 All right, well, I'm absolutely delighted to be here. In fact, I wore one of my DNA ties to celebrate. I've been told it's kind of humorous on one DNA tie. I'm kind of pathetic to own as many as I do. But I really am so excited about this exhibit, in part because science dominates almost every facet of our life. And genomics is becoming incredibly important to the lives of individuals. We saw recently the kinds of decisions that Angelina Jolie had to make. The food that you eat has so much to do with genomic manipulation and the questions that swirl around that. So it's incredibly important to have an educated populace. And as somebody who does a lot of teaching, I'm acutely aware of the fact that teaching is actually a minority of it is simply imparting facts and imparting knowledge. The most important thing in teaching is to communicate excitement and to inspire students. And I think that this exhibit will do that. I think that it has a leg up on trying to excite people about certain other topics because it not only is powerful, it's not only about you and we're all rather narcissistic. I think that's one reason we like genomic sciences. But because it's beautiful, as really evidenced by the actual structure of DNA, it is an intensely beautiful subject. The human genome is not only beautiful, it's also really big. And everybody has their favorite kind of way of communicating this. But what I would point out to you is that this is about 1 1,000th of the human genome. And if I were to show a slide like this every second, we would still be here 12 days from now and we would have only gotten through the half of your genome that your mom or your dad gave us. So it is a really, really big place. Now, we've learned some things about it. We've learned that it's interspersed with gene fragments and we've got a decent handle on what those genes do. We don't have a very good handle on much of the remaining DNA. And within that DNA are polymorphisms. That is, you have an A where the person sitting next to you has a T. You have a G, 1,000 base pairs later, where somebody sitting next to you has an A. And many of those are meaningless. Some of those influence traits, like what color eyes you have. Some of those influence medically important characteristics and occasionally, people carry very serious changes in their DNA that have dramatic impact on their health. So I think that the long-term legacy of the human genome project, of our burgeoning understanding of life through a genomic lens, will be simply a better fundamental understanding of humans and a better understanding of disease. And that will pay off, okay? It will pay off in the long run and the course of science is stuttering and there's a lot of U-turns. But it is the best way we have found to actually have a dramatic and beneficial impact on patients and on health. But as a physician, I'm impatient and my patients do understand cognitively that yes, research is important for the long-term and they're incredibly generous with their time and they will express to you that I know this may not help me, but I hope it will help somebody in the future. But of course, one can hardly blame them for also wanting some results now and we all want that. So what I wanna do in the next few slides is just explore with you where the near and mid-term reality of genomics is and how it is beginning to help patients now and where we may expect real solid advances in a good timeframe and a favorable timeframe. So new technologies are oftentimes derided with the old adage that when you have a hammer, everything looks like a nail. And God knows, you know, we've been wailing away at every organism we can find with the hammer of genomics. But it's also true that a hammer is a fantastic tool if you hit the right nails. And the question then is in 2013, what are the right nails in sick people and in healthy people to really make a difference in their lives? Well, I think that the nearest term benefit of genomics in medicine will be as an unprecedented diagnostic tool. And we are already seeing this in the genome. And let me give you an example. We're fortunate enough to have one of the CSER grants, the clinical sequencing exploratory research grants. And this is a case of an individual, 47 years old, a female with sudden cardiac arrest. She was resuscitated successfully, thankfully. But on EKG, it looked like she might have a syndrome called long Q2 syndrome. It's actually kind of hard sometimes to judge that by an EKG. It's not a great way to diagnose it. But these individuals are at very high risk for sudden death, which you can well imagine is not a fun thing to be at very high risk for. It is a treatable condition if you know that somebody has it. But it's hard to know that until after they've suffered sudden death. And knowledge of which gene is mutated affects your choice of treatments, all right? So it really has some medical management implications. The problem is that dozens of genes have been implicated in this entity. So until we had massively parallel sequencing at our disposal in a clinical context, we were really unable to define the particular mutation that would be responsible for an individual's long QT. We now are routinely in this project applying this technology to individuals with this syndrome by sequencing a whole panel of genes. We can therefore define the mutation in many of these individuals and not only guide their treatment, but we can also illuminate who else in their family is at considerable risk and needs to see a cardiologist get on medication, perhaps have an implantable defibrillator, et cetera. NHGRI is funding