 So I now want to introduce to you two very special guests that I'm delighted we're able to come here and join us for this conversation. The first is Anne Wojcicki, and for those you don't know, Anne, I'll tell you a little bit about her, and then she's going to tell about herself a little in her own voice. Anne got a BS degree at Yale University and then worked in the healthcare investing area for about a decade, focusing on biotechnology companies. But then she decided to find a company, a company you've probably heard of called 23andMe, where she's a co-founder and now CEO. And 23andMe is really a key part of this personal genomics revolution, one with really focusing on amassing now a large database of individual genomic information and doing all sorts of things with it that she's going to tell you about. And then in fact, in November of last year, she was named the most daring CEO by Fast Company Magazine. So this is what Anne had to say about herself. Being on Wall Street and learning about finance and how healthcare works is really fundamental to everything that I've done, because I learned the mechanics, essentially, of the system. So I did it for about 10 years, and then after 10 years, I said, look, one, I don't think I'm going to learn anything else, and two, this is not the system that I really want to be part of. Being surrounded by an environment where people were really just pursuing money really started to conflict with my ethics and my values. I spent a lot of time volunteering in Bellevue Hospital in New York, and then at San Francisco General out here. And I almost did that as a detox, where I'd be on Wall Street, and I'd spend all days trying to monetize obesity. And then I'd go into San Francisco General, and it was tragic, the idea of just thinking of these people coming in in sort of a crisis situation or being sick and seeing people with their families and thinking that I'm just thinking about you as a dollar amount. Like, how do I monetize the situation? And it became pretty disgusting to me. So again, I ended up having feeling like Wall Street did not reconcile with my values, and I had to leave. And 23andMe really evolved out of that frustration that I think one of the ways that you can circumvent essentially this whole system is through the individual, is that the individual owns their data. And if I can empower you to make a difference in your own health, we can potentially really change health care. So please welcome me, please help me in welcoming Anne Wojcicki to the stage. Anne, come up. Take a seat. Middle seat. The hot seat. So the second and other member of this panel that will join me for this discussion is Rick Lifton. Rick graduated from Dartmouth with an undergraduate degree, went on to get an MD and a PhD degree from Stanford University, and has just had a meteoric rise, if you will, of a successful research career. He's now a Sterling professor and chair of the Department of Genetics at Yale University. He's also an investigator for actually many years in the Howard Hughes Medical Institute. And he is a recipient of many awards and accolades, a small subset of which is shown here. You can see the American Heart Association and the American Society of Nephrology and the American Society of Hypertension have all honored him because of major advances he has made. In particular, doing the genetics of disorders related to blood pressure, cardiovascular disease, and bone density with multiple wonderful successes credited to Rick and his laboratory. And this is what Rick had to say about his circumstances. I'm Rick Lifton. I'm chair of the genetics department at Yale and an investigator of the Howard Hughes Medical Institute. And we do human genetics of cardiovascular, kidney, bone, and several other diseases. My favorite applications of genetics are to reveal mechanisms of disease that we've known about the disease forever but have had almost no insight into their underlying core biology. And when we think about where we make our greatest advances in medical therapeutics, it typically starts with understanding what the underlying biology is and that allows you to target what is the real core disease process as opposed to the secondary pathways that revolve around there. And so I think that's what's so beautiful about genetics and the ability to understand complex traits is the opportunity for the first time to really get to the core underlying primary abnormalities and understand those. Now, of course, those will not necessarily tell you everything you need to know about the disease, but they are incredibly strong starting points for unraveling the pathophysiology. And, of course, we expect that these will define what the therapeutic opportunities will be and we can't predict with any certainty what those therapies will be until we really understand the basic biology. So please help me in welcoming Rick Lister to the stage. Thank you so much. Good to see you guys. Good to see you. So let me lay some ground rules here. What we're going to do, we're having a conversation. I'm going to kick it off with a question and both Ann and Rick prepare just a few slides to sort of help answer that opening question and provide a little bit of background. We're going to talk for a little bit, but then we're also going to take questions from the audience. And there will be index cards that will be passed around at some point during this. And you could feel free to write questions out for one or both of them. If you have a really easy question, I'll take it. If it's really hard, make sure it goes to them. And then we will get to, we probably won't get to all the questions, but my staff over there is going to sort through and try to find the best questions and pass them on to me, and we will have some of the questions then from the audience put before our two wonderful speakers. So what we want to start with, which actually I think is a great way to think about it, I think about this a lot, is we're sort of in this decade of incredible advances, and we're almost at half time. 2015 will be about half time. And we knew when the decade began that this was going to be an exciting one. And we sort of see 2020 now really now only about six years of wear sign, and soon it will be five years away. So I'm curious to hear from each of you, and we're going to start with Anne. Sort of in the year 2020, what is going to be the role of genomics and medicine? I tantalized everyone with some of the early examples. But one of the big questions is how quick will this happen? And over the next five, six years, what is this going to look like when we're celebrating the January 1 of 2020 or something like that? So, Anne, you can advance your slide. So you knew that? Yeah. So I will start getting to that question towards the end, but I will go through a little bit on 23andMe, and that will sort of touch in here. How many of you actually have your genome, or have been sequenced, or? 10 or 12? Yeah, yeah, yeah, less than I thought. So part of the whole purpose for me of 23andMe is I grew up as a child of a scientist. And that science, in my opinion, should be more in touch with the consumer. And that you actually want to, like you should all be participating. There's billions of dollars that come from your institution, and that we should all be following it. Like there's nothing more exciting than actually following science and watching it progress. So 23andMe was sort of born out of that idea of, like, how can I actually engage you, the consumer, with this? And one of the things that we do is we, like we said, it started out as a $3 billion adventure. And we've made it affordable and accessible. So it's direct to consumer. It's something that you can actually afford. It's $99. It's something you can get access to. And the idea is, like, then you should be able to explore it. And what we have now is 750,000 people who have actually done this. So what's amazing here is, in a pretty short time period, it's now become accessible, and large numbers of people actually have experimented and played with their own genome. And what we've also learned is that people actually want this information, is that science, when you actually empower people, that it's actually, people can understand it. And so when I think about the future, when there's a big question out there is, how much can actually people understand the science, what we find is that the average individual actually can be empowered with this information, and they can make sense of it. And so here are some of the areas Dr. Green already touched on these things that you can actually learn from your DNA, medication response, disease risks, inherited conditions like cystic fibrosis, and then interesting traits, things like lactose intolerance or caffeine metabolism, and then things like ancestry, and ancestry includes other fun things like your Neanderthal status. Which again is part of the things that we've done because it's science that's coming out. It talks about you, that you're not just as much as we're talking here about disease and wellness, you're not just about a disease. You have your whole, I mean the fascinating thing with your ancestry is that it's your whole history of you, and it's your personal history. And that's so cool, like how much Neanderthal do you have, and then comparing that to other people. It tells your own personal story. So what we've also learned with this information is that people get their genetic information and that it does motivate them to change. And so this is a study by Robert Green that's more of it's coming out soon, but people are getting their genetic information and they're actually showing up to their physician and they actually wanna make a change. And I think one of the things that we're seeing genetic information do is that it gets people interested in their health before they're sick. And for all of you, if you raise your hand and say well I'd actually rather treat my diabetes and prevent it, well then you're part of the old system. But for me personally, I'd rather actually prevent my diabetes. And if I know that I'm at risk for something, how is it that can I actually prevent it? And I think more and more you're starting to see these trends like Walmart and your convenience