Search for tag: "genetics"

Interviewer: What are the symptoms of HHT and what should you do about it? We'll talk about that next on The Scope.

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Interviewer: Nine out of 10 people with the genetic disorder HHT are still undiagnosed. What makes it so difficult is it can have multiple and seemingly unrelated symptoms. If not treated properly, it can have dire consequences. Jamie McDonald is a licensed genetic counselor and Co-Director of the HHT Center of Excellence at University Utah Health Care. I'm not going to attempt to say it. I'd like you to say it and maybe I'll try afterward. What does HHT stand for?

Jamie: It stands for hereditary hemorrhagic telangiectasia. Hereditary, of course, means it runs in families. Hemorrhagic means that it is associated with bleeding. And the word "telangiectasia" that indeed, one has to hear about 50 times to be able to say, refers to a very specific type of blood vessel abnormality. It is, in particular, a blood vessel that is abnormal because an artery is directly connected to a vein rather than connected via a capillary network, which is the normal thing.

Interviewer: And different places, different people have it in different places and different quantities of them? Some people might have a few, some people might have a lot?

Jamie: Exactly. That is the case that there is huge variability and surprising to even many physicians that don't see a lot of this disorder, it's variable even within the same family. So it would be reasonable to expect that if a parent had certain manifestations of this disorder or a certain severity of different manifestations, then maybe it would be likely that their child would as well. It's absolutely not the case. It's very variable from person to person, even within the same family.

Interviewer: And it is a genetic issue, as we've established before so it's hereditary. Why are we just now hearing about it?

Jamie: The fact that 1 in 5000 people are affected rather than the frequency with which people have diabetes or congestive heart failure has decreased the chance that people are going to become aware of it.

Interviewer: So it's something that affects even 1 in 5000 doesn't sound like a lot, it can turn out to be quite a few.

Jamie: Absolutely. And those of us that see many HHT families and sort of collect them, if you will, because we focus on this disorder, feel that 1 in 5000 probably is a significant underrepresentation. When I see families and take a three to four generation family history, as I do, all of a sudden, after having asked the right questions about those family members, I have in front of me on my family tree a pedigree of five people in my patient's family that clearly have HHT but haven't been diagnosed because the pieces of the puzzle haven't been put together.

Interviewer: Let's talk about some of those pieces. What are some of the symptoms that people might have? I've heard nosebleeds commonly referred to. Is that one of the main ones?

Jamie: Absolutely. It is the main one. About 95% of people with HHT will have recurring nosebleeds by the time they're adults, say, 40 years of age. But recurring may mean one every two weeks or it may mean two an hour. So it's extremely variable and you can imagine that if somebody has one nosebleed every two weeks that stops in a minute's time, they may not have even reported that to their physician. So it's the cardinal, most common feature, but not the feature we're most worried about.
The features we're most worried about are the larger, abnormal blood vessels we call AVMs or arterial venous malformations, that can occur in the lung and the brain and liver and lay hidden unless you go looking for the because you've been tipped off that they might be there based on the person's history and family history of nosebleeds. And then, the second thing that can actually be seen on the outside of the body, before we start doing fancy imaging tests to look inside the body, are little tiny telangiectasias or what show up as red spots on the hands, mouth, face of the body.

Interviewer: And are those red spots there all the time?

Jamie: They're there all the time. They don't come and go like a rash would, for example. They're there all the time. Although, people tend to develop more of then with age. At birth, a baby that's born with HHT, for example, because, after all, it's hereditary, a baby gets HHT by inheriting it from a mom or dad. So it's there at birth in some fashion or another. But, usually, the telangiectasias on the skin don't show up until adulthood.

So one of our key concerns as we work our way through families where many people aren't diagnosed yet is people will develop an AVM in their brain in this disorder, usually, years before they actually develop the nosebleeds and red spots on the outside. So the underlying features of HHT that we're most concerned about don't jump out at doctors when they see these patients in their clinics.

Interviewer: The symptoms might not show up so what are some of the damages of this?

Jamie: The significant damage is the baby that has a brain bleed or brain hemorrhage from a ruptured AVM at three years of age before they've had a chance to develop the nosebleeds that begin at average age 11, 12 or red spots on the outside on the skin, which develop average age 20s or 30s. The brain bleed can occur in a young child from an AVM in the brain or a 30-year-old can have a stroke or a brain abscess due to a lung AVM. The blood isn't being filtered out of clots each time it circulates the body and passes through the lungs.

If blood goes through an AVM in the lung and the clot isn't filtered out and that blood then goes to the brain, it's a stroke. So strokes, both of hemorrhagic nature and of a clot blocking off a blood vessel nature, are both risk factors for people with HHT that haven't ben appropriately diagnosed and screened.

Interviewer: So what do you do? How do you find out if you have it if you're not showing the symptoms of the nosebleeds? I guess, first of all, if you have fairly consistent nosebleeds, you probably should go do a little bit more research on that and see if you have HHT.

Jamie: Absolutely.

Interviewer: I could have it and not know it, right?

Jamie: Absolutely. The key there is once HHT is identified in a family in someone old enough to have the nosebleeds and the red spots on the skin and/or brain hemorrhage that leads to the diagnosis, to not let the evaluation stop there. When we have a patient come to our clinic and say it's a 50-year-old mother and grandmother, and we make the diagnosis of HHT, there's an evaluation we're going to do for her to make sure she doesn't have one of these hidden time bomb AVMs inside an internal organ. But, from our perspective, the whole family has become our patient. We're going to talk to her about her kids, her grandkids and what they should have in the way of testing.

