Exploring your Genetic Blueprint - A Panel Discussion moderated by Sharon Terry

[0:00] Mark Guyer: Welcome back to the afternoon session. Iím Mark Guyer. Iím the director of the Division of Extramural Research at NHGRI and Iím going to take over moderating this afternoon so that Eric can relax, which is an oxymoron if I ever heard one. Iím going to just continue with the approach that Eric began and invite our panel members up. And introduce Sharon Terry, President and CEO of the Genetic Alliance, who is going to moderate the panel discussion.

[0:34] Sharon Terry: Thanks very much, Mark and thanks to the planning committee for a really wonderful day so far. And I think the afternoon will be equally wonderful. The brilliance of the planning committee -- you all can take your seats -- is such that they were wise enough to know that the people and the various forms of association with their own genomes needed to be a part of this symposium as well. And I come to this because I have two children with a recessive disease called pseudoxanthoma elasticum. Iím a college chaplain by trade, but now very much in this world and very happy to be part of it. My -- I am also very much in association with all the information weíve watched this morning and waiting, just like much of the public, for the kinds of solutions, therapies, tests, et cetera that we hope to see. My brother died of glioblastoma multiforme, so I was

[1:34] happy to see that as an early entry into the various programs. And then Iím very good friends with Progeria Foundation and several of the others that weíve mentioned so far. Iím also a person who did 23andMe almost as soon as it was available and more recently enrolled in ClinSeq [spelled phonetically], which we are going to hear a little about today. So Iím very interested in our own genome and what we can do with the information. Iíd comment that I think collecting samples as we go, that was certainly mentioned several times this morning and said to be very difficult, will be just like many of the other things we thought are going to be very difficult. And that is it wonít be once we allow the right systems to be put in place including the involvement of citizen scientists, people who understand that they need to be involved, and by that, I really mean all of us, that every one of us, especially through social networks, will begin to understand the importance of being available for science in various ways.

[2:27] Today, weíre going to hear from a number of individuals who have had their genomes sequenced and who have a great deal of interest in understanding this on an individual basis. And weíre going to ask them to answer two questions in a very brief introduction that theyíre going to give us. And then weíre going to ask them to ask each other questions and then weíre going to invite you to ask them questions. So this particular panel which lasts about one hour is going to be a little more interactive than some of the other sessions. So you should be ready to ask these individuals anything you want.

[2:57] Iím also going to dispense with formal introductions and just give you their names and affiliations. And Iím also going to give you the order in which theyíre going to appear, although theyíre here already. So first, weíre going to hear from Dr. Stephen Sherry of the National Library of Medicine. Then weíre going to hear from Rick Del Sontro from -- whoís a ClinSeq participant. Weíre also going to hear then from Misha Angrist from Duke University, and then finally from Dr. James Watson from the Cold Spring Harbor Laboratory. Again, each of them will take about five minutes to introduce themselves and then weíll move into some conversation amongst them and then some questions from you.

[3:37] So, Steve [spelled phonetically], if you could begin. Dr. Stephen Sherry: Thank you, Sharon. So I guess I would like to say that Iím excited about the promise of biology in genomics. And Iíve done this professionally for about 10 years, 13 years at NCBI where I run, or Iíve helped develop variation resources, dbSNP and dbGaP being primary among them. And so Iíve had a scientific relationship with genomic information for my whole professional career and have watched with curiosity about how the consumer reagents are being developed and what this could mean to me personally. I have not participated in a medical research study before, but this year 23andMe put the genome typing kits on sale for Christmas, and so I bought them for my family. And thought this would be something neat to give my parents for a Christmas present, they had everything you know, so what do you give them?

[4:31] [laughter] Now itís going to be an obsessive set of questions about, you know, their drug sensitivity to statins and all sorts of things. I havenít received my results yet, so unlike others on this distinguished panel, I donít have a lot to say about how this has changed my thinking. I can maybe speak briefly to why I decided to do this [unintelligible] trivial curiosity. In developing these catalogues, these resources, at NCBI weíre very concerned about the relationship we have to participants in medical research studies. Their volunteer spirit, their trust is essential to the relationship in scientific research. And so weíre trying to ensure that the resources we develop at the Library of Medicine are responsive to their needs as well as to the needs of the research community.

[5:15] What we imagine is that going forward, genomics are going to be more available to consumers and -- but it wonít be every consumer that is coming forward to look for information. Mostly likely there is going to be a key person in each family who took biology in college or knows some genetics and will be the person that is the authority in a family relationship, the go-to person to say, ìInterpret my genetic test.î In my personal experience, my parents have come to me and said, you know, my father has a degenerative brain condition, what does this mean, you know, their tests. And so Iím looking at them now, not as a theoretical researcher making sure the information is complete, but trying to interpret the data personally for my own family members. And so Iím thinking that the more I can become engaged with 23andMe and these other information providers that are digesting information, that itíll help us inform our design decisions and the resources in the information structures that we provide at the Library because weíre trying to serve everybody, taxpayers included, with our research community. Itís kind of [unintelligible] -- Iíll stop there.