store is getting involved in healthcare, which is where you go to regularly. So more and more there's gonna be more support for a preventive kind of society that's probably gonna be outside of the existing medical system. So again, one of the things that we're doing is we're actually getting people excited about genetic information. And I think the more, one of the best things I think that we can do is to help people like Dr. Lifton and all of NHGRI, is if the entire world gets excited about the genetics research coming out and participates, you'll help clinical trials go faster, we'll all be more excited about funding going to this area and I think we'll uncover what the genome means much faster. So as we see this, this is a slide that's probably shown all the time. That shows Moore's Law and how costs of computing is going down and you can see that the costs of actually getting their genetic information has dropped dramatically. And so this sort of leads to the conclusion, oops, we have one slide I missed, is that at some point genetic information is going to be free? And to me that's actually one of the bigger questions when we think about 2020 and beyond is that so much of population health today is based on the fact that is it actually, is it cost effective for you to get this information? So you look at things like the Angelina Jolife effect and the BRCA testing, right now people are get the BRCA test if they have a history of breast cancer if they're Ashkenazi descent. But at some point if the information's free, everyone's just gonna have this information. And so then how does that actually change some of our population health guidelines? And how does that then change when people are coming into you and they don't necessarily have a history of something like sun and cardiac death and they're walking in saying I have this genetic variant, what do you start to do? So I think that's gonna be actually one of the interesting issues. When the other areas, the obstacles is gonna be how is this actually all gonna become regulated? So what is going to be the path forward to actually get all this information out? And what you're starting to see is there's all kinds of countries. The UK has a massive genome, a 100,000 genome project. Beijing actually has the largest sequencing shop in the world called Beijing Genome Institute. There's tons of other countries, the whole Middle East is actually launching these big sequencing initiatives. So how are we going to keep up? And how is it that we're gonna get through all the ethical, legal, social debates about how to use genetic information? But because the genie's out of the bottle, the rest of the world is engaging in this, what is our role and what is the role that the US wants to be playing? So with that, I'll pass it on. Yes, pass it on. Thanks, Ann. So just to continue framing the discussion a bit, to emphasize the pace at which this work is progressing, if we think about humans as a species, only a 500,000 year history of Homo sapiens, give or take 100,000 years or so, it's only in the last 50 years that we've really begun having the faintest ideas about how the well-known principle of like begets like, which is where genetics really starts, to understanding the fundamental contributions of individual variation to health and disease. We only learned about the structure of DNA in 1953. We unlocked the genetic code in the 1960s. In the 1970s, we just began to be able to get our hands on individual pieces of individual genes. And then this led to the beginning of the Human Genome Project in the late 1980s. I have to say, having started in this area in 1975 as a graduate student, I think if you had asked anyone involved in genetics and genomics in 1975, when would we be able to sequence human genomes essentially at will? I don't think anyone would have imagined that that would have happened within, certainly within my lifetime, or the lifetimes of just about anybody else who was engaged in the activity now. So the pace at which this has happened is really stunning. And if you think about the eras that we've been through in human genetics, it was only in the late 1980s that we really began being able to get our hands on individual disease genes and find these to begin with. And that's been taken over in just the last five years by this dramatic reduction in cost of DNA sequencing, which now allows us to literally identify an individual with a particular disease and be able to think about the question, can we figure out what that person's, the cause of that person's disease might be just from studying his DNA and perhaps several other individuals? Now we've talked at great length over the years about the impact of what this work is going to have on human health. And I'll just give a couple of examples of this. So in the case, Eric mentioned cancer as a particular beneficiary of genomics research, because there we know that there are somatic mutations in the cancers that are not present in the patient's germ line that occur in single cells that initiate the cancer. And those single mutations with large effect are terrific targets for new therapeutics. And in the case of cancer, we now have specific treatments that are aimed at the specific genetic abnormalities in individual cancers. So if you have chronic myelogenous leukemia, there's a specific mutation that is found in nearly all patients with this disease and there's a specific drug that has transformed the history of this disease from one that is uniformly fatal to one that is now highly treatable with a specific drug that inhibits the specific molecular mechanism that is mutated in this cancer. And there are a number of other such oncogenes that cause malignant melanoma, lung cancer, and glioblastoma, multiforma, the most lethal form of brain cancer that have specific treatments that are coming from this. Further, the study of rare patients frequently gives us information about the pathogenesis of common disease. And these suggest particular targets that will be beneficial for therapeutics. So one of my favorite examples of this is if you are missing a sodium channel that is in the dorsal root ganglia in your spine, you are completely impervious to sensory pain. Now, those patients don't need a drug for pain relief. However, our current treatment of pain is very ineffective and has a number of side effects. If you're able to develop a specific inhibitor of that sodium channel, you wouldn't even need that drug to get into the brain in order to have effective treatment for pain. And there are many other examples where rare mutations found in extreme outliers in the population have suggested therapeutic targets. And these are becoming the norm in the pharmaceutical industry to use human genetics to identify what are the best targets where we're going to have therapeutic efficacy. And this is rapidly emerging as these drugs are coming on. And looking down this list, one that I'm particularly enthusiastic about is the treatment of Alzheimer's disease, currently an intractable disease of the aging population. And the best targets that we're likely to get for the next decade have come from rare mutations with early onset Alzheimer's disease that have pointed to a specific pathway for which drugs are currently in development and we'll have to see whether these will prevent the development of Alzheimer's disease in the population. But as both Ann and Eric have indicated, the last several years have led to spectacular ability to rapidly and efficiently sequence large numbers of human genomes. And this is unlocking problems that have heretofore been unapproachable. And one reason that they've been unapproachable is that there are some diseases that are caused almost exclusively by de novo mutations. Not necessarily exclusively, but there are many patients with these diseases where mutations that are absent in the mother and father occur and cause a severe disease in the offspring. One example of this is congenital heart disease where we've now sequenced a large number of unaffected parents with a severely affected child where the plumbing that is required for the oxygenation of blood and its distribution to the tissues doesn't work properly. And we've identified a number of mutations that drive this process and have identified an underlying pathway involved in modification of the proteins around which DNA in the nucleus is wrapped and perturbation in those pathways are driving this disease in a significant fraction of cases. So this is one example of the kinds of discoveries that are happening now. And I want to make the point that when we ask what remains to be done, the answer is almost everything. So there are 21,000 protein coding genes in the genome. We know what happens when humans have mutation in about 3,000 of those genes. So you don't need to put a very fine point on it to say there's much more discovery that lies ahead than lies behind. And that just encompasses the 1% of the genome that codes for proteins. When we get outside the part of the genome that codes for these 21,000 proteins, it's really terra incognita. We don't understand the language of genomes at all. If I were to give everyone in this room the sequence of the genome of a mouse and elephant and a human and said, tell me which one is which, we would be completely incapable without other knowledge of determining which is which. Our genomes are very similar to one another. We all share generally the same, when we say we all in the animal kingdom share the same core set of genes and it's how those genes are used that make the difference. We don't understand that language hardly at all. The last point that Eric alluded to was the ability to use this technology in the clinic. And I want to give one recent, quite dramatic example from our work at Yale. So we were presented with a case of a 15-day-old boy who had severe diarrhea and fever, who was progressing in an unexpected clinical course that the physicians taking care of him in the intensive care unit were concerned that he was not going to survive. He was developing coagulopathy, blood clotting and loss of red cells and white cells. And the physicians were very concerned about his health and they'd been seen by every patient, every consult service in the