Genome Sequencing - II: Presidential Commission for the Study of Bioethical Issues Meeting 8, February 2, 2012

Meeting 8 Session 2  Privacy I: Privacy and the public good

Transcript 

George J. Annas, J.D., M.P.H.

George Annas, J.D., M.P.H., Chair, Health Law, Bioethics & Human Rights, William Fairfield Warren Distinguished Professor, Boston University School of Public Health likened the present state of genomic medicine to two movies: "One is Bill Murray's "Groundhog Day", [that] took an insight, a values insight, for him to get out of that day, and the other is his movie "Lost in Translation", which I think it's fair to say, without getting carried away, a lot of genetics is."

G.J. Annas presentation slide

He drew a parallel between genetic privacy and privacy on social networks -- the latter as described in Lori Andrews' book, "I Know Who You Are and I Saw What You Did."  He noted that many people are not concerned about signing releases for the collection and use of their genomic data by others -- as long as it is described as their "medical record,"  and yet object if what they are asked to release is "their genome."  And of course, very little is known about how that data might be used in the future. 

Mark A. Rothstein, J.D.

Mark A. Rothstein, J.D., Herbert F. Boehl Chair of Law and Medicine, University of Louisville School of Medicine was the second speaker of the session. Areas of concern he delineated were as follows:

• Genomic information in electronic health records may be accessed by healthcare providers without a need to know
• What to do in the research uses of the information

• De-identify it (public surveys have shown great unhappiness with this practice)
• Provision for opting out (many don't exercise that option -- but if you ask, often people are happy to consent)
• Opt-in provision (which researchers find burdensome to implement)
• Non-medical uses of genomic information, without consent or authorization (as required for public health for example - victims of abuse, neglect or domestic violence)
• Compelled authorizations by third parties (as a condition of employment for example)

In follow-up questions, the Personal Genomes Project in Boston was mentioned as an example of present work. The PGP is recruiting several hundred-thousand individuals, whose biobanked genome sequence one day will be made publicly available -- with all of them having consented to that. The question was raised as to whether there ought to be simply consent by individuals or also "social consent" to, or state control of such projects.

By way of exploring social consent in genome research, the National Human Genome Research Institute is sponsoring a clinical trial entitled Informed Consent for Whole Genome Sequencing: Ideals and Norms Referenced by Early Participants. 

In the detailed description, it is stated: "This proposed study approaches both informed consent and genomic medicine as iterative constructs shaped by civic values and social norms."

Understanding the civic and social contexts where informed consent takes place is crucial in order to adapt it to new realities in genomic research."

*********************

Meeting 8 Session 3 Privacy II – Control, Access and Human Genome Sequence Data

Transcript

Jane Kaye, D.Phil., L.L.B.

Jane Kaye, D.Phil., L.L.B., Director of the Centre for Law, Health and Emerging Technologies (HeLEX), Oxford University spoke on biobanking and privacy.

While traditionally consent is seen as a one-time, individual transaction between the subject and the researcher, Dr. Kaye countered "...what has been suggested and what is used within bio-banking is a broad consent..." 

She went on to say "The second plank of medical research ethics, which is actually challenged by global data sharing is that participants should be able to withdraw from research at any time, and withdrawal cannot be promised when data and samples are shared widely."

J.Kaye presentation slide

She summed up the problem: "...as my colleague Eric Meslin said, it's a bit like Hotel California, you can check out you any time you like, but you can never leave."

Dr. Kaye concluded by suggesting a change in thinking to see it as a process of forming partnerships with tissue donors. In her view attempting to anonymize donor data is not as important as paying attention to the public preference to be asked about any uses of their data.

John Wilbanks

John Wilbanks, Founder of Consent to Research and Senior Fellow, Kauffman Foundation, among other positions, spoke on the question of privacy from a Web perspective.  He frames it as “…more a debate about agency, which is the right to decide what is done with my data and the right to see a copy of what people know about me.”  He pointed out that communities on the Web like PatientsLikeMe.org, with over 100,000 people, are generating studies with no connection to IRBs, such as one being done by ALS patients looking at the use of lithium.

He mentioned more ‘do-it-yourself’ Web projects, such as OpenSNP  -- pronounced Open Snip... a website, that would let anyone upload their 23andMe file and let people start attaching papers and annotations to the Snips.  It has zero connection to bioethics in the professional sense.”

J.Wilbanks presentation slide

He also spoke of a project he is involved in, Sage Bionetworks,  which is an attempt to create a “commons” for genome sequences that would help to build “predictive computational disease models” which do not involve patenting.  

