSA: Farming up rouble, Antibiotic Resistance: Telast resort, and Antibiotic Treat (Slaughter 2013).

Supplementing Representative Slaughters concern thattreating livestock with antibiotics increases humans riskof acquiring an antibiotic resistant infection is a new studyreleased by Johns Hopkins University that used data froma major health system, the Geisinger Health System. Tisstudy showed that exposure to swine manure, which containsantibiotic resistant bacteria, resistance genes, and antibiotics,

increases an individuals risk of contracting MRSA (Casey2013). Especially as we see growing evidence of antibioticresistance, it is time the United States takes action to reduceresistance in our own country.

Despite worries of limited antibiotic use leading todecreased animal quality of life, the evidence supportsthat banning antibiotics for use in agriculture reduces thepossibility of infectious bacteria evolving into something

more dangerous. Antibiotics still are magic bullets forspecific ailments, and in order to protect their effectiveness,

we must both carefully use and continually develop drugs tooutpace the development of resistance.

-Lilian McKinley, University of Pennsylvania

Aarestrup, F.M., A.M. Seyfarth, H. Emborg, K. Perdersen, R.S.Hendriksen, F. Bager. 2001. Effect of Abolishment of the Use ofAntimicrobial Agents for Growth Promotion on Occurrence ofAntimicrobial Resistance in Fecal Enterococci from Food Animals inDenmark.Antimicrobial Agents and Chemotherapy 45(7): 2054-2059.

Casewell, Mark, et. al. 2003. Te European ban on growth-promotingantibiotics and emerging consequences for human and animal health.

Journal of Antimicrobial Chemotherapy (52): 159-161.Casey, John, et. al. 2013. High-Density Livestock Operations, Crop

Field Application of Manure, and Risk of Community-AssociatedMethicillin-Resistant Staphylococcus aureus Infection in Pennsylvania.

JAMA Internal Medicine. E1-E11.Chan, Margaret. 2012. Antimicrobial Resistance in the European Union

and the World. WHO.Forslund, Kristoffer, S. Sunagawa, J.R. Kultima, D. Mende, M. Arumugam,

A. ypas, P. Bork. 2013. Country-specific antibiotic use practices

impact the human gut resistome. Genome Research(23): 1163-1169.Prasad, Simon and Phillipa Smith. 2013. Meeting the Treat of Antibiotic

Resistance: Building a New Frontiline Defense. Occasional PaperSeries (7): 1-4.

Slaughter, Louise. 2013. Antibiotics: Support US policy change.Nature500: 400.

Wharam, Barney and L. Lazarou. 2013. Ethical considerations in an era ofmass drug administration.Parasites and Vectors 6(1): 234.

Surrogate Motherhood, Disability, and Abortion in the Case of Baby S

Perhaps one of the most interesting (and morallyambiguous) bioethical news stories to have surfaced this

year is the case of Baby S. Te story began with a surrogatemother, Crystal Kelley, who decided to bear the baby of amother who could not bear children. However, an ultrasoundshowed that the fetus had serious defects, and that the baby

would only have a 25% chance of [leading] a normal life(Cohen 2013). Te parents decided that terminating thepregnancy would be the most ethical course of action, butKelley disagreed. Legal disputesfollowed, with the parentsoffering $10,000 to abort thefetus and refusing to raise thechild if it were born. Ultimately,Kelley fled to Michigan insearch of adoptive parents who

would provide a loving homefor the child. Te child wasborn disabled and given to anadoptive mother. Eventually,the biological parents too cameto support the decision and now regularly visit Baby S.

Tough this dispute was resolved, it raised a staggeringnumber of bioethical issues. With regards to the ethics of

surrogacy itself, some critics compare surrogate motherhood

to prostitution. Tey disapprove of surrogacy because womenare offering their bodies for financial gain (Anderson 2000).

Tis case also raises the issues of commodification ofchildren when financial incentive for abortion is involved,

whether abortion can be right in certain cases, and whethersuch abortions encourage eugenics and artificial selection ofbetter children. Finally, this case problematizes agency andits implications. Can a surrogate mother violate the desiresof biological parents by birthing a child the parents no longer

want for medical reasons? Andif the surrogate mother doesfollow through with birthing anunwanted child, do the parentshave an obligation to supportthe child?

Developing a philosophicalframework to fairly evaluate theethics of this story is challengingindeed. Recent work by notedOxford philosophers JulianSavulescu and Guy Kahane

have publicized one framework in particular to assess suchcases: the Principle of Procreative Beneficence (PB). Tisprinciple states that though the disabled can still lead happy

lives, couples should choose the best outcome regarding their

Bioethics in Brief

Tis case also raises the issues ofcommodification of children when financialincentive for abortion is involved, whetherabortion can be right in certain cases, andwhether such abortions encourage eugenicsand artificial selection of better children.


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Bioethics in Brief

Center for Bioethics, Urban Health, & Policy

temple.edu/centers/cbuhp | facebook.com/cbuhp

cbuh tem le.edu

Temple Universitys MA in Urban Bioethics, offered through the CBUHP, trains

students in the ethics and values of health, health care delivery, and health law and

policy underlying the urban context of density, diversity, and inequalities. Coursework

is practical, methodological, and theoretical. The degree is designed for Temple

graduate students and area professionals who face, or will soon face, the complexities

and disparities of urban health, and want specialized training in the ethics, values, and

politics of health care in our increasingly multi-dimensionally diverse society.

possible children. Parents should support selection againstdisability whenever selection is possible and better outcomeslikely exist. Te principle argues that [the] reason to selectthe child with better prospects is that the child [is likely to]benefit more than the other would by being caused to exist (2009).

According to PB, Kelley should have accepted abortionand helped the couple conceive another child withoutexpected disabilities. However, the case of Baby S involvessome issues not considered by Savulescu and Kahane, suchas monetary concerns and legal issues in kidnapping BabyS. Furthermore, PB overall does not consider the societalimplications of its directivesnamely, that only those withthe education and resources to consider selective abortioncan do so. PB provides a highly relevant framework toinform choices in selective abortion of the disabled, but it isnot complete in assessing this case.

Te case of Baby S provides a good example of bioethicsbeing applied to a real situation with real consequences. Tis

case also illustrates that few real life situations are as simpleas the assumptions employed by PB. Te case of Baby S

demonstrates that we cannot just consider core issues of anethical dilemma one at a timethey are all intertwined. Tatsaid, frameworks such as PB are still essential to makinginformed decisions. Just as this system informs the ethics ofselective abortion, others consider the monetary, legal, andsocietal implications. As bioethics grows as a field, we may

expect to see future frameworks that take all such mattersinto consideration so that future medical decisions may havemore comprehensive ethical guidance in situations such asthe case of Baby S.

-Klyde Breitton, University of Pennsylvania

Anderson, E.S. 2000. Why Commercial Surrogate MotherhoodUnethically Commodifies Women and Children: Reply to McLachlanand Swales. Health Care Analysis 8: 19-26.

Cohen, E. 2013. Surrogate offered $10,000 to abort baby. CNN. Availableat http://www.cnn.com/2013/03/04/health/surrogacy-kelley-legal-battle/index.html?iref=allsearch.