hospital and nobody knew what the diagnosis was. So in five days we turned around the sequence and analysis of all of the protein coding genes in his genome and his parents. And surprisingly we did not find a new mutation that described his disease, but we obtained a hint that there might be a mutation causing his disease that caused an auto-inflammatory disorder, a disease in which the normal inflammatory response pathway was activated in the absence of the normal stimuli for that. Unfortunately, the day before we obtained our complete analysis, the boy died of pulmonary hemorrhage. However, it came as a matter of great surprise when the next day we learned that his father had been hospitalized at the same outside hospital with high fever and was intubated with respiratory distress. He turned out to have the same disease that had been undiagnosed his entire life despite the fact that he had been hospitalized in a hospital his first month of life with a syndrome very similar to his deceased child. Because of this mutation that was identified, we ultimately made the diagnosis of a new, previously undescribed auto-inflammatory disorder and he was put on high dose immunosuppression and recovered. And he then revealed that throughout the course of his life he had had periodic fevers that were up to 104 to 106. They were always triggered by emotional or physical stress. He recognized that with the stress of his son's death that he was kicking off another of these inflammatory episodes but thought he would write it out the way he had every other one that he had had but ended up with this near fatal disorder in the hospital. So this is one dramatic example where sequencing both defined a new disease and led to treatment of individuals in the family and is suggested preventive therapy that can be offered to these individuals. I think that's one of the last points that I'll add now is that frequently the discovery of the fundamental pathogenesis of disease not only suggests the mutations and treatment but frequently will suggest prevention. Eric mentioned that we've had a long interest in high blood pressure, a disease that affects a billion people worldwide and contributes to 17 million deaths from cardiovascular disease around the world every year. Well the mutations that cause this trait converge on how the kidney handles salt which immediately suggests an environmental interaction with dietary salt intake and blood pressure. And this has led to a recognition that we ought to be able to reduce blood pressure in the population by reducing dietary salt and there are now 32 countries around the world that have public health programs to reduce morbidity from cardiovascular disease by reducing dietary salt intake with the scientific fundamentals coming from these rare patients with extreme forms of high and low blood pressure. So if we look forward to 2020 and beyond where are we gonna be and what are we going to be able to do? The things that seem most obvious are we certainly are going to be sequencing virtually every cancer in patients because those are going to drive the therapies that we're going to give these patients as we move forward. Similarly, we're not going to waste too much sleep wondering whether we ought to be sequencing patients who are in the intensive care unit and critically ill in order to try to make what might be unexpected diagnoses. And there are multiple examples of this happening now. The bigger questions I think going forward will be to what extent will the sequence of every individual in the population contribute to their healthcare? And that's a research question at this point in my view. There are relatively few examples where identification of a specific mutation. Today we will be able to say, I, we know what treatment you ought to have as a consequence. The BRCA one in two mutations are wonderful examples where if you have these disease causing mutations this has very strong implications for how your diagnosis, your future diagnoses and susceptibility to disease. And we don't yet know how frequently that will in fact be the case. I think it will be relatively modest impact if we tell our patients, have your genome sequenced and we can tell you whether you have a 1% or a 2% risk of developing schizophrenia. That's not the kind of information that we're likely to be going to our physicians for. What we want to find are those mutations that are going to be driving disease. And for that reason, I think quite conservatively one can imagine that we will be starting in the clinic with diseases that, with patients who have disease or are at high risk for disease. And then newborn screening I think is an open question. We now screen in most states in the country every newborn for a handful of diseases ranging from 20 to 40 different diseases. We might do much better than that with genome sequencing rather than the current screening tests that we perform. But these are questions that we'll have to settle as we go forward, so I'll stop there. So that was great. What I want to drill down a little bit because I think what you touched on and actually each of you sort of put out something to think about really I think relates to prediction. Because I mean, first I want to talk about what's truth, not that we know it but let's talk about what truth might be and then we should think about some of these implementation things because I think there's relevant, I know both of you are very interested in those. But let's focus on truth because we don't know what truth is and when we try to use genomics as a tool, as a predictive tool, that's where I know there's disagreement in the scientific community. So Anne, you made a passing reference to you want to know things to prevent your diabetes and the question is whether it's diabetes or hypertension, something that Rick is passionate about. The question is what do we know now that is predictive if handed as somebody's sequence or handed the kind of data that a 23andMe test might reveal and what do we know now but also where do you think we're going to be in 2020? Of course we don't know the answer but where do you think we're going to be and does that tend to influence sort of how we try to set up the system for the medical system for dealing with this information? I think as Rick says, it's going to be a no brainer for cancer, no brainer for rare diseases, probably for some examples of pharmacogenomics but I know it gets more, so we say, spicy and debating in the community is really when you get into these complicated diseases like diabetes, hypertension, there's environmental component and many genomic contributions. Will we have something predictive enough to really tell us something that can be used for clinical care, especially in the prevention realm? Sure, so I would say for 23andMe, one of the things that we were doing, and again for disclosure, we're not selling our health reports today as we're working with the FDA but historically what we did is we had two sets of information, information that was what we called sort of the four star reports that was clinically actionable. So BRCA for the BRCA one and two, cystic fibrosis, associations with pseudocolonesterase inhibitors, for instance, about drug response. So we had that kind of information that there was sort of unrefuted that was known to have meaning in the clinic and that if you walked into most physicians that they should know what to do with it. And then there was sort of this gray area of disease risk prediction and that's where there's been the most controversy. And type two diabetes is a good example where you can say there's good data, there's interesting science that is being done here that again I've always felt strongly that you, the consumer, the taxpayer since you're paying for this research you should have the ability to go and look at it yourself since you've paid for it. And so can 23andMe engage you in this science and we're never gonna know how to actually predict disease risk unless we have massive sums of data. And so one of the reasons why 23andMe has a huge research component is that what we're looking for is how can we actually create this community of tens of millions of individuals and understand which of them actually go on to develop disease, what are their genetic risk factors that they have and can we actually really develop a risk prediction modeling system that's based on tens and tens of millions of individuals, the genetic information, taking in environmental information and looking at this longitudinally. Because I think that it is a gray science right now but in the future there should be able to be pretty good risk predictions. And again cholesterol is sort of an example of that. Cholesterol doesn't mean that you're going to get a heart attack. It means that you have a risk factor for it. And I think the genetic, this risk prediction, you might have a thousand genes that put you at elevated risk. We might be able to calculate a score and with that information it's another risk factor that gets totaled up with your environmental factors, your family history, et cetera so that you know these are the areas that you're higher risk for that you might wanna actually, there might be something that you can do about and these are things that you're not as high a risk for and potentially you don't need to be as concerned about. So it's definitely one of those gray zones but again part of the reason why we've had this massive research initiative is that you're never gonna get to that solution about what actually is the meaning of all this information until you actually can do these kinds of massive million types of person studies. But 2020 you think by the time we're there you think for most of these diseases what we're talking about hyperlipidemia, cholesterol, high cholesterol, hypertension, diabetes, do you think we're gonna be mostly able to predict based on genomic testing or you think we're gonna be just barely up the curve in being able to predict? Don't worry about it, we'll save the video so we wanna make sure we don't have to save it. I would actually say this dependent upon how quickly we can grow. I mean 23 and me last year was on a mission to get to a million individuals. If I could hit 10 million people I think in