ethics’in’the’genomic’age’ - cornell...
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Timeline • 1906 Pure Food and Drug Act • 1948 Nuremberg Code – (from the 1946 Nuremberg Trials)
• 1962 Kefauver Harris Amendment to the Food, Drug and CosmeEc Act – (in response to the Thalidomide scandal)
• 1964 DeclaraEon of Helsinki (updated 1975, 1983, 1989, 1996, 2000, 2008)
• 1974 NaEonal Research Act – (in reacEon to the 1932-‐1973 Tuskegee Syphilis Study)
• 1979 Belmont Report
1906 Pure Food and Drug Act • Generally considered to be the “birth” of the FDA, although
not named as such unEl 1930 • Up unEl then, many patent medicines had high alcohol
contents, infant syrups contained opiates • Another contribuEng factor was the study of common food
preservaEves such as borax, benzoate, formaldehyde, sulfites, and salicylates • Young men recruited to eat meals with increasing doses of these
common preservaEves were called “The Poison Squad” • Truth in adverEsing
• Required that certain special drugs, including alcohol, opium, cocaine, heroin, morphine, and cannabis, be accurately labeled with contents and dosage
• 1938 Replaced by the Food, Drug and CosmeEc Act
1948 Nuremberg Code • 1946 Nuremberg Trials – Medical experiments conducted on thousands of concentraEon camp prisoners without their consent, resulEng in the death or permanent crippling of many of them
• Includes 10 points: – Voluntary consent of parEcipants is essenEal – Benefits of research must outweigh the risks – Avoid all unnecessary harm and suffering
• First advocacy of voluntary parEcipaEon and informed consent
Nuremberg Code • 1 The voluntary consent of the human subject is absolutely essenEal. • 2 The experiment should be such as to yield fruiful results for the good of society, unprocurable
by other methods or means of study, and not random and unnecessary in nature. • 3 The experiment should be so designed and based on the results of animal experimentaEon and
a knowledge of the natural history of the disease or other problem under study that the anEcipated results will jusEfy the performance of the experiment.
• 4 The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.
• 5 No experiment should be conducted where there is a prior reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.
• 6 The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.
• 7 Proper preparaEons should be made and adequate faciliEes provided to protect the experimental subject against even remote possibiliEes of injury, disability, or death.
• 8 The experiment should be conducted only by scienEfically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.
• 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where conEnuaEon of the experiment seems to him to be impossible.
• 10 During the course of the experiment the scienEst in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a conEnuaEon of the experiment is likely to result in injury, disability, or death to the experimental subject.
1962 Kefauver Harris Amendment • “Drug Efficacy Amendment” • In response to the Thalidomide scandal – Used as a sedaEve and an anE-‐emeEc for morning sickness
– Approved for used in Europe; no FDA approval in the US, although many US women took it anyway
– Caused severe deformiEes in fetuses • Drug manufacturers required to prove to the FDA that their products were effecEve and safe, and to disclose accurate informaEon about side effects – Requires clinical trials with informed consent
1964 DeclaraEon of Helsinki • Set of ethical principles regarding medical research developed by the World Medical AssociaEon
• First significant effort of the medical community to regulate research itself
• Incorporated Nuremberg Code with DeclaraEon of Geneva (updated HippocraEc Oath)
• Not a legally binding instrument in internaEonal law
• Updated 1975, 1983, 1989, 1996, 2000, 2008
DeclaraEon of Helsinki • Basic principles – Research with humans should be based on the results from lab and animal experimentaEon
– Research protocols should be appropriately examined
– Informed consent – Research should be undertaken by scienEfically/medically qualified people
– Benefits must outweigh risks
DeclaraEon of Helsinki • The US FDA rejected the 2000 and subsequent revisions, only recognizing the third (1989) revision, and in 2006 announced it would eliminate all reference to the DeclaraEon – Disagreement over whether placebos were an acceptable control, even when proven treatments were known
• As of October 2008, the DeclaraEon of Helsinki is replaced by Good Clinical PracEce in the US
1974 NaEonal Research Act • In reacEon to the Tuskegee Syphilis Study (1932-‐1973) – ProspecEve longitudinal study on the natural progression of untreated syphilis, even aker penicillin shown to be effecEve
• CreaEon of the NaEonal Commission for the ProtecEon of Human Subjects of Biomedical and Behavioral Research – Tasked with idenEfying basic ethical principles that should underlie biomedical research, and to develop guidelines on their incorporaEon