At this point, thankfully, genetic testing for HHT is available. I can draw a blood sample on that 50-year-old mother/grandmother we just diagnosed with HHT and prove in her down at the genetic level what's causing her HHT, exactly which gene and which mutation in which gene is causing her HHT. Because it's different in each family with this disorder. But once I've pinpointed that in one member of the family, I know that anybody in that family that inherited the HHT will have that exact same mutation. So I can now test her kids and grandkids.

Interviewer: So the key is to think, "Huh, did Uncle Al have regular nosebleeds all the time? He did and he always complained about them. Hmm."

Jamie: Exactly. Exactly.

Interviewer: All right.

Jamie: But again, these are pieces of the puzzle that had to be put together in order to come up with a diagnosis. Often times, it requires looking at the whole family, not jus the individual in front of you.

Interviewer: Most of your patients, do they figure this out on their own or they have a doctor help them?

Jamie: It's a combination. Oftentimes, an astute physician suspects it originally, oftentimes in a member of the gamily that has a particular number of manifestations and then after having had that diagnosis floated to the patient by a primary care doc, the patient gets on the Internet, finds out that there actually are specialty centers and specialty clinics for this rare disorder and makes their way to either us or one of the other specialty centers.

Interviewer: That sounds like if you think you might have it, the next step for most people is to find the specialty center, like here at University of Utah Health Care. If somebody's looking for more information about HHT, do you have a resource that you recommend to somebody?

Jamie: Absolutely. There's a national group called CureHHT, formerly known as the HHT Foundation, that is a resource for patients and physicians alike, including a list of HHT centers of excellence nationally.

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Jamie:

Interviewer:

Interviewer: Eight percent of human DNA originally came from viruses. A new study published in "Science" reveals how our body is putting these viral remnant to work.

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.

Interviewer: I'm talking with the University of Utah Geneticists Dr. Cedric Feschotte and Ed Chuong, who've published a study in "Science" together with collaborator Nels Elde. Scientists for a while have known that some of our DNA comes from viruses. So I don't about you, but I actually find it kind of uneasy to think that I'm not just me, I'm part virus.

Dr. Feschotte: Eight percent of our genome is viruses, but then another 40% on top of that is actually other kinds of selfish genetic elements as well. So one might even say you're less human than you think. Definitely, a huge portion of the genome is represented by these kinds of selfish elements that most scientists often dust under the rug, so to speak.

Interviewer: What you've shown is that our body actually uses some of that foreign DNA for a very specific purpose. What did you find?

Ed: Yes, what we found is that some of these pieces of viral DNA being recycled to serve now some set of functions. Important for the defense of cells against pathogens including viruses.

Interviewer: How did the viral DNA get there in the first place?

Ed: There are remnants of past viral infections that have actually plagued our primate ancestors many, many millions of years ago. And they are descendants and they are been assimilated in the genome of the host and now what we are seeing still is that still some of these elements retain some of the properties, ancestral properties, regulatory properties of these viruses.

Interviewer: So tell me again what you think they're doing. How they're interacting with the rest of the defense system?

Dr. Feschotte: Your body has many ways to sense infection by virus or other kinds of microbes. And one of the first things that happen is that when you sense infections, cells will release, the signal, the warning signal called interferon. In the genomes of our cells there are hundreds of genes that are dedicated to fighting infection, fighting micros, fighting virus but they're normally turned off. Then what happens is when you have responses like the interferon response turned on, these cells sort of awaken from dormancy and then turn on and do their business and eventually sort of turn off. And what we found, basically, was that in addition to a lot of human DNA that gets activated by the signal, a lot of viral pieces are activated as well as thousands of viruses seem to be activated by the interferon response.

Interviewer: So these elements, these viral pieces are basically like triggers that help set off the immune weapons that they're sitting next to?

Dr. Feschotte: When we think about the switches, their original evolved function, so to speak, was to drive transcription of that virus. So I think, initially, 50 million years ago, that was the purpose. But clearly over time, some of these elements have been collocated or domesticated, you know there's different words for it by their host, in this case primates to act then exactly as you say, to act as switches that now instead of turning on viral genes, now they turn on genes that are pivotal for our own immune defenses.

Interviewer: Kind of the cool thing is that you're thinking of this as sort of a coordinated system.

Dr. Feschotte: You can imagine, no one protein is going to be enough against the pathogen. Our strategy is essentially the throw in hundreds of genes that together collectively make a very strong and robust defense system. And I mentioned earlier that the regulation of genes in response to interferon is governed by little molecular switches called regulatory elements. And our question was really, know how do these regulatory elements get there. How do they evolve in the first place? And one idea is that these regulatory elements can sort of evolve through mutation, the code necessary to turn on these genes or response interferon. But what we found was this potential mechanism where these endogenous retroviruses are actually providing these switches.

And what makes that mechanism so attractive is that these endogenous retroviruses have this built in ability to copy and paste themselves throughout the genome. And so if we are trying to think about how do you evolve a coordinative response? Well, it's a lot easier to take a pre bill switch provided by these viruses that are so common in the genome rather than to a sort of "rely" on random mutations to build these switches.

Ed: One reason why we think this mechanism of spreading these elements might be a good way to wire these networks and distribute these switches is that, indeed, the switches already existed. And again, they were serving probably viruses to begin with, but you didn't have to reinvent them.

Interviewer: Do you have evidence that this isn't a one-off thing? That this is happening kind of over and over throughout evolution and in different species too, right?

Ed: Yes, well, this was really another surprise that came kind of late into the study. And what we realized is that some of the elements that were similar are not identical. But very similar to the ones we would see in the human genome and in other primate genomes were actually also present in [inaudible] genome. Now a different location in the genome, but they had the same regulatory properties, it seems. That it contained some of these switches to respond to this infection, essentially. We see them present in multiple species and, indeed, we speculate that maybe the same mechanism has also spread some of these switches in other species to wire their own lineage-specific network of these immunity genes.