five years I think we can actually have pretty spectacular risk predictions over those. So your prediction is that that knowledge can actually be gained if the right study is done? I think completely. I think if we could get 10 to 20 million individuals engaged in research, filling out surveys we could actually understand genetics and what it's going to mean for your disease risk. Okay, Rick I have a feeling you're gonna have thoughts about this. Well so I'm an optimist and I wanna see the experiments done and the question is what are the experiments that one wants to do? There's been a huge effort associating common variants with common disease and we clearly have associations. Sometimes they've been pivotal in giving us insight into disease where we didn't have any previously but in general these have small effect on the disease risk and so our ability to predict who is going to get disease from the assembly of common variants across the genome has been rather modest and so I think the question going forward is will rare variation prove to be of sufficient importance to give us better ability to predict? And that's an experiment that has not yet really been done in a comprehensive way for any common disease and these are experiments that are going to be done over the next five years for I would expect for virtually every common disease as you go down the list we're gonna be sequencing large numbers of individuals and the key question is how large is large? What is the number that we're going to need to in order to actually believe that we have tested the hypothesis and the current estimates are probably that it's gonna require in the tens of thousands of individuals for each disease that we're interested in and that's going to require a lot of work around the world to collect the cohorts, study them and make conclusions. So I think it's a very open question as to where we're going to be by 2020 because as you noted that's a short time from now and we're barely scratching the surface in most disease areas right now and that presupposes that we're sequencing just the protein coding parts of genomes and we as I indicated earlier we really don't understand the language outside the protein coding parts so I'm not sure we're going to be able to digest that part of the genome. Nor do we know the balance between of all the things that happen in the genome that cause disease, we don't even know is what the fraction is happening in the genes themselves versus those happening outside the genes. Exactly so and so for that reason I think we don't know much more than we do know at this point and it is a long way to go before we are capable of making confident predictions. So what was your reaction to the ANOVA healthcare ad that I showed in my talk? What was your immediate gut reaction? Well so I think the field of genomics has always been fraught with optimism that frequently is not tempered by reality and I think my immediate reaction to that ad fell squarely into that. I don't think we're ready to be making those kinds of predictions for most people and I'll give an example. So when exome sequencing became online and suddenly people could do this I must have reviewed one paper a week from a high profile journal that ran as follows. We sequenced 50 healthy year olds and identified variants in known disease genes. We then spent X number of dollars working them up for those diseases and were surprised to find that they in fact did not have those diseases and of course this reflects a lack of knowledge of Bayes' theorem that if the prior likelihood of a healthy 50 year old having a lethal genetic disease is extremely low if you find a variant in that gene the likelihood that that's a disease causing variant is probably very unlikely. And so you can spend a lot of money chasing these kinds of diagnoses and this I think is a major problem that we have as we try to interpret genome level sequence is for example in BRCA1 today we know a lot of mutations that clearly cause are causally related to the risk of breast cancer. There are other variants that change the protein coding sequence but do not predispose to breast cancer. And the bane of our genetic existence today in many cases is the variant of unknown significance. We find a variant that we've never seen before in any of the people who have been sequenced around the world and the geneticists are left with the puzzle. There's a variant there. We haven't seen it before. How do we know whether it's functionally important or not? And there are approaches to try to address all variation in every gene in the genome and these are the kinds of things that we're going to need to have the kinds of diagnostic certainty that's going to increase the power of our tests so that we'll know which variants have an effect on the encoded protein or the genome function and which don't. But the first papers in this are just being published literally now. And what was your reaction to that ad? You're an optimist, I know. I'm definitely an optimist. I mean, I think the ad was not specific enough that it could mean anything. I mean, some of the things that I am excited about is that I do think that this general population health that I just turned 41, so should I get a mammogram? So are all 40-year-olds the same? And I look at other associations, like I'm actually curious how to see this question, there's associations with macular degeneration that actually are discovered out of Yale and that falls in the gray zone. But if you were homozygous for that high-risk variant, would you show up at your ophthalmologist sooner to check for macular degeneration? And so would you. So... And you don't have to tell your age, just because she's a braggy, you don't have to do that. Because we were both once 41, weren't we? So this is actually not a theoretical question. My father had retinitis pigmentosa and he was from, his parents were from the same small village in Russia. And it was no surprise that he was probably, his parents had distant relationship to one another and he was homozygous for one of the genes causing retinal degeneration. And I was actually faced with that question of do you wanna know? And my father had a productive life, had to retire early because of his blindness. He progressed to complete inability to see in his 70s. And I made the conclusion that, drew the conclusion that he had had a productive life and how differently would you want to behave if you knew? And for me, the question was, is there something that you would do about it today? And I'm very enthusiastic about things that you have some ability to change. At that time, there was no treatment for the disease other than laser zapping of the lesions to try to prevent them from progressing. And I decided that I didn't want to have eye exams at that point. So I think individuals will vary in how they respond to that. ApoE4 in Alzheimer's disease today is a very practical example of this. The allele frequency around the world is about 17%. About 4% of the population will have two mutant copies of this gene. And if you have one copy, you'll get Alzheimer's disease on average eight years earlier and if you have two 16 years earlier. And practical question, do you want to know? And currently there are no useful treatments that we know of that will prevent progression if you are an ApoE4 carrier. And I think individuals will vary in their response to that. And in general, in my experience as a physician, patients really want to know if there's something that can be done and if there's not, it's a very mixed impression. Right, but one of the things I think that will be interesting is with population health guidelines, so things like macogeneration or with breast cancer, can I actually get more specific guidelines for me that are based on my genome? And that's when I start to look at, some of these new prevention diagnostics that are coming out that are very expensive. If all women didn't have to get a mammogram, one, that's great for me, but two, that's a big cost savings. And so I look at things as well like macogeneration where it's in that gray zone now still of information, but I can see that actually being a really valuable risk prediction tool to say this group of individuals, not everybody actually has coverage with an ophthalmologist, but if I could actually send these people at 50 to go and get screened and there is now a treatment for delaying and actually stopping the progression of macogeneration, the cost to society of blindness is very expensive. So can I find those individuals who are homozygous and actually get them involved in front of a physician much sooner? And I think that is like, as much as that information is the gray, that's the kind of thing I think that 23andMe could actually start to validate by having this community-based research project and then start doing these types of population health studies to say yes, like I can get these people in ahead of time and actually try and prevent the disease before it actually really becomes costly to society. One of the things I worry about a lot in these situations is managing expectations. And I, of course, like the idea of getting community-based research involvement the way you describe it, but are we convinced people see the distinction between being involved in research and actually having what they perceive as getting this truth? I mean, my reaction to the commercial when I first saw it was, at first it was like, oh my gosh, they're talking about genomics, isn't this fantastic? And then by the end of it it was, oh my gosh, they are really subliminally implying some things that many people may not sort of appreciate is not really here and now. It's the promise, but it's not reality. I worry a little bit about getting people involved. Will they interpret sort of the excitement of doing a study as being the new way that you should make life decisions? How do we strike that balance? I think it's two different questions. So one thing for us is getting our customers to understand how much we just tested them for. So for instance, if I just tested you on 50 different carrier statuses, so including cystic fibrosis and a whole host of others, how do I get you to appreciate the fact that we actually just screened you for all of