 It's great to be here among so many friends and colleagues. There are a few people in the audience who could be giving this talk. Is genetic information different? Here we are at the Smithsonian, and the answer is all around us. It's over at the Museum of American History with its exhibits on eugenics. It's at the Museum of the American Indian, at the Rising Museum of African American History and Culture with its online exhibits already, and of course, it's very much at the Holocaust Memorial Museum. I'm going to give you my punchlines first. I'm not going to hide the ball. Is genetic information different? Of course genetic information is different. You just got a taste from Eric of the tremendous potential, the tremendous promise of genetic and genomic information. It's coupled with a horrific history of abuse, both great promise, some terrible history, behind the misuse of genetic argument. So harvesting the benefits of the tremendous technology that Eric outlined requires protecting genetic privacy, preventing genetic discrimination that's been an issue, and respecting patients' rights. Genetics is powerful. It's predictive, it's basically permanent, and it's profoundly identifying of each and every one of us. It is among the most sensitive medical information. There are other categories of medical information that are sensitive to mental health records, alcohol, substance abuse records, but this is among that category of very sensitive information. Legislatures, the public actually already knows this. Legislatures have tried to create protections. There are some problems with what they've done, some gaps. So it's absolutely crucial, given that history, against that background, to protect patients' rights to decide through informed consent, whether to undergo genetic testing or genome sequencing, to protect the right not to know unwanted genetic information when somebody would rather not know they feel they can't carry that burden, and to protect the right to refuse an unwanted hunt for incidental findings. That's where the fur's gonna fly here today, guys, between Robert and myself, so just to give you a preview. So what I'm really gonna argue is progress in genetics and genomics is essential, but to safeguard it, we have to secure patient and public trust and respect for patient rights. So I'm not gonna dwell on this first slide because Eric did a great job. The power and the promise of genetics and genomics is tremendous, to help with diagnosis, ultimately, to guide drug choice, identify future risks, to clarify reproductive risks. Clinical genomics, the clinical use of my entire genome, that's a work in progress. We're at the outside of that effort. There's a lot to learn before that really goes prime time across the country. But this is, I'm a fan. This is great stuff. Harvesting the benefits of this, harvesting the potential is gonna require enormous care. It already does because, as I've suggested, genetic information is among the most sensitive medical information and genomic information is complex. We still haven't quite cracked the problem of error rates when we do genomics. That's very much a work in progress. So before you think, oh yeah, more information. It's always good, careful. It's not always good if it's wrong and it's not always good if you're surprised, if you didn't elect it, if you're not prepared for it. I've got some quotes here, one from Francis Collins who was one of Eric's predecessors running the Genome Institute and now is director at NIH, talking about the history that genetic information can be used as a basis for insidious discrimination. People have lost their jobs, people have lost their health insurance and it's not just them. Oh, it's a few. They are the ones who have some of these misspellings or genetic problems. It's actually all of us, that's part of the science. All of us carry dozens of glitches in our DNA. So this isn't a we, them, it's all of us. NHGRI, the institute that Eric leads has been in the forefront and there are people in this room who have been in the forefront of the necessary partnering of ethics and law with the science. Establishing what we call the ELSI program, ethical, legal and social issues. You know, it really is astonishing in retrospect that when this enormous effort to decode the human genome, all those A, Cs, Ts and Gs began from 1990, NIH with the Department of Energy said, you know, there's got to be, we know this history. There has got to be an ethics, law, social issues piece of this and they didn't just say it, they put money behind it. Eric himself writing with colleagues in a very important piece in nature in 2011 spoke of the unique, is genetics different? Yeah, the unique and potentially sensitive nature of genomic information. So while the concerns, let me just expand on the history for a second to remind you. Some of you know this history very well. These are pictures up here in the left from the Museum of American History, a picture depicting the US slave trade right before the Civil War. Up there is a picture of Kerry and Emma Buck. A lot of you, the word Buck will remind you, Buck V. Bell, notorious 1927 US Supreme Court case upholding the constitutionality of forced sterilization on the grounds of genetic defect. That's kind of the language used then. And down here, of course, a picture of people incarcerated at a concentration camp in World War II. Let me just dig in a little bit more on each of these. The history of supposedly scientific racism. You know, the use of genetic arguments and pseudo-genetic arguments to justify the horrors of slavery in this country's legendary. Dorothy Roberts, who's a brilliant scholar at Penn, has written about the scientific racism reliance on genetic arguments to say that race is something genetic which we know better now. That's really a misunderstanding of the category. And then to, of course, go on to argue superiority and inferiority. But you know, lest you think, oh yeah, well, that was then, this is now. There are continuing concerns. When we started getting into the business of genetic screening, one of the very first efforts was sickle cell screening in the 1970s. Hideously mishandled, job discrimination, even against those that shouldn't have been against anyone, but even against those who merely carried the trait, who were not symptomatic and not the full-blown disease. And to this day, empirical studies consistently document anxiety, particularly in minority populations, Native American populations and others, about the misuse of genetic argument and information. The history of US eugenics and forced sterilization up in the corner, that