Interviewer: Do you think these viral DNA pieces might be impacting our health in other ways?

Ed: Yeah, so we think this is something really interesting that we need to follow up on. Because some of the genes that we found to regulated by this viral DNA have been implicated in cancer, autoimmune disease, they are themselves mis-regulating this disease. And we also know that some of this retroviral DNA is often activated in the same conditions. So now we've sort of connected the dots and are thinking that this provided mechanism can explain some of this mis-regulations of these genes in cancer and in autoimmune disease, but have been co-opted for a new regulatory function.

Announcer: Interesting, informative and all in the name of better health. This is The Scope Health Sciences Radio.

Interviewer: Precision medicine is all about acknowledging that each of us is different, even our genetics. We'll talk about that more next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs, the Science and Research Show is on The Scope.

Interviewer: I'm talking to Dr. Clement Chow, assistant professor of human genetics at the University of Utah. Give me an example of a particular disease that looks different in different people.

Dr. Chow: Cystic fibrosis is kind of the classic textbook example, and when you take these patients that have the same mutation in the CF gene, what you often see is that there's a lot of clinical differences in the way they manifest their disease, whether they get certain kinds of infections or whether different organs are affected. It can be quite variable between individuals that have the same disease causing mutation.

Interviewer: Why is that important to know and to acknowledge?

Dr. Chow: Right now, a lot of drug development is based on this idea that a certain disease, say, cancer or type II diabetes for example is the same in every individual. It targets a specific pathway, a response and it treats that pathway and response in every individual as if it's the same.

The problem is that that's not the case almost ever in any disease in any group of patients. So in order to think about more personalized therapies and personalized drugs, we need to understand how the genetic makeup of each individual affects how that disease is going to show up in those individuals and how that differs from this other group that has a different set of background genetic variance.

Interviewer: So when it comes to laboratory research, which is how we understand what causes disease and how to treat them, this kind of genetic diversity has largely been ignored, I would say. Why is that?

Dr. Chow: The typical genetic study or model of a genetic study in the lab is done on what's known as an inbred strain and the different fields, the Drosophila fly genetics field have adopted one or two standard genetic backgrounds.

Interviewer: So are they basically genetic clones of each other?

Dr. Chow: Yeah, so basically they are genetic clones, and that's one way of ensuring that the experiments are standardized and that we can make conclusions. They teach us a lot about physiology and the genetic disease but they don't really reflect the variation that's in a population.

Interviewer: So you're investigating how these differences can influence a particular disease called retinitis pigmentosa.

Dr. Chow: So retinitis pigmentosa is a retinal degeneration. It's a hereditary form of blindness. The cells in the retina begin to degenerate for different reasons depending on what type of retina pigmentosa you have.

Interviewer: And what did you find out about this disease in your lab?

Dr. Chow: We know when you look in the literature especially at the papers of studies looking at patients with retinitis pigmentosa, you see that there's a large amount of heterogeneity in the way that retinitis pigmentosa presents in those patients.

And so we thought we could take advantage of genetic variation in Drosophila, the fruit fly, to identify some of the modifier genes that might be driving these differences in the human population. So what we did was we took a model on retinitis pigmentosa in the fly and crossed it on to 200 genetic backgrounds and what that does is it captures variation that's existent in a population, variation that we know is present in living organisms.

Once we cross this mutation on to the 200 backgrounds, we basically found that retinal variation was incredibly variable between these 200 strains, basically ranging from almost completely degenerated retina to almost no degeneration. And so this is quite striking because it's the same mutation on 200 different backgrounds, 200 different individuals and you get basically 200 different versions of the disease.

So then we used that variability to identify the modifier genes using a genetic mapping strategy, and we identified a really nice lists of modifier genes that haven't really been implicated in the retinitis pigmentosa before.

Interviewer: So what kinds of modifier genes? It's hard to imagine what it could be that's making that the disease look so different in different strains.

Dr. Chow: Right, at the heart of retinitis pigmentosa is the death of the retina cells, and we do find a large number of genes that are involved in cell depth which is what's driving these retina cells to die ultimately. What's interesting is that these are genes involved in cell death or apoptosis that aren't typically thought of as the main players in the pathway. And so probably because variation can't really change the main players of any particular pathway too much without hurting the organism, so it can tolerate variation in these peripheral members but maybe not in the main members. And that's what we are finding with natural variation is that oftentimes variation comes from these less important players.

Interviewer: Yeah, that's interesting.

Dr. Chow: Rather than the main drivers of that response in the organism.

Interviewer: Do you have any idea at this point whether any of the modifiers you found in your screens are also seen in people?

Dr. Chow: We don't know yet whether they're modifying disease in humans, but we are collaborating with the group to look at sequences from patients that have mutation in retinitis pigmentosa genes to see if any of these . . . if there are mutations in any of these modifier genes in the background that might be modifying their disease, so that work is undergoing now.

Interviewer: So why is it important to do this type of work?

Dr. Chow: Personalized therapies are dependent on this idea that people are different, that everyone's genetics is a little different and this drives disease differences. So we hope that by studying genetic variation in model organisms we have this nice controlled way to start breaking down some of these effects, which are much more difficult to do in a human population. And so we think that we can make some progress using model organisms this way.

Interviewer: NIH has a push now to make sure that labs do research on female as well as male cells or animals or whatever it is. Do you think this type of work is kind of the next wave?

Dr. Chow: I think that people are becoming more and more attuned to these kinds of differences, though I think that there's also a lot of resistance to it because it complicates the laboratory setting. It makes it harder to make firm conclusions, which is what science is so used to, but there really aren't any firm conclusions in science.

Announcer: Interesting, informative and all in the name of better health. This is The Scope Health Sciences Radio.