The question of consent for the use of individuals’ data has arisen here and through his work with Consent to Research and Sage Bionetworks he is now seeking to develop a web model of consent that would be acceptable to IRBs and thus would encourage researchers to take advantage of a large number of personal DNA genome profiles. He calls it the Portable Legal Consent for Genomics Research, the about-to-be-launched project is described by Erica Check Hayden in Nature News.

A lengthy discussion ensued, with Commission members and members of the public exploring the contrast between the socially-cooperative nature of Web-based genomics projects and the fear of losing control of one’s own personal data – which it was pointed out, is not intellectual property in a legal sense, but rather, as John Wilbanks suggested, a kind of individual "trade secret."

Related article            Flash videos of all sessions with slides

Issues in Familial Searching in Forensic Investigations

Source: Wellcome Sanger Trust article on the NDNAD

Erica Haimes, Professor of Sociology at Newcastle University, Newcastle-upon-Tyne, United Kingdom,  discusses familial searching in forensic DNA databases. Professor Haimes was the Founding Executive Director of the Policy, Ethics and Life Sciences (PEALS) Research Centre at the University.  Familial searching of DNA databases is the process of searching to see if there is a close match to a crime scene profile when there is not an exact match.  In the United Kingdom the UK National DNA Database (NDNAD) is used in this fashion to determine whether crime scene DNA belongs to a close relative of someone profiled in the NDNAD.  The purpose of this paper is to discuss the social and ethical problems of this process with an eye to family studies.

Potential problems with forensic screening are:

• Violating the privacy of the person in the NDNAD;
• Violating the privacy of the pool of relatives who are not the subject of forensic investigation;
• Reinforcing the view that the prevalence of criminality is higher in certain families;
• Revealing to relatives the presence of a family member in the NDNAD;
• Revealing a previously unknown genetic link or a lack of genetic connection between persons.

Haimes raises the following questions on the impact of familial DNA searching on the family members.

The Person in the Forensic Database

• What obligation does this person have to provide information about his/her relatives? This person is the entry point into the family network – a genetic informant.
• How does a previously unknown genetic link or lack of a genetic connection affect this person? 
• Is there a right ‘not to know?’

The Immediate Family

• What is the impact of exoneration or genetic scrutiny on family members?
• How does a previously unknown genetic link or lack of a genetic connection affect the family?

The Wider Family Network

• What effect does being related to someone in the genetic database have on family relations?
• How does a previously unknown genetic link or lack of a genetic connection affect the group?
• What is the effect of being a part of a family under criminal investigation?

The following suggestions are made to mitigate the effect of forensic screening on all parties involved:

• A detailed study of the practices currently involved should be done;
• Current guidelines in the UK for forensic screening should have input from family specialists and genetics personnel;
• Careful consideration of the method of contacting all involved should be taken;
• Careful training of genetic, forensic  and social service personnel would be beneficial;  the end of inquiry for the forensic investigation may be just the start of inquiry within the family involved;
• Error rates in the database should be considered;
• Ethics awareness training may be beneficial to for all personnel.

Haimes, Erica. Social and Ethical Issues in the Use of Familial Searching in Forensic Investigations: Insights from Family and Kinship Studies. Journal of Law, Medicine and Ethics. 2006 Summer; 34(2): 263-276.  doi: 10.1111/j.1748-720X.2006.00032.x

Genome Sequencing - I : Presidential Commission for the Study of Bioethical Issues Meeting 8, February 2, 2012

Commission Chair, Amy Gutmann (l) and Vice-Chair, James Wagner (r)

In her opening remarks, (Transcript) Chair Amy Gutmann, Ph.D observed that the Commission has completed three reports in the last year and a half. “Turning now to the future…” she said, “…We're going to focus on issues related to genome sequencing and privacy and access to the data available, as the result of whole genome sequencing and its use in research and clinical care.”

Session 1 Ethics and the practice of whole genome sequencing in the clinic: Transcript

Retta Beery described her family’s personal success story, the result of whole genome sequencing done of her twin children, Noah and Alexis. They suffered for several years after birth from the many ill effects of a genetic metabolic disorder similar to, but misdiagnosed as Cerebral Palsy.  Finally, when the sequencing was done while they were in their early teens, a problem with serotonin uptake was discovered.  Administration of 5-HTP amino acid cleared up the symptoms and today the children are healthy.