[6:16] Sharon Terry: Great, thanks very much. Rick? Rick Del Sontro: Well, I come at it from a completely different angle. Iím not a scientist, Iím just a layman. My storyís kind of interesting. I bought into the myth that if I was physically active, if I ate properly, if I kept my cholesterol in check, and had low triglycerides and, you know, I was on the road to success. And having had a mother who died at age 69 during her third open heart surgery, having had a grandfather who died of heart disease as well who was one of the first 100 people to get open heart surgery, I was always sensitive to that. And a few years back, my sister at the time was, I believe, was 48 years old and she started to feel not right. So she went in and she saw a doctor who sent her over to see a cardiologist. Long story short, she -- it turned out that

[7:20] she had three blockages, two of them they stented, one they did not, and she strongly encouraged the family to go get checked. Now, I come from a large family, thereís eight children. Interesting note, my sisterís cholesterol level, combined cholesterol level, was about 104 and remains there today without taking statins because she -- her body doesnít do well with them. So, anyway, on that I went to see my doctor who, you know, again, Iíd seen for years just the regular practitioner who put me on the treadmill with an EKG machine which basically was only going to tell me I guess if I was ready to keel over from a heart attack. So I checked out fine and went home. I had a brother at the time who was 38, cholesterol level roughly 150, low triglycerides, physically active, and he went in and got a nuclear stress test. They didnít like what they saw, did a catheterization. He went in

[8:21] for emergency double bypass surgery at the age of 38. So I panicked, went and saw a cardiologist. And he walked into the room and said, looked at my file and said, ìWhat are you doing here?î And I said, ìLook, just let me tell you my story and if you really want me to leave after that, Iíll just leave.î So I told him and he thought it was interesting. And told me to go and get a heart scan done, which I did. It came back that my calcification was through the roof. So at that point in time, I went through a number of tests. He said that the only way weíll really know whatís going on is if we do the catheterization, thatís the only way youíll get any piece of mind. So I did, and fortunately for me none of my blockages were severe enough that they needed to stent them. And as I was lying there in recovery, for -- I think you had to lie on your back for four or five hours, someone came over to me and said, ìTheyíre doing a study over at NIH called, you know, with ClinSeq. You might be interested in this

[9:23] and you might be a good person, a good candidate to go over there.î So I called and called and somebody finally called me back. And I said, ìYeah, Iíll participate.î [laughter] Well, they were busy doing research, you know, lot of DNA out there, you know. So anyway, I went in and told them my family history and they were real giddy about the whole thing to be honest with you as I was going through and telling them, you know, what had gone on and what was going on. And so, they did a bunch of tests that day and about a month or so later, I got a phone call and I could -- I really didnít understand, but I could tell that they were excited about something. And they said, you know, ìWe think weíve come across something pretty, pretty interesting here.î And I said, ìOkay, great.î And they said, ìDo you think your entire family would be willing to participate in the study?î I said, ìSure, but theyíre not all here local.î They were like, ìOh, donít worry about it, you know, just see if theyíll come in and theyíll participate.î So, you know, I got in touch with all of them and said, ìWould you guys be game, go in

[10:25] for study. Theyíre doing a study on, you know, heart disease and your DNA.î Yeah, okay, theyíll go. And so I think from there it sort of has blossomed is the best way I can put it. The study has gone layers and layers now, and in fact I was just talking to Dr. Biesecker [spelled phonetically] before I came in and theyíve done some, you know, family history and theyíve traced ancestry back to Italy. And I think heís going to be going over there to make a trip and theyíve now tested extended family, cousins, and things of that nature. And I personally have been fully sequenced, so I went through that, had no idea what it was. They said, ìWow, do you know what that is?î I said, ìNo, I have no clue as to what that means.î [laughter] [unintelligible] and Dr. Watson, I donít mean to, you know, I just -- [laughter] -- sorry about that. Iím a layman, Iím just a guy. So anyway, they said, you know, ìAs we go through the sequencing, we come across things that we find, do you want to know about

[11:32] them?î And I thought to myself, ìWell, yeah, I think I do.î So they said, ìGreat.î So I got a call one day right before Christmas and they said, you know, ìCan you come in?î and, ìWe found something and we want to talk to you about it.î And Iím like, ìOkay, well when do you want me to come in? Well, no, Iím leaving for the holidays and oh, well then the doctor is away for a week after that, and so itíll be, have to be like mid-January.î And Iím like, ìOh, well, can you give me an idea of what youíve found?î ìNo, weíre not allowed to do that.î [laughter] Oh, this will be a good Christmas, right? So anyway, it turned out that they found a condition called HNPP, which during the sequencing -- and if you donít know what HNPP is, itís okay because I didnít know either. But basically I get numbness; I get sporadic stages of numbness throughout my body. Itís been going on since I was about 20 years old. I had no idea what caused it and nobody else could tell me what caused it candidly. And parts of my body could

[12:34] go numb for days or weeks or even months. And then ultimately it would go away. And so I got to learn a lot more about that and subsequently also got to learn some of the things that I am potentially, I am a carrier for. Most of them seem to be, you know, obscure, so nothing really to worry about. But Iíve been asked before how has this changed me? How has this impacted me, what does it mean? Itís really been interesting because I did the study not necessarily for myself, maybe not even for my children, but for my childrenís children because I thought there would be a point in time when, you know, youíre born and there you have it, your blueprint is right in front of you and you know what to do. I liken it to using a GPS, right, so youíre going down the road and youíre going to run into traffic and your GPS is going to tell you to take a turn the other way. Thereís nothing you can do, youíre getting from point A to point B, but along the way you might -- there might be better ways to go, right? There might be better things for us to do to prevent things or avoid certain

[13:36] situations. And so from my standpoint, I want to know. I know thereís a lot of people out there that I talk to that probably say, ìLook, I donít want to know whatís going on.î But for me itís been important to know, itís been very eye-opening. I will say this, the energy and the excitement of everybody on the staff at the ClinSeq study has been amazing. Itís really -- theyíre just very excited about the work that they do and from my perspective, thatís pretty neat. So hopefully thatís a good background, probably took over five minutes, but thatís my story. So thanks.

