 Okay, we're gonna have the lights up. We have microphones at either aisle. And thank you, Zach and George, we're very confident you would set the stage and really cover this area in both a fun and provocative and informative way. And I had a strong suspicion there was gonna be interest to have a dialogue with you now. So now we're unscripted, so here we go. Hi, Tom Markello. I'm part of the Undiagnosed Diseases Program here at the NHGRI. And we have a limited amount of funding that we can decide whether we see more patients and sequence more exomes, or whether we send the research findings out for a clear certification to return. Now we're getting like five to 15 Sanger-validated hits that are in clinically significant genes. I'd like your personal comments on what you would recommend in terms of the balance between the amount of total funding we have to do the research and the amount of funding we have to certify these things to clinically return them. Just before we answer, just a point of clarification. What is the ratio of costs in your opinion? Well, we do most of the work in-house for the research. So we're spending a little bit of money to pay these young people here to the interpretation, it's costing us about $975 for the exomes, and it costs us about $380 per individual variant that we CLIA certify in a clinical laboratory environment. So it's really only a 30% tax if you wanna get that? No, no, no, wait, wait, wait, it's per variant. And for the compound hits, you have to double it. And we're getting between five and 10 that we Sanger-validated in-house that would then have to be CLIA certified to return to clinical environments. And then if you wanna talk about phasing, it's the parents too, although they only charge us $150 per parent. Well, the nice thing about my answer is, I just have to virtually point to that very impressive fall-off of a cliff that George showed in the Supra-Morris law curve. And to say that I think the right validation is not necessarily Sanger sequencing, but far higher depth coverage sequencing in a CLIA certified next-generation sequencing lab, which I don't think is, I'm going on the limb to say, next year it'll be much less than the $300. Well, $300 times 10, for sure, it's already there. And one last thing is, in the end, our budgets are driven by Congress, and Congress is driven by patients. If you could show that you're curing patients, if you could show that you're helping patients, the dollars will come out. Very quickly, I didn't talk about something that shows the same phenomenon. We have something that children call the Clarity Challenge, where we put out three rare kids with their genomes and their family's genomes. We have 30 teams internationally competing for it. Then one of the mothers put out a birthday cake with a gene on it, Titan, that they had diagnosed. I have to say afterwards, a philanthropist came up to me and said, how many of these could you do? Because I'm always used to building infrastructure. You actually help this kid, this international set of teams, in three months, help this kid. And so I think it's by focusing on your genuinely limited budgets, you're avoiding the greater budget that you might have if you actually embraced a mission that would actually help these individuals by actually returning the research results back to them. My name is Bishira Charles. I'm from NHGRI. And I have a question regarding the Personal Genomes Project. And do you have a mechanism, a feedback mechanism built in to determine how or if people's insurance rates and coverage are being affected by them being tested or their relatives being tested and having positive results? Right, so the question is, do we have feedback in the Personal Genome Project about insurance? Now, Genetic Information and Non-Discrimination Act prevents health insurance from being impacted in our project, which is the United States. Some of the projects that are in other countries is a different matter. Also, insurance is not health insurance is a different matter. We are tracking all adverse events whatsoever in the project, not just insurance, but somebody phoning them up that they didn't wanna hear from or anything. And all of this gets reported back to our Data Safety Monitoring Board and to our IRB. So far, there are no adverse effects. I'm not, that's just, as far as I know, that's the way it is. But it will almost certainly change. I'm personally skeptical that an insurance company, a life or long-term care insurance company would be looking in our database. It would be bad public relations for them to do that and our cohort's still small. Even if it got to be large, I think they would wait to see, I mean, the American public has spoken pretty loudly about Gina. I think it would just be bad public relations at this point, even if it's legal. Hi, I'm Julissa Gray. I do microbial genomic sequencing. And here in the hospital, one of the projects that we are rolling out is to sequence the microbiome of patients and healthcare workers on a voluntary basis to look for multi-drug resistant organisms. How does it change in your mind if that genome is, the microbiome is somewhat human? It's the bacteria that live within us. But it's plastic. I mean, it may be that you carry a microorganism that you could transmit to other people, but that you could also be cleared of. And we could be reporting, returning those results to people, but then their status might change in three months because it's different in that the human, what we call human genome, except for somatic mutations is more set. Yeah. Well, so we have a microbiome component of the personal genome project, and we consider it sort of like going physician about any health problem that's transient. By the time you go to the physician, sometimes it's gone away because the appointment took a while, or by the time they get back to you, it's gone away, or it's gotten worse. So it's not the same as an inherited genome, but it's very similar to medicine