Savulescu, J. and Kahane, G. 2009. Te Moral Obligation to CreateChildren with the Best Chance of the Best Life. Bioethics23(5): 274-

290.


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Bioethics in Brief

In June 2013, Sarah Murnaghan, a 10-year-old girlsuffering from cystic fibrosis, was admitted to the ChildrensHospital of Philadelphia (CHOP) in desperate need of alung transplant. In the current framework of organ donation,

adolescent patients are placed on a waiting list behind adultpatients; hence, adolescent patients have a low success ratein obtaining organ donations. Te reasoning behind this ruleis based on the fact that childrens bodies are still growing,and the organ transplantation often needs to be performedagain. With Sarah Murnaghans worsening condition, herparents mounted a suit that resulted in a local judge orderingthe Organ Procurement and

ransplantation Network toadd her to the top of the adult

waiting list. CHOP surgeonswere then required to resize

the adult donor lungs and takea portion to transplant intoSarahs body. With the successfultransplantation, Sarah has slightly below 50% chance ofsurviving past one year, but significantly less chance ofsurviving past five years. Hence, transplants for adolescentpatients suffering from cystic fibrosis and other diseasesdelve deep into the bioethical issues of organ transplantationand equity.

Sarah was not alone in her predicament: an estimated30,000 American children suffer from cystic fibrosis, a raregenetic disorder. Te disease causes cells to produce excessivemucus, sweat, and digestive juices that clog passageways

throughout the body, most notably in the respiratory anddigestive systems. Te thickened mucus damages the airways,causing coughing and difficulty of breathing. Tis mucusalso serves as a breeding site for bacteria and fungi thatincrease the risk of infections such as sinusitis, bronchitis,and pneumonia. Additionally, mucus restricts the passage ofdigestive enzymes to the small intestine, inhibiting digestion.In combination, these complications lead to systemic failurethat requires organ transplants (NIH 2013).

While Sarah was not alone in her need for transplantation,she received special treatment, which raises equality and

judicial issues within bioethics. Currently, children in theU.S. are only eligible to receive organs from other child

donors (under 12 years) and have lower priority than adultson the waitlist for adult organs (12 years and above). Tispolicy is rooted in biological constraints: adolescents growafter the operation and the transplant needs to be resized. Inaddition, there is a less than a one in three chance of survivalfor lung transplantation past 10 years. Tere is not a highprevalence of child donors, especially for lung transplants,so Sarah had been waiting for over six months. With her

situation worsening, her parents used their resources to suein court to amend the rules and to allow their daughterto be placed atop the adult waiting list and to receive thetransplant. Te Department of Health and Humans services

reviewed the appeal and eventually it was decided by a singlejudge to give Sarah a temporary ten day period to receive atransplant after which the national policy will be reinstated.

Tough children across the nation are in need of organtransplants, Sarahs familys resources are ultimately whatallowed her to be was pushed to the top of the waiting list.

Tis case raises serious questions in equity and justice withinbioethics. Can children onlycompete for organ transplantsif their families have theeconomic and political meansto fight the federal law? Why

should one girl be able toobtain the transplant whilemany other patients within

CHOP still are waiting on the adolescent waiting list? Is itequitable that families with resources can circumvent the lawfor a temporary time while others must wait for the nationalpolicy to be reviewed? Is it fair that a patient can receive atransplant when national studies indicate that the adolescenthas a greater chance of mortality than surviving past five

years? Or rather, is the system unjust and are Sarahs parentsstarting a national conversation about allowing children inneed of transplants to receive them more fairly in the future?

Now, Sarah has received her lung transplant is recouping

at home in Delaware County and has bright hopes. Sinceher transplant in June, she has shown 0% lung rejectionand does not need to breathe through an oxygen machine.She is relearning how to walk making progress. Troughan emotional legal and medical process, Sarah has shownbravery. However, it also raises issues that should bethoughtfully considered by bioethicists to better deal withcases similar to Sarahs in the future.

-Sudesh Raju, University of Pennsylvania

CBS News. Web. 7 Sept. 2013. .

NBC. Web. 7 Sept. 2013. http://www.nbcphiladelphia.com/news/local/221150671.html>.

CNN. Web. 7 Sept. 2013. http://www.cnn.com/2013/08/26/health/sarah-murnaghan-update/index.html

NIH. Web. 7 Sept. 2013. .

Klugman, Craig. 6 June 2013. Bioethics.net. Bioethicsnet Blog.Bioethics.

Can children only compete for organtransplants if their families have theeconomic and political means to fight the

federal law?

Adolescent Organ Donation at the Childrens Hospital of Philadelphia


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Environmental Applications of Synthetic Biology

Bioethics in Brief

In 2010, President Barack Obama convened the newlyformed Presidential Commission on Bioethical Issues toevaluate the field of synthetic biology. Synthetic biologyaims to modify the genome of organisms to endow them

with specific qualities, which are often transferred fromgenes of other organisms or synthesized in labs. Tecommission, comprised of leading scientists, ethicists, andpublic policy experts, spent months hearing the testimoniesof numerous experts in relevant fields to determine whetherthis developing field posed significant biological, ethical,or ecological risks. While the commission acknowledgedpotential for harm, it outlined potential benefits of syntheticbiology and encouraged individual scientists to be responsible

when conducting research (United States 2010).Te field has since continued taking shape, and in mid-

April 2013, the University of Cambridge in England held

a meeting of synthetic biologists and conservationists todiscuss how synthetic biology could be used to benefit theplanet. One such proposed application of synthetic biologyis to genetically endow susceptible frogs with resistanceto chytridiomycosis, a fungal disease that threatens someamphibians with extinction. Already, it is likely that thisfungal disease contributed to the recent extinction ofRheobatrachus silius, a species of frog last seen in the

wild three decades ago (Callaway 2013). In May of 2013,Australian scientists revealed they were close to cloning R.silius, and many biologists believe that adding geneticallyengineered chytridiomycosis immunity is necessary to ensuresurvival of the cloned species (Sanderson 2009).

Another recent example of what synthetic biology canaccomplish is the development of genetically modifiedEscherichia coli bacteria. Tese bacteria move into plantroots and stimulate the production of auxin, a plant growthhormone. Roots of plants with these bacteria were foundto be longer, resulting in greater water retention in soil.

Tis discovery has potential for preventing desertification,the loss of vital soil nutrients that causes the degradation offertile land (Callaway 2013).

However, skeptics worry that synthetic biology couldhave unintended consequences. One major concern is thespreading of engineered genes into populations that were notmeant to be modified. While genetically engineered bacteria

may be able to help regulate pollution, bacteria can efficientlypass their genetic information to other bacterial cells

through the process of conjugation, potentially spreadingmodifications in an uncontrolled way (Sanderson 2009).Some environmentalists also worry that if synthetic biologyis used to help solve problems like reducing greenhouse gaslevels, other necessary public policy steps will not be takenbecause people will assume scientific advancements will takecare of the problem (Callaway 2013). Additionally, there is

the possibility that animals affected by genetic modificationmay be harmed. For example, the insertion of the fungalresistance gene in the R. silius frogs could have unforeseennegative consequences for the frogs themselves and for otherorganisms that interact with them, especially their predators.