Ø Belmont Report
1979 Belmont Report 1. Respect for persons – Individuals should be treated as autonomous agents – People with diminished autonomy should be protected
Ø Informed consent – ParEcipants must be given the opportunity to choose what shall and shall not happen to them
– Consent process includes • InformaEon • Comprehension • Voluntary parEcipaEon (no coercion)
hlp://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html
Belmont Report: principle 2 2. Beneficence and non-‐maleficence – Human parEcipants shall not be harmed unnecessarily
– Research should maximize possible benefit and minimize possible risk
Ø Assess risks and benefits in a systemaEc manner Ø ProtecEon of confidenEality
Belmont Report: principle 3 3. JusEce – Benefits and risks must be distributed fairly Ø Research parEcipants must be selected using fair procedures
Ø PaEents have a right to access and receive care that is non-‐discriminatory, suitable and fair
Ø Healthcare resources should be allocated in a fair and equitable manner
Other principles • Many other factors also in play here • When we talk about ethics, we also implicitly include ELSI: ethics, legal and social implicaEons – Introduced by the Human Genome Project
• This implies that we not only take into consideraEon the medical ethics from the Helsinki DeclaraEon, and the research ethics put forward in the Belmont Report, but also various legal rights (e.g., privacy), as well as implicaEons of informaEon for the individual, the individual’s family, and society in general.
Right to privacy • First implicit declaraEon of a U.S. right to privacy
– 1890, Warren and Brandeis, Harvard Law Review • Many people argue that no such right exists or that the right to
privacy ‘should not be defined as a separate legal right’ • Universal DeclaraEon of Human Rights, ArEcle 12:
– No one shall be subjected to arbitrary interference with his privacy, family, home or correspondence, nor to alacks upon his honor and reputaEon. Everyone has the right to the protecEon of the law against such interference or alacks
• The U.S. Supreme Court finds: – The ConsEtuEon implicitly grants a right to privacy against
governmental intrusion – Also, many states grant the right to privacy and recognize the
following torts: • Intrusion upon seclusion or solitude, or into private affairs • Public disclosure of embarrassing private facts • Publicity which places a person in a false light in the public eye • AppropriaEon of name or likeness
Privacy • How does health data fit into privacy concerns? • It can be harmful to the subject for certain health informaEon to be made public – Imagine that a poliEcian has been diagnosed with a predisposiEon to Alzheimer’s. Public knowledge of this informaEon may result in his not geqng re-‐elected.
• But privacy is not absolute… – Imagine you have been diagnosed with SARS. Do you have a right to keep that private?
• HIPAA ensures some protecEon of healthcare informaEon
HIPAA 1996 • Health InformaEon Portability and Accountability Act – Requires that health care providers and others protect the privacy of health informaEon
– Sets boundaries on the use and release of health records
– Empowers individuals to control certain uses and disclosures of their health-‐related informaEon
– GeneEc informaEon is considered health informaEon, and is covered by HIPAA
Genomics data • SNPs, CNVs, genotype data, complete sequences
• Trying to decipher the geneEc basis for diseases – Many of the single-‐gene Mendelian diseases already known (OMIM)
– Complex diseases will be affected by many genes, some of which will have very small effects
– Need large amounts of data to get enough staEsEcal power to be able to alribute causaEon to variants
Benefits • Ideally, knowing the geneEc basis of an illness will allow for – Earlier detecEon of disease (perhaps while sEll asymptomaEc)
– Knowing risk can lead to steps to reduce chances of developing a parEcular disease
– More targeted drug administraEon (pharmacogenomics: variaEon in drug response related to geneEc variaEon)
– Beler therapies (although individual variaEon complicates malers) [precision medicine] • Different molecular signatures will respond to different treatments (e.g., Cancer Genome Atlas Network Nature 2012 paper: 4 geneEcally disEnct types of breast cancer; significant molecular heterogeneity within each subtype)
Pharmcogenomics: CombaEng adverse drug reacEons
• Fikh leading cause of death in the US • About 50% of drugs are metabolized by the cytochrome P450 family (~30 genes)
• Many adverse reacEons are caused by variaEons in enzyme-‐coding genes that can increase or decrease drug metabolism rates
• Increased metabolism rates → the drug is metabolized too quickly to have an effect
• Decreased metabolism rates → the levels of drugs in the body quickly reach toxic levels
Caveats • Genomics is not the end-‐all and be-‐all of scienEfic explanaEon – Also environmental, social, cultural, economic factors