is a picture of something that was common in the 20s. Fitter family contests. That's from the Kansas State Fair in 1920. Better baby contests. This was sort of the light side of what was a pretty serious and problematic practice of US eugenics, involving immigration restrictions and involving forced sterilization, unsuccessfully challenged in Buck v. Bell, leading to that notorious statement from Justice Oliver Wendell Holmes Jr. Three generations of imbeciles are enough. We know from subsequent research that actually there was no evidence at all of impairment in that family before you get to the obvious injustice of subjecting people to forced sterilization on genetic grounds. And finally, the history of deadly medicine. This is the logo. I hope you all saw this. This was a breathtaking exhibit at the Holocaust Museum about the use of medicine, the use of science to justify Nazi genocide. Rudolph Hess himself said, you know, Nazi ideology, it's just applied biology. All sorts of genetic claims used to justify euthanasia, genocide, the horrors of the Holocaust. And again, lest you think, oh yeah, well that was then, that was the Nazis over there, that was, you know, we're past that. The colleague here in this audience, Karen Rothenberg, with colleagues has written about continuing concerns. You know, there were headlines when we started studying the BRCA gene, which can elevate in some variants risk of breast and ovarian cancer. And some of the early studies focused on Ashkenazi Jews and Karen and colleagues writing about careful red alert because we are seeing some misunderstanding. We're seeing some bad headlines. The Jewish gene, a problem that recurred when we began looking at genes associated with colorectal cancer. So we always walk that tightrope. We cannot forget that we walk that tightrope. Well, we are here now at a time of enormous progress. I went this morning to this great exhibit. If you haven't been, you gotta go to the genome exhibit over at Natural History. This is a slide from the online gallery connected to that exhibit, which I commend you as well. The point here is that as we've learned more about genetics and now genomics, the reasons to be careful have gone up, not down. Because it turns out that genetic understanding leads us to recognize that your genetics, your genome is personal. It's unique to you. It's powerful, as Eric's already explained. It's potentially predictive of disease and disability not yet manifest that you may know nothing about. It's pedigree sensitive. It ain't just about you, your whole family in one way or another is walking into that room. It's essentially permanent. It can be quite prejudicial. We talked about employment discrimination. We talked about insurance. We haven't talked, maybe we will, in the questions about forensic uses of DNA. And you know what? It's become harder to protect because of the enormous capacity of computers and informatics now to re-identify you. We used to talk about anonymizing genetic information. Most of us have stopped pretending that we can truly anonymize it. We tried darned hard to de-identify it so it's difficult to find someone. But with a reference sample, you can't really anonymize. So we know that genetics and genomics are incredibly powerful tools that we have to handle with care. And this is just more demonstrating that. A quote from Kathy Hudson about, we've got to make people confident. Give them grounds for confidence in the privacy of their information. Kathy is a deputy director at NIH. And why don't you skip down to the bottom one? I hope a lot of you have read the book, The Great Book, The Immortal Life of Henrietta Lacks. NIH did something tremendous last year. You probably saw it in the news. Which is after decades of working with the HeLa cells, you know, derived really without what we would call adequate consent by a long shot. Today from Henrietta Lacks. NIH restricted use of her entire genome. We were at the point where publication of that whole genome was the issue. And this is a committee that was put together including her family members. This is unique. This is a recognition that genetics and genomics is different. Legislatures, as I've said, have tried to build protections, but big gaps remain. Look just at the Genetic Information Non-Discrimination Act. Tremendous accomplishment in 2008 took years to get it through Congress. It forbids genetic discrimination in health insurance, but it is dead silent on your life insurance, your disability insurance, your long-term care insurance. There are all sorts of gaps in these laws. And go down to the bottom, state statutes. There are state statutes in DC, Maryland, Virginia, actually most states, and they suffer from some of the same gaps and problems. So let me get to the last bit, implications. Where do we go from here? I'm arguing that we need to be careful. We need to protect patients' privacy and rights. We need to forge a strong partnership with patients and research participants and the public to make this work. And I'm gonna focus quickly on three. Patients' rights to decide whether to undergo testing, the right not to know unwanted results, and this incidental findings thing that I alluded to before. The right to accept or refuse genetic testing is just a specification of a broader right that was established a century ago. Justice Benjamin Cardozo, famously in 1914 in a great case called Schloendorf, which is kind of the font of all of American jurisprudence in health law, not just genetics, wrote that every human being of adult years and sound mind has a right, has a right to decide what shall be done with his own body. This was a revolutionary and for quite a while embattled rejection of whatever you say, Doc, you decide in favor of a partnership where it's the patient's body, it's their future, they decide through a process of shared information and support with their physician. Patients have the right to accept or refuse medical tests, period, and that includes genetic tests. You need informed consent. Some people argue, well, once the patient is here and they're saying, work me up, then you've got a general consent to treat, isn't that enough? And I would argue it's not enough. You need specific consent when you're talking about genetic tests. Some people refuse some genetic tests. Some people experience immediate burden. Some people experience long-term burden. You've got the risks we've talked about and the professional societies, not just ACMG, the American College of Medical Genetics and Genomics, more to come from them in a couple slides, but most professional societies have concluded the same. So genetic