While remaining wary of these concerns and others thatwere discussed, biologists, environmentalists, and ethicistsalike are optimistic about the potential for synthetic biologyto make meaningfuland safecontributions to the field ofenvironmental science.

-Ruchita Pendse, University of Pennsylvania

Callaway, Ewen. 2013. Synthetic biologists and conservationists open talks.Nature496: 281.

Sanderson, Katharine. Synthetic biology gets ethical.Nature. 12 May2009. Web.

United States. Presidential Commission for the Study of Bioethical Issues.

Synthetic Biology. 2010. Web. .


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Penn Bioethics Journal:What are the unique challenges ofproviding ethically appropriate care for adolescents?

Jennifer K. Walter: When caring for competent adultpatients, providers have responsibilities to adequately informpatients about their health conditions and guide themthrough decision-making. Ultimately, however, competentadults can choose to ignore medical advice and maketheir own decisions about whether to continue to receivecare. Adolescents are not yet considered legally capable ofmaking decisions about their own care, unless they havebeen legally emancipated. However, they possess many, ifnot all of the capacities to make decisions for themselvesthat do not substantially change when they become the ageof majority, 18 years old in most states. Terefore, whenadolescents express a strong opinion about their care that is

different from their parents wishes for them it is importantto engage them in a discussion about why they are makingthat choice and the potential consequences of their decision.Some ethicists have argued that parents should maintainthe right to override their adolescents choices in seriousillness if they are refusing care, because this preserves thechilds opportunity to survive the illness and exercise theirautonomy in the future.1

PBJ: What is the physicians obligation to protect theautonomy of adolescent patients?

JKW: Physicians have an obligation to support thedevelopment of capacities for autonomy, or self-governance,

for adolescent patients because these capacities should benurtured in the relationships adolescents have with others.Decisions made while ill have a significant impact on allpatients, including children, and having control over someof these decisions impacts how individuals understandthemselves and the kind of control they have over their ownbodies. Adolescents may not yet have legal control overconsenting for treatment, but it is expected that outsideof emergency situations, assent, or the childs agreementto proceed, should be sought by healthcare providers toacknowledge the burgeoning autonomy of children andadolescents.2

PBJ: Why are goals of care conversations important inproviding good care?

JKW:When a child has a serious or chronic illness, datafrom parents demonstrate that they want honest, timely

information about their childs condition

3,4

and want toparticipate in choosing between different treatment options.Tese conversations discuss what goals or hopes parentshave for their child and how they would like to prioritizedifferent care options. Only by engaging families in thesediscussions about what they value most can we as healthcare providers offer truly family centered care. In fact, the

American College of Critical Care Medicine recommendsthat these kinds of conversations happen with patients andfamilies within 24-72 hours of patients being admitted tointensive care units.5

PBJ:How do you assess the quality of these conversations?

JKW:Tere is a whole body of research that assesses thequality of communication in healthcare and quantifieseverything from the amount of time that different membersof a conversation speak, the number of empatheticstatements used, and even different aspects of nonverbalcommunication. Most of this research relies upon at leastaudio taping of conversations (or video taping in cases thatassess nonverbal communication) and a standardized scoringsystem that is applied to the interaction.6,7

PBJ:What are some of the barriers for providers that preventthem from engaging families in goals of care conversations?

JKW: In the interviews

Ive done with pediatriconcologists and intensivecare doctors, they describeseveral barriers to havingfrank conversations withpatients and families aboutprognosis and goals ofcare. First, often thereis significant medicaluncertainty, and providersdo not want to be inaccurateabout a bad prognosis and

Interview

Jennifer K. Walter is an Assistant Professor of Pediatrics at the Childrens Hospital of Philadelphia at the University of

Pennsylvanias Perelman School of Medicine. As a clinical lecturer, she has taught the ethics and procedures for carry-

ing out pediatric medicine. Dr. Walter earned her MS in Health and Health Care Research at the University of Michigan

and her MD and PhD in Philosophy at Georgetown University. The Penn Bioethics Journal spoke with Dr. Walter about

the unique challenges for bioethics in pediatric care, the theory behind healthcare policy, and her own professional

trajectory.

Bioethics of Care for Adolescents

Adolescent Care and Health Policy A Conversation with Jennifer K. Walter


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upset families unnecessarily. Also, they want to preserve apatients or familys hope for recovery, so they may not beas frank as they could be. Finally, physicians in the hospitalare often caring for patients that they do not have a longterm relationship with, so they find it challenging to sharebad news with them because they believe it would be better

heard from a trusted provider who is not as readily available.Tese all contribute to delaying goals of care conversations.

PBJ:What were the conclusions of your study?JKW: I completed a study in the pediatric intensive careunit (PICU) where I examined how long after admission tothe PICU that a physician documented having a goals ofcare conversation with the patient or family. I found thatonly 1/3 of the sickest patients admitted to the PICU hadgoals of care conversations documented, which means thateven if other conversations were occurring, the informationof what they covered was not easily accessible to theircolleagues who cared for those patients later. I also looked to

see whether there was variation in how often conversationswere documented by different patient diseases categories anddiscovered that oncology patients were most likely to havehad a conversation documented. I also found that patients

with a cardiovascular diagnosis went longer from admissionto the documentation of a conversation. Tese differencesdemonstrate that different subspecialties may have differentthresholds for documenting these kinds of conversations.8

PBJ: How would the concept of equality function inhealthcare policy?

JKW: In terms of healthcare policy, equality refers to a

reduction in the disparities of health outcomes and kindsof care offered to different classes of patients. Tere issignificant evidence that there are health disparities basedon race, gender and class in the US.9,10 Many theoriesof justice defend an equality of opportunity, which wouldinclude access to health care that treats all like patients alike,regardless of race, class, gender or education.

PBJ:How does ACA ignore discussions of equality?JKW: Te ACA, while doing many important things toexpand access to health care to millions of Americans whoare currently uninsured, has largely focused on improvingthe quality of care, while not emphasizing the importanceof ensuring that all Americans receive similarly high qualitycare. In our article, we argued that this approach of ensuringequality-in-quality will improve health in important ways.Empirical evidence for this approach can be found in vaccinepolicies that worked to prioritize improving vaccinationrates among impoverished children and thereby reducingthe disparity in vaccination by this group, which lead toimproved immunity for the entire community.11

PBJ: Are there any real world examples of successes indecision making for bioethical issues utilizing deliberativedemocracy?

JKW:Deliberative democracy is an ideal described in politicalphilosophy of how citizens would respectfully discuss socialand political issues in terms accessible to other citizens while

holding each other accountable to the decisions agreedupon. Tere are some examples of how this process canbe approximated in smaller scale discussions about publicissues, but unfortunately, it has not been achieved by anygovernment at a large scale level. Choosing Healthplans

All ogether is a deliberative democratic exercise which hasbeen successful in allowing citizens to deliberate about justhealthcare systems.12

PBJ: How do bioethicists impact policies? What areexamples of particular individuals and their work?

JKW: Bioethicists have impacted political policies in severalareas. US Presidents have appointed a group of ethicists to a

Council on Bioethics, which under Obama is known as thePresidential Commission for the Study of Bioethical Issues.

