Genetic Future

Mark Henderson breaks the news of the first sequencing of an entire nuclear family for non-medical (read: recreational) reasons. John West, his wife and two teenage children (aged 14 and 17) apparently paid the full retail price of almost US$200,000 (update: in the comments, Mark writes that West apparently got a “small” but not “hefty” discount off this retail price) to sequencing company Illumina to generate their complete DNA sequences.

The West family members are no strangers to sequencing – John West is the former CEO of Solexa, the sequencing technology company purchased by Illumina in 2007 and whose platform is the basis for Illumina’s market-dominating Genome Analyzer sequencing instruments.
Much of Henderson’s article explores the intriguing ethical conundrum posed by sequencing children without a compelling medical reason to do so:

Some doctors and ethicists argue that while DNA data may prove medically useful, there is not enough evidence of benefit to warrant testing healthy children. Sequencing could reveal unwelcome information, such as a high risk of Alzheimer’s disease or misattributed paternity, which an individual may later decide he or she would rather not have known.

John West himself is seemingly unperturbed by the ethical issues here:

“A few years from now I think it will be ethically improper if you don’t have your children sequenced. What kind of parent are you if you don’t give your children a small amount of money to find out things that can help their health? We could easily get to the point where it is considered negligent not to do this.”

(As an aside, I love that $48,000 is a “small amount of money” – perhaps I could borrow some pocket change from West to get my own genome sequenced?)

Frances Flinter, a consultant in clinical genetics at Guy’s and St Thomas’ NHS Foundation Trust, London, argues the opposing case:

“I don’t think you can argue at this point that genome sequencing is in the best interests of children, or that it couldn’t be done when they are older.”

I’ve personally got no ethical problem whatsoever with the Wests deciding to get their genomes sequenced. The medical benefits will likely be negligible, but then so are the potential harms (weighted by their probability), and a bright 14-year-old is more than capable of weighing these harms and giving informed consent. 
There’s also a good scientific rationale for sequencing multiple family members: it improves the accuracy and interpretability of each individual’s sequence. This was ably demonstrated in a recent publication in which a family of four was sequenced by Complete Genomics in a hunt for a serious disease gene: that paper showed that combining data across multiple family members allowed analysts to dramatically improve the accuracy of sequencing. In a press release West points to a second advantage:

“By sequencing a family of at least four we can go a step further to interpret compound heterozygote variations in genes – those cases where multiple variations in a single gene, but on opposing chromosome copies, combine as a virtual homozygote. I expect that these are much more prevalent, and the source of much more phenotypic variability, than previously understood.”

This is a little opaque, but West is referring here to the ability to use family data to very accurately determine “haplotype phase” – that is, to infer which genetic variants are derived from maternal vs paternal chromosomes. If phase is known, it’s possible to determine whether two potential loss-of-function variants in the same gene are present on the same copy of that gene, or whether the person carries two separate defective copies. The latter case is far more likely to prove medically relevant than the former, but for an individual genome without family data these scenarios are extremely difficult to tease apart.
Anyway, my sense here is that the ethical problems posed in this case – especially the far-from-compelling “right to ignorance” claim – are outweighed by the principle that individuals should have autonomy to explore their own genetic data should they wish to do so. So long as the Wests have weighed up the benefits and harms and are capable of providing informed consent there’s no compelling reason for them not to be able to access their own DNA.

Comments

  1. #1 Mark Henderson
    April 19, 2010

    Thanks for highlighting my piece! Just a couple of quick observations…

    First, John West told me he had a “small discount” on the list price, a detail that got subbed out of the final piece. He wouldn’t tell me how much off he got, but said it was not a hefty discount — “near list price”.

    Second, before being sequenced, the West teenagers were both genotyped by 23andMe 3 years ago — when they were 14 and 12 (the ages West gave me). Would be interested as to views on this. On one hand, the fact they’ve already consented to 23andMe obviously makes the sequencing consent less controversial. On the other, is 12 really old enough to consent to non-medical genotyping?

  2. #2 razib
    April 19, 2010

    i guess ethicists always need to worry about things. but this seems like small potatoes compared to in vitro fertilization. i mean there is some evidence that this causes some issues in terms if risk for various illnesses over the long term right, but no it’s pretty much accepted now. in this case all you have is information.

  3. #3 Vito LaBella
    April 20, 2010

    Mr. Henderson’s position that “Sequencing could reveal unwelcome information, such as a high risk of Alzheimer’s disease…” is suspect.

    If a child’s grandparent developed Alzheimer’s, would it be acceptable to keep that information from him or her because of the possibility that they may develop the disease sometime in the future? I think not.

    If a test shows a genetic predisposition to develop the disease, it is in a person’s best interest to know about it. In the case of Alzheimer’s, there is some evidence that Statin drugs might lower risk. A person with a genetic predisposition, as evidenced either by family history or genetic sequencing, needs that information in order to make an informed decision on prophylactic treatment,whether currently available or potentially available in the future.

