 We will now hear from Dr. Robert Green, by the way, no direct relation. Of course, we're all related, but just happened to both have the same last name. Dr. Robert Green earned his MD from the University of Virginia School of Medicine and completed his residency in neurology at Harvard Medical School's Longwood Neurology program. And afterwards, he completed research fellowships at the Beth Israel Hospital and Children's Hospital in Boston. Now, Dr. Green is an associate professor of medicine in the Division of Genetics at Brigham and Williams Hospital in Harvard Medical School and also associate director for research at the Partners Healthcare Center for Personalized Genetic Medicine. His research interests have evolved from a focus on clinical trials and genetic epidemiology to a focus on translational genomics and health outcomes. He has been continuously funded by the National Institutes of Health for 21 years and has published over 300 articles. His key contributions have included the development of risk estimates based on family history and genetic markers, leadership and analysis of large multi-center treatment and prevention trials, including trials and enriched through family history, and design leadership and future planning of the first large-scale randomized clinical trials in translational genetics. He serves on a number of advisory, editorial, and grant review boards, and he's been invited to participate in NIH planning workshops in the future of genomic medicine, and has been a featured or plenary speaker on translational genomics and personalized medicine at meetings both national and international in scope. So we will please ask Robert Green to please come up and we will hear from him. Well, thank you. Thank you to the organizers of the Smithsonian. Thank you, Eric. Thank you, Professor Wolff. And thank you all for coming out. It's an exciting night. I hope you were as impressed by Professor Wolff's historical review as I was. And I think we can all agree that racism is wrong. The Holocaust was evil. Patients' rights should be respected, including privacy, including the right to refuse treatments and tests. And in your final and stirring ending, that patient privacy, patient rights, and public trust are critically important. So if that is where we're going to go, there is no debate. We totally agree. But as we'll talk more about, I think, in the give and take portion, I believe Professor Wolff has fundamentally misread the nature of the practice of medicine. And I'll go more into that after I make my prepared remarks. My prepared remarks, however, are that genetic information is fundamentally similar to other types of medical information and that we need to beware the FUD. Now those of you with smartphones don't look it up right away. Let me surprise you with it. I'm going to start my talk by disclosing, as I disclose with every talk, that my research is primarily funded by NIH, especially NHGRI, to which I'm grateful, that I have financially unentangled collaborations with some of the direct-to-consumer companies that I occasionally speak. And I'm compensated for speaking from Illumina, a maker of genome sequencing. And I occasionally advise some other companies in this space. But I'd also like to disclose something else. I grew up around here. I went to school in Winchester, Virginia, only a few miles away. And I'm so pleased that some of my friends from Winchester have joined us here tonight. And we all got our start with teachers and mentors. And Laura Rob, my fifth-grade teacher, and John and Marjorie Lewis, my sixth-grade church group mentors, are here in the audience. And just as, before I continue, if you just give them a round of applause for me as I stand up, stick your hand up for me. And I don't know if it was fifth-grade or sixth-grade or seventh-grade, but somewhere along the way, I and most of you probably learned about Gregor Mendel and his peas and plants. And this fundamental and early historical example reinforced in your mind that genetics was somehow deterministic, that if you put the right traits together, you always got this trait. Or if you had that funny recessive thing going on, you had that probabilistic situation with the traits. But that fundamentally, genetics was destiny. The genetics meant that if you had this particular gene, you had the particular pea color or the particular disease. But with the Human Genome Project, with the extraordinary knowledge that Eric outlined and that we've learned, and with what has happened since 2003, we've actually learned that genetics is very rarely deterministic. Sure, genetic variation is responsible for everything, what we look like, what we perhaps some degree to our temperament, or at least partly responsible for some of these things. And Eric mentioned to you that we've got these, most of our DNA is exactly the same, but we've got these variants throughout the genome that make us slightly different. And most of the diseases that we have, especially all the common diseases, are not the products of one variant or two variants. They're the products of hundreds of variants. That deck is shuffled and it's like throwing a deck every time, it's like throwing a new paradise every time you're born. So yes, there are a few mutations that are really deterministic, just like there are a few situations in medicine that mean, yeah, you're really gonna die. But they actually turn out to be the exception. So determinism in genetics and genomics is the exception, not the rule. Now this principle, determinism, has somehow embedded itself, whether it's early, whether it's being an elementary student and studying about Mendel, or it's a number of other things that I'll tell you about, this principle has embedded itself deeply in our