 We clearly were successful at generating considerable interest, and I am overwhelmed with index cards, and I'm told we can only go to 8.45, so we are not going to get through all of these by any means, but I'm going to do my best. And there's a lot of overlap in some of the questions, so I'm quickly trying to synthesize some of these questions and bend them, and I will tell you right off the bat we're going to start with what I can immediately see is the most common issue that was raised, which is straight out of the news, which really shows that we've enriched for an audience that is following the news carefully when it comes to genomic testing in particular. And a series of questions relate to a development with this company 23andMe, which Robert mentioned, and that is a direct-to-consumer genomic information company that the FDA recently got involved in telling them to stop providing health information to their customers, at least for now, for a variety of reasons, and the basic set of questions can sort of be consolidated on, as here from each of you, what your views are on FDA stepping in and dealing with 23andMe the way they have. Robert, do you want to go Susan first? Mine are on record, so you... So I did 23andMe. I didn't do the fancy exome that you did, Robert, because I don't have that much money. What is it? So 23andMe is sort of, was a direct-to-consumer company where they had a kit. You could sign up online with exquisitely poor timing. I pay $299 instead of $99 if I had waited. And then they send me a kit and I spit into a tube and send it off to them. And then a few weeks later, Bing, on my email, it says, your genetic report is ready. And I opened it up, and I read about something in the order of about 250 results, because I was just getting those single misspellings, those single nucleotide differences, not the fancy one that Robert can get. By the way, I'm sure that the ethicists have brought in a fraction of the research money that you have, Robert. I mean, I would love to have your resource, but anyway. So I will tell you that when I did it, a lot of good news, a lot of reassuring news and one piece of bad news, that I was a carrier for a variant that was extremely serious. And I'll confess to you that that has kind of haunted me for the year or so since then. So then FDA comes out and says, the quality, the validity, the realness of the findings that 23andMe is generating is not established. And unless you are giving people back validated, reliable information, you can't do it. Because they make decisions on this basis, they seek medical care on this basis. What I think is that that decision was right. And it kind of shook me because I thought, well, wow, I've been worrying about this for a year. I mean, is it real or is it not real? That said, if we could get a direct-to-consumer company that had jumped through all the hoops and was making available to each one of us, if we so chose to do this bet and the money and the whole thing, their results and the results were reliable and valid, I think that's good. I think that is a way for people to be empowered and get their results and that's why I did it. So just to summarize, if I might try to understand, your position is that it's good that FDA is doing what they're doing now. And if there could be a company that provided this, that's fine as long as it's FDA approved and sort of accurate and have it right here, OK? Robert? The singular achievement of our time, I think, certainly in medicine is the Human Genome Project. And after that, the thing that has probably done the most to popularize genetics and to kind of move it forward fast has been direct-to-consumer genetic testing. It made it accessible, easy. People were interested. They got ancestry information. They got risk information. In fact, it educated most people about how little was in the genome and when they saw that they were predicted to have curly hair and blue eyes when they actually had straight hair and brown eyes, they said, huh, this genetic stuff isn't all that accurate. It's not that deterministic. So it was a great educational tool. What it didn't do, what it's never been proven to do, is do harm to people. And therefore, I thought that the FDA was premature in shutting it down. Well, I think what we found is there are a lot of people out there like me who get some results that are not so good and worry about it or pursue it. And I think if you're going to give people back genetic results, they ought to be the right results. I mean, anything else is kind of silly and really can produce harm. I don't know why I'm not connected as you are, Robert, with 23andMe. I don't have a relationship with them. I don't know why they stopped working with the FDA to validate their tests. They ought to do it. I totally agree. Validation is hard, though, because the FDA, I don't know the details. They haven't shared with me, and I'm not that connected with them. But validation of 254 different tests, the FDA may have asked them to go and do a separate validation experiment, not just for the accuracy. They obviously have to be accurate. But for everything they say in terms of the computational risk profiling that they did, now they drew all that out of the scientific literature. They melded it together with their own algorithm. The algorithm was placed on the website in a fully transparent manner. It's been vetted by all sorts of scientists who pretty much quibble with it sometimes, but some mostly agree with