[14:10] [applause] Sharon Terry: Thank you. Misha Angrist: Well, thatís a tough act to follow. So I got involved in this -- Iím not going to talk about clinical utility or even personal utility, but maybe existential utility. I spent from the age of 25 to 35 or so in a human genetics lab. I was the board eligible genetic counselor. And then I studied a birth defect and we actually found some Mendelian mutations. We were not a CLIA certified lab; we could not give results back to those patients and families. Eventually we became a CLIA certified lab, but that sort of disconnect from the people we were studying always sort

[15:12] of stuck in my craw [spelled phonetically]. And so many years later, I opened up Scientific American because there was a story in there called ìGenomes for All,î written by a guy named George Church at Harvard. And I read that article and I felt like here was a guy who was articulating many of the things that I had felt, that the time had come to sort of start thinking about how do we put this technology out into the world, at what point do we start sequencing healthy people like the gentleman to my right? And so that sort of started this odyssey of my enrolling in George Churchís personal genome project and getting my genome sequenced and living with it and making it public and thinking about the implications of it. And spending a lot

[16:17] of hours in front of Excel spreadsheets and learning a lot about next generation sequencing technology. And so, here I am. [applause] Dr. James Watson: It was now I think almost five years ago when the founder of 454, a new company [unintelligible] DNA sequencing came to my office, he telephoned me and said he wanted to -- they had this instrument that would be able to sequence me at a reasonable cost and would I be the first person to be sequenced? So I said yes, right away. I didnít -- I said, might as well make it public, but I donít want to

[17:19] know anything about apolipoprotein E because I have a grandmother who died of Alzheimerís in the late í90s -- no, mid í90s. And it was pretty awful, so I didnít want to know anything about it. And then really didnít think about and two years passed and he called me up and said, ìYouíre half sequenced and weíre working with Houston Genome Center, Gibbs and the group -- and George Winsock [spelled phonetically] was the key.î And then with time, you know, I went down to Houston and there was publicity for the Genome Center for the Baylor College of Medicine and they told me I was heterozygote for a lot of bad genes. They said I had a variant of the breast cancer, BRCA1. Okay, but, you

[18:26] know, I didnít know what that meant and I donít think they did either. But they told me I was homozygous for something like a terrible disease DNA repair [spelled phonetically] like Helmanís Disease [spelled phonetically]. I mean, you just donít reach my age if you had that, so I just didnít think about it. And -- but I did think that if, you know, I didnít know which variant I had in the breast cancer gene, so I thought I should tell my nieces because it is an awful gene if youíve got the Jewish variant. Weíre not Jewish, so, you know I didnít think I should have it.

[19:02] [laughter] But I wanted to find out and -- but before calling them, I called Mary-Claire King [spelled phonetically] and my sequences on the Web. So she looked up and called me back and said you have a harmless Irish variant. How she knows that itís a harmless Irish variant, but, you know. So I didnít think about it again, didnít call my nieces, and so didnít think much about it. And then someone called me up and said, ìYou havenít deleted or let me know that you havenít deleted enough from your sequence [unintelligible] apolipoprotein is, do you want to know?î Of course, I didnít want to know and I couldnít tell them donít publish it and, you know -- but the story is more complicated.

[19:57] Then something actually useful happened, an article appeared from Craig Venterís [spelled phonetically] that compared his sequence with mine with regard to the cytochrome P-450, the enzymes which metabolize drugs. And Craig was fine, but I had a very slow metabolizing form of 2P6 [spelled phonetically] something, the one which not only metabolizes beta blockers, but antipsychotics. So itís an important one. And I had been put on beta blockers and they had put me to sleep and I had to go off them. And then suddenly I had the explanation, that instead of taking one every day, I should maybe take one a week, which Iím now doing and it controls my blood pressure. So that was extremely useful fact which I wouldnít have known without -- it was also the question came up where someone said, ìWell, in getting

[21:02] yourself sequenced, you are going to know something about your children. Do you have the right to invade their privacy?î Okay, no, no, I mean, thatís the sort of thing that these, you know, these bioethicists have nothing better to do but to think about. [laughter] And -- it turned out my son, I have a son who is schizophrenic, and he had been given antipsychotics after he had hit the doctor, who was a Freudian, and I would have hit any Freudian too.

[21:35] [laughter] But anyways, he hit the doctor, a really miserable, fat, little man, and Chestnut Lodge [spelled phonetically], itís gone now, but it was a place outside of [unintelligible] and he went into neuroleptic malignant syndrome and almost died. I think we now have the explanation, he didnít metabolize the drugs. And so itís a very useful fact. He doesnít want his DNA sequenced, but I know was homozygous, so heís heterozygous. And it turns out probably the -- that some psychiatrists are really measuring this now before they give out antipsychotics to schizophrenic people, so itís quite important. And if I was younger and, you know, living on an academic salary, I would certainly start a company to do just the cytochromes because no one who, you know, who goes to a doctorís office for blood pressure should be given