psyche and it is really hard to dislodge. We've all got it. And it's certainly that this principle has been abused, just like other principles have been abused. But in fact, there's a bunch of historical antecedents to genomic medicine that have stressed determinism and stressed caution. Some of these are justified, some are less justified, but it has been an insistent drumbeat of determinism and caution, caution and determinism as we have moved forward with genetics. Some for very good reasons. We learned about Mendel and his peas early. Pre-conception and pre-natal testing around the birth of a baby are highly charged. If a woman is gonna terminate a pregnancy, she has to do so in a limited amount of time with tremendous emotional distress. Caution is warranted there and those were some of the first examples of applying genetics and genomics. Newborn screening is one of the greatest public health successes of all time and newborn screening involves testing for some very, very rare deterministic mutations. Misattributed paternity. Turns out there's a small percentage of babies whose father is not who they think they are. And that's throughout most societies around the world. And guess what? Genetics reveals that pretty easily. That's a sensitive subject. Talk about patient partnership. The current caution attributed to this in genetics. I was shocked to find actually has geneticists and genetic counselors being advocating to misrepresent the truth to families on whom they stumble across this. I'm troubled by that. It's an unhappy truth perhaps, but it's still the truth. Huntington disease was the first disease for which we had a reputable genetic test and for many years it was the only disease for which we had a test, a predictive test. And it is by far the exception. It is a horrible disease that comes on in adult life is always fatal and there's absolutely nothing you can do about it. That example colored our perception until today. The complexity that Eric referred to is pretty daunting and it colors our view toward the entire field of genetics and genomics, even in situations where things are pretty straightforward. We've had a certain amount of optimism about genetics. I've shared in it, Susan says she shares in it. We've even probably used it to sell genetics to the Congress and to the public. Maybe we've oversold it, part of that overselling at times or at least oversold the timeframe. Some of that is a reflection of determinism. Hey, we can tell you everything about yourself because genetics is so deterministic. And as Susan said, the budget of the human genome project had a set aside earmarked, millions of dollars earmarked for ethicists to study the ethics of genetics. Now listen, that's a good thing, don't get me wrong. I've benefited from this, Susan's benefited from this, the world has benefited from this. But if you're an ethicist coming into a field searching for funds, are you gonna say everything's fine? Go ahead, no. You're gonna say this is bad, this is dangerous. Be careful about that, watch out for that. So there has been, I would propose, all of the historical antecedents have created a bias toward FUD. What is FUD? Fear, uncertainty, and doubt. And so I lay this groundwork because I really believe that in the long run, I believe that some of these early examples have created certain sensitivities that we absolutely need to respect. But in the long run, as genomics becomes part of medicine and part of our everyday life, fear, uncertainty, and doubt will do more harm than it will do good. FUD number one, genetic information is different because it's gonna frighten people. Well, 14 years ago, every Alzheimer's specialist in the world said you should not disclose their genetic risk for Alzheimer's disease because it will terrify people, there will be catastrophic psychological reactions. There's a gene called APOE, and if one in four of you actually carry that, the allele that puts you at increased risk for Alzheimer's disease. That's maybe, I don't know, 25 of you, 30 of you. So 30 of the people sitting in this audience are at increased risk for Alzheimer's disease, about three times the risk of other people. How many of you would like to know if you're going to be at that increased risk? How many of you would like to know the answer? Okay, well, it's usually higher, but then usually Susan isn't speaking in front of me. I don't think you should have to know either, actually, but I think you should have the right to know. And pretty much every ethicist of the day, 14 years ago, said under no circumstance should this even be offered. We put that to the test in a series of randomized controlled trials over 10 years in which we enrolled over 1,000 people in something called the Reveal Study and people who wanted this information did very well. I'll refer you to all the papers if you'd like, but that's the bottom line. FUD number two, genetic information is different because it's too complicated to be understandable. You heard themes of this. We didn't get to see each other's slides before this, by the way, but I kind of thought she'd touch on some of these. It's just too complicated. People are going to misunderstand. There's going to be errors. Well, it's not like there's no errors in the rest of medical testing, right? I mean, really. And it's not like your doctor understands all the complications of every technology that he or she is using. It's not like every patient understands everything that the doctor is saying. In fact, we have hands-on evidence from the Coriel Institute's Personalized Medicine Initiative where they're giving thousands of common complex snips back to doctors and patients together. From the radically progressive personal genome project where George Church is