this and that we did not find any variance there? So one is like getting you to realize that there's all this information. One of the things that we have done is we include this whole section on traits is that traits are actually really fun for people. So if I can tell you what your likely eye color is or I can do things like caffeine metabolism, every one of our customers gets something. And they love that. Like they love thinking about lactose intolerance or caffeine metabolism. Everybody was thinking about lactose intolerance. Whoa, but it's interesting. It's actually interesting. So I look at things like my child who was having stomach pain and then I looked into the genome. I was like, oh, you're genetically likely to be lactose intolerant. Like I'll just try out that lactose-free milk. It's a relatively, it's cheaper than going to the doctor. So like, and it seemed to work. So I think those are things like it's just, it kind of just fits in with your life. And I think that's part of it is I think part of the reason for the success of 23andMe is that we can give everyone some kind of piece of information. And I think that the research, I think one of the things that we have found is that people, you look at Susan G. Coleman and Livestrong and there's this like goodwill sense where people wanna contribute to the world but we kind of make it hard. And in part, one of the insulting factors that I found on Wall Street is how we treat people like a human subject. And again, you have the Henrietta Lacks up here. Like it's kind of insulting how you are in a clinical trial. We get as much from you as we can and then you are deemed too complicated to ever return any results for. There's not a single federally funded study that returns the data back to the, the genetic data back to the subject. And I find it kind of insulting even just to be treated as a subject. So part of what 23andMe's tried to do is humanize it. And we do all kinds of research studies. Like we did a big study we've done now the largest study on human sexuality. And no one else, like it's gonna be tough for me to get an NIH grant for that. But it's one thing consumers actually wanted that. And if you don't wanna participate, you just don't take the survey. And if you wanna participate, you take the survey and you look at the success of this ALS ice bucket challenge and you imagine like if you had a family member with Parkinson's disease and you could email out to all your friends and say, take this Parkinson's survey, you're gonna contribute to real research. That's like then you can really make a difference. And I think that's part of what we've done. So the customers like they have their information that's their meta like their information of their genetic data, what they should do. And then these surveys about like what is it like how can I answer the questions? What are the genetic associations with type two diabetes? Why is it that it says I have this genetic risk factor but I don't have a family history? How can we actually understand that? And that's the responsibility of 23andMe to keep innovating on that and make sure it's clear to customers that we don't know everything. There's this fascinating world of gene and environment and the more environmental information we can learn the more we can understand of how your genes interact with your environment and then we should be able to give you better information about actually how to manage your health. So this is all about what truth is gonna be as I said earlier, what we're really going to learn through whatever means, whatever studies of the interaction of genomic variation and diseases and traits and the environment and so forth. And I wanna talk a little bit about implementation, the real world. And I'm gonna start with Rick as a practicing physician, a geneticist and someone who deals in some cases with rare diseases but much of your career has also been looking at very complicated common diseases such as hypertension. But you encounter patients and you don't have hours with them but project to 2020. You're seeing patients in the clinic when they come in with their particular circumstance whether it be hypertension or whether it be some other renal disorder and they come up with a lot of genomic information. What's that encounter gonna be like? How certain are you gonna be to be able to give an answer and how certain are you gonna be that they're gonna understand what you're about to tell them? Cause it's not gonna be black and white. It's gonna be some shades of gray. Yeah, I think in the long run both physicians and patients are enormously practical. If things make a difference to patients' individual health patients and physicians will want the information. And I think BRCA 1 and 2 are perfect examples of that. When the tests became available there was a paternalistic strain in the community that said, well, we're not ready for this testing. We need time to figure everything out and patients and physicians in the community said, wait a minute, my patient or as a patient I've got a family history of early onset breast and or ovarian cancer. I believe I'm at risk. I want this information now and because I'm going to do things with it. And physicians I think were pretty quick to pick that up and a few more daring ones said, yeah, of course we're gonna start. It was pretty black and white, right? Those examples are pretty black and white. So I think the black and white examples are the ones that in the long run and it's the getting from where we are now to the long run because in the long run I think it's going to distill down to a manageable number of things that matter. And physicians and patients will coalesce around, here are the things that really matter for your health in the long run and these are the things that we ought to be measuring in everybody. We have a rather shaky period going from where we are today to that point where there's going to be a lot of uncertainty as to what individual variants mean in individual patients. And this of course comes right back to Eric because his job is to get as many people sequenced for as many diseases as rapidly as possible to settle which variants actually matter so that Anne can put on her diagnostic list. Here are the things that we're testing now because these are the things that we're certain really will matter to patients and we'll be able to hopefully use this to improve public health. But I think we will have a period in the near term where we will have a lot of variants of uncertain significance. Which is why I'm picking on 2020 because I think I share a lot of the optimism that will eventually understand a lot of this but we will be in awkward phase. So 2020 though, think about our medical colleagues and our pharmacist colleagues and our nursing colleagues and genetic counselor, they're either in training now or they're out there in practice and it's just a tsunami of uncertainty. I think the BRCA1 is an easy example but I purposely point it to hypertension to diabetes so I know it's going to be great for a while and yet some of it will start percolating in and what is that going to look like? I mean both from the patient point of view and for this busy healthcare professional point of view. Yeah, I think it's going to be quite taxing in many instances and I think we need to be prepared for uncertainty. We're going to be dealing with a fair degree of uncertainty in many cases about what the significance. And for this reason, this is where I come back to my earlier comment. I'm most enthusiastic about using this technology for people who either we have good reason to think they are at risk or they are presenting with a particular disease. And the element that you and I have discussed previously is we've got a long list of genes to figure out what they do and what they mean in the context of humans and the more rapidly we populate that space, the better opportunity we're going to have to understand when a patient comes to us what disease they actually have if it is genetic and if it's genetic, which gene is mutated and how that's driving disease. Another element that we haven't touched on yet is the potential impact of all the information coming from electronic medical records and the ability to do very large amalgamations of that data with genomic data. And this again poses both opportunity as well as enormous challenge for trying to make all of this coalesce into new knowledge pathways that will benefit the public health. And as you know, we're very interested in that and research going on actively to try to see what that future is going to bring. So, Anne, I think you alluded to this. I mean, are the great discoveries the next five years going to be in the United States or are we at risk of losing our lead on this? So I definitely, there's two things. So I want to answer that and then I want to go back to your robust question. So I do really fear that the US is going to be falling behind because there are major initiatives going in a lot of other countries. So the UK has their 100,000 genome project. Like I said, Beijing Genome Institute has just a massive, it's the world's largest sequencing shop. You look at other countries like the Netherlands where they actually have some of these massive half a million person studies where the medical records already are integrated. And I think that's where we have this dream and this fantasy of actually having all electronic medical records integrate. But I actually have, I mean, raise your hand here if you've ever downloaded your medical record or if you've ever used, oh, some of you, anyone ever used Blue Button? Oh, we've been looking for you. So, I mean, that's part of it is that trying to find people who are actually getting this data is hard because medical records are not really integrated and that's part of the problem with not having a single patient identifier in this country and actually really being able to get all this data. But there is massive potential for doing these types of studies and I look at in the Europe. I mean, in the UK, they have like this million woman study where it's just like this one woman who runs a study and they just have amazing amounts of data. So I do worry that at this time because we don't have a clear