it. So I guess the question is whether the FDA is setting a bar that would be impossibly high. So another set of questions we've gotten, which, again, is not surprising that many of you ask questions about it, because it probably is the hottest topic in this area in genomics right now is incidental findings. And you've heard each speaker talk about this. And one analogy that each of you touched on is the analogy to x-rays. And this has gone on a long time. You know, what's the responsibility of a radiologist to look over? What's the responsibility of a genomic scientist to look all over, you know, to find things? And several people asked questions about this. And in particular, one person asked a question, which I also had remembered, because last week, as part of this series, we had Wayne Groty here, who was a member of this ACMG panel. And even Wayne talked a little bit about incidental findings and took exception to actually had thought that the x-ray analogy had limitations, which I thought was interesting to hear him say that. So I want to explore this more, because I think that's something that the audience probably can identify with, this analogy that, you know, when they get a chest x-ray, they expect everywhere to look, not just on the one broken rib, for example. That's often the example that's given. So, Susan, I want to start with you. Why is that, go over why you think that is not a valid analogy between what radiologists do with a chest x-ray or CT, and what we would do with the genome sequence. When I break my arm or fill in the blank, something else, an x-ray is taken of that part of my body, not my whole body, kind of trolling around looking for other stuff, because you'd find it. I mean, we know enough about, at my age, there's going to be some else there, but they don't do that. They just x-ray that field. And then the radiologist reading that scan actually reads it per protocol. Radiologists themselves, if you go to their professional societies, worry a lot and rigorously about what to report and not report. They're not kind of out there looking for every single little thing. They have rules. Does the nodule, the lung nodule, if it's there, have to be above a certain size to report the answer is yes. And they reach consensus on that. So, they are following certain rules. It's within a particular field. And when the radiologist, I'm in there with my broken arm crying and screaming, is looking at the x-ray, I know what field they're examining. It's not going to blow me out of the water, or I'm going to think, well, why didn't someone come back in the room and ask for my consent if he or she sees something right there adjacent? That is completely different from saying, whenever my genome is sequenced because I have a terrible cancer and we've run out of treatments and they're looking for a genomic target, let's look throughout the entire darn genome. Robert, you made allusion to this, like a whole body scan when the only thing wrong is my broken arm. Let's look through the whole thing and let's specifically hunt down a selected list, even though that list includes stuff like BRCA that we have always sought specific consent for. No, no, no. While we're in there, we're going to go do it anyway and report it all back. The President's Commission on Bioethical Study just issued its own report on incidental findings. And Amy Guttman, their chair, made very clear in the brief science piece that accompanied it that they were parting ways with the ACMG on this whole issue, that they didn't think this was an appropriate way to go. And I think they're entirely right that a kind of hunt throughout the whole genome without very specific consent, some people may want it, a lot of people won't want it, is a big mistake. May I respond? Yeah, please. Well, first of all, the President's Commission, my reading of it was that they endorsed nearly all of the ACMG principles. In particular, they endorsed the right of a professional organization to set the kind of practice parameters that the ACMG set. So we have a different reading of that. But let's take it away from the X-ray analogy for a minute. Let's say I go in and they're only looking, I have a rash and I go to the dermatologist. And the dermatologist doesn't necessarily have to strip me down and look at every square centimeter of my skin. But next to the rash, there's a mole. And the dermatologist does have a professional obligation to examine all the skin in their field of view. That's one of their professional fiduciary duties. And they do have a professional obligation if they see something to report it. So if they see a mole that looks like it could be an early melanoma or even might be, you know, you guys have all done this. They'll say, you know, we better take a look at that. Maybe we better take a sample that something happens. So that's an incidental finding. It's really not so different in genomics. It's not hunting through this enormous jungle of genome. It's very strategically picking 56 out of 20,000 genes. It's very specifically picking some very dangerous variants out of the myriad of variants. And it's saying these have been associated with disease so profoundly, not 100%, but so profoundly. And these diseases are something we can do something about. We can save your life. That the laboratory would have to close its eyes. I mean, you have to understand how this works. The genome, the computer spits out all of the information. And it would be like the radiologist going