• Fostering a gene-‐centric view of health may be detrimental by making everybody a “paEent” – May be appropriate for people with clear high risks for diseases with appropriate treatments (e.g., staEns for familial hypercholesterolemia)
– Most probably not appropriate for the vast majority of the populaEon
Specific genomic issues • Issues specific to genomic data include: – Large amounts of data produced – Future (unknown) uses of that data – ImplicaEons for family members – Ability and expectaEon of public release
• Main challenges are respecEng autonomy and protecEng privacy
• Need robust governance and oversight schemes – Ensure research integrity – Balance protecEon of interests of all involved
• ParEcipants, family members, communiEes, public, research community
Caulfield et al, PLoS Biol, 2008
Sample ethical quesEons • Who has access to personal geneEc informaEon? • If geneEc tesEng becomes standard pracEce, who should
have access? • Should parents have their children tested for adult-‐onset
diseases? • Should genes be tested for associaEon with behavioral
alributes? – If the goal is to treat “unacceptable” behaviors, who defines what
is “unacceptable”?
• Should only people with health insurance have access to precision medicine?
More sample quesEons • Is it okay to use paEent’s data to develop risk profiling and
diagnosEc tools? Is it okay to offer free profiling, in exchange for allowing use of that data in research?
• Should we profile paEents for diseases even if there is no known treatment?
• Will pharmaceuEcal companies focus more on secEons of a populaEon who are “geneEcally right” for the drugs they want to sell? – 3rd world countries would be less profitable – TargeEng smaller paEent populaEons may make the cost of developing a drug (~$500m) economically unviable
Genomic data: challenges to consent • Future unknown uses of sample (re-‐consent?) • Public release of data • Return of results (including far into future) • CommercializaEon of results • How do implicaEons for family and community members impact individual consent?
• PracEcal limitaEons (rapid and widespread disseminaEon of data) on the right to withdraw
Right to withdraw • Central component of exisEng research statements – Right to withdraw, at any Eme, for any reason
• MinimizaEon of this right may impact on public trust • DestrucEon of biosamples and wrilen informaEon feasible, but destrucEon of widely disseminated electronic data may not be – LimitaEons must be clearly communicated – RecogniEon (and communicaEon) of how far along in the research process withdrawal is sEll possible
• Genomics projects should design collecEon, storage and disseminaEon so as to maximize right of withdrawal
Return of results • Right not to know is implied in the principle of autonomy • Projects may result in informaEon ranging from:
– Clinically relevant – Genealogically relevant – RecreaEonally interesEng
• Do researchers have a moral duty to return such results to parEcipants? – What about associaEons found by researchers using that data for secondary
analyses? Do the secondary researchers have a duty to noEfy parEcipants, that they may never have had dealings with?
– What if the finding has no treatment? What if a treatment is developed years later?
– What if minors are used in research? Should acEonable data be returned to them or their parents?
• IniEal consent forms should specify whether results (incidental or otherwise) may be returned, and if the parEcipant wishes to be noEfied
• If results are to be returned, they should only be returned – If they are valid and confirmed (and have health implicaEons?) – Done so by professionals who can clearly explain the implicaEons
Public release of data • Strongly encouraged by internaEonal policy
– Provides significant scienEfic research uElity • But major implicaEons with respect to risk to privacy • Once data are public, cannot be withdrawn
• What are the actual harms and benefits that arise from public access to data?
• What are the implicaEons for family and community members?
• What is the appropriate balance between public access and individual privacy interests?
• Should there be a mechanism for compensaEon for harms or losses associated with making their data publicly available?
Restricted-‐access databases • May be appropriate to restrict access to data to researchers only – AuthenEcaEon requirement
• Databases with increasingly sensiEve or idenEfying data (e.g., linking genotypic to phenotypic records, such as medical health records) may benefit from access restricEons – Balance between uElity and risk to privacy
• Stringency and pracEcality of security and oversight will vary
Re-‐idenEficaEon • Anonymized parEcipants in large genomics projects can be idenEfied by cross-‐referencing their genomes with genealogy databases [Gymrek Science 2013] – Surnames can be recovered by profiling short tandem repeats on the Y chromosome (Y-‐STRs) and querying recreaEonal geneEc genealogy databases.