path for actually how we're gonna do these types of massive research studies and there has actually recently been a hold on some of these research studies like there's baby seek, for instance, there's this big sequencing program where they want to sort of understand their approval, the regulatory process before they're gonna return all this data back to the individuals. So I think that right now we're really kind of stuck because we don't know the right way to deliver all this information back. So the second thing I was gonna say on the variance of unknown significance, I do see that as actually one of the biggest challenges is that you get tons of this data and you don't know what it means. And so this is actually a project that Rick and I ironically ended up working on where somebody came to Rick where they had three generations of pancreatic cancer. Rick did the sequencing. We found that there was a mutation in MLH1 which is associated with hereditary colorectal cancer and we thought this was the likely mutation. So it was a variance of unknown significance that had a high probability of being this mutation. And what 23andMe did is we took that mutation and we looked back in our database and we said, oh, we have 157 other people with that same mutation. If this is really the highly penetrant mutation, those 157 individuals also should have had hereditary cancers. And so we ran a survey. We got 12,000 people to respond in 12 hours and we could see almost instantaneously that this mutation had, that those individuals with that mutation had nothing above baseline. And so we could conclude then with a high degree of probability that this variance of unknown significance was likely not the causative mutation for this hereditary pancreatic cancer. And so this is something that 23andMe is looking to do more and more is that it's not our job to mine all the data. We wanna be the sort of representing the consumer so we are looking at ways that we can actually make our entire database accessible to people like Rick, to you, to all researchers in the world where they could run a query in the database and they can instantaneously see is this variance of unknown significance? What is being found in other individuals like this? And that's, I think, part of how you, the individuals, are actually gonna be able to contribute to research like us decoding the genome really fast. And if we had that ability in five years, if we had massive numbers of people, we really could decode a massive amount of this genome. So I wanna completely agree with this point. If we sequenced our individual genomes today, the best annotation tool that we could possibly have for understanding what is interesting or potentially actionable in it is to know the sequence of, not just everybody else in this room, but a million other people. And today, the largest publicly available database, you could put together maybe 20,000 people from available databases. And I know NHGRI is passionate about trying to get this data available. And of course, it raises many issues with regulatory authorities. And I think it is one of these, will be one of these individual responsibilities where we will need individuals to be willing to make their data in some way accessible because we all will benefit to the extent that everyone makes their data accessible to be able to correlate genotypes with phenotypes. And I think that's critical. Getting back to your question about how the US is faring, we're in a somewhat ironic time when having spent enormous taxpayer dollars since the end of World War II for basic biomedical research that has led to this point where we are today, that we are now in the throes of cutting back on our investment, on our public investment in research at just at the time when the fruits are most likely to benefit the public. And I think this is a poor decision to be making at this time. And we need to reverse it. So changing topics slightly, one of the things to be careful about is making sure that in the process of using genomics in a productive way to improve how we can practice medicine, we don't leave behind certain elements of the population. So health disparities, is I think genomics is gonna exacerbate or reduce health disparities in America and elsewhere in the world? Not an easy topic, I realize. It's not an easy topic. I mean, it's a couple of things that we've done. Part of the whole mission for 23 Me was the accessibility and the democratization. So at $99, there's a massive difference between us and the entire genetic testing field. So we've tried very hard to make this information accessible for individuals. And we're trying very hard to make it so it's understandable that it's easy for people, that you just go online and you order it. I do think that one of the differentiating factors is gonna be when you get your information, you show up to your physician. And if your physician doesn't know what to do with it, then it's a challenge. So I think there's two things. One, it's part of the reason why 23 Me has a community, is that people are learning a lot because genetics is still so new. They need to have a community resource to ask questions. And then we find those community members are pointing each other to other resources. And we also have a list of resources for our customers. I think second, I think you're gonna have to have things like telemedicine where you're gonna have, we have a partnership with InformDNA, a group of genetic counselors that are trained on all the genetic information. So it's again, relatively inexpensive, but then someone from their home can then go and get this information. But I think it's a challenge and it's part of the reason why we've put in, we're starting to put in significant resources into education because most of the medical community is not educated about genetics. And I do believe it's part of our responsibility to make sure that we are at least supporting the physician as much as possible. And I was an investor in the days of WebMD when it first came out and it was hated, it was just wreaking havoc on the world. And so I've at least learned from that and that I wanna be able to enable customers to get a report on Factor 5 Leiden, print it out and actually have the basic information on it where they can walk to a physician and the physician feels capable and competent at actually answering those questions. So that's our goal and that's gonna be the direction that we're going. I'll take a somewhat different tack on the question. When I was a medical student, the first time I walked into a dialysis unit was in Palo Alto, California and I was astounded to see that most of the patients in the dialysis unit were of African-American ancestry because Palo Alto at that time, African-Americans constituted a small fraction of the population and yet they dominated the dialysis population and I asked the attending physician, what's the explanation for this? So yeah, socioeconomics, access to healthcare, don't know, wave of the hands and that was the end of the conversation. But it was something that was persistent and stuck with me over the years. And just recently in 2011, really remarkable study came out that provided an explanation that this major health disparity is actually genetic in origin and it turns out that if you have one copy of the particular variant in a gene called Apol-1 and you live in Africa and are exposed to tropanosomes, you're protected from development of tropanosomiasis and that's a very beneficial thing to have. But if you have two copies of the allele of that variant in Apol-1, you are likely to end up on dialysis at age 50 or 60. This was a mystery that was completely unknown and people dealt with what's the origin of this health disparity for a very long time until this genetic explanation came forward. So I think there's a path forward there to actually address one of these health disparities and of course the challenge now is to understand the pathogenesis, how this variant in Apol-1 translates to this predisposition to end stage kidney failure. But it's a nice example of where in genetic discoveries have the opportunity to reduce a health care disparity in a rather dramatic way. So do people get screened for that now? Well, so right now it's in that gray zone of we don't really know what to do and it's a very recent finding but it clearly has a very large, unlike many common variant studies, this has quite a large effect on risk of disease and clearly is of importance. I just looked down on one of the questions, Ann, I don't know if you want to extend any more but specifically related to this where they wanted to ask you what do you envision 23andMe can contribute to discussions on health disparities for various populations? What can we con- What can you contribute to discussions on health disparity? In other words, as any or either I would imagine some of the studies you're doing or whether you're doing enough population, collections to be able to answer some of the questions like what Rick was giving examples about. Yeah, so one of the things that we have found is in a lot of, I mean you guys certainly know is that most genetic studies are done on European populations. So I think it was three or four years ago we actually launched an initiative called Roots into the Future where we gave away, we partnered with Skip Gates and we gave away 10,000 free kids to African-Americans because we wanted to see could we do sort of a massive replication study. So could we find this type two diabetes or factor five, like all these genetic variants that are found in European populations do they replicate in the African-American populations? So 23andMe I think has recognized us that genetic studies are not done in all populations. And again I think it's part of where we tried to rectify it at least a little bit there by having this sort of major initiative and when we gave away 10,000 free kids we found them that each family member then goes and they get other family members to start to sign up as well. So that actually expanded it quite a bit. But that it's important for us to make sure that the genetic information is relevant and meaningful to all populations and today it is decidedly not. So it's one of the things that's definitely on our