genomeboy.com

Genetic Future summarizes the PGP POV on informed consent and genomic privacy. The crux of the Nature Reviews Genetics article (subscription only) is this:

Current developments in genomic technology challenge the traditional normative framework for biomedical research and its well-known components. It has become clear that the common interpretation of the concepts of privacy and confidentiality as being absolute or near absolute cannot be sustained. Whenever genetic samples are involved re-identification will be possible. Although the research community is well aware of the facts, until now this awareness has not been reflected in the language of consent. Therefore, in many cases, existing consent cannot be assumed to be fully valid.

Although I love him dearly, I think Steve has overstated what George Church is proposing with the PGP. No one I know of is advocating immediate wholesale abandonment of the current model; the idea is simply to begin to integrate other informed consent approaches into human genomic research. Of course, whether the powers that be buy into that notion is another matter.

Hi Mike:

…Thank you again for running the Promethease report on my genotype data. It’s quite remarkable and something one could spend days perusing–I probably will. When the time comes I will have no problem making it public.

But, having thought long and hard about this, I’ve decided that that time is not today. I want to wait until the PGP-10 data are released en masse before sharing my SNP data. There are three reasons for this:

1. Time for reflection. I will only get to make an initial disclosure once. Yes, my Affy 500K results are 500,000 “facts” about me, but collectively they still represent but a single, lonely organismal data point–just 0.02% of one guy’s genome. Thus, the data are not of much scientific use to anyone and so I don’t see a pressing need to throw it all out there without at least availing myself of the opportunity to look it over in private first. Plus it will certainly make my wife happier if I wait (the value of this last point cannot be overstated).
2. Mediation. Your site is fantastic, but it is finally a DIY, labor-of-love endeavor–you have no contractual, fiduciary or medical obligation to me (nor should you). I understand, I hope, that these are just risk alleles, the changes in absolute risk they confer are still pretty small, these alleles don’t work in a vacuum, some associations are tentative, everything is subject to change, etc. I am not a genetic determinist. But I do think for my first time out of the box, I would prefer to go through the process in a slightly more mediated, hand-holding way, which I am hopeful the PGP and perhaps a commercial service will provide. Yeah, I know: some Genomeboy I turned out to be…
3. The PGP process. I have absolutely no problem with what my fellow-PGP participant John Halamka did in disclosing and blogging about his SNP results — he is an early adopter extraordinaire and he should be commended for his willingness to do all of the courageous things he does and to do them alone. But for me personally, I want my data release to be part of something bigger. In one of my early interviews with George in February 2007, he talked about some of his own misgivings about outing himself as the first PGP subject and about how he would like the PGP to function as a team:

…’fessing up that you’re in a study is different from putting your DNA out into the public domain. Hopefully the PGP subjects will confer with each other and with the PGP team before they do that, [though] it will be within their rights [not to do so]. I won’t get very upset about it…

…I just think it’s a team effort and you need to have a little bit of team consideration. Even if it’s something you all plan to do eventually, maybe you all want to do it together, maybe you want to have a press release, maybe you want to make sure that the look and feel of the database are up to snuff before you do it. There are timing issues, there are issues about [how to] portray it in a positive light but with enough discussion of the negativity. I think that requires some nuance that the really gung-ho people will be too impatient to do. I think this is a work in progress, a successive approximation…

In the post-23andMe, post-Venter/Watson age, that view may seem quaint and naive, but it’s a sentiment that still resonates strongly with me and so this slight delay is what I am opting for. The world has waited this long for my SNP data–I suspect it can survive another few weeks.

best regards,
Misha

Update: Mike says, “All good reasons, but only one is necessary: It is your data.”

Well, lookie here: Nature seems to have jumped on the PGP bandwagon:

Technology development guru George Church — aka the information exhibitionist — is playing a salutary social role with his Personal Genome Project. Church is in the process of gathering phenotypic data and sequencing portions of the genomes of ten volunteers, including himself (see page 763). He intends to study how the genes of these people — all but one of whom have revealed their identities — influence their phenotypes, and to make those data public. Church’s point is simple: information, including genetic information, can and should be freely available.

Whether or not one agrees with him, society had better be ready to deal with the results of such research, which is occurring against a background of explosive growth in the availability of genetic information.

The rest of the piece goes on to rightly excoriate Senator Tom Coburn (R-OK), a practicing obstetrician*, for singlehandedly putting the kibosh on GINA.

*What in Hippocrates’ name is up with these physician-legislators? Dr. Ron Paul is one of three (!!!) Representatives to vote against GINA versus 420 in favor! And remember Bill Frist and Terri Schiavo? Physician, heal thyself.