• A systemaEc review of re-‐idenEficaEon studies [El Emam PLoS One 2011] showed that in the 14 papers that they studied, on average, 25% of people could be re-‐idenEfied – Wide variaEon; most of the re-‐idenEfied people were in small-‐scale studies that did not adhere to exisEng standards
Public release implicaEons • IniEal consent form should clearly explain – Any data security mechanisms – Possibility of idenEficaEon – Possibility of geneEc profiling – Loss of right to control access to individual’s data (i.e., finality of release process)
– Any issues associated with family or community members • CollecEve consent may be applicable in small communiEes
Case study: 23andMe 2010
• Web-‐based, self-‐reporEng paradigm, 9126 parEcipants, 535076 SNPs
• Looked at 22 traits (none of them disease-‐related)
• Hair morphology (curl and color) • Eye color • Freckles • Methanethiol (asparagus) • PhoEc sneezing • Handedness • Footedness • Ocular dominance • Hand clasp
• Alached earlobes • AsEgmaEsm • Glasses • CaviEes • Braces • Wisdom teeth out • MoEon sickness • OpEmism • Sweet vs salty • Morning vs night
Eriksson et al, PLoS Genet 2010; Gibson et al, PLoS Genet 2010
23andMe study 2010 • Concerns: – No IRB review for human subjects research
• Exempted by commercial IRB
– Concerns over the consent document • Technical jargon an obstacle to understanding • Ambiguity over what data will be published • Agreement to parEcipate in research not separate from the rest of the document
– No access to raw data • Contrary to open access policies
IRB review • Human subjects research as defined by the Office for Human Research ProtecEons (OHRP) – Will the invesEgators obtain the data through intervenEon or interacEon with the parEcipant?
– Will the idenEty of the subjects be readily ascertained by the invesEgator or associated with the data?
• In both cases, commercial IRB said “no”
Consent document • All 23andMe parEcipants required to sign extensive
consent and legal agreement document – Services not intended to diagnose disease or be used to provide medical advice
– Acknowledges risks associated with obtaining unanEcipated self-‐knowledge
– Samples will be used to further the field of geneEcs and human health
– Before embarking on collaboraEons, further consent will be sought
• Consent for research bundled into an agreement to buy a service, not a freestanding decision
• One author clearly from Columbia – is he a “collaborator” for whom addiEonal consent should be sought?
Data access • 23andMe consent form clearly precludes open disseminaEon of parEcipants’ geneEc data
• Limited aggregate data not enough to idenEfy parEcipants
• PLoS GeneEcs editors had to balance: – Public good of open access to research – Public good of disseminaEng valuable science performed by a commercial company
• Decided on the laler, given that data was alainable via re-‐consent
Centralized databases • Enable the decipherment of geneEc basis of complex diseases
– StaEsEcal models require very large N • Enable examinaEon of gene-‐environment interacEons • Reduced reliance on parEcular populaEons
• Chance of idenEficaEon (even if data de-‐idenEfied) • Linking of genotype data to medical data may erode some of the privacy
safeguards • UlEmate lack of control
– Unreasonable to expect that in the long term you can control who has access to the data. Somebody at some point will make a copy
– Possibility of unintended unauthorized access to data – Push to make genomes publicly available
• Uncertainty of future applicaEons
• Does the individual's right to privacy outweigh the societal benefits that would arise from such a database?
PopulaEon effects • PopulaEon effects could be miEgated by use of large databases – Not applicable if using a homogeneous populaEon
• BRCA1 discovered by Skolnick using Mormon records – Mormon populaEon considered an excellent model for geneEc studies • Homogeneous • Strong founder effect • Good genealogy records • Large families • High rate of consent
– Some argue that the results of the study are highly specific to that populaEon and have been over-‐generalized
Biobanks • AmalgamaEon of bio-‐samples and databases • Samples may come from clinical seqngs, research projects, judiciary domains
• Oken naEonal resources
• Many issues similar to research databases: – Impact on rights of individuals – Future uses – CommercializaEon of knowledge
• Some specific – How to define the priority rights of researchers and companies over samples and data
Previous samples • How do we deal with consent for previously collected samples (e.g., millions of Essues stored in pathology labs)? – Can we even do genomic research on samples that were not consented for this type of research?