mind. It's some of the things that we think about. We've put as an early non-profitable startup we've put pretty substantial resources into this already and we try to advocate for this. Like Southeast Asians as well, are you routinely not part of these big genomic consortiums? So that's again something that we're very aware of and that we think actually needs to be remedied. So we are thinking about that and we try to recruit potentially certain populations but it's a problem in the industry. So one of the members of the audience pointed out that we're talking a lot about prediction but let's also maybe explore a little bit about therapeutics and what is now possible. And they gave us an example which is one that I know Rick you probably hear about frequently and the examples where we've known the genomic base of a disease like sickle cell for many years and yet we really haven't been able to come up with good therapeutic or improve therapeutic options. So when you look in the crystal ball, what do you sort of see is genomics gonna be mostly a diagnostic and predictive tool or is this gonna lead to new therapeutics including obviously gene therapy, drug development and so forth? Yeah, so key question. I think the starting point from my perspective is always the biology is going to tell you what your options are and sickle cell anemia is a good example of how difficult it can be to go from understanding biology to developing a new therapeutic. We've known the molecular cause of sickle cell anemia since 1953 and yet we still don't have effective therapy for that. And part of this gets to the nature of what the gene is and what the specific mutation is and what would be the path forward. So some of the examples that I gave in cancer where we've gone in stunningly short time from identifying a mutation that's driving a particular form of cancer to a new therapeutic has occurred specifically because the nature of the mutation suggested an immediate path to therapy. The genes in cancer that I illustrated were types of mutations that cause increased activity of a particular pathway and suggested immediately that we could turn off that particular pathway and have a beneficial effect on the development of that cancer. Much more difficult are situations where you have lost the function of a particular gene or protein and then are trying to figure out how to reactivate that gene or some downstream pathway and that's frequently much more vexing. Similarly, structural proteins are very difficult to figure out how to deal with their replacement. So thinking about potential magic bullets going forward, gene therapy is always, it's one of those areas that the future is always just around the corner and I think that we haven't really cracked that nut yet. For trying to correct genetic mutations, there are I think quite promising technologies that as you know just over the last year the development of general approaches for either knocking out gene function or potentially replacing, correcting specific mutations with technology called CRISPR technology which came from basic biomedical research identifying fundamental pathway used in bacteria to ward off invaders has really quickly caught on in the biomedical community and is being widely used and there are potential therapeutic approaches to using this that clearly are not likely to happen immediately but are of the sort that are clearly getting a lot of interest in the public. So I think the bottom line is we don't know what we're dealing with until we understand the biology and as I always tell my students and fellows the surest path to therapy is understanding the biology. It's just not the case that every time you understand the biology it's going to immediately suggest a therapeutic. So Anne one of the people in the audience is asking questions about privacy issues. I am quite sure you've thought about this. Sort of what are some of the, do you think we're properly situated in the United States to deal with a lot of genomic information on a lot of patients in their electronic health records? Do you think this is something that's gonna come in backfire or do you think we need a better framework for putting that future together? I mean I think in electronic medical records I wouldn't say I'm as much of an expert in that but I think that in general genetic information is sensitive information and I think it's in some ways the consumer just needs to be really informed with the fact that it's impossible to de-identify you from your genetic information. So it's part of where there's a responsibility you need to understand what it means when you share your genetic information and what those risks are. One of the things 23Me has tried to do is what we have found is that most consumers actually, most of our customers at least, are comfortable with sharing their genetic information but they wanna be in charge of that. So they wanna know am I sharing this with my mother? Am I sharing this with a stranger? You potentially wanna share different levels of information. I might wanna share more information with my physician, less information with my sister, less information with random people on ancestry. So I think it's important that the privacy controls when we spend early, in the early days when we met with all the privacy experts, one of the things that they just said is they're like, look, the definition of privacy is giving individuals that choice of maintaining whatever level of privacy they want. And so 23Me, you can join us. There's no legal chain of custody that we have. If you've ordered a kit, I don't necessarily know that that kit actually was spat in by you. So we don't have that direct chain of custody and we do everything we can to protect that privacy of your genome. At the same time, we give you those controls if you wanna share it with individuals that you can, if you don't wanna share it, you can't. But I think it's the reality for this country is that we need to make sure that people understand that there is always a risk with this information and when you're sharing it. And I would advocate that there is a reasonable risk benefit reward. What Rick was saying is that we're all gonna learn from each other if we can all get over this, but we all need to understand what those risks are. And I think that there does, like Gina is in place here. I think Gina is the genetic information non-discrimination act. So there is federal legislation now that's going to protect you from having your employer and your insurance company from discriminating against you. It could be made stronger. It could include life insurance. And I think what we're gonna wait to see is some severe penalties. If there are breaches of privacy, there needs to be sort of that severe penalties coming after those individuals. I do think just to follow on to that, I think we have placed enormous weight on theoretical harms that are rarely met and have placed almost zero weight on practical benefits that will come from data sharing to the sort that Anne is alluding to that is really necessary to make full utility for the information that's available. I mean, it's one of the things that when we get asked these questions, I look at all of you in the room and could I hack into your genome or would I rather hack into your bank account? And the reality is like, I'm sure your email or your bank account is much more interesting. Actually, a lot of these are federal employees. Our bank accounts are really boring. You never know. So it's still that there's more of that incentive and there is a lot of really great sophisticated technology that's evolved that we're able to copy and we're able to sort of understand what is it that they do in the banking industry with your mail, other things that we can then emulate with 23Me. And actually the team that originally built the infrastructure for 23Me was a group that had come from PayPal that were specifically from that banking industry and brought that kind of security obsession. So it's clearly important and again, I would agree with Rick like it's that risk benefit. We worry so much about the theoretical but there's a massive benefit to society if we actually all can pool our data together and I think that's also part of the reason why we have 750,000 people pretty quickly that they'll all come together and 80% of them are consenting to research and sharing information. So Rick, another question came in. This is a person who is clearly gonna be recruited to be one of your reviewers next time you're up for a huge evaluation which I know is a very stressful evaluation that comes in so they said hypertension which you've spent much of your life studying is a challenging example but we can easily and cheaply see if a person is suffering from it and there are large numbers of effective drugs. So why do we need genomics at all to study hypertension? Terrific. So when I started working on hypertension I chose to work on it specifically because it was one of the common diseases that as I said affects a billion people and when we started our research on it it was passionately debated as to whether hypertension was a primary disease of the heart, brain, kidney, adrenal gland or vasculature and as a consequence of that inexact understanding two thirds of patients with hypertension are inadequately treated and we continue to have 17 and a half million deaths annually around the world from cardiovascular disease remains the leading cause of death worldwide. The rare outliers that we studied with extremely high and extremely low blood pressure settled the question that probably only the salt lobby really wanted not to be answered which is that the kidney is a central regulator of long term blood pressure by determining how much salt is reabsorbed by the kidney and the impact of this is it is immediately suggested how you might want to try to attenuate the age dependent rise in blood pressure that occurs in western societies by modest reduction of salt intake and as I mentioned 32 countries now on the as an accumulation of knowledge implicating renal salt reabsorption now have modest reductions in salt intake as a uniform goal for the entire population which is modeled to and in the UK there's evidence has reduced cardiovascular mortality so if