Te previous chairs included ethicists Edmund Pellegrinoand Leon Kass and the current chair of this Commission is

Amy Gutmann. Tese Councils have significant influence indescribing the ethical issues around public policy issues likestem cell research, newborn screening and our responsibilitiesto the aging members of society. Additionally, bioethicistslike Ezekiel Emanuel have been influential in the design ofthe Affordable Care Act and have advocated for wider accessto health care in the US.

PBJ:Please explain your academic trajectory. How did yourinterests in philosophy develop and lead to medicine?

JKW:I have wanted to be a physician since I was about 7years old, but when I started college my parents encouragedme to major in whatever I enjoyed, since I could completemy premed requirements at the same time. I fell in love

with philosophy and the way it taught me to critically thinkabout many different aspects of life. I thought my trainingin philosophy would end when I started medical school,but then I learned about the program at Georgetown thatpaired both a PhD in Philosophy with a medical degree. Idont believe the program still exists, but Edmund Pellegrino,

who started the program, was a visionary in recognizing thatclinicians who were bioethicists have a unique understandingof bioethical challenges and the potential solutions to thosedilemmas.

PBJ: How does your knowledge of philosophy, and bioethicsin particular, inform your day-to-day practice as a physician?

JKW:Because of my training in philosophy, I developed theability to recognize how individual behaviors or institutionalpolicies perhaps could have a larger impact on how we ashealth care providers fulfilled our ethical obligations to carefor patients. For example, I realized that when physiciansavoided the difficult conversations with families and patients

Healthcare Policy

Deliberative Democracy, Bioethics, and Policy

Making

Professional Experience

Adolescent Care and Health Policy


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because those were uncomfortable to have, they could also befailing to meet their obligation to ensure patients have theinformation they need to make decisions about their care.

Tis avoidance and lack of communication could actually bedisrespectful and not acknowledge the patient and familysautonomy. Tis concern led me to consider the system

level barriers that prevent providers from having thoseconversations and find ways to help providers live up to thoseobligations in a way that is authentic and compassionate.

PBJ:Conversely, how does your experience as a physician giveyou a unique perspective within the bioethics community?JKW: Philosophers and other ethicists are incredibly skilledat solving puzzles and separating out the individual threadsof an argument to distinguish the different things at stakein a moral dilemma. However, because they dont live in theclinical world, they may not understand the large distancebetween ethical issues that have been resolved theoretically,but still on a day to day basis are challenges. Tere is

significant consensus on issues like the reasons for andimportance of obtaining informed consent. However, thepractice of informed consent is still incredibly murky andimperfect. My experience of actually practicing medicine,offers a new perspective on how to translate what appears tobe a simple solution to the complicated real world reality ofthat lived challenge.

PBJ: How can undergraduate education be improved toenable students to pursue interdisciplinary studies in fieldslike the life sciences, humanities, healthcare management,and related fields that eventually affect patient outcomes?

JKW:I benefited from attending a true liberal arts school

where I both was required to take many classes in thehumanities and social sciences, while still completingmy science requirements for medical school. I think theuniversities which offer a broad curriculum, like the one I wasexposed to at Loyola Chicago, gives students an opportunityto be exposed to different methodologies and bodies ofliterature which offer cognitive flexibility when confrontingnew problems and recognition that different disciplines maybe encountering similar problems methodologically and canshare resources in solving problems. rue interdisciplinary

work requires true experts in different fields to be indiscussion with each other about novel solutions to problemsand problem-solving.

-Interview and questions by Anand Muthusamy, Universityof Pennsylvania

-References and responses written by Jennifer K. Walter

References

1. Ross L. Children, families and health care decision-making.NewYork: Oxford University Press; 1998.

2. Walter JK. Supporting Her Autonomy: Te Obligations ofGuardians and Physicians in Adolescents Refusals of Care.Journalof Clinical Ethics.2012;23(1):56-59.

3. Shudy M, de Almeida M, Ly S, et al. Impact of pediatric criticalillness and injury on families; a systematic literature review.Pediatrics. 2006;118(S3):S203-219.

4. Meert KL, Eggly S, Pollack M, et al. Parents perspectives onphysician-parent communication near the time of a childs deathin the pediatric intensive care unit. Pediatr Crit Care Med.Jan2008;9(1):2-7.

5. Davidson J, Powers K, Hedayat K, et al. Clinical practice guidelinesfor support of the family in the patient-centered intensive careunit: American College of Critical Care Medicine ask Force2004-2005. Crit Care Med. 2007;35(2):605-622.

6. Curtis J, Engelberg R. Measuring success of interventions toimprove the quality of end-of-life care in the intensive care unit.Critical care medicine.2006;34(11 Suppl):S341-347.

7. Roter DL, Stewart M, Putnam SM, Lipkin M, Jr., Stiles W,Inui S. Communication patterns of primary care physicians.

JAMA : the journal of the American Medical Association. Jan 22-291997;277(4):350-356.

8. Walter JK, Rosenberg A, Feudtner C. ackling taboo topics:how to have effective advanced care planning discussions withadolescents and young adults with cancer.JAMA Pediatrics.2013;11:1-3.

9. 2010 National Healthcare Disparities Report.Rockville, MD:Agency for Healthcare Research and Quality;2011. 11-0005.

10. Medicine Io. oward Health Equity and Patient-Centeredness:Integrating Health Literacy, Disparities Reduction, and QualityImprovement: Workshop Summary. Disparities Reduction, andQuality Improvement: Workshop Summary 2009.

11. Davis MM, Walter JK. Equality-in-Quality in the Era of theAffordable Care Act.JAMA. 2011;306(8):872-873.

12. Goold SD, Biddle AK, Klipp G, Hall CN, Danis M. ChoosingHealthplans All ogether: A Deliberative Exercise for AllocatingLimited Health Care Resources.Journal of Health Politics, Policyand Law.2005;30(4):563-602.

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Penn Bioethics Journal:How did you become interested inethics?David Perlman: I actually have a book on that. It talks abouthow I got into the fieldmainly, I was watching relativesdie and how poorly that was managed back in the day. Wevedone a much better job nowadays, but there are still a lot ofmyths about dying and end of life care.

Te other [reason] is that ever since I was a young kid, Iwanted to be a cardiothoracic surgeon. Te joke answer is Ifound out that doctors usually have to wear ties, and I hateneckties. But thereal answer is that

when I was inundergrad, I wastaking more and

more philosophyclasses and becameinterested in theintersection.

PBJ: What aboutfiction-writing?DP: Ive alwaysbeen interested inscience fiction. Interms of writing, Itried to practice myhand in undergrad

and thought aboutgetting a creative

writing degree andmaking less moneythan you do as aphilosopher, but I said I can do this on a part-time basis justfor fun. Ive always written, whether it is scholarly stuff orfiction. Te computer and I have always been one.

PBJ: So tell me a little bit about the premise behind TeOrgan Farm.DP:Its set in the future, when we have the confluence of

several different things. Weve had major healthcare reformin the US. Weve realized that we have to make cost cuts,and one of those thats natural to think about is we spend abillion dollars a year taking care of patients in a permanent

vegetative state.