  4. #4 AB
    April 20, 2010

    I just don’t get it. Where is all this misplaced angst coming from over the ethics of having your kid know his genetic info? The real tragedy is the complete lack of any ethical issues being discussed surrounding adoption, and egg and sperm donation kids.

    Identity theft is a much more serious problem than identity knowledge. No one seems to mind denying a kid their own bio parent, ethnic and medical history. Where are all the ethicists on this?

    I find this a sad commentary on the values system of so many that we worry when we give information but not when we take it away and make it illegal to obtain.

    Paternalism anyone?

  5. #5 Steven Murphy MD
    April 20, 2010

    Dude,
    The West Family should charge Illumina for that research kindred…….

    The only way to make sense of the gobbledeegook of genomes is to have the families…….Why should the family have to pay for the information Illumina will glean from sequencing families? Or, won’t they?

    -Steve

  6. #6 dave chamberlin
    April 20, 2010

    I think the most important scientific ratiomale for sequencing family members isn’t even discussed yet. It will shed light on actual human mutation rates, somebody put this data in the hands of John Hawks.

  7. #7 Daniel MacArthur
    April 20, 2010

    Dave,

    Those calculations were done for the four-member family sequenced by Complete Genomics, giving mutation rates very much in line with expectations from population genetics. There’s also a very elegant analysis of de novo mutation in two families (one European and one African) currently being done as part of the 1000 Genomes Project.

  8. #8 gitch
    April 20, 2010

    “….a bright 14-year-old is more than capable of weighing these harms and giving informed consent….”

    It depends on how the harms are outlined to the patient (any patient, really. Not just adolescents).

    If you are seeking informed consent solely based on the current landscape of genetic testing and availability/usage of genetic information: You tell the subject that the probability is low that your genetic information could be used for theft identification and its consequences in discrimination/security/forensics. Everything you’re saying is accurate and consent will probably be granted. But, shame on you researcher/parent/genetic counselor!

    If you are seeking informed consent based on the future landscape of genetic testing and availability/usage of genetic information: You tell the subject that you have no idea how to gauge the risk of harm from the activities mentioned above during the next 60 years (their estimated lifespan). You further give them a list of potential harmful activities such as discrimination/security lapses/forensic activities and tell them that you will do your best to protect their information, but can offer no assurances. You then go even further and discuss with them that not only can their own identity be compromised, but those of their parents, sibllings, kids, and grandkids could be compromised. Everything you are saying is accurate, but consent will probably not be granted. Good for you, researcher/parent/genetic counselor!

  9. #9 Mary
    April 20, 2010

    Of course they are entitled to get this done if they want.

    But good lord–as if today’s helicopter parents are intolerable enough. Imagine once they take this to the doctors and teachers and start making demands…going to be insufferable.

  10. #10 dave chamberlin
    April 20, 2010

    Daniel,
    I have no idea who is right or who is wrong but John Hawks commented on March 18th that the mutation rates from this family of four was half the mutation rate expected. The title was Low Human Mutation Rate May throw Everything Out of Whack.

  11. #11 MS3
    April 20, 2010

    Coming from a clinical practice standpoint the ethics behind sequencing minors has less to do with whether or not they consented to the process of scanning but also whether or not they consented to release their genomes to their parents. In essence this violates their rights to medical privacy as the scanning may disclose future medical issues to their parents which they wouldn’t have volunteered. Considering that medical record privacy is quite a very highly considered value in this country from both ends of the spectrum I am surprised that it wasn’t mentioned.

  12. #12 AB
    April 21, 2010

    @MS3 I don’t see how this violates their rights to medical privacy any more than any other medical issue of a child/parent relationship. On the other side it might require more responsibility from the parents to insure a potential harm does not arise now that one knows the genes potentials.

    re: medical record privacy. I think you live in a dream world. There is none. I see privacy violations all over the place.

    And just last night I received the password for an online (dental) account for someone I don’t know who lives in a state 3000 miles from me. I have no idea how this doctor’s office got my email. The only connection is the last name – the parent of the child has the same last name as I do. But we are of different genders and my first name is nothing like the parent’s name. The pw came in a very excited letter explaining how I could now access my account online. No, I can now access a stranger’s account, change his PW, name of insurance company, address and anything else. Sad, really. They are lucky it came to me and not someone who will use the information for harm.

    Electronic records are not the panacea people think.

  13. #13 Daniel MacArthur
    April 21, 2010

    Hi Dave,

    The error bars on that family-based estimate and the population genetic estimate overlap substantially; certainly there’s not yet any compelling evidence that we need to revise the traditional estimate for the human mutation rate. We’ll need a lot more families and better sequencing technology to pin this number down convincingly.