multiple types of investigations into how to apply this. So the thing that I wanna emphasize about genomics is it's like in many ways any other highly complex and wonderful technology in medicine. Think about the MRI for a minute. MRIs are miraculous technology but we don't just go willy-nilly getting MRIs on everybody who walks into our office. That would not only be wasteful, it would be begging for false positives that would do people harm. We need to understand how to use genomics in a targeted and rational way where it will really benefit people. And I think that for the time being it's a subset of patients, very important subset, but nevertheless a subset of patients who stand to benefit in the near term. For example, those patients who have disorders that are caused by mutations in many genes, like the entity I just told you about, LongQT, there are many such disorders. Those with enigmatic conditions but who have clues to suggest a primary genetic etiology, for example, a family history. Progressive neurological disorders seem to be disproportionately caused by underlying genomic issues. And children with multiple malformations. This is a particular interest to me in the sense that many diseases have many different components, but when you think about it, you turned into a human for one reason and one reason only, and that is that you have a human genome. Had you had a bat genome, no matter how you were raised, you would have turned into a bat, okay? So when we see children with birth defects, all right, there's a high probability, many of us suspect, that we will see defects in the genome that have given rise to those. And this is another group in which we're applying whole exome sequencing and beginning to elucidate these problems. It is really thrilling to be able to go to patients as I did twice in the last week and tell them that because of their participation, we actually have elucidated the condition that has caused this problem that you have suffered with for, for example, in one case, 30 years, a woman last week with a neurological problem. And in that particular instance, it led to a recognition of what would be dramatically effective treatment, so it's a real thrill. Eventually, these things will inform our approach to common diseases, but that will come after we've picked off the easier targets of things that are predominantly or almost wholly genomic. I will just spend one quick slide on this because it's been alluded to. The genomic analysis of cancer is an area where even in my somewhat, you know, I try to have a fairly sober view of applications will, perhaps, and I don't use this word lightly, revolutionize the treatment of cancer in the midterm. For over a century, we have defined cancer by its appearance under the microscope and its presumed tissue of origin. We are now, because of genomics, able to dissect tumors in a functional way and really define the specific mutations that are driving the growth of that tumor. That leads to an ability to guide treatment by identifying the Achilles heel of each tumor. And I think that eventually, it's not gonna go away the need to know where a tumor came from. Its appearance under the microscope, I suspect will matter, and there's some interesting new evidence to support that. But I think our categorization of tumors will rely at least as much upon the genomic profile of an individual tumor as on its source. Again, the NHGRI is funding some very important studies to try to exploit this underlying genetic aspect of cancer. So this is the world's happiest colonoscopy patient, Katie Couric. She has a real interest in promoting colon cancer screening because her husband, Jay Monahan, died of colorectal cancer in his 40s. And he almost certainly had Lynch syndrome, a syndrome that causes an extraordinarily high risk of colon cancer, but is very preventable if you know about that risk. And the thing, though, that we have to be careful about as we apply any medical technology to healthy people is it's much trickier than even applying it to people who already have disease. In some ways, people who are healthy have more to lose, right? In some ways, we can only hurt you when we start inflicting medical care upon you. There's also a different relationship between the provider and the recipient, right? Patients come to us for help. They oftentimes recognize the limitations. In a public health setting, we're going to people who aren't patients and saying, hey, we've got a deal for you and we want to do something. That's a very different relationship. The benefits are less obvious. In the public health setting, what you get to say is, hey, I've got good news for you. You didn't get sick, right? And that's a little hard to internalize because not getting sick isn't quite as evident as getting cured of a disease. And the downsides are easy to see. And the point is that every intervention has a downside. I tell the students that there is only one kind of drug that doesn't have side effects, and that's a new drug. Because no matter what, the more experience we get with something, we know that we will see downsides. So we have to be very careful as we start to approach healthy people with our genomic tools. That said, I think there are tremendous opportunities. I think that we will benefit from the preemptive delineation of certain pharmacogenomic variants, variants that influence how you will react to certain drugs. I think we will see it as an adjunct to newborn screening. And indeed, NHGRI is about ready to announce a series of grants that will explore the use of genomics in the newborn screening setting. Pre-conceptual