sequencing hundreds of individuals and putting their entire sequence on the internet for anyone in the world to use. From the multiplex study, an NHGRI study that has given SNP information that's common risk information to hundreds of individuals about common diseases. And from the incredible ClinSeq project, another internal NHGRI project led by Les Beesiker, where nearly 1,000 people have been sequenced and make no bones about it. He's maybe sequencing them for some cardiac risk issues. But he's telling them whatever he finds. And he's found some fascinating things, including making diagnoses on people who had problems and never knew they had the problems. Sequencing has allowed us to peer inside previously completely unsuspected diagnoses. In our own NHGRI-funded Impact of Personal Genomics study where we've questioned thousands of people who took these online direct-to-consumer genetic tests and have all done pretty well. You know how many people have taken these tests? Well, people don't know. A couple hundred, a couple thousand, 10,000, 100,000, 700,000. Do you not think we would have heard of terrifically tragic anecdotes, or there wouldn't have been lawsuits if there had been? FUD2A, genetic information is different because people won't act upon it. Or if you want to turn that around, people will act on it. But they'll do so inappropriately. They won't take their doctor's input. Well, in that very same PGN study, we found that people are acting all right. Most of the things they learn are encouraging to do basic public health improvements. And 30% of the people who get direct-to-consumer genetic testing, something that's been pretty roundly criticized by many ethicists, make improvements in their diet or exercise. And you know what else? Only about 1% of these direct-to-consumer customers actually changed their prescription medicine without consulting their doctor. That was another concern. So fear, uncertainty, and doubt raises these questions persistently over and over and over again. But like the mist, evidence dispels them. FUD number three, genetic information is dangerous because it's going to confuse regular doctors. And sure enough, there is a lot of information in the genome. And it's a pretty big challenge to figure out how to condense it, collapse it, distill it. And you've got to think about a lot of things, where are their eras, what's been proven, what hasn't. We've been funded by NHGRI to do something called the MedSeq project, which is a study in which we're giving genome information back to doctors before we could even get started in that way. We're going to hand them a hard drive with 3 billion bits of information? No. Before we do that, we created a one-page summary report that a primary care doctor can understand and work with that has a segments on the more deterministic mutations, the more risk mutations, the pharmacogenomic variants. And we're testing that right now. It's not perfect. But you know what? Our primary care doctors, after only six hours of orientation, are getting it and working with it and talking to it about their patients. You don't have to be a nuclear physicist to get an MRI report. You don't have to be a radiologist to get an X-ray report. All you have to do is put the report in a format that a doctor can understand and work with. FUD number four, genetic information is particularly different for children. There's all sorts of hypotheses about bonding problems. If we tell the parent of a child that the child is at risk for an adult onset genetic disease, we're somehow changing the nature of the child in the eyes of the parent. Well, that's a reasonable hypothesis. There's only one problem. The evidence doesn't support it. What the evidence does support is that a parent dying is really bad for a child. So if you sequence a child and you find out something about an adult onset risk, say of cancer, one of those parents passed on that mutation. You've just given that parent a chance to save their life and be around for that child. Do parents want this? You bet they do. I went on to the newborn unit where parents have just given birth and I said, would you be interested in genome screening for your baby? And over 80% were somewhat very or extremely interested. Now my friends in ethics would say to me, yeah, but they're at a vulnerable moment. They've just given birth. They don't know what they're saying, right? I repeated it three months later and nothing changed. My friends in ethics would say, oh yeah, but you haven't really educated them about what this is. I went through a whole process of telling the worst things they could possibly find out. And not just the worst in terms of medical outcome, but the most uncertain, exactly the same number still wanted the information. And so we've been funded to do something called the Baby Seek Project where we will be sequencing newborn children because if you believe as I do that some predictive information is good as an adult, then perhaps it's even better as a child. I think that's a testable question. I'm not sure that's right, but we're gathering evidence. And as Susan pointed out, there's a lot of information in your genome and one of the key questions of the day is about incidental findings. And Susan and others would have you believe that a standardized process for seeking and reporting incidental findings should be different in genomic medicine than for the rest of medicine. And I would argue that's simply not true. That doesn't do you any good, that doesn't do me any good. And by the way, it has nothing to do with the Holocaust. It's about the practice of medicine and doing well for the patient. And possibly, just possibly, saving that patient's life. What is the right analogy? I continue to maintain that