[22:37] the drug without knowing whether you can metabolize it. I mean, some people are -- Iím a slow metabolizer, some are super fast, it never works. So it probably would be cost-effective for the big health insurers to do it. So I think, you know, and then the only other thing is after a, you know, remark I never intended to make, Kari Stefansson [spelled phonetically] announced in The London Times that I was -- he had looked at my genome and I was 16 percent black and four percent -- six percent Asian, and it didnít go with the pedigrees of my family. And he never published how he concluded that I was 16 percent black and six percent Asian, probably, you know, the Asian probably means that one of the Watsons [spelled phonetically] in Tennessee consorted

[23:38] with an Indian woman. [laughter] And -- but I just have no interest in it. So, you know, I could have followed it up. I havenít sent my DNA to 23andMe which could give me really quite a good ancestry. But Iím afraid, I, you know, live with the myth that Iím only English, Scotch, and Irish, no Welsh, and -- [laughter] -- so I donít want it disturbed [spelled phonetically]. You know, itís a myth and why destroy my myth? It might discover I have German blood or something, you know, that I wouldnít have wanted. So, you know, thatís where I am, I am remarkably uncurious. And -- but what I have been surprised is that, you know, people really havenít looked at my sequence and written about me that they found out something. So there seems to be a total lack of interest in me as far as I can tell.

[24:39] [laughter] You know, people giving me good or bad. Then it turns on the Alzheimerís; whoís interesting, me [spelled phonetically]. One thing that 454 canít do is count Ts [spelled phonetically], you know. And it turns out that apolipoprotein E, the key to it, the work of Allen Roses [spelled phonetically] is that adjacent to it is a gene called tom-D [spelled phonetically] standing for the Aldrich [spelled phonetically] mitochondrial membrane, itís a pore [spelled phonetically]. And people have either a long one -- or depending, itís very closely linked to the aprol [spelled phonetically], so the three has its own poly -- tom-T [spelled phonetically] polymorphisms. And thereís a long sequence of about 50, which is very bad prognostic for Alzheimerís. If you had that long sequence and youíre three, youíre going to -- no, probably 80 percent chance youíll get Alzheimerís. If you have the short one, youíre pretty safe. And so, those who would have never been measured and you would have to go back to

[25:48] Sanger [spelled phonetically] sequencing to do it, or Pacific BioSciences could do it. Craig, having released his entire sequence, you know, it would be interesting looking him up to look at his tom-T and if I were Craig, I wouldnít look at it because heís 60, you know, getting old.

[26:19] [laughter] And, you know, people do, you know, a bad four [spelled phonetically] with a long tom-T means you have a chance of Alzheimerís in your 60s. Sharon Terry: Thanks, Jim, so you [inaudible] -- [laughter] Dr. James Watson: Anyways, so thatís the [inaudible] the story, so -- but I think that just to come back to the general point. I think DNA sequences should be known. I donít think the average person should really ever look at them. And I donít even think the average doctor can look at them, thereís going to have to be consultants.

[26:52] The doctor says, whatís the message from the genome that I should -- I can better treat my patient. And then the doctor has to show sense of not telling you that we found out that youíre going to die of Huntingtonís, you see. Because, you know, thatís not good news. So thereís got to be old fashioned medicine and common sense by which you only tell people things which are useful and donít tell things which are just another reason for worry. I donít see any way to regulate it, it just depends on -- I wouldnít want it regulated.

[27:37] Itís complicated enough, I donít know how you can even get a certificate that you know youíre competent to look at a genome and predict someoneís future. Sharon Terry: Great, thanks Jim. Dr. James Watson: Okay, well thatís -- [applause] Sharon Terry: So I think you teed [spelled phonetically] up a really good question and one thatís a very interesting one thatís been debated since genomes were available to those of us who are lay public and even those of us who are scientists but working in the various fields. And that is the -- who should know what, when, and who should be telling who what? And I think of even -- there is a new tool out by 5AM Solutions [spelled phonetically] called Snip Tips [spelled phonetically]. And essentially you download the 23andMe sequence and it flags every snip you read about in any article, and you can click on it and it shows you your variance.

[28:20] So more and more, thereís tools that make it very much available to each of us to look at these things. And I wondered if some of you would comment on, what do you think you should know, who do you think should be telling you what you know or donít know? And also thatís the kind of common perception, at least among the scientific community, that none of this is ready for what they say is prime time. Dr. Stephen Sherry: I just talked to my parents last night about this thinking about today and asking them what they hope to know when they get their results back in a few weeks. And theyíre very interested in the pharmacodynamic set of cytochrome results and their sensitivity to drugs. Theyíre in their 70s and theyíre starting to look at statins and other issues, and want to know when findings come out about drug sensitivities or dosing. Is it relevant to them? And I think itís a great, you know, kind of personal use. And so theyíre, I think, looking for either their doctor to interpret their results or a professional, you know, that they [spelled phonetically] would be referred to, a qualified professional. I donít think that occupation is really flushed out

[29:22] yet. Dr. James Watson: It doesnít exist now [spelled phonetically]. Dr. Stephen Sherry: So the Web is going to do that for them, itís going to be these Web services, 23andMe themselves, itís a monthly subscription model where as new findings are published, you can go reinterpret [spelled phonetically] your genome or like what you mentioned. And so I think there is a question about how do -- how accurate are they or do they oversimplify? Thatís the risk that Iím wondering about. Dr. James Watson: I would be very afraid to trust the Web, you know, for something thatís fairly important. I called Mary-Claire King, I was lucky because she knew all the variants in BRCA1 or you know, [unintelligible] would let her know about. That the -- I think weíre going to have to have some experts, that you just donít believe that, you know, this database is perfect. I mean, the decisions are too important and I would, you know, in the sense of a second opinion now, I was lucky and knew the, you

[30:26] know, the person who probably knew BRCA1 as well as anyone in the world and how you get this advice. But I do think thereís going to eventually have to be human beings that you trust that they know all the polymorphisms, and theyíre doctors, and they donít want to practice. But they sort of specialize in, you know, all the genes of your immune system or, you know, they really know about arthritis. You get help from them. So I think thereís got to be sort of specialties of people that you can call. Just because itís on the Web and, you know, whoís put it there and how, you know, has the FDA certified it, and if they have, you know, I wouldnít, you know, the data is so old you wouldnít want to use it.