carrier screening is a very exciting arena because the ability to look at many genes is an ability to inform parents as to their risks of having children with very severe diseases. And right now, we are very constrained in the kind of pre-conceptual carrier screening we can do because we've only traditionally been able to look at a handful of genes. And we're going to be able to expand that dramatically. One idea I'm particularly excited about because I think it could be a near to midterm benefit of applying genomics to the healthy if we study it appropriately and the evidence bears this supposition out is what I like to think of as newborn screening for adults. There's me as an infant with one of my DNA ties. The point is that about 1% of people walking around out on the street harbor a mutation that leads to a very high risk of a preventable serious disease. Think for a minute about Lynch syndrome. This is a syndrome that I alluded to a minute ago. Individuals who carry mutations in one of four genes have a roughly 85% risk of colorectal cancer during their life. But if they know about that risk, screening modalities with colonoscopy can reduce that risk of ever being diagnosed with cancer by at least 10-fold. So it's highly preventable if it's known. The problem is that currently this is how we detect people with Lynch syndrome. We wait for several people in their family to get cancer and or die of it. Well, the horse is kinda out of the barn at that point and it's very appealing to think that perhaps we could use our new genomic technology to screen part of your genome at the right time in your life to detect those individuals who carry these serious mutations. If you add up other conditions like Lynch syndrome, what you get is that somewhere around 1% of people have mutations that are conferring upon them a very high risk of a serious but preventable disease and we could benefit millions in the US if we pursue this and if indeed these suppositions turn out correct. And we actually are very excited because we've just gotten a grant from NIH to start on a very small scale to investigate whether this might work and what some of the ethical, legal and social implications of going to healthy people and doing this kind of thing are. There are a lot of challenges as we go forward. I'll name just a few of them. One is accuracy. Most of our next generation sequencing platforms have about 99.99% accuracy. That's really good until you remember how big the genome is. Cause when you multiply that by three billion, it means that you have about 300,000 errors per patient every time you do a whole genome sequence. That's not trivial, right? Interpreting the variants we find, I feel is the single biggest challenge going forward in genomics. We, I cannot tell you how often, every week at our molecular sign out conference, we see a variant. This person has disease X. There's a variant in gene Y that has been associated with this disease, but we don't quite understand how to figure out in many of the cases whether that variant is just a chance event in this person or whether it's causative of disease. And these are tough, tough problems, but I think that that is one of the biggest challenges and one we're beginning to make progress on, but it remains very big. Storage and access in the medical record, I've been treating patients long enough to remember when charts were paper charts and you couldn't read the writing and you'd get a patient and the charts would be this high. Things are a little better now, but could get very ugly when you think about the fact that we all have four million variants. Are we really gonna put those into your medical record? Do we need to put all those into your medical record? How do we retrieve them? We've got to figure those things out. Obviously, education of patients, providers and public is important. Again, I'd emphasize how important this kind of exhibit is in the general public feeling more comfortable with this field and understanding it and hopefully seeing how exciting it is. We have to craft policy regarding the use of genomics and you can't go very far with genetics and genomics without talking about reproduction because that's what it's all about in the end. And this gets to be very, very delicate when one starts to craft policy around those areas. I would also just mention as has been alluded to that you are actually not mostly human, right? Only one out of 10 of your cells in your body is human. Now, most of your weight is human because human cells are a lot bigger, but if you just look at the number of genomes we have, viral, fungal, bacterial genomes outnumber your human genomes by about 10 to one. I think this is a huge area of excitement and with potential for medical application. We aren't there yet. We don't have microbiome clinically ready tests to do, but I think that's coming. And NA and HDRI again has been at the forefront of funding some of these things. I wanna end with just a caution and that caution is that when you analyze a person's genome, you inevitably obtain what we call incidental information, all right? Your genome is not necessarily a warm and fuzzy place. When we do sequencing, say whole genome sequencing on you, we're gonna find things we simply weren't looking for, all right? I think actually LMO needs whole genome sequencing. You notice he only has four digits on each hand. But some of these will be trivial, some will be beneficial, right? I wanna know, it wouldn't make it a good day to be told that I have a Lynch syndrome mutation, but actually I think I wanna know that if there's something preventable that