Te book lays out the premise that there are these people whowill knock on your door and say, Te government can nolonger provide support, what do you want us to do? We canoffer them terminal sedation to ease their death or you cantake over paying this on some kind of private mechanism.

We still have anorgan shortage.

Teres this surgeonin the military, and hegets the bright idea

to take advantageof this health policyissue, and he buys upthe old GuantanamoBay medicalfacility in Cuba.He finds peoplein this permanent

vegetative state andoffers to the family tomaintain their lovedone in perpetuityfor something in

exchangea kidney.Tey also want toexpandwhy cant

we also get womenwho have this

condition who still are of reproductive viability and use themto grow babies for people who cant have them? It gets reallycreepy. I fictionalized all of this, but at the end of the book,theres an essay about how were one venture capitalist awayfrom an organ farm coming true.

Its also an interactive novel, which means you get to make

The next science fiction thriller might just be based on a recent book by University of Pennsylvania School of Nursing

senior lecturer David Perlman. The Organ Farm, an interactive eBook offered on Kindle, tells the story of a secret operation

that offers end-of-life care in exchange for donated organs. Not everyones reading of the story is necessarily the same

thoughthe book is written in a choose-your-own-adventure style, with crucial choices along the way. The Penn

Bioethics Journal sat down with Perlman to discuss the books premise, future prospects, and implications for society.

Interview


The Penn Nursing senior lecturer speaks on his interactive bioethics thriller,

The Organ Farm


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your own choices throughout, which is a remnant of mychildhood. Te idea I had for the book technically was allthe way back in 1993, but as a country, I dont think we werereally ready until erri Schiavo, where we had this come intopublic consciousness.

PBJ:You mentioned that you wanted to expand the series inthe future. Whats coming up?DP: I already have a prequel and a sequel planned. Teprequel will be a series of character sketches, and theyll allmeet in the end. And spoiler alert, theres room for a sequelin one of the branches of the ending.

PBJ:How did you come up with all the different choices?DP:Te first thing you have to do is map it all out. It becamelike I was programming a computer software. If this happens,then this. But it was really fairly easy to do with hyperlinktechnology. Hyperlinking is a nice way of having it be cross-platform.

PBJ:You offered to give readers who send in feedback afree book and a donation to a non-profit. How have peopleresponded?DP: People who have respondedits a handful rightnowhave said that they really like this book, so Im givingit away to people for free whove said that they would[send feedback]. I just made my first donation to Kivva.orgbecause someone finally sent me a question and an answer,and I put it on the Facebook page. Im not looking to get richby any stretch of the imagination, although I do have plansfor a screenplay. As long as I can get someone interested inHollywood, I think this would be a really cool idea.

PBJ:Would that also be interactive?DP: Im hoping people would be able to do it via their cellphones or clickers. Ive thought about the novel and turningit into a screenplay, and I have people Id love to play certainparts. For the Latino woman who gets a transplant, Id loveto have Jessica Alba because I really liked her in the seriesDark Angel. For the black male surgeon, Id like Will Smithbecause hes a homeboy from West Philadelphia.

PBJ: What do you want readers to learn from the choicesthey make in the interactive novel?DP:Te feedback that Ive had from readers is that whattheyll do is sit down first and use their gut instinct, butthen theyll go back and explore the various options, so itsalmost like getting 15 books in one. I hope that when theymake those choices, theyre also reflecting on why a charactermight choose that. But its also designed as a page-turner.

Its just like any other science fiction movie or book that hasscientific and societal implications. Gattaca doesnt talk aboutethics, but if you look behind, we really are talking about

what we do value as a species.

PBJ: You mentioned health policy reform as one of the

reasons for the book. Where do you think we are as a countryin terms of all the recent healthcare reform?DP:I dont think you can really be involved in healthcareand in ethics and not support some kind of universal access.

Were the only industrialized nation that doesnt have somekind of system. Weve seen whole-scale attempts to reviseour system in the past 50 years fail. What we have today islargely an incremental change, and I think that works bestfor our country. Its not necessarily what I would support, butsomethings better than nothing. We have a long ways to goin terms of health and social policy. I became a new dad andsaw what it was like for working moms, and we encouragepeople to have kids and then we dont offer them the support

they need to raise them.

PBJ:Why did you choose organ donation as one importantissue?DP:It lent itself to where I was headed. At the time, I had

just finished reading the book Coma, which talks about bodysnatchers. It just seemed to make sense. One of the goalsof the book is to get people to think about these kinds ofissues. I tell my students, Have you had a discussion with

your family member about what you might want to do ifsomething untoward were to happen to you? Very fewpeople have thought about it, especially 18 to 22 year olds.

You think youre invincible, but you really should be thinking

about those issues.

PBJ: Do you think university students should have to takean ethics requirement?DP:It depends on which students. Before we send anyoneout into the world, you know, its like Socrates said, Teunexamined life is not worth living. You dont want peopleto be robots and do their jobs without thinking about whattheyre doing. You have to know what the ethical demandsare for your particular discipline. But what Id really like tosee is to have [ethics] integrated into various facets of thecurriculum. What you dont want is people to think of theethics course as separate from their discipline. You shouldalways be thinking about those things because youre goingto run into them in real life.

-Interview and questions by Lucy Chen, University ofPennsylvania



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Introduction. Te code of life is more than a sequenceof As, Cs, s, and Gs. Muscle cells in the human heartcontain the same DNA as skin cells in the foot, yet thesetwo cell types behave in radically different ways. Bothcontain the DNA for over 20,000 human genes but expressonly the ones needed for their own form and function.

Tese differences in gene expression are modulated byepigenetic controls. Epigenetics refers to any heritablechemical modification of DNA that alters expression

without changing genetic sequence. Neurodevelopmentaldisorders, immunodeficiency, cancer, and other illnesses canresult when these mechanisms go awry.

Methylation. In humans, enzymes calledmethyltransferases add methyl groups to short DNAsequences, called CpG sites, abundant in the genome.Methyl groups block transcription factors (gene activators)from binding to DNA and performing their normalfunction. Although epigenetic factors do not change thesequence of DNA, they can affect the phenotype, theobservable characteristics of the organism. Specific patternsof methylation are necessary for a cell to modulate the levelof expression of each of its genes.

Cancer. DNA methylation has been referred to as the

hallmark of cancer (Szyf 2004). Abnormal methylationpatterns throughout the genome that cause blockage of tumorsuppressor genes have been linked to many types of cancer.For instance, breast cancer generally exhibits inactivationof the gene BRCA1. In sporadic (i.e. non-familial) cases,this suppression is usually caused by hypermethylationrather than mutation of the gene (Rice 2000). In othercases, hypomethylation causes overexpression of the flapendonuclease 1 gene and lead to breast cancer in somepatients (Singh 2008).

Neurological. Methylation abnormalities have beenlinked to a wide range of diseases. Fragile X syndrome,

one of the leading genetic causes of intellectual disability,is characterized by hypermethylation, which disrupts

the production of protein necessary for normal braindevelopment. Patients suffering from this disorder are atrisk for autism, ADHD, decreased IQ, infertility in females,and distorted facial features (Jacquemont 2011).