Interviewer: New insights into how the brain might be set up differently in certain people intellectual disabilities and autism, up next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. Megan Williams, assistant professor of neural biology and anatomy at the University of Utah. Dr. Williams, despite the fact that autism and intellectual disabilities are pretty prevalent, not much is known about the biological changes that take place early on that might set these people down that pathway. But you've found some new insights here.

Dr. Williams: Our new study has shown that there's a very specific defect in connections between neurons in the brains of mice that are missing in autism associated gene. And I think what's unique about our study is that autism and intellectual disability, these are disorders in which it's not going to be easy to see connectivity changes because they're going to be very subtle and probably quite small. It's not like people with autism are missing a whole part of their brain.
And so we've looked at very high resolution at two very specific neuron types and identified a very subtle but very important change in connectivity.

Interviewer: Your research focuses on a gene called Kirrel3. Why did you focus on that gene?

Dr. Williams: I become interested in that molecule almost 10 years ago. It was identified in the C. elegans, which is a round worm, as a very important molecule for synapse formation, and then there started to become a lot of human autism and intellectual disability genomic studies that implicated this gene in these disorders.

Interviewer: And just quickly, what is the synapse?

Dr. Williams: A synapse is the special cell junction between two brain cells, and that's really the essential point of communication between the cells. So your brain cells require synaptic connections really to process any kind of information to see, to hear, to think.

Interviewer: Your research was investigating what defects are caused by changes in that gene. So you approached that question by disrupting that gene or knocking out gene in mice. And what did you find there?

Dr. Williams: Kirrel is expressed in two cells and it probably helps these cells stick together, and because synaptic junctions are places where the neurons sort of stick together and send their signals to one another, it signaled that Kirrel may be important for the synapses between these two very specific cell types. So the two types of neurons that express Kirrel normally have a synaptic connection, and when you're missing Kirrel, they have about one-third fewer of these synaptic connections.
Although that seems like a fairly small change, what happens is it greatly impacts the whole network activity. So all neurons are sort of interconnected to other neurons eventually, much like roads are in a city, and when you disrupt about 30% of them, of this one kind, you end up affecting basically the traffic or the flow of information in the whole brain.

Interviewer: Okay, so that part of the brain is not as active?

Dr. Williams: Actually it's interesting because we're very interested in understanding exactly which synapses might be defective in these disorders. These mice are missing some excitatory synapses, so that means these are synapses that activate the network. But the trick is that these are excitatory synapses that form on inhibitory neurons, so we are really talking about missing excitatory synapses or activating synapses onto neurons that quiet the network.

Interviewer: Okay, interesting.

Dr. Williams: And so this is sort of a double negative and what ends up happening is that we end up exciting the network too much in these knockout mice.

Interviewer: How can we think about that is the idea may be that there's more chatter going on in the brain and it's just harder for the brain to control.

Dr. Williams: That's right. Actually in the hippocampus, this brain region we investigated, synaptic transmission is usually very sparse and that sparseness allows you to have . . . it's thought to allow you to have distinct memories, and so what could be happening is that there's much higher chatter or electrical noise in your brain and it may be sort of inhibiting that encoding of unique memories and they may blur together or not be as crisp and this of course affects learning.

Interviewer: You looked at sort of young mice, do we know whether those changes persist through aging?

Dr. Williams: So we looked at young mice first because this is where these disorders become most diagnosed, but we also looked at older mice, so what we would call adult mice. So it seems like the brains older mice missing Kirrel, though their synapses are not normal, the overall network activity seems to be back to normal.

Interviewer: They kind of compensated for that change later on.

Dr. Williams: That's right.

Interviewer: Could it also be that those early changes might be setting off another chain of events that you just haven't been able to find yet?

Dr. Williams: That's right. In the adult, the older mice, the synapses are still not normal and so especially if the system is stressed, we don't know how the brains would respond. Kirrel3 is also expressed outside the hippocampus, so all our work was in this brain region, but it is expressed in other places and we would imagine it is probably affecting synapses in other brain regions.

Interviewer: And you had mentioned that Kirrel3 had been found to be associated or mutations or variations in that gene was associated with people who have intellectual disabilities or autism. How common was that association seen?

Dr. Williams: Autism linked genes are still only a few percentage of people with autism and Kirrel is one of these and it's still going to be very low percentage of people that have autism and intellectual disability. So this is common and this is one of the reasons we know so little about the brain changes underlying these disorders, but as the buzz words of personalized medicine grow and genome sequencing becomes easier, it's possible that in the future patients with autism and intellectual disability if we can identify their mutation that caused it, if it is a genetic cause, then knowing if they have a Kirrel mutation and whether what the exact defects are in the Kirrel, patients can at least inform those patients' treatments.

Interviewer: Is there anything else you'd like to say?

Dr. Williams: I think one of the really big take-home messages of our paper is that a very small and subtle synaptic defect can have a very big impact on circuit or network function, and so this is why it's really key to identify these very seems so small and possibly insignificant, but these defects in your brain which is hyper connected can amplify to cause some major problems.

Announcer: Interesting, informative and all in the name of better health. This is The Scope Health Sciences Radio.

Interviewer: A glimpse into the history of the Utah Genome Project, up next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs, the Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. Ray Gesteland, emeritus professor of Human Genetics at the University of Utah. Emeritus. I guess that means you've been around a while.

Dr. Gesteland: I've been around a long time.

Interviewer: When did you start at the University of Utah?

Dr. Gesteland: I came here in 1978.

Interviewer: What was it that brought you to Utah from the East coast, I believe, right?

Dr. Gesteland: So I had been at Cold Spring Harbor Laboratory, hot bag of genetics and molecular biology for about 11 years. Jim Watson was the director of that institution. And I worked with him as assistant director and had not known much of anything about Utah.