[31:21] So, you know, again, you know, the whole thing will favor people who are rich and who can get good advice and with time, it will percolate down. I donít see much that will change the situation. Dr. Stephen Sherry: Can I ask if you see a difference between a physician that orders a test, returns it, doesnít know how to interpret it, and hands it to the patient and the company that just does it for profit and just returns it to the patient? Dr. James Watson: I think I feel [spelled phonetically] responsible because, you know, if you give it to Eric, he can, you know, interpret it, but most people wonít know what it means. Itís just too complicated.

[32:01] Dr. Stephen Sherry: Thatís been my parentsí experience in the diagnostic tests in this brain disorder. It was ordered, the genetic tests came back, the physician said, ìI donít know how to interpret this,î and handed it to my father. Dr. James Watson: Yeah, so I think, you know, with time there will be virtually -- whether they call it a medical specialty or something. A lot of people who donít like to deal with human beings, you know, are autistic people, they can be in charge of the significance of the data and they never have to talk to the poor person whoís sick. No, I mean, Iím really looking at this for the first time in human history when these informatics people who are unsocial have -- [laughter] -- we have a real need and they have jobs.

[32:52] Dr. Stephen Sherry: If we open the data -- Dr. James Watson: What? Yeah. Misha Angrist: So youíre saying this is a public works program. Dr. James Watson: No, no, no, no, no, I think youíve got to eventually -- someone has got to pay for someone to look into genome. I asked George Church, I said, ìWhat does my genome mean?î And he said, ìWell, youíll have to give me money, it costs money to examine someoneís genome.î So -- you know, and not an inconsiderable sum, probably to get your genome, and I can easily see $10,000 or $20,000 expended [spelled phonetically] to have someone look at it. And in the sense the cost will go up, both go up and down, because thereís going to be so many more regions we can look because we have some experience that that polymorphisms mean something. And we can have this all on an NIH Web, but I think for something, you know, before we were scared shitless of learning

[33:59] something, you should get a second opinion. Thatís all Iím trying to say. Sharon Terry: Letís hear your thoughts on that. Misha Angrist: Well, so in quote, unquote preparation for this, I went on SNPedia [spelled phonetically] last night because all of my data are there. This was a website that was essentially started by two guys in their basement that links out to the literature, all of the GWAS and Genetic Association literature, and so I have, I donít know, 9,000 or 10,000 annotated genotypes there. And it makes some subjective evaluation, these seem to be the most interesting snips and itís based on allele [spelled phonetically] frequency, and severity of condition, et cetera. And so I looked at the top of the list, I said, ìI wonder what my most interesting snip is,î and it says, ìYou are male.î

[35:05] [laughter] Sharon Terry: Which we now know is important after this morning. Misha Angrist: I thought they nailed that. [laughter] And then, you know, it was followed by some other sort of phenotypically [spelled phonetically] obvious, if not flattering things like, you know, 7X [spelled phonetically] risk of male pattern baldness and that sort of stuff. And so we can say thatís frivolous and we donít need to know that and whatís the point. But I guess I see that as sort of an educational tool that, yes, I know I am going bald, but hereís an opportunity to maybe understand why, and to look at any of these biochemical pathways that have been discussed so eloquently here today and to just get an insight into perhaps at some superficial level how this

[36:12] affects me. Sharon Terry: Great. Dr. James Watson: Good luck. [laughter] Misha Angrist: Iíve got time. Rick Del Sontro: Yeah, I sort of -- I think Iím kind of in Mishaís camp here on this one. Again, I mean, there -- when I did the testing, it was really about my children and their children. So if there was something that I found, there was something that they could find that potentially could impact them or would impact them, is there something that, you know, could be done to prevent it or keep them from going down a, you know, a slippery slope with things. So -- but itís been interesting. Itís been interesting to at least try to understand things and why theyíre happening to me and even just, you know, just the one condition. But I think in listening to Dr. Watson, it becomes evident that there are much more critical issues that you could find that I think would

[37:17] be of concern. And I would be, you know, itís sort of like my general practitioner just putting me on a treadmill with an EKG machine saying, ìHere, you have no heart disease.î You know, I donít fault the guy, but by the same token, I probably could have found out years ago that, you know, maybe I could have done something to prevent it. So my other thing, if I could ask a question of, I wanted to ask Dr. Sherry and -- two things. One, you got the tests for, you said, for Christmas? You know, Valentineís Day is Monday, what have you got in preparation for that?