As Hsien observes, everyone’s blogging about their $1000 personal variomes…so I confess to feeling a little sheepish posting yet another breathless update about the PGP. On the other hand, it beats wrapping Christmas presents…

• The Church lab-invented, Danaher-manufactured Polonator — the high-speed sequencing platform that will, um, soon be used to sequence our 20,000 genes — is now available for purchase (hurry and and you can leave it under the tree…some assembly required…).
• The Affymetrix SNP chip has been done on most of the PGP-10. I know you’re all dying to know my relative risk for restless legs syndrome.
• The Church/Danaher team has put its hat in the ring for the X-Prize. This means the PGP-10 will almost certainly have their complete genomes sequenced in the next 1-2 years. Which means we won’t have to scratch that check for $350k. Which means more money left over to buy my kids bobblehead dolls. Yay!
• The PGP is also exploring the transcriptome. George reports that his lab has improved its protocol for converting skin-derived fibroblasts to pluripotent stem cells. For those who want to know why: “We have been doing allele-specific quantitative RNA sequencing assays, since we feel that this is complementary to sequencing the non-coding regions and in many ways preferable to standard RNA assays of tissues from individuals. This provides an assay for nearly all cis-elements (enhancers, promoters, splicing signals, RNA termination, poly-A sites, etc.).”
• In the next couple of months, I expect the PGP-10 will reconvene in Boston, at which time we will:
  • receive our initial sequence data and help in interpreting it
  • donate skin samples for stem cell studies
  • donate saliva for microbiome sequencing (”Look, Ma, it’s my very own E. coli!”)
  • complete phenotypic questionnaires
  • learn more about the plans to scale up to 100,000

Things may be quiet here for a while (yes yes, what else is new?). For now, Nat, Frank and I would like to toast you with a wish for peace on earth and good will toward almost everyone…

• A friend emailed me yesterday, referenced this article on how Knome will offer complete personal genome sequencing for $350,000 and asked, “And you get yours for free??” (Alas no!)
• And last week, The Economist (still unencumbered by bylines) wrote, “Two firms have unveiled products that allow the ordinary punter to get his genome decoded [emphasis mine] for about $1000.” (The article also says, “All people are 99.9% identical, genetically speaking.” Come on, mates–you’re better than that!)

What we have here, I think, is a failure to communicate. According to the New York Times, for a thousand bucks deCODEme will test about a million DNA variants or SNPs, while 23andMe will test about 650,000 SNPs. That’s 0.033% and 0.022% of the haploid human genome, respectively. These “variome” analyses may prove to be incredibly useful and perhaps even a terrific bargain for punters of all stripes, but is it accurate to call them “getting one’s genome decoded?”

What PGPers will get — we think:) — are our complete exomes, that is, the entire protein-coding portion of our 20,000+ genes*. This, I’m told (anybody have a reference?) works out to about 60 million base pairs or roughly 1% of the diploid human genome. George (who, it should be noted, co-founded Knome) has told us our exomes will cost…drum roll please…about $1000. Do I sometimes tell people I’m getting my genome sequenced? As a shorthand, yes, but I shouldn’t. It’s an exome, not a genome.

For their $350k, Knome customers, I presume, will get something like 6 billion base pairs, that is, essentially complete diploid genome sequences just like Venter and presumably, Watson, received. (Read Hsien’s interview with the Knome CEO.)

Are any or all of these services worth it? I have no idea and I’m not sure anyone else does, either. This issue — a genome: what is it good for? — is at the heart of what the PGP is all about. It’s partly a matter of personal taste, of course: is an incomplete and often inscrutable translation of the Rosetta Stone at whatever resolution still worth some amount of money and the space it takes on your bookshelf? I’m inclined to say yes, but I can’t say until I’ve seen mine and lived with it for a while. I have no sense about how the rest of the world feels; however, I will say that in contrast to the enthusiasm I see in the blogosphere, a fair number of my colleagues at Duke, to say nothing of people I’ve talked to at the NIH, tend to roll their eyes when I start yammering on about personal genomics.

Can these companies make meaning out of this stuff? What are customers’ expectations and what should they be? Will new information bring clarity or confusion?

I hope to find out. Next week I will be in the Bay Area visiting some of these folks, asking questions, learning more about what they do, and eating obscene quantities of Asian food.

*Behold, the incredible shrinking genome!

UPDATE: I should add that we will also get our variomes typed via Affymetrix Genome-Wide Human SNP Arrays (don’t quote me on the version).

Thanks to Jason Bobe et al, the PGP website is now up and running. Yay! As congenial as George’s previous DIY version of the site was, I think PGP 2.0 and its easy navigation will answer almost any question one might have about the project, its mission, goals, philosophy, how and why one might participate etc.

And not only is the content put together in a clear and intuitive way, but I think it looks great, too…okay, well, with the possible exception of a certain dork’s kelly green shirt….No doubt my Y chromosome will reveal a congenital lack of fashion sense…

George sends me this note:

…Dana brought to my attention your mug shot blog.

It’s common practice to also show a profile view and booking number.

So here’s the full photo from the archives of the Coriell maximum security repository (where the “cells” are kept at inhuman temperatures with no lighting; and where a life-term of over 150 years is more than a legal technicality):

…Thanks,

–George

If there’s a point to be made here (beyond the collection of further evidence of George’s well developed sense of humor), it’s that researchers will soon be able to order both cells and DNA from the PGP 10 via Coriell. The advantage, we hope, is that those samples will come with unusually detailed phenotypic and genotypic information (to say nothing of flattering snapshots). The question is: assuming someone else will pick up the tab (not a trivial assumption, I don’t think) how many of the next 99,990 exomes will be willing to make their cells and DNA available to anyone with “institutional approval?”