  14. #14 Daniel MacArthur
    April 21, 2010

    Getting back to Mark’s earlier question:

    Second, before being sequenced, the West teenagers were both genotyped by 23andMe 3 years ago — when they were 14 and 12 (the ages West gave me). Would be interested as to views on this. On one hand, the fact they’ve already consented to 23andMe obviously makes the sequencing consent less controversial. On the other, is 12 really old enough to consent to non-medical genotyping?

    This is a pretty tricky area, and I honestly don’t know where the line should be drawn.

    However, it’s worth pointing out that we routinely subject even younger children to tests that are (in most cases) substantially more predictive of their future life than a 23andMe test (e.g. academic testing). I also think the educational benefits of something like a 23andMe test for teenagers shouldn’t be underestimated, especially as we begin to move into an era where genetic literacy will become ever more important.

  15. #15 MS3
    April 21, 2010

    Oh joy, the fun of swapping anecdotes. I see your dental story and raise you one about my own parents. It happened after I was 18 and my doctor told them anyway that my vision, even corrected, won’t be 20/20 (more like 20/40 L 20/60 R). Oh noes, I am blindz. Still, my parents became quite over-protective and just going away to college, something which was simply assumed to happen before, turned into a huge fight. They loved me yes, though it would have been in my best interests had I the choice to keep it to myself. Sob story over. Is it a dream world? No, but that shouldn’t stop us from holding ourselves to ethical standards and emphasizing that our principal priority is the best interests of the patient. Even or perhaps especially if that means protecting them from “well intended” parents.

    We are also much less concerned with random strangers knowing private information as we are about our loved ones. What if these tests had revealed the children to be illegitimate? That certainly wouldn’t have been in their own best interests. What about a prediction for developing schizophrenia? And the knowledge that just cause the grandparents had it, so there is a chance, isn’t even close to the same. Say for example if little Billy had the alleles and his brother Johnny didn’t, it could certainly turn into a self-fulfilling prophecy that only one of them will go to college. Hell, or maybe they both have the alleles and now their parents put in slightly less to their college savings. Or what if the parents slip and in jest call their kid “crazy” in front of his prom date. Now he may not end up marrying the girl of his dreams even if he never even develops the disease.

    Current standards are that age 14-18 year olds have autonomy when making medical decisions unless otherwise indicated. So if they consent to learning about their own genome I am fine with that. We should though separate the sequencing from the disclosure into two separate issues both of which require informed consent. Informed consent is all about weighing pros and cons of which the disclosure aspects has very few pros and a whole lot of potential cons. The parents are their own interested party. Therefore, a medical decision by proxy that just happens to end up in their favor is highly suspicious.

  16. #16 Neil
    April 22, 2010

    Interesting that this piece should come hot on the heels of Daniel’s injunction to read the latest Nature mag celebrating 10 years since the publication of the draft human genome.

    One opinion piece:

    http://www.nature.com/nature/journal/v464/n7289/full/464680a.html
    A reality check for personalized medicine (2010)
    Khoury, MJ; Evans, J & Burke W
    Nature 464, 680 – doi:10.1038/464680a

    which is reviewing

    Personal Genomics and Personalized Medicine
    by Hamid Bolouri
    Imperial College Press: 2010. 280 pp. £34

    Points out that:

    The idea that genomics information should be afforded special status has encouraged researchers to allow it to pass too easily as clinical evidence compared with other interventions. The most conspicuous example is the rapid commercialization of personal genomic tests, based on limited studies of clinical validity and none on health benefits and outcomes. Bolouri assumes that personal genomics will decrease health-care costs “as a result of better diagnostics, more effective treatments and fewer episodes of severe illness”, yet out of a list of applications for personalized medicine tabulated in the book, only a few have withstood the rigour of evidence-based reviews.

    Are we in the midst of a general backlash? Or is this the beginning of genomics as proper medicine?
    Or perhaps both.

    I ask, because rummaging around in Wiley’s

    Encyclopedia of Life Sciences
    http://www.els.net/

    I came across the somewhat skeptical (and with my added emphasis):

    Genetics as Explanation: Limits to the Human Genome Project
    Cohen, IR & Atlan, H

    http://www.mrw.interscience.wiley.com/emrw/9780470015902/els/article/a0005881/current/abstract

    Abstract

    Living organisms are composed of cells and all living cells contain a genome, the organism’s stock of deoxyribonucleic acid (DNA). The role of the genome has been likened to a program that encodes the organism’s development and its subsequent response to the environment. This computer metaphor teaches that the organism – the hardware – is controlled by the software – the genome. Thus, the organism and its fate can be explained by genetics, the plans written into the sequence of genomic DNA; the Genome Project was devised to decipher this program. However, it is now clear that the genome does not directly program the organism; the computer program metaphor has misled us. The genome is only one class of vital information that serves the organism. Metaphorically, the genome can be likened to a vocabulary of words that can be deployed to make meaningful sentences, or to a toolbox for accomplishing specific tasks.