I can do. Some, however, are highly problematic. We're gonna occasionally discover dramatic risks of lethal, untreatable, unpreventable disease. And some people wanna know that or think they wanna know it and some don't. So let me just ask you two questions, all right? I'm gonna show of hands. Think about a few serious but highly preventable diseases that sometimes are highly genetic. I talked about Lynch syndrome. There are four, well, at the Angelina Jolie story with BRCA mutations, certain types of thyroid cancer, aortic aneurysm. If you personally carry a mutation that essentially guarantees you will develop a serious but highly preventable disease, who here in the audience would wanna know that? I would wanna know. Is there anybody who wouldn't wanna know that? Who's willing to raise their hand? Okay, I think that's certainly typical of my experience. But let's turn that around and think about a few really ugly diseases, okay? There are forms of Alzheimer's disease that are essentially totally genetic. You will get Alzheimer's disease if you have inherited one of these rare mutations. One of the more grim, named diseases I'm aware of, fatal, familial, insomnia, everything that sounds like it is. These are diseases that have no prevention, no treatment, and if you carry a mutation for it, you're gonna get it, essentially, 100%. So let me ask you personally, if you carry a mutation that essentially guarantees you'll develop such a severe, unpreventable, untreatable neurological disease, do you wanna know? So who would say yes? Who would say no? Who would say I'm not sure? I think you guys are the ones that are right and I say that because we do have some empiric data and we have these data on people with Huntington's disease in their families and it turns out that individuals, even though many of them say, yeah, I'm gonna be tested, in the end, if you look at who votes with their feet and who gets testing for Huntington's when mom or dad had it, so they really understand the disease, fewer than 20% decide to take the test. I think what that says is denial is a great mechanism we all use every day to get through our lives, but the point is we're going to have to grapple with these kinds of questions as we go forward with an increased understanding of the genome. I'll end with just a few other social challenges for which I don't have any solutions, but we're going to have to grapple with them. Genetic discrimination is a reality, okay? Not in the sense of healthcare because with the genetic information non-discrimination act with healthcare reform, it's really not an issue. And I can tell patients, thankfully, finally, that no, you don't need to worry about losing your health insurance if you get this genetic test. But there are other kinds of insurance that are very important to people. Long-term care insurance, disability insurance, life insurance, there are no laws, all right, there are no regulations that limit discrimination based on your genomic profile for those. If I were the nefarious CEO of a life insurance company, I would be thinking about whether it made sense to start doing DNA sequencing for certain genes on people who applied. And I think we're going to need to figure out how to deal with that. The threat of allealism, okay? I thought that was a little conjectural and hypothetical until I saw this quote in the Washington Post, we envision a new type of community where people will come together around specific genotypes. There is a dark side to that, right? And I'll let you think about that. Gene potting, right? As of today, the Supreme Court has made a ruling that my, you know, I was really delighted to hear what Karen Rothenberg and Larry Brody had to say about it because my initial take is that this will open things up for people who need genetic tests and I think that'll be good. There are real privacy issues. Genomic information is digital, right? That's not a metaphor, it is truly digital. And we live in a digital age where that kind of information is easy to disseminate and increasingly easy to hack. And we're gonna have to figure out how to deal with that. I like Scott McNeely's comment that privacy is dead, deal with it. I think privacy is dead. I mean, if anybody's been following the news lately, we have to figure out how to deal with that, right? And it extends into genomics. One of the major direct-to-consumer companies offering genomics went bankrupt a couple of years ago and one of the envisioned solutions for restructuring was that the data that that company had collected would become the property of a venture capital firm in Cambridge, Massachusetts. That is not probably what the people who spit into a tube and sent it off to that company had envisioned for their data. We're gonna require an educated public and educated policymakers to successfully grapple with how we handle these challenges. And that is probably the biggest reason that I'm delighted that this exhibit is opening and was really, really flattered to be able to play a very small role in it. The Smithsonian's been an inspiration to generations of scientists and I certainly count myself among that group. So thank you and if you have, I don't know if we have time for any questions. I think if we have a burning question for Jim, Dr. Evans, we'd probably want to entertain it. Great. Okay, then I would like to introduce Dr. Lara Rodriguez from the Genome Institute. She runs her division of policy, communication and education and she can wire herself or if you just don't walk around, you can stand at the podium. And Dr. Rodriguez will talk about what do we do with all this data?