and putting a sticky note over the parts that you don't want to see. The molecular geneticists in the laboratory would have to write a computer program to block the results of the bad genes in order to attain what you want. So really the only practical way is to say, I want this test and give me what you think are the minimum important things to give back as incidental findings or don't give me this test. And you should absolutely have a right to turn down that test under those circumstances. The second point is informed consent. Informed consent is not just consent. It's informed consent. If I ask you, I'm going to take you through a list of 24 different rare conditions, scary conditions. And I'm going to ask you one by one if you want them. And by the way, the answers to whether you should want them or not is probably different depending on your age, your gender, your family history, your blood chemistry, your body habit. It's almost an impossible task. You can't get to informed consent that way unless you spend about a six-week seminar with your patient. What you can do, and that's why it's different than BRCA testing if you have that in your family. If you have BRCA in your family, you know you're at risk for it. You know what the implications are. You know your gender. You know your age. The genetic counselor knows how to counsel you. You should absolutely take that standard genetic practice. You should absolutely understand those things and then make your decision about that particular test. Different circumstances. So I just have to respond quickly. Where I think we're going with this, I hope everyone is watching, is to the doctor-patient relationship and how it should operate. Robert is saying, I can't possibly, as a physician, explain all these 24 conditions. Robert is one of the great explainers, in case that's not been obvious. He has a fleet of the top genetic counselors probably in the world at Harvard working with him. He can explain it. It's not too complicated. We have a bunch of cancer genes. We have a bunch of cardiovascular genes. And then we have malignant hyperthermia. I can practically explain it. So they can explain it. So if ACMG had said, we've gone through a 14-month consensus process to identify highly pathogenic genes that are actionable, that we think we could do something about, and we're going to offer this panel to people. They may take it. They may not take it. We feel some confidence that we're learning how to explain all this, but it's going to be up to them. They have the right to refuse. I would be very happy. You know, we're very close. I mean, Susan is one of the great ethicists. But my point is not that I can't explain it. My point is that it's unethical to try to explain 100,000 nuances to a patient, which are the nuances they would use to decide if they want that test or not. I can't possibly take even those 24 conditions and explain that it's lifesaving if you're 20 and female, but it doesn't matter if you're 80 and male. It's lifesaving if you have a family history, but it doesn't matter if you don't. This was the contextualization I said I'd get back to. The reason that it's unethical, and we didn't make this point clearly enough in the article to be sure, though we tried to make it later in a JAMA article. The reason it's unethical is not because the patients aren't smart or doctors are stupid or doctors are lazy or any of those reasons. The reason it's unethical is because there are too many contingencies, too many variables. What we have to do is if we've looked at the genome, we have to make us some sort of cutoff as to what we're gonna report back to the doctor. Then there's part, that's just part one. Part two is the doctor says okay, you're among the 2% who has a variant that puts you at risk for something. Let's go back and get you your family history. Let's go back and check your physical exam. Let's think about the symptoms you've been having that we've never been able to explain. So I believe it's actually unethical Susan to try to pretend that we can give a patient informed consent for a mass of very, very agated findings. Robert, you can do it. NHGRI is funding all sorts of people all over the world to do it. You ought to be making a video of yourself doing it because you're so good at it. So other people can learn from it. And what's unethical is saying my gosh, it's just so darn complicated, we're not gonna do informed consent. That is dangerous. That's not quite what I'm saying. I believe we absolutely do informed consent for the genome test. And one of the factors of informed consent should be Mr. Mrs. Smith, when we do this genome test, we will be following the ACMG recommendations and you will get back, if we find them, you will get back a small subset of dangerous and highly actionable variants. Please be aware of that, that's informed consent. Dangerous and actionable variants to be named later. I think you can go the extra step. I think you can talk to them about what variants and get real consent. But if you wanna take this autonomy argument to its logical conclusion, then it's no more, you're not giving them more autonomy by giving them a dichotomous yes, no response, which is how a lot of the critics of the ACMG recommendations have suggested we solve this. What if they desperately want cancer predisposition and they desperately don't want cardiac or vice versa? Are we supposed to go back and create a Chinese menu within the laboratory so they write a specific