Psychological. Epigenetic mechanisms can alsoimpact psychological states. In an animal study, rat pupsthat received better maternal care in the form of licking,grooming, and arched-back nursing had lower levels ofmethylation at the glucocorticoid receptor gene. Tese ratsdisplayed less intense responses to stressful situations thanthose who received poor maternal care. Te researchers wereable to eliminate these differences via epigenetic interference

(Weaver 2004).

Fundamental Advantages. Te aforementionedepigenetic roots of disease are attractive targets for therapy.

Aberrant DNA methylation patterns are more easilyreversible than genetic mutations. In the case of cancer,epigenetic therapy coaxes tumor cells to return to a healthystate, rewiring their methylation patterns so the cellsexpress genes that halt their cancerous uncontrolled growth.

raditional chemotherapy strategies, on the other hand,aim to kill cancer cells and are fundamentally more toxic topatients since healthy cells are also harmed.

Recent Successes. Tere have been some excitingclinical successes with the first generation of epigenetictherapies. o date, four epigenetics treatments have beenapproved by the FDA for use in cancer patients: Zolinza,Istodax, Vidaza, and Dacogen (Claus 2005).

Te first two are histone deacetylase inhibitors andprevent histone modifications, a type of epigenetic change;the second two inhibit DNA methylation. Tese compoundsare chemical analogues of the DNA base cytosine (C),and at low doses, they bind to the methyltransferases so thatthey dont come into contact with the patients actual DNA,preventing the DNAs methylation. At high doses, they

Epigenetic phenomena are known to be a root cause of many common diseases. To date, the FDA has approved four

epigenetic therapies that show promising results for prolonging lives of terminal cancer patients. However, there is

a relative lack of knowledge about long-term epigenetic effects, especially those that affect future generations. We

propose a heightening of standards for epigenetic therapy: therapies should be targeted to specific genes in specific cells

and cannot affect the germline and patients epigenomes should be sequenced before and after treatment. Moreover,

further research should be performed to answer questions about transgenerational epigenetic effects, to analyze the

effects of altered epigenomes in the long term, and to develop superior assays for screening epigenomes. We highlight

current research in the field, including the work of the Penn iGEM group.

Article

U P, P GEM

Te Potential of Epigenetic Terapy andthe Need for Elucidation of RisksJosh Tycko, Danielle Fields, Daniel Cabrera, Mahamad Charawi, Bradley Kaptur

Epigenetics Background

Epigenetic Diseases

Epigenetic Therapy


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can incorporate into the DNA or RNA itself and reducecell viability. Tese treatments are used, at low doses, toreverse hypermethylation in patients with myelodysplasticssyndromes (MDS), a spectrum of blood cell disorders thatcan lead to anemia and heighted susceptibility to infections.

Te drugs effectively reverse cancerous hypermethylation

and return standard function to cell-cycle genes, restoringnormal growth rates. However, fewer than 10 percent ofpatients experience a complete response, a total reversalfrom diseased to healthy bone marrow and blood (Silverman2002).

Problems. Te results of first generation epigenetictherapies are promising, but these drugs should not beseen as the ideal model for future developing therapies,especially if doctors want to treat younger patients withnon-lethal epigenetic diseases. First generation drugs fail tosatisfactorily address many issues. For one, they all inhibitDNA methylation processes. As previously mentioned,many cancers can be caused by low methylation levels, and

would need to be treated with drugs that restore normalmethylation levels (Feinberg 2004).

Second, the current drugs work by blindly affecting allgenes in the genome of all the cells they encounter. One ofthe scientists behind the Dacogen studies noted there is apotential for harm, but so far the adverse events, includingred blood cell suppression, diarrhea, anorexia, and others,have been deemed acceptable by the FDA (Issa 2007). It ispossible that the potential for greater harm will be realized ifepigenetic therapies are used on patients with a much longerexpected life span than the current patient population.

Long Term Risk. Research has not yet fully elucidatedthe effects of DNA methylation (Rothstein 2009). Terapiesmay have off-target effects that are difficult to observeespecially if they appear years after the initial therapy.

o date, approved trials have been conducted with verysick, elderly cancer patients, but research has confirmedepigenetic modifications can affect us on a longer, eventransgenerational, time-scale (Rothstein 2009). Clinicaltrials however do not normally track side-effects ten, twenty,or thirty years after treatment. If these treatments alleviatedisease in the short term but eventually cause unforeseeableepigenetic abnormalities, are they acceptable for youngerpatients with non-terminal diseases? Most would arguethis depends on the gravity of the adverse effectsa risk/benefit analysis similar to that performed for any drugapproval should be conducted. Terefore, clinical trialsmust be designed to take these risks into account. rialsand follow-ups should last for a sufficient amount of timeto assess these risks on the decade time scale. On theother hand, if the drug does show an immediate benefit inthe trial subjects, the ethics of delaying its medical use untilthe conclusion of the trial must be assessed. Certainly, trialsof such durations with these looming questions would beunfavorable for the pharmaceutical investment community.Comprehensive diagnostic tests could help balance the

need to push new drugs and ensure safe use. Methylation-sensitive genome sequencing in multiple cell types foreach patient would reveal potential off-target effects. Tiskind of personalized medicine could obviate the need ofa longitudinal clinical trial. Tis is difficult and expensive

with existing technologies, and these procedural problems

must be overcome so that adequate assessment of epigenetictherapies can be performed (Laird 2010). As more researchis conducted, the balance between clinical trials and personaldiagnostic tests and the responsibilities of those involvedmust be considered.

Trans-generational Risk.Te issues discussed thus farare not unique to first generation epigenetic therapies. Teyact blindly not only on a genomic level, but also in termsof affected cell type. We cannot exclude the possibility thatthese treatments will affect the epigenomes of germlinecells. In fact, recent studies demonstrate that Dacogen couldinterfere with embryo implantation and harm the fetus ifgiven to a pregnant woman or to a man or woman planning

on having children (Ding 2012). Tere is evidence thatepigenetic modifications can be inherited by children andeven grandchildren, so doctors need to keep the health offuture generations in mind (Grossniklaus 2013). Te effectof epigenetic therapies on germline cells should be measurednot only while the drug is being administered, but also infollow-ups after the treatment is finished. It is critical thatmore basic research is performed to determine the extent oftransgenerational epigenetic effects. If we acknowledge thatsome patients will have children regardless of any warnings,

we must consider if it is acceptable to have syntheticallyaltered epigenomes in the population.

Higher Standards. Continued development of firstgeneration epigenetic therapies that affect whole genomesand any cell type should be accompanied with openacknowledgement of potential undetectable harm. o date,epigenetic therapy has been held to the same safety standardsas other cancer therapies. However, as these drugs affect geneexpression, the basis of our existence, it is more appropriateto hold them to the standards of gene therapies. Tat entailsan expectation to target only the genes, pathways, and cellsrelevant to the disease (U.S. Food and Drug Administration).Germline transmission of epigenetic modifications shouldbe unacceptable. Animal model studies are always carriedout before therapies are tested with humansthese mustcontinue to be carried out rigorously before epigenetictherapies are more widely applied. In particular, researchersmust consider non-mouse models as most mice can onlylive for around two years, which may not properly modellong-term epigenetic effects. Patients epigenomes shouldbe screened, so doctors can be sure the proposed therapyis relevant to the individual, just as they would sequence apatients genome to be sure of a genetic disease. Genome

wide epigenetic sequencing has recently become feasible,although it is still difficult and somewhat error prone (Laird2010). Tere is a need for further development of this

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Ethical Questions

Second Generation Epigenetic Therapies

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technology to enable the promise of personalized epigenetictreatment.