– Possible pracEcal problems with geqng re-‐consent • Permiled if samples were anonymized, or research is ‘minimal-‐risk’ (i.e., few implicaEons of research for the individual)
– RecogniEon that loss of individual’s control over their samples might be okay if for the common good?
– IRB approval necessary – If it is possible to re-‐idenEfy a sample, and a life-‐threatening condiEon is discovered, is there a duty to track down that person and tell them? Or is there a duty not to?
PopulaEon Biobanks • Iceland HSD
– First large populaEon-‐based naEonal biobank • deCode GeneEcs granted a private license to build the HSD
(Health Sector Database), 1998 – AmalgamaEon of health records, genealogy and genotypic database
– Sold to the government as an instrument to improve health services in the country (in large part via pharmacogenomics)
• Intended to find correlaEons between genes and diseases; the findings were to be sold to pharmaceuEcals and HMOs – $200 million deal struck with Hoffman-‐LaRoche to idenEfy genes associated with common diseases like stroke, heart disease, Alzheimer's disease, and emphysema
– Icelanders would get access to drugs resulEng from this for free
Concerns with deCode database • Fears that personal health informaEon could be accessed by
unauthorized persons, violaEng individual’s privacy • “Presumed consent” to have medical records entered
– Changed to an opt-‐out scheme – Only six months noEce from Eme of database construcEon to deny
inclusion of records – 140k/260k eventually gave bio samples (blood and Essue) and access
to medical records • Danger of naEonal geneEc stereotyping • deCode had monopoly control of data
– Exclusive commercial rights for 12 years – Sole arbiter of who else could use the data – Exclusive arrangement with Hoffman-‐LaRoche prevented others from
studying those diseases in the Icelandic populaEon • deCode could make data available to pharmaceuEcal and insurance
companies for a price
deCode and Icelandic government • Much internaEonal opposiEon to the database act
• ConstrucEon of database ceased aker Gudmundsdóqr v. Iceland (2003) – Ruled that ‘the 1998 law governing the creaEon of the database is unconsEtuEonal because it fails to protect personal privacy adequately’
• DeCode focused on gene hunEng instead • Introduced deCodeMe • IPO in 2000, went bankrupt in 2009, delisted from NASDAQ – Had never made money, and was increasingly indebted to its creditors
Who owns biodata aker bankruptcy? • EDH set up as a subsidiary of deCode, with access to database and
biosamples, Stefansson as execuEve chair and head of research • Bought by Saga Investments, but public facing company sEll called
deCode • Promised to do whole genome sequencing of 2500 Icelandic
genomes – According to Stefansson, no need for re-‐consent
• Amgen bought deCode in December 2012, primarily for use of its database – Stopped the DTC arm of the company
Conclusions • Much peer-‐reviewed science accomplished
– E.g., 2012 Linked age of father to incidence of auEsm, discovered gene predisposing to Alzheimer’s, and a gene protecEve against Alzheimer’s
• But, all genomic data now in the hands of a for-‐profit commercial company, with no direct benefit to Icelanders
UK BioBank • Will follow 500,000 volunteers (aged 45-‐69 at Eme of enrollment) for decades, trying to correlate genes, lifestyle and disease
• Lengthy and rigorous public debate period • Set up as a charity (not for-‐profit) – Any profits will be re-‐invested in the BioBank
• Well-‐structured, clearly wrilen ethical guidelines, including anonymizaEon of data and right to withdrawal; re-‐consent required; no return of results
• Open to scienEfic community • PosiEons itself as custodian of the data • In the event of closure: – “A detailed strategy is being developed…”
Direct-‐to-‐Consumer geneEc tests • An enabling tool for exercising one’s autonomous quest for personal health informaEon
• Has value in raising awareness of geneEc tesEng and screening, as well as prevenEve medicine
• Concerns: – Quality – UElity – Harm – Unclear privacy policies – False adverEsing
DTC: Possible harms • Unique seqng of DTC is highly accessible, potenEally anonymous, oken free from involvement of professional third parEes
• Anonymity – DTC companies oken have no effecEve way of authenEcaEng personal idenEEes
• Non-‐consensual use of other people’s samples – CollecEon of geneEc material (saliva, hair, etc.), leading to unauthorized usage of personal informaEon
– ConsEtutes an intrusion on basic human dignity and autonomy, violaEon of source’s bodily integrity, breach of informaEon privacy, deprives the source of opportunity to exercise right not to know
– UK “DNA thek” offence under the 2004 Human Tissue Act