QUASI-RELATED UPDATE: George makes the list of The Ten Hottest Nerds (thanks Dana!)

They asked us to put a tape ruler on our foreheads before they took 3D images of our faces in order to have a baseline measurement of our facial features. And to, you know, make it easier for law enforcement…

A friend asked me about my decision to enroll in the PGP and the effect it might have on my two kids. By releasing my genome, he wanted to know, am I potentially limiting my children’s claim to privacy?

The short answer is yes. “Personal” implies it’s only about you, the sequencee. But you don’t have to be Gregor Freaking Mendel to know that it ain’t just about you. In the near term, familial disclosure may be the biggest elephant in the room for personal genomics.

If you want an idea of how this will play out again and again, read the front-page article in last Sunday’s NY Times about the 33-year-old medical resident, Deborah Lindner, her positive test for a mutation in the breast cancer gene BRCA1, her reaction, and the effect it had on her family.

Within the Lindner family, you see two types of folks, which Jason Bobe presciently summarized: the infovores and the ignotarians. The former see knowledge as power. The fact that their relative was found to carry a mutation was a call to action. They got tested for the mutation and, if they were positive too, they either continued to monitor themselves closely through mammography or else elected to have prophylactic surgery. The others, the ignotarians, did not get tested and in some cases derided Deborah’s decision to have a mastectomy–”Why is she mutilating her body?” they wondered. I suspect their objections were as much about being forced to confront and perhaps lose their ignotarian status as it was about anything else.

Despite my participation in the PGP, I am very sympathetic to the ignotarian position. Just because I have a toothache doesn’t mean I want to rush off to the dentist. My first course of action will be to ignore it and hope it goes away. I reckon that most of us have aspects of our lives in which we choose to be ignotarians.

I pray that nothing in my genome will cause my daughters anxiety. I can’t change their genomes, but as they get older I can counsel them about the evils of genetic determinism, I can tell them that what’s known about my genome is only probabilistic as far as they’re concerned. In other words, I can try to help them interpret what the information in my genome and/or theirs might mean. The option of choosing to remain a card-carrying ignotarian, however, will only get harder as time passes, and for them it may well be impossible.

I’m guessing that in the end it won’t matter–they will probably both have blogs and Facebook profiles and all the rest by the time they’re adolescents, just as they can’t get enough of that goddamn Webkinz right now. And I imagine by that time, posting one’s genome online will be no more taboo than posting one’s CV, or at worst, one’s slightly drunken Flickr photos.

But I could be wrong.

I think most if not all of us PGPers are motivated by a desire to begin to desensitize people to their own genomic information, chip away at notions of genetic exceptionalism and convince folks that, even in a climate where the 14th Amendment might have become a hazy memory, public release of individual DNA information need not inspire fear.

I also think that, even when we disagree with him, we all have real affection for and trust in George.

Not long ago I gave someone something I’d written about the PGP in which I went on at length about him. She didn’t get it. “What is it with this guy? Why the man crush?” I’m not sure I’d call it that, but I suspect even his fiercest detractors (he has a few) would admit that he is a charismatic dude. This is a guy who was adopted twice, flunked out of Duke, and somehow landed on his feet at Harvard, in Walter Freaking Gilbert’s lab no less. Yet to meet him is to meet someone warm, outgoing, at peace, and who moves with a kind of Zen deliberation–not your stereotypical high-strung gene jockey.

And he’s unique in other ways. Not only has he distinguished himself in sequencing technology development, he is making a real effort to figure out how that technology will actually be used by average people en masse. It seems to me that just about every PGP communique is marked by variations on the same refrain: “When we get to a million” or “How do we scale this up?” And it’s that failure to recognize the PGP as a template rather than as an end in itself, I think, that may be the biggest misunderstanding surrounding George, or at least, the one that makes me the batshit craziest. Those who insist that George has assembled a little band of “celebrities” (I wish) pursuing “vanity genomics” just like Craig and Jim, and that this whole enterprise is a tragic misuse of the noble cause of human genomics (summarized beautifully here), don’t really understand either George or the project.

Could I have gulped down the PGP Kool-Aid in too much haste? Could my man crush be a manifestation of Stockholm Syndrome? Perhaps. But to suggest that the nine of us are somehow Paris Hilton to George Church’s Steve Wynn seems to me a bit of a stretch…alas…(I mean, I could do without the video and the jail time, but let’s not diminish Ms. Hilton’s achievements as a recording artist and author. Heh.)

Ultimately history will judge the PGP by what happens when people get their data and begin to make sense of it. Or not: How will the project deal with bad news lurking in subjects’ genomes (and not just the first ten, but the next thousand)? I’d be lying if I said I am feeling completely sanguine about that prospect and what it might mean for my family.

But for now I take no small comfort in the knowledge that the buck stops with George.