The story is detailed in Bloomberg News Online: Genome Proving Cure for Ailing Twins Paves Breakthrough to Doctor’s Office By John Lauerman - Jan 30, 2012 5:40 PM ET.

Richard Gibbs, Ph.D., Wofford Cain Professor, Department of Molecular and Human Genetics, Director, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX spoke on "Genome Data: Research to Clinic to Consumer"

He described recent advances in sequencing. For example, instead of doing whole genome sequencing the "next gen" rapid sequencing of isolated gene portions only, costs 1/5 the amount.

In his "armchair futurist's view of genomic and genetic data," Dr Gibbs stressed the importance of medical record and social/other factors is growing versus the population studies to which they are tied.

Responding to questions posed by commission members at the end of the session Gibbs said, "Tomorrow's challenge is community genetics education."  On 'snake oil' salesmen selling genetic sequencing for individuals he added, "Don't slow the pace of genomics... there's a tension here -- the danger of not knowing is as enormous as the risk of knowing."

On patenting he said, “As more specific genotype and phenotype information becomes available, we need to look at patenting that information -- we need to avoid a "land-grab" as a private company attempted to do in attempting to file for a wide patent during the race to sequence the human genome.”

Daniel Masys, M.D., Affiliate Professor, Biomedical and Health Informatics, University of Washington School of Medicine, Seattle, WA addressed the question of “Electronic Medical Records and Genomics: Possibilities, Realities, Ethical Issues to Consider”
He described an electronic medical records system set up at Vanderbilt to link doctors pharmacists and patients, to detail personal genetic data that suggests the efficacy or not of particular drugs in treating a patient's condition.

By taking genome-wide association studies a step further, and looking at phenotype-wide association studies, scientists are now able to look at associations of diseases within phenotypes -- for example, diabetes type II and asthma, or myocardial infarction and peripheral vascular disease -- as studied by sites in the eMERGE network (electronic Medical Records & Genomics) that link biorepositories to electronic medical records in doing genomic studies.

He underlined the magnitude of the task of finding the molecular data:

• Structural genomics, “the DNA in residence" studies about 22,000 genes per genome.

• Functional genomics, looks at the 1-2% of genes switched on

• Proteomics examines the 400,000 proteins coded for by the 22,000 genes

He suggested the caption of a New Yorker cartoon says it all: "The good news is we have the human genome, the bad news is, it's mostly just a parts list."

He stated the issues to consider:

• Is it ethical to allow health care providers to continue to practice without a systems infrastructure for decision support?"

• Is it ethical to discard person-specific DNA data that currently has uncertain or unknown significance?

• How does 'genomic consent' differ from standard consent for healthcare services?"

Flash videos with slides are available here.

Yes, Genes Should be Patentable

Stephen H. Schilling thinks so. The author proceeds from the point of view that those who object to patenting genes "...fail to adequately consider the role that gene patents and patents on similar biomolecules play in facilitating investment in the costly, lengthy, and risky developmental processes required to transform the underlying biological discoveries and inventions into marketable products. "

Discussing the biology of genes, and the appeal of gene patents, he then deals with litigation on patentability requirements. He refers to the 1980 case that opened the door to gene patents (Diamond v. Chakrabarty) and by contrast, Funk Brothers Seed Co. v. Kalo Inoculant Co., (1948), in which "a mixture of root-nodule bacteria that aids plants in fixing nitrogen was held unpatentable, because it was a "handiwork of nature." 

Since the 1980 decision, the author contends courts have agreed on the following status quo:  "An isolated and purified DNA molecule that has the same sequence as a naturally occurring gene is eligible for a patent because

• (1) an excised gene is eligible for a patent as a composition of matter or as an article of manufacture because that DNA molecule does not occur in that isolated form in nature, or 
• (2) synthetic DNA preparations are eligible for patents because their purified state is different from the naturally occurring compound... 

Source: Biopolitical Times: Cathy Wilcox Cartoon

It was the status quo, at least, until the arrival of the hot topic case of Associated Molecular Pathology v. USPTO. Popularly called Associated Molecular Pathology v. Myriad Genetics it deals with Myriad's patents of the BRCA1 and BRCA2 genes, of associated methods for screening for breast cancer, and for testing drugs by comparing BRCA gene sequences to patients' gene sequences.

The author states: "This status quo, however, was called into question by the district court's holding... that isolated DNA is an unpatentable product of nature because the unaltered information-encoding function of DNA is also central to the utility of DNA in its isolated form... Although the Federal Circuit reversed this holding on appeal...  the case has not been finally resolved by the courts..." 