computer program to hide one but reveal the other? I mean, it goes quickly to the point I think of absurdity. I told you this was gonna be easy. So we're actually essentially out of time, but I wanna ask one last question, which amalgamates one of the questions that came in from a very insightful member of the audience who drew an analogy to something that has gone on in the United States for nearly 50 years, which is newborn screening, and which also has had a lot of ethical issues studied for many years. And the question that was specifically asked is in sort of 50 years of newborn screening, did we get it right in year one? And I don't want that question directly answered. What I wanna do is set that as a sort of a theme to ask one last question to each of you, and that is really more looking to the future. If we did this same debate, let's say 10 years from now, or certainly even five years from now, let's say we do it in 2020 or so, what I'd be very curious to get each of you to say is, do we think it's gonna be much clearer what the issue, or do you think it's gonna get more complicated or less complicated? What are the things we're gonna be arguing about? Because I do believe that if you go back and look at what went on 50 years ago with newborn screening, there are lots of issues and lots of debates, and many of those got sort of dampened down with time, especially as the methods got better, the clarity about the evidence got better, and so on and so forth. Is that a good analogy, and is it gonna get simpler, or are we gonna phase a whole other set of issues or similar ones, because it just won't get resolved? So we'll start with you Susan. So here's what I hope it looks like in 10 years. I hope we have much better informatics, much better ways of tracking what people want. There's some folks, one person I admire greatly is a colleague of Robert Zachohane at Harvard who's kind of pioneering even computer interface ways that people can say, yes I want the cancer genes and I don't want the cardiovascular genes, and without a lot of effort and money, that can track through to the lab, it can track through to the physician, and maybe later on as the person ages, they could say, I would like my genomic information re-queryed, now I am interested in the cardiovascular findings. So I think we'll hopefully have the capacity to track all that in an individuated way. I hope medical education greatly improves so that people are trained in genetics and genomics and know what to do when they get some of this information. I don't think they do right now, and I dearly hope that we have not just said, oh well this technology is so fancy we can compromise patients' rights and public trust, because I don't think we can. I don't think that's going to let us successfully adopt a technology we should completely embrace with the right protections. Well, I think it's really important to remember that Susan and I agree on a great deal and it doesn't sound like what we really do. And a debate format, as my friend Debra Tannen who's here, best-selling author of a book called The Argument Culture, points out, when you set up a debate, we're gonna concentrate on the small areas we disagree on. So it's not surprising that I agree with Susan on a lot of things that we haven't discussed. One of those is that actually. If we could create a system that would allow an individual to authentically give informed consent on a more granular basis, and we could demonstrate together that that really worked, I think that might be acceptable. I'm not sort of saying that this bundling is the end point at all. But that system's far away from applicability and sequencing is here. We've sequenced probably over 3,000 people, maybe 5,000 medically in this country already, and it's going to grow by leaps and bounds, probably by millions. In five years, I predict that you won't walk into your doctor's office without your doctor having a report about the things that are in your genome. And anybody who does is gonna be at a disadvantage. I think that however, so I think we'll actually settle a lot of the things that are going on about sequencing, but I think the crazy thing is there's gonna be new cutting-edge issues. There's gonna be gene expression information. There's gonna be metabolomics and proteomics. So I think this rapid cycle of discovery and implementation into medicine, discovery and implementation will continue. I'm afraid we'll probably be having exciting conversations like this reliably for years to come. So let me just conclude by pointing out that this has been fantastic. We knew these two folks would really engage and would raise some of these issues in ways that I'm sure are leaving your head spinning in some ways. It really is complicated. I think that's where you're hearing from both of them. And I do wanna point out and echo this notion that there's no reason to think any of this is gonna get simpler with time. It is the reason why we study these things in national institutes of health. This is why your taxpayer dollars are going to study these very hard problems. And at the same time, you can see enormous benefit, but you can see with this comes great challenges. And we've deliberately set this up as a debate to really bring out, which we successfully did, some of these very vaccine dilemmas, all of which I can guarantee you we are studying, including by these individuals on the stage. So please welcome me in thanking them for a terrific evening. Thank you.