in general. But I suspect you have more to your question than that. Yeah, because this is about, this is about that you carry pan-drug resistant acinetobacter balmani, which you might then transmit to other people. I don't see that as any different than what we have today. Today, we actually, in the hospital, label patients as having meth-resistant staff. We already say it, and it's no different than we are today. And incidentally, genomes, we are reporting changes in genomes and in cancer genomes because they change, they evolve, and we are having to begin to report these changes. So one answer is, what you described is no different than the current state of infection control and the public health interest in infection control, and the same privacy trade-offs that exist before, exist today. And, fascinatingly, we're gonna learn how genomes evolve within individuals. There is one interesting thing to add to that, which is that right now, when you get a disease, you typically don't know what it is in a typical, clinical setting. And if you're sick for 14 days, you don't know whether that was two diseases or one. You don't know whether it was the one that your partner had before or will get. And you don't know who in the daycare gave it to you, but if you start getting barcodes with all these things, you're gonna start knowing all that stuff. Whether or not the government's involved, private individuals will start pointing the finger at who brought their kid into daycare with a particularly nasty bug. Brad Ozemer from NHGRI, Zach, there's, what are the barriers, what do we need to do to get to the information commons from the healthcare system to make those data available? In the UK, there's talk of any test, including exome sequencing, supported by the national health system, will be put into a research database like that. Well, I actually think we've already done it. It's just doesn't, it's not obvious that we've done it. So for the Framingham Heart Study, we have available at DBGAP a lot of clinical data and you can mash it up against an enormous amount of multi-axial clinical data. Echocardiograms, EKGs, inflammation markers, family histories, it's all there, but what's happened? You agree as a researcher not to be a peeping tom, not to get out the laser and see what they're saying in the window, you agree to behave as a proper ethical citizen and study these patients for the advancement of healthcare and you don't try to out them in terms of their privacy because that's anti-social behavior. So I think the short answer is all we need to have are a formalization and an expansion of the kind of guidelines that we did around DBGAP. Maybe not require the same centralization because that may be hard to scale and I could talk longer about that, but nonetheless, a framework which allows researchers to safely do it in the way we described in our information algebras without themselves being at risk and allow patients to control to what degree their information is used or not. If we have those two components, patient control and protection for the researchers under a set of guidelines, I think it will happen quite smoothly and only people who will complain are those who have made an industry out of these concerns. Hi, I'm Joy Boyer with NHGRI and my question is for George Church. How do you deal with the privacy implications of family members of people who have agreed to participate in the PGP? That's a great question. The Harvard Medical School IRB, like most IRBs said that the responsibility and the decision-making was in the hands of the individual research subject. They did not need to confer with their family in order to join such a project or for that matter, almost any medical project, some exceptions. We decided as a project, even after getting that IRB approval to do it on an individual basis, that we put on the exam and encouraged each of them to contact even the strange first-degree relatives and to communicate what they're getting ready to do and if it didn't work out, then they shouldn't join the project and Zach might even have a personal anecdote about this. Absolutely. So George came to me, asked me if I wanted to be one of the first PGP volunteers and I asked around my relatives and I found one who has an affected child and she was relatively private about it and she thought she'd rather that I'd not do it. And so I went back to George and said, thank you for your kind offer, but no thanks. And we think that's a very important thing at least in the formative stages of these projects. We don't need to recruit seven billion people. The number of people who volunteer for medical research in general is quite small. This is not a huge additional burden. And in fact, people that have family complaints shouldn't be participating in medical research if there's any chance of it being disclosed because knowing in advance it's gonna be disclosed is much safer than thinking that it's not going to be. Now I have to say if there was a, so I had a certain level of privacy and so I do believe privacy matters, but if for example there was a study where I could actually contribute my genome and there was a good faith attempt made to not link it to my name so that my cousin would not be affected, I would be fine with it. Now of course, certain hackers could, again, there's no technology protection that could prevent them from re-identifying me, but most researchers behaving properly would not know who I was or who my cousin was and I could thereby contribute without invasion of privacy. I think it's that, again, going back to Stalman's comment, that sort of good enough level of privacy that we have to shoot for. Yes, the question is are participants in the personal genome project required to say they checked with their family and the answer is yes. We do not confirm that, but it's a good faith again. Most of these participants are good, altruistic people are not going to be messing up their family. That's an act of faith and I