And then two things happened that made my ears perk up. One was Mario Capecchi, who I had worked with as a graduate student years ago. Had made the decision to move to Utah, and he was leaving Harvard to go to Utah. So that told me something special must be happening there because I had great respect for him. John Roth spent a sabbatical year in my laboratory at Cold Spring Harbor, a very smart geneticist from Berkeley, and he was moving to Utah. And I said, "If those two guys are going to Utah, there must be something really unusual going on."

Then I had the opportunity to come out here and look at a job, and it was love at first sight. Staying at the Alta Lodge, looking at High Rustler in the springtime was hard to turn down. But it was really the genetics opportunity, when I saw what the genetic resources were here.

Interviewer: And what were those resources?

Dr. Gesteland: Well, it was mostly people, a great bunch of people who are at Utah with the idea of doing long-term projects that would be hard to do many places, where quick return is expected. And there was the Mormon genealogical database, which I really didn't know much about, but realized this has got to be important for the future of understanding genes in humans.

But I think it was the style of the place more than anything else that really appealed to me. That the guy down the hall is a colleague, not a competitor, and he's someone you can do things with, collaborate with, made it very appealing.

Interviewer: And what was it like then?

Dr. Gesteland: There was already a genetics effort going on here and really goes back to some of the early founders. George Cartwright, Frank Tyler, Max Wintrobe, Eldon Gardner, who saw the opportunity of pursuing genetics long before any of this technology came along, partly because of the unique resources here in Utah.

In fact, the very first research grant that the National Institutes ever gave out, the only one at the beginning in 1945, came to Utah to Frank Tyler to study a family with muscle disease. He had assembled a huge family with many, many members, some of who had the disease, some of who didn't. And he got this $300,000 grant from NIH to begin to study that family. So that goes back to 1945.

Interviewer: Yeah, that's amazing.

Dr. Gesteland: And then Mark Skolnick came in 1974, I believe, to begin to computerize the genealogical database. That was really started by a planning grant for cancer research from NIH. And the thought was that if we could get the genealogical records in a computer database, we could begin to search and assemble families that would be useful to study for understanding their genetics.

Interviewer: And that's what's called the Utah Population Database today.

Dr. Gesteland: And then it built from there. When the human genetics department was founded with Ray White and I as the initial leaders. That is building on a base that was already here.

Interviewer: Really the seeds of all this is the unique population that's here in Utah, I imagine. The fact that they keep detailed records on their ancestry and have large families.

Dr. Gesteland: Yeah. So I think it's more than that. The population has a real innate interest in genetics. They're interested in their heritage, their families, and keeping track of that. Plus, they're very willing to be involved in studies. You go to a family that might have a disease you wanted to look at and ask people to participate in the study, 95% of the people will sign up and say, "Terrific. Here's 10 little liters of blood. Let's see what you can do." That's very different than other places in the country.

But the value of that large database has taken on even greater meaning just in the last few years. The hope was that just by looking at large numbers of people with different diseases, you could find all the genes that cause disease. All that turned out to be not so simple because many genes are involved in most diseases. So if you would take some common disease, say, high blood pressure, you can find a thousand different genes, each of which contribute some small amount to that predisposition to high blood pressure.

Well it turns out, scanning the population at large for those genes and figuring it out just doesn't work. What works is to identify families and sequence genomes of five or six people from one family, some of whom have the disease, some of them don't. That's the way you'll find the specific genes involved in that family and then by extension to other families. So the family structure has become absolutely crucial now, for the next stage of finding genes involved in the predisposing to human disease.

Interviewer: That's what is becoming the precision in medicine initiative today.

Dr. Gesteland: Precision medicine, personalized medicine, whatever you want to call it, but it's here. It's got a long way to go, but it's going to be a fun ride to watch.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.

Interviewer: Some call it the world's richest source of in depth information for advancing research and genetics, epidemiology, and public health. We'll talk about the Utah Population Database, next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. Ken Smith. He's not only Director of the Utah Population Database, but he's also a scientist that uses the database for his research. Dr. Smith, let's start this way. What is your favorite research that you've done using the Utah Population Database?

Dr. Smith: One of the topics that is of long standing interest to me has to do with the relationship between how we reproduce and how long we live. Women who seem to be able to reproduce at very late ages also tend to be much more likely to reach the age of 100.

Interviewer: Oh interesting.

Dr. Smith: These women are able to live a very long life and there's almost on every indication they do better in their older years.

Interviewer: Well that's interesting because that database seems to be very versatile in how it can be used.

Dr. Smith: Without sounding too modest but I think the database has been transformative in contributing to what we know about a great many diseases. There are easily 30 to 50 major genetic discoveries that have happened here in the state of Utah because of the Utah Population Database, in part or in full. These have come about and I think they're the scorecard for publications and federal research grants are . . . it's a very long list.

Probably one of the most well known examples of this with the database is for breast and ovarian cancer. The discovery of the BRCA1 and 2 or some people say BRCA1 and 2 genes and the mutations of those genes. They predispose women to really a quite high lifetime risk of getting breast or ovarian cancer. BRCA1 is probably again one of the most notable examples but there are others with colon cancer, and melanoma, and prostate cancer.

Interviewer: So tell me, what is the database?

Dr. Smith: Well certainly in the U.S. we are the only such database. So what it is, is a collection of data of genealogies, of medical records, of birth records, death records, information that will identify where people live, because we care about the environmental exposures. So all of these sources of data are coming to us from different agencies who are all mandated to collect this information.

So, for example, the Department of Health is mandated by law to collect information about all deaths and births in this state. So that's something they must do. Well they're also willing to share that information with us for the purposes of doing research. The Utah Cancer Registry is another really good example. They're mandated to collect the information they shared. So we work with all these organizations and at the level of the individual. So if we see John Doe in one record we can identify John Doe in another record and this requires a substantial amount of work to just put together the records.