if I fall off my mountain bike and get a chest x-ray for a possible broken rib and you see that little nodule, the radiologist sees that little nodule up in the corner there, they need to tell my doctor about it. In fact, they'd get sued for malpractice if they didn't. Susan and I actually agree on a lot of things, but one thing she said is, I believe, fundamentally wrong. It is not stumbling across this nodule. It is not noticing this nodule. If you look in radiology textbooks, radiologists are required to systematically review the information in front of them. They are required to go down the ribs one by one. They are required to look at the shape and size of the heart, and they are required to look at the lung fields and tell your doctor in their professional report that there's something there, whether it's related to the reason that the x-ray was put up in front of them or not. Period, fast and simple, no questions asked. I admit, there's a real question here. Is the proper analogy a chest x-ray or is the proper analogy a total body scan? Critics have argued that the point we're making is more like a total body scan when you only needed a chest x-ray, but I reject that. Total body scans aren't bad because of incidental findings. Total body scans are bad because they're overly expensive and they expose you to unnecessary radiation. It's apples and oranges. Yes, we came out after a 14 month process with 16 experts plus 20 outside experts plus the entire board of the American College of Medical Genetics and Genomics in an exercise of imagining a future in which not 5,000 people, not 10,000 people, but 20 million people are getting sequenced weekend and week out. How should you think about managing incidental findings? Do you really want a system where someone who walks in the door out of fear gets sequenced and says, oh, I don't want any of that cancer stuff? No, no, no. And do you make that easy? It's not a question of whether they have a right to refuse as we'll see in a minute. They have a right to refuse, but do you make it easy for the frightened patient or the lazy doctor to avoid all that? Don't look for those incidental findings. No, you don't make it easy. You make it hard. They should have a right to refuse, but they should have to be thoughtful about it. This is a minimum list. It's basically standardizes the search and reporting of a very few variants. It's consistent with the practice of medicine and this is what it really is about. You've got about 45,000 exome variants in this bar on the left. And if you take just the ones that are associated with diseases, you've got about 015,000. And if you take just the variants that are in the 56 genes, you've got that little purple line at the top. And if you take only the variants that were pretty darn sure are really bad, the very pathogenic variants, you've got a tiny, tiny, tiny fraction of the genome. That's all. It's the tiniest fraction of the genome that we think actually means something. You know what the criteria we used in this group working group? I can tell you, we didn't sit around saying, let's violate patients' privacy and their rights. We sat around thinking, if we did a genome on our patient and they had a mutation in one of these variants of this kind and we didn't tell them, what would keep us up at night? What would make it so we could not sleep? That was the criteria. We rejected lots of nominations. So again, if there's, let's say, 100 people in this audience, two of you are carrying one of these 56 variants, a pathogenic variant. Two of you are carrying that. Now, I'm not going to take a poll, but the situation you have to ask yourself is this. You go in for a genome sequence for, let's say, a heart issue or your child goes in for one. And the genome is done and a cancer predisposition that could affect you and your entire family is uncovered. How easy do you want to make that for us to bury that information? And how problematic is it? Well, Baylor, which is the most advanced laboratory in the world for doing clinical sequencing today, not research, but this is a real patient. They've got a real problem. Send it to Baylor to get sequenced. They have all this information. They have, without hesitation, implemented the ACMG recommendations, and they put it up black and white on their requisition. If you get your genome here, you get these back. Or your doctor gets these back in their report. And by the way, we'll get into this in the talking, but your doctor doesn't actually have to follow the recommendations. And your doctor doesn't actually have to tell you if you make it that important for him or her not to tell you. We'll get into that. It's hard. We wanted to make it hard, but it's possible. So to conclude, I urge you to reject the FUD, reject the fear, the uncertainty, and doubt. Certainly there have been abuses of genetics in the past. Certainly there are sensitivities. I don't think those abuses are specific to genetics and genomics. I don't think those sensitivities are specific to genomic medicine. HIV testing, life and death decisions of all type. But I'll tell you what Susan has been polite enough not to use this term, but other critics of these recommendations have used the term mandatory, have used the term coercive. I'll tell you that when you look up this term, FUD, fear, uncertainty, and doubt, its origin was in companies trying to get a competitive advantage over each other and people reviewing business ethicists considered fear, uncertainty, and doubt to be coercive. Think about that. It's kind of a weird way to think of it, but think about that. I want to thank all of you for being here. I want to thank NHGRI and all my colleagues for supporting the research that we've done and that we're doing. Thank you.