Non-‐consensual DNA thek as “art”
• Heather Dewey-‐Hagborg
• Uses markers for sex, ancestry, eye color, hair color, freckles, lighter or darker skin, and certain facial features like nose width and distance between eyes
• No informaEon on age, so makes everybody around 25
MtDNA Haplogroup: H2a2a1 (Eastern European); SRY Gene: present; Gender: Male; HERC2 Gene: AA; Eye Color: Brown
MtDNA Haplogroup: D1 (NaEve American, South American); SRY Gene: present; Gender: Male; HERC2 Gene: AA; Eye Color: Brown
GeneEc tesEng of minors • SensiEve issue, protected under principle 1 • Opponents:
– Can cause emoEonal distress (psychological harm) – Adverse effects on self-‐esteem and self-‐percepEon – Loss of future adult autonomy, privacy and confidenEality
• Proponents: – Benefits of certainty outweigh the harms of ambiguity – Learning geneEc informaEon can be liberaEng (can provide valuable
preparaEon acceptance Eme) • Consensus that predicEve tesEng is jusEfied if there are evident medical
benefits, but inappropriate for adult-‐onset disorders or carrier-‐status (relevant for reproducEve decisions) [not necessarily relevant wrt DTC]
• Other factors to take into account: – Growing emancipaEon of minors – RelaEve maturity of some minors
• DTC offers unrestrained access (although all require the signatory of the consent form to say that are over 13 or 18) and is not supposed to be used for medical purposes
GeneEc counseling • Absence of adequate geneEc counseling – Consequences of unanEcipated knowledge – Impose professional decision-‐making on naïve laypeople – Lead to adverse clinical and personal decisions such as unnecessary tesEng or harmful reliance on misinterpreted test results • ProphylacEc mastectomies, pregnancy terminaEons, cessaEon of prescribed medicaEon usage
• Healthcare professionals are not necessarily trained in geneEc counseling – How to convey genomic informaEon to paEents – Whether to withhold informaEon from paEents – Whether to share informaEon with close relaEves – How to allow paEents and relaEves the right not to know
Ethics challenges wrt DTC • Autonomy: – Promotes availability of geneEc tesEng – Allows anonymous tesEng (decrease concerns about discriminaEon)
– But fully informed consent is difficult to guarantee • No (or perfunctory) geneEc counseling offered • MulEple geneEc tests compound complexity of pre-‐test counseling
– Tenet of non-‐direcEve decision making unduly influenced by commercial adverEsement
– Ease of misrepresentaEon (sending somebody else’s sample, or pretending to be older than you are) breaches autonomy and non-‐maleficence
DTC ethics • Beneficence/non-‐maleficence: – Enables beler health and lifestyle decisions
• Dependent on actual uElity of DTC tests • MarkeEng may exaggerate medical uElity
– Lack of follow-‐up counseling may lead to harm from inappropriate medical or lifestyle decisions
– No strategy in place to either inform or educate ‘at risk’ relaEves
DTC ethics • JusEce: – Low cost of geneEc tesEng makes it available to all – But, follow-‐up worries may put addiEonal strain on the healthcare system and may not be available to the uninsured • 2009 survey: 78% of potenEal DTC users said that they would consult the family physician for help interpreEng the results • May lead to expensive follow-‐up screens (especially due to pracEce of defensive medicine)
German oversight • GeneEc tesEng only carried out on doctors’ orders and following detailed counseling
• Outlaws non-‐consensual tesEng by requiring receipt of explicit wrilen consent both to geneEc tesEng and sampling
• Seen as overly restricEve “policy of geneEc excepEonalism enforced by paternalisEc regulaEon” [Clark, Genomics Law Report, 2009]
HeLa cell line • Controversial topic: the original cell sample cultured to grow them was
taken without consent from a paEent, Henriela Lacks • IdenEty protecEon and consent
– In the 1950s, the pracEce of taking rouEne Essue samples without consent from paEents was not uncommon, and anonymizing the source wasn’t a primary concern. A 1976 McKusick paper on HeLa geneEcs specifically idenEfies family members
– Other Lacks family members later asked to contribute blood for research projects • Unclear if their consent was “informed”; some thought they were receiving ‘cancer tests’
• Can we predict future uses of biospecimens and do we have to be explicit in the iniEal consent form? – Possible that Henriela Lacks could have been told that her cells would be
used for cervical cancer research, but what about research on the effects of zero gravity in outer space, or for the study of leukemia or lactose intolerance or longevity or the maEng of mosquitoes? Would specific consent have hamstrung future research?