Interviewer: I can imagine and how many records are we talking about?

Dr. Smith: It grows every day. A number I'll give you today will be wrong tomorrow but the number of people that we have in the database right now is approaching 8 million people.

Interviewer: Wow.

Dr. Smith: So this is pretty much everybody in Utah today and for a number of them who have some family connection to Utah then it's also going back. Our earliest record takes us back to the late 1600s.

Interviewer: You mentioned a little bit about genealogical data. How does that change what you can do with the data?

Dr. Smith: So we can identify these families where there are more cases of some interesting and serious condition in that family. And to know that is one thing, but to then to know the genetic basis of that is yet another. So once we know about these families, then we have a mechanism where we're able to then recruit these individuals. And by recruit I mean we consent them. So obviously we have to get their permission. And then we're able to collect tissue, typically blood and from this tissue we're able to extract DNA. Now increasingly, partly because of the cost, and the infrastructure, we're able to sequence, to get all the letters of the genome for that individual identified.

Once you get that information and once you get that information on multiple people some who are affected with a condition some who are not and then know the relationship between these individuals. Is it a mother daughter? Is it a couple of third cousins? Then it all becomes possible to start isolating the actual location or locations of the genes that are likely the causal genes affecting the risk of getting this disease. So the union of genealogies with medical records with the ability to recruit and consent and to collect DNA, this is a winning recipe for Utah to be able to contribute to this unbelievable genetic revolution that's going on right now.

Interviewer: And why is it that we have this genealogical information here, but it's not necessarily a component of other large databases that you can find across the country?

Dr. Smith: It probably won't surprise people too much to know that we have a church here that one of the aspects of that church is to collect genealogical information and because the Church of Jesus Christ of Latter Day Saints is right here in Utah and is prominent in Utah, a lot of the data that they collect genealogically pertains to the state of Utah. So through the Genealogical Society of Utah we have been able to get this genealogy going way back in time and so we're unique in that respect. I would add that is not the only way we get genealogy data. We construct our own genealogies from all the records that we collect.

Interviewer: But I couldn't look up my records using the Utah Population Database, could I?

Dr. Smith: Right. We are not a service for you to find Aunt Tilly in your family history. We're really for the medical research community. So we have many, many data safeguards to protect the data and the identities of the individual in the database. So no, we don't allow individuals to get to the identifiers.

Interviewer: Is there anything else that you want to make sure to get in there?

Dr. Smith: Going forward we hope to contribute to national efforts where we can partner with other organizations who also have as their quest to identify causal genes on these important diseases. And I will say we're a sought after organization and we're a sought after database because it's hard to reproduce this and hard to get this in enriched information about these high risk families. And yes these families largely live in Utah, but quite often they have . . . we all have relatives who live everywhere and those everywhere places likely harbor the genes that are being discovered here.

So going forward we working on trying expand our genealogical muscle to be able to connect to the rest of the country and that's an effort we've just begun. And that will allow us to take a discovery here in Utah and connect it to the rest of the country. So we are 3 million in Utah. We are 300 million in the United States. So if the 3 million can inform the 300 million then we would have done really a great thing.

Announcer: Interesting, informative and all in the name of better health. This is The Scope Health Sciences Radio.

Announcer: Examining the latest research and telling you about the greatest breakthroughs. The Science and Research Show, is on the scope.

Interviewer: Geneticist Dr. Lisa Cannon-Albright, is perhaps best known for finding that the genes BRCA1 and BRCA2 cause breast cancer. Now she's taking a step back and developing tools that can be used by anyone to evaluate their risk for common diseases. Dr. Cannon-Albright, what motivates you to take on this project?

Dr. Cannon-Albright: We've been very successful. We identified BRCA1, and BRCA2, and P16. P16 is a melanoma gene. Those genes don't explain all familial cancers of those types by any means. So to me, the question still arises, what about all the other people who are at risk for these cancers and other diseases, but we haven't found their gene yet that explains their family.
People say someday you'll go to the mall, and give them a drop of blood, and get your profile. I think that's a long way off. So what I see is, let's use family history, which is one of the best indicators of risk for many, many common disorders. Use that to classify people according to risk. So number one, we can do it today. Number two, it doesn't cost you anything. It's your family history. You might have to call your brother and ask him about your mother, etc., but it's available to everybody.

Interviewer: Don't physicians take family histories as it is?

Dr. Cannon-Albright: If you look at the literature, very often people who say they're studying family history have a simple question. "Do you have a family history of colon cancer?" That's not the way to take a family history.
The better studies maybe say, "Do you have any first-degree relatives affected with colon cancer? And what we've discovered, it's not just your first-degree relatives. Your second-degree relatives can affect your risk estimate, and even, to a lesser degree, your third-degree relatives can affect it.

Interviewer: So this is what you're developing, some sort of tool for keeping track?

Dr. Cannon-Albright: Well, you could call the paper a tool. It has quick, easy tables for clinicians or even patients to look at. And we've started on the breast cancer and lung cancer analysis.

Interviewer: Have you done proof of concept? I mean, do you know that this works?

Dr. Cannon-Albright: We're so lucky in Utah, because we have this genealogy, and this it's linked to a tumor registry. And the tumor registry goes back to the early '60s and later. So we can study all the cases of colon cancer, people who have genealogy, which is basically more than half the people in Utah. And so we use that to create our models.
We went back to create our models. We went back in time in the database and just locked the data 20 years ago, and said, "Okay, here's what all these people's risk of colon cancer is today." And then we went forward 20 years in time in the database and said, "So did the people whom we thought would get colon cancer actually get colon cancer?"