I combine a couple of questions related to education I want to ask each of you do you think the bigger challenge is going to be in educating and preparing the healthcare professionals for this future or is the bigger challenge going to be preparing patients and the general public for genomics and its use in medical care or is it going to be a tie and I'll let you go first I think it's going to be the physicians I think the physicians are harder and other healthcare professionals and I think part of it is that we had at one of our early conferences we had a physician stand up and say look the biggest problem with 23andMe is that you generate non-billable questions and I think that that's actually true is because there's not we've seen doctors make lots of changes when there's a massive reimbursement incentive so LASIK for was one example when everyone was getting their eyes cut people made a ton of money off that so everyone learned that new technology there's not a lot of money to be made off genetic so it's hard to justify with such a busy world that you already have why is it that you're going to learn all this information and I think that physicians have been generally it just hasn't been taught it's not really taught that much in medical school or it's taught just about things like cystic fibrosis so it's a whole new class of information to learn and what we find is that no one cares from the consumer perspective no one cares more about your health than you and if your genetic information is all about you and you're worried about how you can stay as healthy as possible and you see your family has a history of one thing or a history of other you're really motivated to learn as much as you can about you and that's where I think what we're seeing is like our customers really get educated we have these videos called Genetics 101 it's a YouTube series and we have over a million views on these videos collectively so people want to understand this and so I do think that you have more of an incentive because it's about you versus the physician where it's part of your workload and there's not a reimbursement structure to really support that right now So Rick or all the Yale first year medical students watching these videos and getting educated about I can trace them back I'm curious what you think about where is the bigger challenge going to be the public or healthcare profession I think they evolve just about in parallel in my experience and I go back to BRCA1 where I think patients and physicians patients were a little bit ahead because of exactly Anne's point that it's me, it's my family and I really want to know but physicians were pretty quick to pick up that this was practical and important and made a difference and surely physicians currently in medical care don't have huge amounts of time to spend with each individual patient and so they're gonna be focusing on main effects what are the things that actually are going to matter most to long-term health of patients and I think to the extent that things matter people will be paying appropriate attention to that certainly in the first year Yale medical school curriculum we teach a lot of genetics now genetics is there is no better framework for understanding human biology today than focusing on the diseases of every organ system from what happens when you have a specific mutation and you take essentially one piece out of this working organ what happens it's a wonderful way to organize a curriculum and how much has that changed in the last decade that curriculum so I think in medical schools around the country it's quite common now to have aspects of genetics and genomics tie into almost every organ system because it provides such a special way of understanding the biology of what happens when you mutate this gene and why does all of the secondary consequences evolve from this primary abnormality okay we're winding down and we wanna end at an appropriate time to have a break before the next panel so I'm gonna ask each of you one more question the question is when thinking about everything we've discussed what keeps you up at night and Anne your answer can't be the FDA you have to come up with something other than the FDA so we'll let Rick start and then we'll come back yeah I know I think about it well so I think we've already touched on the part that keeps me up at night which is how do we get from here to there you know we can see over the event horizon to see to once we've got a million people sequenced maybe more than that a million genomes we're gonna have ideas of what variants are highly most strongly predictive of particular diseases or their outcomes and trying to get from where we are today to that point I think is going to have a lot of challenges because a lot of genomes are going to be sequenced and just as Anne articulated people are gonna show up say I've got this variant what does it mean and right now we're not going to know with nearly the precision that we want in many cases what those variants actually mean and I'll add the FDA part for Anne so she doesn't have to answer that I think there's huge opportunity for innovation in healthcare and I do have serious concerns that if we over-regulate I think the FDA has a completely appropriate role in making sure that tests are being done well and appropriately and the information is accurate but I do have reservations that about if we go down a path where we insist that these are the only tests that people can offer at any one time that that will really stifle development and innovation in this area Anne although now I realize your answer is gonna be your young children keep you up at night my young children do keep me up actually they wake me up early rather I mean there's things that I lose the most sleep about is that the most rewarding part of 23 and me is I always wanted to be a doctor and help people and I get an email almost on a weekly basis of somebody who says like oh you know you saved my life because I learned this information or you know there's a man who came up to me recently who said you know my son hated sugar I couldn't figure out why we took him to all these specialists and then my sister was pregnant and she did 23 me she found out she's a carrier for fructose intolerance lo and behold I go to another five physicians I get my son tested and he's homozygous for fructose intolerance he can't absorb fructose and that's why I hate sugar it's normally only detected in their 20s once they actually have severe disease and so this little boy like we we've just impacted his life we prevented him from actually having this disease and you know information you know significant percent of 23 me customers really learn something that influences their life and it could be that you know it could be on their ancestry it could be that they find a relative it could be that they you know actually have Jewish ancestry and they didn't know about it or they didn't know where they're adopted or it could be on the medical side and so it keeps the input light that people can't get this information right now and I think more than that I'm impatient like I am I'm 41 which is young but it's also sort of old I'm actually disgusting but that's okay but I really like I feel this you know this this this pressure and I was looking back for this talk I was actually looking back at where were cell phones 10 years ago just to look at that delta and you know and it was like the old flip phone like that was really hot like having like one of those star tacks I just got rid of my flip phone like six months ago don't admit that so and then I compare that to the iPhone 6 which just came out and then I think about well we want that same kind of evolution to happen in genetics and so how are we gonna get there and at this current pace of funding individual little studies it is not gonna happen frankly and so we need a massive community of individuals to help us decipher what this genome means and I am definitely the big believer I mean I spend every single day doing this because I believe that if we can have the world's information combined with genetic data you really will be have a much better path for making drug discovery you'll have much better diagnostics you'll have just a much better much better way of living your life so how can we get there faster and I don't want 23 and me being the only one sitting on this data I want to enable every researcher in the world to get access to our data so when I think about what keeps me up at life like I want to empower this revolution it's so like it is so exciting right now like it's the most exciting time in science and I just like we're on the cusp we're just slowly getting there and I want to see it happen faster because I'm impatient yeah so so thanks so I would say in case anybody's interested what would keep me up at night actually in some ways is exactly what you were just saying but brings a different dimension is that this incredible enthusiastic opportunity but also knowing that not only we have to do a lot of things right to make this happen in here in the US in particular we also have to convince the next generation that being part of this revolution at many different levels whether it's as a healthcare professional it's a researcher whether it's a data science expert we need them to come into this and embrace this as part of their professional career and I'm just what I lose sleep about is then seeing them be discouraged because of a decaying support for biomedical research in the United States and seeing other opportunities that seem much more exciting to them I really worry about the workforce in the next generation because I think without the well some of us on this panel are as young as you and the next generation are gonna be needed to really see us through some of the things we talked about today so we need to change the course and make sure they get enthusiastic and some of your infectious enthusiasm needs to be part of what they bring into their profession so we will please thank Ann and Rick for a wonderful conversation and thank the audience for some terrific questions please you get a 15 minute break now do not wander far because the next panel is gonna be just as good as this one I promise thank you very much