FALL MEETING IN NEW YORK CITY AND BIOETHICS FORUM Response to Discussions on the Human Genome Dr. Stephen Prescott Click here for Dr. Prescott's bio I’m going to start with a couple of responses, I do know Jeff Friedman, but we did not meet at a prayer breakfast and we did not coordinate our presentations. We’d only talk about novels of eccentric nature. What I plan to talk about with my slides is very, very similar to his, and I was going to start with an argument for why personalized medicine or individualized medicine has to be the future because it is a way to insure that the treatments we give are effective. Currently, of all the medications that are approved by the FDA that are used in the marketplace, only 20-80% of people who receive those actually respond to the medication. So the responsiveness is far, far lower than we’d anticipate and as Jeff told you over 100,000 people die a year of adverse reactions and over two million are hospitalized. So there is a tremendous burden on our health system both by adverse events caused by responses to medications and lack of responsiveness to other medications overall. So, it’s a pretty sad track record to be honest. And this will be, actually, there’s tremendous promise for revolutionizing that with this approach that Jeff talked to you about with genetics and genomics. And it’s coming very fast. Actually today’s New York Times has that they’re now marketing that implantable chip that Jeff talked to you about. It went on the market yesterday. The second one is, I planned to show you another picture of the New York Times, showing that this issue of us planning to get ready and of how we’re going to handle it with genetic counselors and so forth, is coming much faster than we think, because about 3 or 4 weeks ago, maybe a little before that, in the New York Times, it showed a photograph of a pretty bedraggled looking character from somewhere in Ohio, who had ordered genetic testing online, on the Internet, a kit that tests for his responsiveness to certain medications. There’s a whole panoply of medications and drugs. So, it’s already out there on the Internet, an uncertain quality of unknown prominence, and these are things that are going to be very rapidly on us, apart from the ethical side of it we’re talking about through medical practice. So it’s already coming. And I want to talk briefly today about some of the approaches we’re taking and as you heard earlier from Jim that is likely to involve collaboration with the Oquirrh Institute. The University of Utah has a long history of work in genetics of the things that have been talked about today. That breast cancer gene that was talked about, the colon cancer gene, the Long QT gene, all were identified at the genetics institute or the cancer institute at the University of Utah. There are a lot of reasons for that. First, faculty members who cared about it. But there’re some unique resources, and that’s what I planned to show you slides of—an interactive network of materials that we actually call “genet-work” that began with a database that describes the entire population of Utah. So, it now has over 2_ million living individuals listed in that database with all their demographic information. And that was through a collaboration with the state of Utah and with the Department of Public Health there. So we have access to a variety of other registries, including a cancer registry interlinked in there. Now, of course, all states have such abilities because this comes from computerized birth certificates and death certificates and driver’s licenses. So, there are actually over 7 million individuals listed in the database; 2 _ million of them are living. And there are more than 20 million total records and they’re all linked electronically. Now the particular virtue of ours is that the population of Utah and some of the surrounding states, is predominantly derived from people who immigrated there in the mid-nineteenth century, part of a religious migration, the people from the Church of Jesus Christ of Latter-day Saints, often known as the Mormon Church, and even today about 70% of the people in Utah and some of the surrounding areas are descended from those pioneers. It’s important now to say that this population is entirely representative of European populations because the founding population was quite large, and has been continuous immigration over the ensuing hundred and fifty or sixty years. So, it’s not an isolated population in this study. For example, as in Iceland, Newfoundland, or Tasmania, but has some of the certain characteristics which is that we can sort of capture the population with respect to records. Secondly, again, because of partly a religious basis, individuals who belong to that church capture information about their ancestors; their genealogy. So we have access to that information, linking back through this entire population set. So, about 70% of the people in this database and over 7 million individuals can be linked into very large family groups; sometimes extremely large. So one of the examples I wanted to show you today is a couple who immigrated to Utah and who have over 5,000 living descendants that we can identify. If you go back one generation beyond them it’s something like 10,000 on the paternal side and 15,000 on the maternal side. Those are not necessarily typical families, but they’re not atypical either. It’s quite common that we have that. And the power of it is, that we can look back at these founding members of the population and look at their descendants, living