It's a population-based tool. It's not going to do that, but it is going to find the people who are at the highest risk, and that's a very small portion of the population. And it can tell those people the correct screening to get. You know, it saves the healthcare system and individuals money, and it saves people time, and it makes sure the people at highest risk get screened with the highest dedication to finding cancer.

Interviewer: I suppose the caveats are not everybody knows what their third-degree relatives health was.

Dr. Cannon-Albright: Yes, lots of caveats. Because first of all, probably only 20-30% of cancers are familial. So an only child of a small family, or people who were adopted, or for whatever reason separated from their family's medical knowledge, wouldn't have that opportunity. You know, but the nice thing is there are normal screening guidelines. So everybody would automatically fall to the baseline, which is, if you need to be screened for colorectal cancer, it starts at age 50.

Interviewer: So what would you recommend to people who might be interested in knowing what their risks are for different diseases?

Dr. Cannon-Albright: I actually got genotyped by 23andMe, which is one of these one of many companies that will give you your kind of personalized genetic picture.

Interviewer: Yeah.

Dr. Cannon-Albright: And I helped them out with a project. They were collecting some data, and so my colleague and I, they just said, "Oh, you can have the test, gee. Just spit in this tube." And so we did it, and we both just kind of laughed at it, because it tells me that I'm at low risk for several pretty serious diseases, breast cancer and stroke, that I've already had! So, hello!
But that's been my feeling all along. We don't have a handle yet on just simply using genetic markers to try to assess risk. It's way too early in the game. I'd say the most important thing would be keep an accurate genealogy and keep an accurate medical history for your family, as far out as you can go. And make sure that your children recognize that that's a part of your legacy, and it stays in a safe, and they're going to take over when you're not here, and in my mind, it's really your duty to carry this around in your head and act on it appropriately. So talk to your doctor about it and be proactive about it.

Interviewer: What is your vision for the future?

Dr. Cannon-Albright: My view is someday a national resource. I mean, how wonderful would it be if you could go to a resource and find yourself, your family, maybe add some genealogy, or add in your medical data, and we'll be able to track and estimate risk. So that's kind of my view, and I'm sort of working on something like that with the VA right now. It's a genealogy of the United States. It's already got 38 million individuals in it. We're going to link it to the VHA patient population. We tried to link 11 million vets, and we linked about 5% of them, half-a-million. But if you have a half-a-million people with medical data that you've linked to a genealogy, already imagine how powerful it is.

Interviewer: So you have this database. So I guess I'm a little unclear on how you intend to use it.

Dr. Cannon-Albright: So for instance, the VA population has some phenotypes that are pretty uncommon in the rest of the population. If I wanted to study Gulf War illness, or post-traumatic stress syndrome, I'd have a really hard time finding high-risk pedigrees. Because that environmental exposure of having been to the gulf or of having had some traumatic event is so rare that you could study giant pedigrees and not have very many events.
So using this resource, I can do it the opposite way. So I find all the veterans without identifying anybody. Just using ID numbers, we can find all the veterans who have, for instance, a diagnosis of Gulf War illness, and them link them to the genealogy and see what clusters we find, clusters meaning pedigrees, sets of related people who have Gulf War illness.

And now, again, we've developed tools to test whether that pedigree has more cases of Gulf War illness among the veterans in that family than you would have expected. And so maybe you take that into account when you decided who you're going to deploy to the Gulf War, or who you're going to put in combat versus not.
And then, hopefully like I say, one day, when we study those families, if we actually find the variance that is responsible, then maybe we'll understand what's happening, and possibly we could develop treatments that would reduce the morbidity.

Interviewer: Could you even use those risk models to find people who might be more likely to commit suicide, or undergo drug abuse, or something like that, which I would think is higher in that population?

Dr. Cannon-Albright: Absolutely. And again, I have this terrible bias of believing that everything has a genetic predisposition. And I'm only calling it a bias to be polite, because in my head, it's the truth. But yeah, so there is no phenotype that I think should be ignored, especially, like you say, pretty significant things like suicide and harmful addictions. Wow, if we could find out there was a predisposition, and we could actually do something about it, how powerful would that be?

Announcer: Interesting. Informative. And all in the name of better health. This is The Scope Health Sciences Radio."

Interviewer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research show is on The Scope. In the near future having our genetic code sequenced will be as routine as taking a blood test. Dr. Gabor Marth has been recruited to co-lead the new Center for Genetic Discovery at the University of Utah. They are building a pipeline for quickly translating a patient's genome into meaningful health information.
Dr. Marth, how long do you think it will take until it becomes routine for a patient to have his DNA sequenced?

Dr. Gabor Marth: It's probably anywhere between two to five years depending on the hospital, depending on the healthcare system.

Interviewer: Oh that soon you think?

Dr. Gabor Marth: Technologically, it will be possible in just a couple of years I believe.

Interviewer: So the stumbling block at this point is not the sequencing itself. That technology is pretty much there. What are the hurdles that still need to be overcome?

Dr. Gabor Marth: The price of sequencing has come down significantly. Sequencing the very first human genome took in the neighborhood of a billion dollars. Today it's much, much cheaper. Maybe in the neighborhood of $10,000. It's also possible to do it for cheaper in bulk.
So it's not necessarily the price but also it's that it takes time to sequence a human genome. The analysis of the human genome is still not quite worked out so there are analytical challenges there are also challenges for interpreting the information that comes out of it. As I mentioned in some cases we actually understand, we know how to interpret it, but for many diseases we don't quite understand the link between genetics and disease.

Interviewer: It seems like if we're going to incorporate genetic information into healthcare it'll take sort of an overhaul of the healthcare system because you have to go all the way from, as you said, the analytics to getting the physicians and genetic counselors to know how to interpret that data.