tests, you need informed consent. Second, there's a right not to know. Genetic results that you don't want. People vary in their desire to hear bad news. We first started worrying about this when we could test for Huntington's disease, which is an inevitably fatal disease that we still can't do much about. But whether it's something we can do something about or can't do something about, people really, if properly educated and ideally with genetic counseling and a caring clinician, are the best judge of what they're prepared to hear and undertake at this time. Think about it for a second. We know that everybody in this room has the right to refuse life-sustaining treatment. You can elect to die. You can elect to bleed out in front of your dog right there. For sure, you can elect not to receive probabilistic genetic information about some disease that may or may not occur in the future. And if many people turn out to want a particular genetic result, maybe because it is something that we could do something about, that paradoxically makes it more important, not less, to protect the right to decide, to protect the minority of people who want to go another way. I mean, I like to tell my students, you don't need patient rights if you're agreeing with everybody else. When you need them is when they think you're off. You're not, and you're not agreeing. You wanna go your own route because of your values. So the last thing, incidental findings. This has become a big deal. There's a big debate about this. Incidental findings are extra results. They can come up in research. They can come up in clinical care, extra results beyond those you were looking for, beyond the reason you were doing the test. And when you're doing a whole genome sequence and generating all those billions of A, Cs, Ts, and Gs, you can find a lot of incidental findings. The American College of Medical Genetics and Genomics, ACMG, in 2012 issued a pretty good statement about this. They said, yep, we can see clinical sequencing is going to produce incidental findings so informed consent. Before you do all this, tell patients what's your plan, what kinds of incidental findings you're likely to find, and allow patients to opt out. Right not to know, so far so good. Little bit of squish, little bit of trouble here. Exceptional cases might arise. Not clear what exceptional case is. Something on the horizon, ACMG 2013, led by Robert Green and Les Beesiker and a whole group of people. They dug in an expert group on incidental findings specifically in clinical genome sequencing and said something different. They came up with a minimum list, it could grow of 56 extra genes that they said labs really should analyze whenever they do sequencing for a different reason. So they may be doing sequencing of a patient. This is clinical, not research. Sequencing of a patient because they have an intractable cancer. We've run out of therapeutic treatment options. We're looking in the genome for some target to go after to help save this person's life or a kid. With some psychodevelopmental, neurodevelopmental disability, diagnostic odyssey, nobody can figure out what it is. Let's sequence. So there are some indications that are moving into clinical use right now. And ACMG here said so we should tack on these extra genes because we feel that they are serious enough in terms of the conditions that they predict, increased likelihood of, and also that there are things we can do something about that it is important to test for them. But the problem was how? They said really no patient consent to analyze these specific genes. And in part because they said, we're going to be here forever if we have to counsel people on all of these genes. And a person who doesn't want these incidental findings is kind of stuck declining the sequencing altogether even though they really may need it medically. So not really the kind of informed consent we were talking about, about specifically ascertained genes and that the lab has to report these to the clinician. The clinician report sees to the patient, no patient right not to know. They do talk about a shared decision making process between clinician and patient, but a shared decision making process which is always good isn't the same as a patient being able to say, no, I disagree. So there's been a firestorm of reaction. There were some pieces I contributed to one of them in science on this because what you're hearing I hope is this is not protection of these long established patient rights. Some patients are going to want these 56 extra or maybe tomorrow it's 100 extra three years from now it's 156 extra, but some people are not and we need to respect patient choice. We also need to worry about the reality that we've still got an error rate problem. Some of what we generate may actually be wrong. And I would argue this is not like doing an X-ray or a scan of a broken arm where radiologists may spot additional pathology in that field because ACMG says hunt. Here's the predetermined list. You go hunt and hunt throughout the entire genome including genes like BRCA that we've long asked consent for. So what is being proposed here I would argue by ACMG is a genomics exception. It's like here are the rights we've protected and this goes below that floor. Respect for patients rights to accept or refuse testing and results has been basic not just in medical genetics but healthcare and just because the technology advances and does create some challenges in getting consent doesn't mean you give up on patients rights. So let me conclude. I think the lessons of the past sadly over and over and over again as documented on this mall are clear. Genetic information can be abused and it has been hideously abused. Privacy and protection from discrimination and preservation of patients rights and control are essential. To argue that genetic information is just like other medical information not that sensitive stuff but the kind of baseline stuff I think ignores the past and it also ignores the present. The growing enormous power of genetic and genomic information all of these special laws and efforts that NIH and elsewhere to avoid abuse of genetic information and protect patients rights and privacy. People do have, they do have established rights to decide what tests undergo and what risk information to receive. They have rights to refuse a hunt throughout their whole genome for extra findings. Successful adoption of the brilliant technologies that Eric introduced you to. Capable of generating huge amounts of data on each of us requires protecting patient privacy, patients rights and securing the public's trust. Thank you.