agree with that. Maybe that's... So in spite of what the other questioners have done, I'll choose not to reveal my identity to start with. Several of the things that you've mentioned, Gina and essentially reliance on social mores for the system to work and potential for hackers and things, do you think that there is need for any kind of additional legislation beyond Gina to make this whole system work better? I would actually say that there is. The Gina protects against non-discrimination but I think more broadly we have to have legislation that actually protects both the researchers and the patients and that makes it very clear that attempts to re-identify are just not acceptable. And I think having that in the legislation, I think would go a long way to making people much more comfortable Dr. or Mr. Anonymous in response to your question. Although the penalties for that to researchers who invite where one of their graduate students believes in free and open software, if the principal investigator is the one who's spending time in prison, you know. George, you look really good in stripes. I'm gonna stick to my project, thank you very much. Which has a lower risk, yeah. Let me take a variant of Dr. Geyer's... Oh, I just gave away his identity. Dr. Geyer's question. See his first name that I call him by his last name. Will you have a science article though? And at the risk of giving you too much opportunity here, so that was about legislation. What about NIH? So there is even some comments you made. I mean, along the way, there's a lot of NIH leadership in this room. You know, what could we be doing, but what are we not doing that you would like to see done that would help advance the dialogue, the framework, the protections or lack thereof and so forth? I'd like to hear each of you individually. So what I think we could be doing better is mobilizing the public. And perhaps I don't understand what it's like to be inside the NIH, but I'm a true believer. I believe that as a public, those of us who are willing to contribute to our data can increase the public wheel. And I am quite sure that the overlap of all the different disease groups would result in an enormous public support for this kind of activity. And I think that if we went high profile and saying we want to move forward to the information comments, we are going to look how we are diagnosing new diagnoses every day at time or 30% of the times we're doing whole genomes. Think of how much more we can accelerate if we did it. And actually make the vision and I think this is one that is not an idle promise and then allow ourselves very, very strongly with those patient advocacy groups. And I know we've done some of that, but I think we've been sort of gentile and cautious about it. I think we could be much more proactive and say and really engage them. So we press you on that because there's various ways we could do that, of course. We could be more public and that have advantage, disadvantages, people who either want to hear from the government don't want to hear from the government. Or we could be more behind the scenes. Do you sort of advocate one more than the other? So I think so long as you're clear from the outset, you don't have to do this. And I think you have to say at the same time, you have an opportunity to contribute. We're going to do our best to protect you, but we're not going to require that you do this. But if you do, there's a risk. And I would go for public. George has been very effective in being public. He didn't go quiet about the PGP. I think if you had gone quiet, too many people would be glad to create lots of obstacles. But by saying out loud, I'm doing this for the public good. Tell me the ways in which this is bad. You really stop the death by 1,000 cuts. You have a large and honest discussion. It's a little bit harder. It takes a bit more leadership, but I think it's a much more direct path to where we want to get. I think if you go behind the scenes, frankly, you allow the, just to pick on one group, the conservative lawyers for each institution to have their say and not for the big vision. So I would agree with Zach that having some outreach, and there are a number of ways that you can do it. One is having education programs. My wife actually has one called pged.org, which is aimed at high schools. And so it's now throughout the United States. And getting this on the curriculum, I think that genetics should be on the curriculum much more than trigonometry and calculus. Even though I've published papers on trigonometry and calculus. So she puts it in the health curriculum, which is one of the few places that is unaffected by the SATs rather than biology curriculum. Anyway, so that's one way you can do it. Another thing is have a more diverse portfolio of mechanisms of consenting. Right now, they're fairly uniform. And if you had some where you consent people, where you don't have to worry about some investigators going to jail, that would be a good thing. It doesn't have to be a big part of the portfolio. But right now, as far as I know, it's a zero part of the portfolio. I mean, there are two NIH institutes that have used personal genome project in technology development or what have you. But there's no real infrastructure for such projects in other very valuable NIH projects. Going forward, that's an option. There is no technical reason why we can't allow the full gradations of the dial of these consents. And I think that it's, again, if you look at what's happening on the web, there's a whole spectrum of information donation to complete lack of it. And so I think we should provide that to our public. And so I agree. We need more diversity in the consent regime. Any other questions? If not, thank you, George. Thank you, Zach. Great, we appreciate it. And just as a reminder, the April 25th, all-day symposium in nature. And then our last of our paired speakers are back here on May 6th. Carolyn Lerman and Alexandra Shields. Thank you very much.