In the reversal the Federal Circuit upheld the patentability of the genes and Myriad's patent of a method of screening for breast cancer using the genes, while affirming the unpatentability of a process that analyzes BRCA gene sequences and compares them with cancer-predisposing mutations in so-called "normal" or "wild-type" gene sequences.

He goes on to discuss the patent law's concepts of utility, novelty and nonobviousness. He gives the example of the case  Brenner v.Manson, 383 U.S. 519, 534-36 (1966) which notes "...that 'a patent is not a hunting license' but rather is 'compensation for [the] successful conclusion' of a search for something useful;" adding that "[a]n invention is novel if it has not been previously disclosed;" and to be eligible for a patent an invention must not be an obvious conclusion from "prior art," but rather, "nonobvious" as in providing the resolution to a previously insoluble problem.

The author then proceeds to describe "Alleged problems created by gene patents." Noting that "20% of human genes are allegedly patented," he critiques the arguments against patenting genes:

• Diminishing Patient Access
• Diminishing Quality of Patient Care
• Impeding Research and Innovation

The remainder of the article contains a fuller discussion and critiques of the Myriad case and of the "SACGHS Report on Gene Patents and Licensing Practices and [its]Impact on Patient Access to Genetic Diagnostic Tests"

The author proposes a "narrowly tailored solution:"

• Limited exemptions for diagnostic testing or whole-genome sequencing to address patient-access and standard-of-care concerns
• Increased transparency in genetic diagnostic testing, gene patents, and licensing

Since the article was published a decision was taken by the both the plaintiffs and Myriad to appeal the Federal Circuit's reversal, and when that was denied, the American Civil Liberties Union asked for the Supreme Court to rule on the case. It has been accepted for the court's 2012 Spring session. 

Schilling, Stephen H. DNA as patentable subject matter and a narrow framework foraddressing the perceived problems caused by gene patents. Duke law journal 2011 Dec; 61(3): 731-73

Further reading on the topic, from GenomeLawReport: 

• Pigs Fly: Federal court invalidates Myriad's patent claims 
• Pigs return to earth Federal Circuit reinstates most -- but not all -- of Myriad's patents
• ACLU and Myriad both seek further Federal Circuit review
• Has the Federal Circuit lost interest in patentable subject matter?

Genotype-driven Recruitment

Emily E. Namey, past coordinator of qualitative research at the Duke Institute for Genome Sciences and Policy (IGSP), and Laura M. Beskow, Assistant Research Professor at the IGSP present results of twenty-nine interviews of epilepsy patient-participants from the study, “The Genetics and Pharmacogenetics of Epilepsy” conducted at Duke University Medical Center. The interviews were conducted between February and October 2010.

Brain. Source: National Institutes of Health

In the initial study, some participants were found to have large heterozygous deletions. The significance of this deletion for the study of epilepsy is not known and participants with the deletion were recruited for a follow-up study, so-called genotype-driven recruitment. 


Namey and Beskow sought to better understand how research participants with a known condition (in this case, epilepsy) give meaning to their personal genetic results. Because the validity and utility of such results are not known at this time, some researchers are reluctant to give individual results to which patients may over-respond. 


The interview group for the current empiric study consisted of nine (9) persons with the deletion and twenty (20) persons without it. The consent form of the original study stated that individual results would not be given. Thus, the researchers faced an ethical quandary:  avoiding giving confusing information when recruiting while at the same time providing true informed consent.


The following questions were asked:

• If you had been contacted for the follow-up study, would you want to know your results?
• - 28/29 responded Yes.
• If the results were of "uncertain validity" or "limited utility," would you want to know your results?
• - Results of "uncertain validity"- 50% Yes 50% No
• - Valid results, but not clinically actionable 75% Yes

The questions participants hoped would be answered by knowledge of their individual test results were:

• Why do you want to study me more?
• What have you learned about my condition?
• Can epilepsy be passed on in a family?
• Is there anything (more) I can do?

This cohort of persons has a specific broad-based condition, epilepsy, for which they want specific, in this case genetic, answers. This poses a problem for the way that genetic researchers recruit participants.


The authors conclude that clear communication concerning the validity and clinical utility of genetic results are necessary if patients do receive results in the process of recruitment for additional research.