[37:51] [laughter] No, I mean -- what was it, was it your parents that inspired this? Did you want to learn more about what could cause this, you know, the brain issue? And what was it that really -- and what are you hoping to find? Dr. Stephen Sherry: So the brain issue is a heredity generative condition, my father got tested for last summer and that was -- got me thinking about it. But there has been a 12-year enterprise NIH and the Genome Institute has lead about finding these catalogues of variants that Eric mentioned this morning so nicely. And, you know, one of our tasks at NCBI has been maintaining that catalogue, trying to relate it to disease and so, you know, Iíve worked it. I am one of those [unintelligible] social types that sit in a computer room -- [laughter] -- and try to put out accurate data. Iíve always wondered personally what would it mean to me? You know, I donít have any, you know, personal knowledge of disorders that are coming up. Thereís not a lot of hereditary disease that I think I am facing. So it wasnít that

[38:54] curiosity, it was more of how would I -- but one is, you know, I see all these people that volunteer to put their genotypes into public scientific repositories, you know, and working with that data, I should have that same level of commitment to the enterprise. So it was a personal decision, I would put this data out just because itís asking no more of anyone else than I would expect of myself. And the care that I take in operating the database and making sure that, you know, all of the consent is followed. You know, I want to understand that process from the participantís side. Thatís what Iím saying, I have never been in a study, so this is a consumer-driven approach to that. And I think as Sharon was saying, there should be more of that, people are very interested.

[39:37] The price was right, you know, at Christmas and it wasnít like my parents were particularly sick or anything. I was just like they have everything but whatís something that you could give them would be knowledge of themselves. And in weíre finding is that itís starting a lot of conversations in our family about science, about how these studies are funded and what weíre learning. And thatís turned into discussion moments that I think that are much broader than just the health question, itís about how public research is really relevant to American lives. So Iím finding that as a hook, they donít understand what I do. They havenít understood since graduate school, now itís relevant. So I think that could be a broader opportunity for a lot of Americans.

[40:19] Sharon Terry: Great, how about from the audience? We want to leave some time for you to ask some questions. Thereís two microphones. Male Speaker: That was great. I was thinking of asking the panelists, except Dr. Watson, if they are in interested in getting resequenced so that will tell us about the technology that has been used in the past versus new [spelled phonetically] versus the effect of aging. Do you like to get resequenced? Dr. James Watson: I am -- probably, you know, 80 percent of people my age canít hear, so -- [laughter] Male Speaker: I agree with you.

[40:58] Sharon Terry: So the question is -- Misha Angrist: Would you like to get resequenced? Dr. James Watson: No. [laughter] No, I mean, the only thing would be to sequence the tom [spelled phonetically] sequences in the thing [unintelligible] and, you know. But I -- no, they did a pretty good job and -- [laughter] Anything which, you know, it turned out the [unintelligible] they said, ìWe looked at your sequence, youíre one base pair off from the bad one.î So I never, you know, I was never at risk. And -- but I try and not be a worrier and so I try and avoid the information which will worry me. So thatís why I, you know, whereas -- and I want to make the emphasis, these cytochromes are really quite important in medical treatment and thatís information which probably we should -- and I canít say any way except small companies doing it, that

[42:03] the average -- that will reach the average person fast enough. But you should deal with cardiologists, you know, itís a [unintelligible]. But, you know, who would pay for the information and so on, but in my case it was important. Beta blockers really do control blood pressure, [unintelligible] they work for blood pressure. And as I learned, 80 percent of people above 80 have really -- blood pressure to the point where you have to control it. And, you know, I -- Male Speaker: [unintelligible] on clinical [unintelligible] participant. Did this genome -- gene that has been found for arterial calcification has got any similarity with the peripheral artery calcification gene that has been [unintelligible] sequenced by Dr. Gall [spelled phonetically] and his group [unintelligible] disease?

[42:52] [laughter] Male Speaker: [inaudible] Male Speaker: I think [unintelligible] 73, if I could recall. Dr. James Watson: You had one question [unintelligible] -- [laughter] Sharon Terry: Go ahead, Rick. You can -- yeah. Rick Del Sontro: The answer is I just donít know. I apologize. Bert Gold: Iím Bert Gold. Iím at National Cancer Institute.

[43:25] I must say, Dr. Watson, that I saw you the first time when I was seven years old and thereís no question in my mind that if you want another career, that you could always do standup comedy. [laughter] You are absolutely as good as Jerry Seinfeld. [applause] Dr. James Watson: No, it gets you into trouble. Bert Gold: Okay. Dr. James Watson: In an academic -- Bert Gold: My question is for Dr. Watson. Iíve had the great honor to look at his DNA in the region of the Duffy locus [spelled phonetically] and so Iím aware that you are at least a Duffy heterozygote, which would suggest that like the rest of us, you have some origin from Africa but perhaps yours is a bit more recent than some of the rest of us at some level, yet I hear you kind of disavowing or not being certain of that or identifying with Scottish or Irish ancestry more, so Iím wondering

[44:29] what you think. Do you think it was a DNA mistake or what are your thoughts? Dr. James Watson: I have no thoughts. [laughter] Kari Stefansson has reason to dislike me; I have reasons to dislike him. [laughter] I called him a leech once at a meeting, you know. Bert Gold: Affectionately. Dr. James Watson: No. [laughter] No, you know, heís Icelandic, about six foot eight in height and heís, you know, heís Craig Venter-like [spelled phonetically]. I mean, you know, they -- itís a strong personality.

[45:11] And heís done -- like Craig, heís done some good things, Iím not trying to say, you know -- no. But, you know, you donít publish in The New York Times without at least [unintelligible] why he thinks Iím, you know, it did cause me to look at a few ancestors but -- pictures, I mean, you know. But -- Sharon Terry: So very good reasons for where he gets -- Dr. James Watson: Itís sort of irrelevant, Iím just -- Iím telling jokes because I donít frankly give a damn.