– Recent court case brought by Havasupai Indians whose original consent was for diabetes, but also used in schizophrenia and migraEon studies. Offensive due to cultural ancestral origin stories. Sued and won
Profits from HeLa cell line • Should companies be able to profit from cultured cells?
– George Gey, the doctor who treated Henriela Lacks, didn't profit from the cells
– PharmaceuEcal businesses who culture HeLa cells do • Ethicists support a “common good model” for Essue donors:
‘compensated’ by knowing that research on their biomaterials may contribute to science – Issue of JusEce and shared benefits – Historically, those on whom the research has been done are oken
from the poorest segments of society and in the least posiEon to benefit
– The Lacks family are unable to afford healthcare. Henriela Lacks did receive free healthcare treatment for her cervical cancer (such as it was)
• But could argue that the scienEfic accomplishment of creaEng the immortal cell line is what is actually being compensated
Moore v. Regents of the University of California, 1990
• Dealt with the issue of property rights in one's own body parts
• Ruled that a person's discarded Essue and cells are not their property and can be commercialized
Johns Hopkins consent form “Johns Hopkins may dispose of any Essues or parts that are removed during the procedure. Johns Hopkins may retain, preserve, or use these Essues or parts for internal teaching or other educaEonal purposes without my permission, even if these Essues or parts idenEfy me. However, Johns Hopkins may only use or disclose Essues or parts that idenEfy me for research with my permission or with approval of a review board governed by federal laws protecEng these acEviEes. If the Essues or parts do not idenEfy me, Johns Hopkins may use them for scienEfic (research) purposes without my permission or acEon by a review board.”
Myriad GeneEcs – BRCA1/2 genes specifically patented by Myriad GeneEcs
– Screen for mutaEons costs $3000 – High-‐profile case: Angelina Jolie
• Public announcement of bilateral prophylacEc mastectomy
– Media tended to emphasize the “naEonal conversaEon” without leading people to helpful sites like cancer.gov
– Missed opportunity to highlight the absurdity of patenEng genes?
– Gene patenEng is a very complex debate
Overview of patenEng arguments • Commercial enEEes argue that they would not engage in research where there is no hope of financial gain
• ScienEsts argue that patenEng of genes is sEfling their ability to do research – Assert that companies could patent the tests or treatments that arise out of research on genes, but that patenEng the geneEc material itself is over-‐reaching
• Maler currently before the Supreme Court, ruling expected later this year
• Is it ethical to create financial benefits from free donaEons and who has the right to a share in these profits?
GeneEc tesEng • TesEng for Mendelian traits – E.g., Tay Sachs or Canavan disease
• TesEng for risk of disease – E.g., HBOC
• TesEng for desirable traits – E.g., Intelligence
• TesEng for undesirable traits – E.g., Mental disease
Worst case scenarios • DiscriminaEon [employer, insurance] • Eugenics [personal, state] – MiscegenaEon
• Pace v Alabama 1883; Loving v Virginia 1967 • Last state to repeal: Alabama 2001
– Forced sterilizaEon – “Designer” babies
• Galaca – “Valids” qualify for professional employment while “invalids” are relegated to menial jobs
Group discriminaEon • Many geneEc condiEons may be associated with a parEcular racial or ethnic group, leading to discriminaEon against that group – 1970s: state law mandated geneEc screening of all African Americans for sickle cell anemia
GeneEc discriminaEon at LBL • Norman-‐Bloodsaw v. Lawrence Berkeley Laboratory 1998 – Blood and urine samples tested, without knowledge or consent, for sickle cell trait, syphilis, and pregnancy
– District court iniEally dismissed the claims • General consent to medical exams covered the tests
– Dictrict court decision reversed by the Ninth Circuit Court of Appeals on February 3, 1998
– Upheld the right of an employee to be free from nonconsensual geneEc tesEng during a pre-‐employment medical examinaEon • "[I]t goes without saying that the most basic violaEon possible involves the performance of unauthorized tests -‐-‐ that is, the non-‐consensual retrieval of previously unrevealed medical informaEon that may be unknown even to plainEffs.... One can think of few subject areas more likely to implicate privacy interests than that of one's health or geneEc make-‐up.”