Research at Penn and Beyond. Tese more stringentsafety standards demand the development of second-generation epigenetic therapeutics that are properly targetedat the genomic and cellular levels. In the past few months,

we have seen promising initial published work on new toolsfor manipulating the genome in a careful, targeted manner.Histone methylases, histone demethylases, and DNAdemethylases have all been engineered to act on specific DNAsequences (Konermann 2013, Mendenhall 2013, Maedner2013). Our research team at the University of Pennsylvania,Penn iGEM, took initial steps to complete this suite oftools by designing a novel enzyme that selectively restoresmethylation at specific DNA sites. More importantly, wehave developed an alternative DNA methylation assay, calledMaGellin, which is significantly simpler, faster, and cheaperthan methylation-sensitive sequencing for applications likeours to accelerate the optimization of these tools. Tese efforts

would not have been possible without the expert advice ofthe University of Pennsylvanias epigenetics research labs. Dr.Marisa Bartolomeis lab is actively studying how methylationpatterns are transmitted across generations. Additionally, Dr.Rebecca Simmons lab in the Perelman School of Medicinehas discovered a way to reverse epigenetic modificationsincluding DNA methylation and prevent the onset of obesityin a rat model.

Conclusion. Epigenetic phenomena have a significantimpact on the way we live and grow and can be responsiblefor the way we die. Te need for epigenetic therapies is clearand the initial successes are promising for cancer patients,but the model for future developments is not yet set in stone.

If doctors want to treat younger patients with non-lethalepigenetic diseases, the consideration of risks must includethe long term, and the decisions in the clinic must be basedon data from researchers asking fundamental questions.

Te proposed second generation epigenetic therapies couldovercome the hurdles of restoring methylation, as opposedto only inhibiting methylation, and targeting specific genesas opposed to the entire genome. However, the issues oftheir delivery and cellular targeting still loom. While it willrequire significant effort from basic researchers to determinethe relevant mechanisms to optimize the clinical strategies,the path forward is promising.

About the AuthorsPenn iGEM is an undergraduate research team that

only exists because of the generous support of many

individuals and companies (see http://2013.igem.

org/Team:Penn). Dr. Brian Chow of Penn Bioengineer-

ing advises and directs the team. Dr. Jordan Miller of

Bioengineering at Rice University also advises the team.

Spencer Glantz, Mike Magarici, Avin Veerakumar, and Dr.

Orkan Telhan have also provided invaluable expertise.

Drs. Brian Chow, Benjamin Tycko, and Marisa Bartolomei

reviewed and provided comments on this manuscript.

The Potential of Epigenetic Therapy and the Need for Elucidation of Risks

ReferencesCampion, J., Milagro, F., & Martinez, J. A. 2010. Epigenetics and

obesity. Progress in Molecular Biology ranslational Science 94: 291-347.

Claus, R., Almstedt, M., & Lubbert, M. 2005. Epigenetic treatment ofhematopoietic malignancies: in vivo targets of demethylating agents.Seminars in Oncology32(5): 511-520.

Ding, Y. B., Long, C. L., Liu, X. Q., Chen, X. M., Guo, L. R., Xia, Y.

Y., et al. (2012). 5-aza-2-deoxycytidine leads to reduced embryoimplantation and reduced expression of DNA methyltransferasesand essential endometrial genes. PLoS One 7(9): e45364.

Feinberg, A. P., & ycko, B. 2004. Te history of cancer epigenetics.Nature Reviews Cancer4(2): 143-153.

Grossniklaus, U., Kelly, B., Ferguson-Smith, A. C., Pembrey, M., &Lindquist, S. 2013. ransgenerational epigenetic inheritance: howimportant is it?Nature Reviews Genetics14(3): 228-235.

Issa, Jean-Pierre. Interview by Nova.Nova. Public Broadcasting System.October 16, 2007.

Jacquemont, S., Curie, A., des Portes, V., orrioli, M. G., Berry-Kravis,E., Hagerman, R. J., et al. 2011. Epigenetic modification of theFMR1 gene in fragile X syndrome is associated with differentialresponse to the mGluR5 antagonist AFQ056. Science ranslational

Medicine 3(64): 64ra61.Kerkel, K., Schupf, N., Hatta, K., Pang, D., Salas, M., Kratz, A., et al.

2010. Altered DNA methylation in leukocytes with trisomy 21.PLoS Genetics 6(11): e1001212.Kondo, ., Bobek, M. P., Kuick, R., Lamb, B., Zhu, X., Narayan, A.,

et al. 2000. Whole-genome methylation scan in ICF syndrome:hypomethylation of non-satellite DNA repeats D4Z4 and NBL2.Human Molecular Genetics 9(4): 597-604.

Konermann S, Brigham MD, revino AE, Hsu PD, Heidenreich M,Cong L, Platt RJ, Scott DA, Church GM, Zhang F. 2013. Opticalcontrol of mammalian endogenous transcription and epigeneticstates.Nature500(7436): 472-6.

Laird, P. W. 2010. Principles and challenges of genomewide DNAmethylation analysis.Nature Review Genetics 11(3): 191-203.

Maeder ML, Angstman JF, Richardson ME, Linder SJ, Cascio VM,sai SQ, Ho QH, Sander JD, Reyon D, Bernstein BE, Costello JF,Wilkinson MF, Joung JK. 2013. argeted DNA demethylation andactivation of endogenous genes using programmable ALE-E1

fusion proteins.Nature Biotechnology.Online publication ahead ofprint.Mendenhall EM, Williamson KE, Reyon D, Zou JY, Ram O, Joung JK,

Bernstein BE. 2013. Locus-specific editing of histone modificationsat endogenous enhancers.Nature Biotechnology. Online publicationahead of print.

Rice, J. C., Ozcelik, H., Maxeiner, P., Andrulis, I., & Futscher, B. W.2000. Methylation of the BRCA1 promoter is associated withdecreased BRCA1 mRNA levels in clinical breast cancer specimens.Carcinogenesis21(9): 1761-1765.

Rothstein, M. A., Cai, Y., & Marchant, G. E. 2009. Te ghost in ourgenes: legal and ethical implications of epigenetics. Health Matrix19(1): 1-62.

Silverman, L. R., Demakos, E. P., Peterson, B. L., Kornblith, A. B.,Holland, J. C., Odchimar-Reissig, R., et al. 2002. Randomizedcontrolled trial of azacitidine in patients with the myelodysplastic

syndrome: a study of the cancer and leukemia group B.Journal ofClinical Oncology 20(10): 2429-2440.Singh, P., Yang, M., Dai, H., Yu, D., Huang, Q., an, W., et al. 2008.

Overexpression and hypomethylation of flap endonuclease 1 gene inbreast and other cancers.Molecular Cancer Research6(11): 1710-1717.