[45:45] [laughter] Sharon Terry: Next question. Male Speaker: So I wonder if I could ask the panel for their thoughts on where they think this kind of data is going to be stored going forward given the fact that there is probably going to be multiple vendors, multiple companies, multiple technologies being able to sequence your DNA. You could have multiple copies of your own sequence, how are you going to be able to keep track of this? Are you going to be able to -- are consumers going to handle it themselves, or is there going to have to be some central repository thatís trusted that can keep track of it for them? Thereís a lot of open issues there, I am just curious what your comments are on that.

[46:15] Dr. Stephen Sherry: I think theyíll treat it like music downloads. I think itíll be personal libraries or there will be private companies that step into that market. I donít think it needs to be centralized for any reasons other than efficiency or convenience for individuals. I donít think itís appropriate in a government database because itís not research, itís not funded for that. I know that, you know, what Iím having done and what others have done are going to be in a company databases. They may get sold and then that goes to some new company and, you know, thatís all in the informed consent. I plan on keeping a personal copy of it. Iíll download it and consolidate it that way. Is that your experience?

[46:56] Misha Angrist: I think itíll -- for most people, itíll probably live in the clouds and some people who are more worried about privacy will insist that it live, you know, on their nightstand or whatever and not in a public or remote location. Male Speaker: Thanks. Rick Del Sontro: I just thought Apple was building an app for that, I didnít -- [laughter] Sharon Terry: You can tell heís an entrepreneur. Yes. Female Speaker: Hi there, Iím Layla [spelled phonetically].

[47:27] Iím a genetic counseling student here. And so I wanted to just point out, I guess, something that you all maybe have in common, which is that when you decided to do this you had a lot of -- you had relationships, first of all, with the people who were doing it to you for some, you know, to some extent. And you had a lot of control over what you did and didnít see and who did it and sort of how the process unfolded. And I guess I wanted to know whether you think thatís an early adopterís prerogative or do you think everybody has the right to that? And if so, if the latter, like how would you scale that up once this is more common? Sorry, very wordy but -- Dr. James Watson: I didnít understand that.

[48:08] Sharon Terry: Rick, do you want to try that one first? Rick Del Sontro: Well, yeah, I mean, for me it was sort of, Iíll be honest; I didnít know what was going on. I mean, and so, you know, to look at the -- and get access to the information, Iím just happy to share it with whomever. I would love to, you know, whenever I -- I mean, I havenít actually seen any of the data, right?

[48:40] I just get the results. So I havenít actually looked at what it looks like yet. So I am sure if I asked, I could. But for me, itís just Iím happy to share it, Iím happy itís out there. I personally didnít have to pay for it, it was paid for as part of the study. So Iím very fortunate in that, it is my understanding that itís fairly expensive to do, you know, full sequencing. So, I mean, I think thatís the best answer I can give. Misha Angrist: I think itís an excellent question. I think we are privileged as early adopters, that we got a lot of handholding. And then, of course, the more people do it, that becomes a difficult thing to scale. How do you provide flesh and blood genetic counseling for everyone? And so this, I think, to some extent, gives rise to the 23andMeís of the world. And even the Personal Genome Project, there is a move

[49:43] away from sort of these intimate interactions with the neighborhood medical geneticist and more toward software because I donít know how else you can scale up. Dr. Stephen Sherry: Just add one point because this is where Iím at in the process in trying to decide how open to make the results. And my parents are very concerned about ensuring that I can see their data, but right now itís just our immediate family. We want a clear way to, you know, to share these with our extended family as other people get tested. And then once weíve seen the results, open it to the world. I donít think Iím ready to, you know, having no idea whatís coming to say itís out there like personal genomes. I believe you make the commitment up front, right? Itís part of the consent. So I think that on the consumer model, it will be more incremental and to have that clearly provided and architected, I think, is essential for the ethics of this as it reaches the late adopters.

[50:43] Male Speaker: So, as you just mentioned, you would be open to the possibility of sharing these data with the world. Would you share your genetic information with insurance companies? This maybe a little bit early on in the process to ask this, but as somebody whoís gone through this, you know, would you want your insurance company to know about this, if not, where do they stand on this? Misha Angrist: Would you share your data with insurance companies? Dr. James Watson: Sure, but I think, you know, if I were, you know, running one of these big projects, I would, you know, sequence only people who are about 70 years old.

[51:25] [laughter] No, no -- a reason is that you have their entire past medical history rather than going, you know, the other way. And on the whole, people who are retired, they are not worried about necessarily putting the information public. And I think unless we have some phenotypes correlated with genotypes, itís going to be hard to interpret it. So if we emphasize too much secrecy, so Iím trying to get at, I didnít worry in part because of my age.

[52:02] You know, they werenít going to, I wasnít going to, they werenít going to find a hetero-gene for Huntingtonís disease, you know. So -- I think itís important that a lot of people realize that they are more likely to benefit, like I benefited by looking [unintelligible] so I could help my son, thatís all. And that you could discover youíre a carrier for cystic fibrosis and therefore your children should look at this. So I think -- I wouldnít worry about sequencing for the most part, I think itís overblown.

[52:45] Sharon Terry: Other thoughts on the insurance issue? Misha Angrist: Well, I mean, with the exception of his -- Jimís APOE locus [spelled phonetically] our genomes are both public, so insurance companies donít have to ask us. Dr. James Watson: Yeah, but they donít have the tom-T, they really donít have the data that they need to interpret, so you have to really go back and now look at it and then you can make really pretty scary predictions instead of, you know, if you have the three, itís 50 percent, now if itís three long, 80 percent. So, you know, I think itís one you really have to -- I would advise people not to learn it or, you know, not to have it released because thereís no benefit.