Namey, Emily E. and Beskow, Laura M. Epilepsy Patient-Participants and Genetic Research Results as “Answers.” Journal of Empirical Research on Human Research Ethics. December 2011; 6(4): 21 – 29. DOI: 10.1525/jer.2011.6.4.21


Related article: 
Beskow, Laura M.; Linney, Kristen N.; Radtke, Rodney A.; Heinzen, Erin L.; Goldstein,  David B. Ethical challenges in genotype-driven research recruitment. Genome Research 2010 June; 20:705-709 doi:10.1101/gr.104455.109

Informed Consent Forms for Genome-Wide Association Studies

The authors, from the HeLEX Centre for Health, Law and Emerging Technologies at the University of Oxford, U.K., looked at current European practice for genome-wide association studies (GWAS) consent forms. They confined their remarks on legal aspects to British law.

Genome-Wide Association Study. Source:
Coriell Personalized Medicine Collaborative

They observe that "[g]enerally, the content of consent forms seems to be a mix of legal requirements, ethical principles, and accrued practice ..." and add that for new research projects or new technologies consent forms are often based on criteria that were used successfully in the past.

Since “[t]here are no detailed national or international mandatory standards for the format of consent forms,” “... there may be an incremental development of the content of informed consent forms that may inadvertently deviate from current legal requirements, but may also fail to address all of the concerns of the new research approach in question."

They describe the varying requirements for research protocols with tissue biobanks in Europe, and state that "[a] common misconception about data protection law is that processing of personal data, be it in research or other contexts, cannot occur without some form of valid consent on behalf of the relevant individual. This is not always the case."

A table of characteristics of typical GWAS consent forms illustrates that statements about commercial involvement are "often absent," but if "…commercialisation is a possibility, it is always made clear that there will be no personal benefit.  In these instances they [research subjects] are occasionally asked to sign a waiver." Thus there is no suggestion of the subject having any ownership of intellectual property arising from a research project, by way of the tissue they have donated to it.

They conclude by discussing the difficulty of withdrawing consent once tissue is used for DNA research due to the anonymizing process for preserving confidentiality.

They give an example of a new approach to consent for GWAS studies --EnCoRe (Ensuring Consent and Revocation.)  “The EnCoRe Project is developing IT mechanisms to allow individuals to give and revoke consent to the use of their biological samples and associated data in biobanks.” 

Boddington P., et al. Consent forms in genomics: the difference between law and practice. European Journal of Health Law. 2011 December; 18(5):491-519. [All Internet sites accessed December 20, 2011].      

Rationality and the Genetic Challenge: Making People Better? -- book review

Source:
Google Books

John Coggon begins his review of Matti Hayry’s book Rationality and the Genetic Challenge: Making People Better? by noting that the term ‘genethics’ was coined in 1984 by James Nagle to describe “… instances where medical genetics and biotechnology generate ethical problems that warrant societal deliberation."


Hayry’s book focuses on conflicting approaches to the societal deliberation of the following genethics issues: 

• the best babies and parental responsibility
• deaf embryos, morality, and the law
• savior siblings and treating people as a means
• reproductive cloning and designing human beings
• embryonic stem cells, vulnerability, and sanctity
• gene therapies
• considerable life extension and the meaning of life

Hayry scrutinizes the arguments on these topics by six authors who represent “…the three normative doctrines of Western philosophy: consequentialism, …teleology, … and deontology.”  Coggon posits that by contrasting the work of these scholars — Jonathan Glover, John Harris, Ronald M. Green, Jurgen Habermas, Michael J. Sandel and Leon R. Kass — “…the book invites engagement at various levels.”


Hayry employs two devices to help readers navigate among these approaches”: the “nonconfrontational notion of rationality” wherein a decision “…is rational insofar as it is based on beliefs that form a coherent whole and are consistent with how things are in the world;” and the “polite bystander’s point of view” in which one “…compares distinct theories presuming each may be valid, ruling out only what fails the test of rationality.”

Coggon praises utilizing the "non-confrontational notion of rationality" to elucidate the various philosophical approaches to a topic, but contends that this device does not work well when it is applied to the political and legal aspects of the issues addressed in Hayry’s book. Nevertheless, Coggon sees the book as a valuable “…attempt to draw a revised map of the normative landscape surrounding genethics.”


Coggon, John. Confrontations in ‘‘Genethics’’: Rationalities, Challenges, and Methodological Responses. Cambridge Quarterly of Healthcare Ethics 2011 v.20:46-55 dx.doi.org/10.1017/S0963180110000617  [Accessed: December 13, 2011]


Hayry, Matti. Rationality and the Genetic Challenge: Making People Better? Cambridge: Cambridge University Press, 2010.