descendants, and say here’s someone with a rare syndrome of colon cancer, and over here is somebody else with a rare syndrome of colon cancer and actually they’re distantly related and the pieces of DNA that they share is .1%. That they shouldn’t share, they should be scrambled, is they do share, so it allows us to go find those rare genes that Jeff talked about before. So there’s an extraordinary resource that’s available for investigators and coupled with these large families, which again for technical reasons, that makes obvious why that’s more powerful. All the slides Jeff showed you, you noticed that they all have 6 or 8 children in those generations. I would guess that where most of you live now, that’s quite uncommon to find families with 6 or 8 children. It’s still common in Utah, so that the power of these genetic studies is tremendously enhanced. Now all of this has been coupled with an approach to try and find out this clinical information that Jeff talked about, matching up DNA variations with the disease, or the human traits. We began that with a subset of 45 families, and these families were the original reference set for the genome project you’ve heard about today. So, when the genome project began, the first phase of it was to create a map, not all that sequencing, but just a road map of all those chromosomes. And again, for technical reasons, I won’t go into we needed a reference set or goal standard, if you will, that everybody in the world used to benchmark against. All those people came from Salt Lake City. Actually, there were 60 families collected worldwide. Forty-seven came from Salt Lake City, and actually the only ones that turned out to be useful came from Salt Lake City. And they were collected over 20 years ago, the DNA samples, and they’re the most intensively studied DNA samples in the world. They’re often referred to as the so-called SEPH Set. SEPH stands for Santer d’Etude Polymorphosis Humaine from Paris who distributed the DNA. Well, we’ve gone back in the last 10 years and re-identified all those families, got them to consent to come in to create a study of humanness basically. Or it’s called a quantitative trait study. Why are people tall? Why are they short? Left-handed, right-handed, color of their eyes, blood pressure levels? All of these things that contribute to at least predisposition of disease have now been determined in these folks, and we can match it up with their DNA sequence. Now it’s very powerful, a lot of the discoveries have been made based on that, but as Jim mentioned the next phase of this for us is to expand that now for doing some of these very large families with like five or ten thousand members for collecting this comprehensive information as well as DNA samples on all of them. So, it’s a very great enterprise that we think holds tremendous promise for both understanding the predisposition of human beings to diseases, their likelihood of responding to treatment, the likelihood of side effects to many, many other important contributions. We too have wrestled with a lot of the issues you’ve heard about already today, including public policy issues and I can tell you there was a paper published recently about how we do this, to manage it in an ethically robust way, to protect the confidentiality of the people. For example, those 45 families that have been studied intensively all over the world for 20 years, there’s only like 2 people in the world who even know who they are—one of the physician investigators and a clinical coordinator. I’m the principal investigator of the project; I don’t even know the names of the families. So we protect it so carefully, so that information can’t slip out around the sides. We’ve evolved very robust ways to do all the different elements of that we believe. So, I complete by saying that we believe just as Jeff challenges us with what would you want to know and when, that I would argue that most advances of medicine come from improved diagnostics. The ability to make a diagnosis, or in this case a prognosis; a prediction about something. That is where most advances come from. However, a diagnostic without a treatment that goes with it is pretty much worthless and has failed all throughout medicine. There are many, many examples of that. So this is really going to be highlighted now as we move toward these tests that are going be prognosis or your relative risk of this or that or the other. Particularly if there’s been a treatment coupled with it. And I think it particularly was raised as well this morning from a public policy point of view, this will be tremendously important. My own opinion of the 30 tests is it’s quite a big reach for these newborn screenings. Again, because there are many cases where you can’t do anything; and the whole basis for screening or for a public entity holding health information, essentially for the public good to override privacy issues, has historically been the risk to the public. And those are typically communicable diseases. So that you know if you have tuberculosis I need to know about that to keep you out of the room so you don’t contaminate everybody else. But now we’ve moved into, for example, cancer’s reportable in most places. It’s not communicable and the argument becomes a little more abstract, that I need to know about your cancer so that we can plan for the future in a better way, understand it better. Another big extension of that, it will have, I think, tremendous public policy implications and there are a lot of issues that need to be adjudicated in that forum.