Szyf, M., Pakneshan, P., & Rabbani, S. A. 2004. DNA methylation andbreast cancer. Biochemical Pharmacology68(6): 1187-1197.

U.S. Food and Drug Administration. Cellular and GeneTerapy Guidances. Last modified July 2, 2013. http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTerapy/default.htm.

Weaver, I. C., Cervoni, N., Champagne, F. A., DAlessio, A. C., Sharma,S., Seckl, J. R., et al. 2004. Epigenetic programming by maternalbehavior.Nature Neuroscience7(8): 847-854.


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Monetary Compensation of ResearchSubjects: Te Shortfalls of Research

Standards in Preserving Autonomy

Respect for autonomy is one of the cornerstoneprinciples of bioethics. According to om Beauchamp andLeRoy Walters, two leading bioethicists at the KennedyInstitute of Ethics, personal autonomy refers to personalself-governance: personal rule of the self by adequateunderstanding while remaining free from controllinginterferences by others and from personal limitations thatprevent choice (2003). Te idea that one should respect

another persons right to decide his or her own fate islargely a product of Western culture and has become deeplyingrained in biomedical research ethics. Te principle ofautonomy is rooted in the Kantian conception of humanbeings as ends in themselves and never only as means toan end ( Johnson 2012). Tis paper explores the principleof respect for autonomy as it relates to the practice ofmonetarily compensating human research subjects.

In the United States, in 1979 the Belmont Report: EthicalPrinciples and Guidelines for the Protection of Human Subjects of

Research, Report of the National Commission for the Protectionof Human Subjects of Biomedical and Behavioral Research,hereafter the Belmont Report, helped establish an ethicalframework for biomedical research involving human subjects.

While the Report has no legal enforcement mechanism, thescientific community has embraced the Reports guidelinesto help resolve potential ethical dilemmas. Te BelmontReports principles also guide institutional review boards(IRBs) and executive bodies in the US that oversee mostresearch projects involving human subjects. IRBs are usually

affiliated with academic institutions and consist of at leastfive professionals of varying backgrounds. Tese individualshave the authority to approve or reject any research projectin which human subjects are involved (DHHS 1993). Eachmajor institution conducting human subject research willhave at least one such IRB panel that must approve anyproposal of such research.

Te Belmont Report highlights three ethical principlesthat serve as the moral backbones for biomedical researchethics: respect for persons, beneficence, and justice (HEW1979). Central to the principle of respect for persons isthe notion that every person be treated as an autonomousindividual. According to the Belmont Report, an autonomousindividual is someone who is capable of making personaldecisions through careful deliberation. o respect autonomyis to not obstruct this decision-making process.

Te Belmont Report underscores the importance ofinformed consent as a way to ensure respect for autonomy.In order to provide informed consent, a potential humanresearch subject should be made aware of what a researchproject entails and be afforded the right to choose whetheror not to participate in the project. Informed consent is

contingent upon three factors: information, comprehension,and voluntariness. A potential research subject mustbe given a thorough overview of a research project in anunderstandable manner. Ultimately, the subject must usethis understanding to voluntarily give consent to participatein the project (HEW 1979).

When voluntarily giving consent, an individual mustbe free of coercion or undue influence (HEW 1979).

Te Belmont Report states that undue influence occursthrough an offer of an excessive, unwarranted, inappropriate

Shivam Amin

Biomedical researchers are expected to respect the autonomy of human subjects through the process of informed con-

sent. The Belmont Report established the principle of respect for autonomy as a cornerstone of biomedical research

ethics in 1979. However, researchers can find it difficult to uphold this ideal when compensating human subjects. Ambi-

guities in both the Belmont Report and government guidelines complicate pinpointing exactly how to preserve the au-

tonomy of research subjects. The process of informed consent itself poses a set of problems for researchers. Specifically,

the term undue inducement, describing a concept central to the preservation of a subjects autonomy, is particularly

vague and warrants further investigation. It is certainly possible that researchers can undermine a subjects autonomy

through the offer of a monetary payment. However, the magnitude of this problem is nearly impossible to measure

because inconsistencies in policy make it extremely difficult for researchers to respect the principle of respect for au-tonomy in practice. Once some of these inconsistencies are resolved, researchers can then explore the underlying so-

Article

U S A, @..

Introduction

Inadequacies of the Belmont Report and U.S.

Government Guidelines


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or improper reward or other overture in order to obtaincompliance. Also, inducements that would ordinarily beacceptable may become undue influences if the subject isespecially vulnerable (HEW 1979). Te problem with termssuch as excessive and vulnerable is that they are vague.

At what point is an award excessive? In what situation is a

person deemed vulnerable?While the Belmont Report does not rigorouslydefine undue influence, excessive, or vulnerable, itis important to note that its purpose is simply to providea foundation of moral guidelines. It is necessary that theBelmont Report be vague so that it can adequately addressa wide range of ethical quandaries. Te real issue arises

when IRBs consider exactly how much vulnerable humanresearch subjects should be monetarily compensated. Anoffer of payment could unduly influence potential researchsubjects and compromise their autonomy, especially if theyare at the lower end of the socioeconomic hierarchy. TeIRB Guidebook and the Code of Federal Regulations

(CFR) are meant to guide researchers in dealing with suchambiguities, but neither provides enough specifications toguide practice. Te IRB Guidebook states that IRBs shouldprovide special safeguards when economically vulnerableindividuals or populations are involved in research that offersmonetary compensation. However, the IRB Guidebook doesnot offer any insight into what these special safeguardsshould entail (HHS 1993). CFR itle 45 Part 46 alludesto the protection of economically disadvantaged individualsand, like the IRB Guidebook, states that special measureshave to be taken when these disadvantaged individuals aremonetarily compensated (PHS 2009). Yet neither of thesedocuments elucidates exactly how these disadvantaged

individuals can be protected.Furthermore, just as the Belmont Report does not clearly

define the term undue inducement, neither does the IRBGuidebook, which makes it difficult for IRBs to preserveindividual autonomy. Te Belmont Report delineates a setof ideals to build a foundation for the protection of humanresearch subjects, but these ideals need to be expoundedupon as IRBs and researchers cope with specific situations. Itis difficult to reconcile the principle of respect for autonomy

with the actual practice of monetary compensation if IRBsare forced to act upon a set of vague axioms. Ultimately, the

vagueness of the IRB Guidebook means IRBs have littlemore to rely upon than the Belmont Report itself. DifferentIRBs often have different working understandings of theterm undue inducement, and even within a single IRBthere may not be a standard set of rules for how monetarypayments should be determined (Klitzman 2013).

Te definitions of terms like undue inducementare crucial because they are meant to protect individualautonomy through the exercise of informed consent by thepatient. Te purpose of informed consent is to formalize thedecision of an individual to be a research subject. Informedconsent is more than just a signature; it is more accurately

described in CFR itle 21 as a dialoguebetween researcherand subject, in which the researcher ensures that the subjecthas a comprehensive understanding of his or her role inthe project (2012). Trough informed consent, researchersand IRBs try to prevent undue inducement and uphold theprinciple

penn bioethics journal vol viii, issue ii

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