[53:34] Dr. Stephen Sherry: Do you think that the insurance companies would do anything with the information if they had it? Dr. James Watson: Well, weíre -- right now theyíre prohibited by law of using it, I think. This wonderful law that Francis [spelled phonetically] got through, I think you canít be discriminated against. Misha Angrist: In health insurance and [spelled phonetically] employment? Sharon Terry: Right. Dr. James Watson: Yeah, I think thatís the least of our worries frankly. Dr. Stephen Sherry: I would just add that I think thereís a difference between sharing my genetic information and the phenotypic information. And that was my momís one concern on some of these -- the 23andMe surveys, what they collect phenotypically.

[54:13] And Iíll just say that she really objected to bra size. [laughter] Misha Angrist: I think the other point to make is that this can cut both ways, so if I know that I am homozygous for ApoE4 [spelled phonetically] and I have not shared that information with anyone, there is nothing to stop me from loading up on long term care insurance. So -- Sharon Terry: Right, so weíre going to take the last two questions and weíre going to ask the panel to be very brief so that we can get back on time. And I think weíre over here.

[54:48] Ahmed Kablan: Ahmed Kablan [spelled phonetically], NIDDK [spelled phonetically]. Do you think sequencing the genome for everyone is something -- is the right decision to do and telling them that they might have in terms of SNPs [spelled phonetically] or possible genetic disease development because, for example, telling them that you have this disease, once they have this disease is different from telling them that they might be developing Alzheimerís or dementia in 20 years from now knowing that it is only a prediction, not a certainty. Because, again, other factors [unintelligible] besides genetics, [unintelligible], environmental factors and others and maybe some people, they will not be able to take the news well and they might lose it. Like if I knew I am going to lose my hair, I might take a million pictures before I lost it. So, do you think thatís a suitable thing to do for everyone even if it [unintelligible] that everyone can do the genetics sequencing?

[55:43] Sharon Terry: Rick, you look like you -- Rick Del Sontro: Yeah, thatís a great question. The answer that I come down on is, no, itís not. Itís not for everyone and I think there needs to be some filtering. I think Dr. Watson said it earlier of exactly what you do tell people, right? Because I think that could be, you know, look, there are people that are worriers. Dr. Watson is not one; he avoids the worry, thatís good. Thatís why he is, you know, what are you, 73 now? [laughter] Dr. James Watson: That would be nice [spelled phonetically].

[56:14] Rick Del Sontro: But I guess thatís the point, there are people who would deal okay with the information, there are people that would not deal well with it. And certainly from the standpoint if it was something really catastrophic, would you want to know? That changes the way that, I think, you look and react to life every day and that probably wouldnít be healthy. But if there was something that you could control, right, that you knew, that would be important to you, those things are the kinds of things that I would like to know about. Like you said, if I was going to have Huntingtonís disease, I donít know that I would want to know that necessarily.

[56:49] Dr. James Watson: No, I would sue the doctor who would tell me that -- [laughter] -- for, you know unnecessarily messing up my future life. Rick Del Sontro: Yeah, because thereís no guarantee youíll get it. I mean -- Dr. James Watson: I think you have got to have some common sense. Misha Angrist: What if someone wants to know? Dr. James Watson: If they want to know, sure, you know. Male Speaker: Sort of a legal question -- Dr. James Watson: [inaudible] but, I mean, theyíre taking a big risk. But, you know, finding [unintelligible] you can tell me if I -- Iím going to get Huntingtonís disease, the chance of your getting it is so low that itís not -- but the Alzheimerís is a more real one.

[57:25] Male Speaker: Sort of a legal question, there is considerable discussion in the academic and regular press about patenting of various sequences in the genome. If we knew Dr. Watsonís specific genome that gave him the humor capability, could -- what do you feel about being able to patent that and reserve it for just me? Or Iíll sell it. [laughter] Male Speaker: Iíd be rich. Dr. James Watson: No, I got fired for being here, for opposing [spelled phonetically] that, so Iíve had a long view of this thing that theyíre just -- they set back genetics, thatís all Iím trying to say. Theyíre -- Sharon Terry: All right, well, Misha, did you have a last word on that?

[58:13] Misha Angrist: Well, as probably most in this audience know, Judge Sweet in New York last year ruled against Myriad Genetics, some of their patents on BRCA genes and that decision is now being appealed. I think most of these patents are set to expire this decade anyway. I expect gene patenting for monogenic diseases will probably die of natural causes, maybe thatís wishful thinking.

[58:47] Sharon Terry: Great, well, weíve heard from a variety of individuals who have learned about their sequence in a variety of ways, from a variety of different prophecies. I think 10 years ago we wouldnít have been able to have this panel, so in a sense weíve come a very far way. And this morning when I listened to Eric give us a charge for a million genomes or give us another [spelled phonetically] Eric, I think we have not yet begun to explore what it means to do that in a social context. If we had said 10 years ago would we be able to sell books in every attic and basement across the world to each other, we would have said thatís crazy. And we do it today quite easily. So I think we are also going to find that as these needs arise and as individuals themselves step forward to be partners with NIH, with Wellcome Trust [spelled phonetically], with other entities around the world, that we are going to be able to solve these problems together.

[59:36] And weíre really going to be able to build hope and not hype. So I want to ask you to all join me in thanking the panel. [applause]