GINA (GeneEc InformaEon NondiscriminaEon Act) 2008
• Prohibits employers and health insurance companies from discriminaEng on the basis of geneEc informaEon – Employers: Prohibits the use of geneEc informaEon in hiring, terminaEon, or making decisions
related to compensaEon, terms, condiEons, or privileges of employment – Health insurance companies: Prohibits geneEc informaEon requests or requirements before
enrollment, premium increases or denial of coverage based on geneEc informaEon. • Difficult to segregate geneEc from non-‐geneEc informaEon; if employers require
health records, they may inadvertently end up geqng geneEc informaEon too [“Safe harbor” language]
• Does not include other types of insurance such as life, disability, long term care or mortgage insurance
• Does not cover members of the military • Insurance protecEon only applies to as-‐yet-‐asymptomaEc condiEons
– Target of healthcare reform (i.e., Affordable Care Act) • Designed to allay fears about consequences of undergoing geneEc tesEng • Defines “geneEc informaEon” with respect to any individual, as
– The individual’s geneEc tests – The geneEc tests of the individual’s family members – The manifestaEon of a disease or disorder in family members of the individual
California SB 559 (2011) • Expands protecEons by prohibiEng discriminaEon based on geneEc informaEon for: – Housing – Mortgage lending – Public accommodaEons – Emergency medical services – Licensing exams – Programs administered or funded by the state
• Also much greater potenEal for damages (no statutory limit on compensatory or puniEve damages)
Eugenics, really? • Early geneEc science led people to believe that they could
get rid of undesirable traits by sterilizaEon – Mental diseases, epilepsy, blindness, deafness – 1907: Indiana state sterilizaEon law – 1909: California – 30 states ulEmately had some kind of sterilizaEon law – At least 64000 people (many poor young women) sterilized
• Most state laws repealed in 1963 or earlier – Up to 25% of NaEve American women sterilized in the 1970s – Oregon the last state to repeal its laws in 1983 – Virginia sEll allows it within strict guidelines
• Do we dare risk history repeaEng itself? • In whose hands do we want to leave these decisions?
Designer babies? • At least 2 papers in 2012 that can non-‐invasively decipher a baby’s genome in utero, based on the premise that fetal DNA circulates in the mother’s bloodstream – How many prenatal tests will deliver “bad” news? – What are the consequences of finding something “bad”?
– Who decides what “bad” is? Risk vs. certain pathology • How about Tay-‐Sachs? Propensity for heart disease?
– What if the “bad” trait has no known treatment or cure? What if it does?
– How about selecEng for “good” traits (e.g., intelligence, height)?
Kitzman et al Sci Transl Med, 2012; Fan et al Nature 2012
Human height variaEon • GWA data from 13665 individuals • 39 variants from 16482 individuals • 20 variants associated with human height • Account for ~3% of height variaEon
• Known that diet and environment also have a large role to play in height
Nature 2008
PredicEng intelligence • TesEng for intelligence @BGI (China) • Using 1600 super-‐intelligent people with excellent maths and verbal reasoning skills from the Study of MathemaEcally Precocious Youth (SMPY)
• Raises the specter of eugenics – Plot by the Chinese government to breed super-‐intelligent populaEon?
• Other problems: – Sample size too small and intelligence is too complex – Argue that if intelligence is as complex as say schizophrenia, then they’ll need a minimum of 10000 samples and 10000 controls
Yong, Nature, 2013
Closing remarks • As scienEsts, between the thrill of discovery, and the need to publish, we can someEmes forget the people by whose generosity we have data with which to work
Autonomy Beneficence Jus2ce
• Important to keep these ethical principles in mind, at all levels, whether during the grand concept and design phase, or in the decision of which staEsEcal test to use. We have an obligaEon to research parEcipants to carry out science ethically and with integrity