Dr. Gabor Marth: Yes, so it's a very large bottleneck. In the research domain we can interpret a sequence and interpret human genome but to turn these into diagnostic knowledge and therapeutic decisions requires a whole infrastructure that's simply not there yet. The information has to be somehow entered into the electronic medical record and those avenues, the data standards, a lot of the technical underpinnings are still not there so this in fact one of the missions for The Center for Genetic Discovery that Dr. Mark Yandell and myself will be co-directing is to build that information highway that is necessary to sequence genetic DNA information all the way down to clinical use.

Interviewer: So you said there are many steps to get to those treatment choices. What is your specialty?

Dr. Gabor Marth: My specialty is actually fairly early on in the process. So my laboratory is developing algorithms, computational algorithms and software to analyze DNA sequences after the come off the machine. The specialty of my laboratory is the detection and discovery of genetic sequence variations which are the genetic changes that cause genetic disease or can contribute to susceptibility to genetic disease.

Interviewer: So is the problem that when you're looking at maybe tens of thousands or hundreds of thousands of sequences, how do you distinguish the harmless changes from ones that may have an impact on health?

Dr. Gabor Marth: That's a very, very difficult problem and this is the primary expertise of the other co-director Dr. Yandell who has developed the computational algorithms that does just this. Is able to, based on sequence information and additional information about the disease also potentially family relationships, is able to separate out and pick out the very few sequence variations that are likely to causative of the disease.

Interviewer: Part of what you work is the problem of big data. What is big data in this context and what are the problems that you're trying to overcome?

Dr. Gabor Marth: The type of big data The Center for Genetic Discovery will be mainly concerned with are mainly DNA sequence data. Each individual genome has over three billion nucleotides or bases and that data has to be stored efficiently and analyzed for us to make genetic discoveries.
Now you can imagine if you have to store thousands, tens of thousands or millions of genomes that represent a tremendous storage and data analysis problem, so one of the research areas that I'm involved in is to organize data in such a way that we are able to quickly access just those sections of the data that are relevant to a particular question and analyze these potentially in seconds.

Interviewer: And I'm sure that problem becomes more and more difficult as more and more people get their genomes sequenced. I mean, you may be talking about analyzing millions of sequences.

Dr. Gabor Marth: At some point all of humanity will be sequenced. Potentially not just one genome per individual because remember we may be talking about cancer patients. Individual tumor biopsies have different genomes that all need to analyzed so we might be talking about a large number of genomes per sample so we're talking about a lot of data that will be collected over the next few years.
The current systems are not really prepared to organize and analyze these data so although this potentially can be viewed as purely technical but being able to do that will determine our ability to actually analyze millions of genomes effectively over the next few years and that, as you asked earlier, this will be, in my opinion, one of the biggest bottlenecks for analyzing cohorts of samples.

Interviewer: There are different types of genomes that you'll be looking at. Can you explain that?

Dr. Gabor Marth: The genomes of almost every cell in a human are almost identical with slight changes that can occur in the lifespan of the individual. These are called somatic changes, for example, induced by radiation. During tumorigenesis, that is the formation of tumors, the genomes of cells can be altered very, very significantly. You can, in extreme cases, you can lose complete chromosomes, you can have multiple copies of other chromosomes, a large number of smaller scale genetic changes. Each tumor cell in effect has its own genome that's different from the tumor cell next to it. Because of this tumor sequencing is even more data intensive and more analysis intensive and this will be one of the areas where we have a lot interest moving forward.

Interviewer: And how does tumor genome analysis potentially help a patient with those tumors?

Dr. Gabor Marth: If you're able to sequence an individual's tumors you're, for example, able to classify the tumor sub-type, understand the specific mutations, the genetic mutations that are present in the tumor genome. You will be able to find the right therapy, the right drug, to treat that human's genome.

Interviewer: Now you've been involved with sequencing and analyzing the human genome since the beginning really. I mean, for the last 20 or 25 years with The Human Genome Project. Are you surprised at how far things have come?

Dr. Gabor Marth: That's a difficult question to answer. In some ways I talk to people about sequencing technologies and I look at DNA sequencing, the technologies that were available to sequence the first human genome and the technologies that are available today. We're seeing that today we're able to sequence a genome somewhere in the neighborhood of a million times faster than we were able to during The Human Genome Project and that's staggering progress.

Interviewer: Yeah.

Dr. Gabor Marth: But of course we don't sit on our laurels, we always want faster, we always better data, we always want more accurate data, we want more data and of course we want more understanding of what these sequences tell us about genetic predisposition to diseases.

Interviewer: And have you had your genome sequenced?

Dr. Gabor Marth: I have not, I have not yet. Maybe once I come here I'll get around to it. It will be interesting to see what my genome says about my health and my genetic future.

Interviewer: Interesting, informative and all in the name of better health. This is The Scope Health Sciences Radio.

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.

Interviewer: Just one tiny change within our vast genetic code can put someone at risk for developing disease. Using a unique resource, the Utah Population Database, University of Utah professor Nicki Camp has made headway into finding the variations that trigger inherited cancers, including multiple myeloma. Dr. Camp, what's multiple myeloma and why is it important to study?

Nicki: Multiple myeloma is a cancer of the plasma cells and your bone marrow. Until recently it was one of the cancers that had the shortest survivals so we've been trying to figure out ways in which we can both diagnose and maybe understand the disease a little better so we could develop new treatments and therapies for myeloma.

Interviewer: What is your approach to identifying the genetic variations behind this disease?

Nicki: Our specific way of doing this, and we do this for many cancers, is to try and study families where they have an increased rate of, in this case, myeloma because the idea is that if we can see it clustering in a family and we study that family, that that's more likely to be due to genetics. So we've increased our chance to be able to find those underlying genetic factors.

Interviewer: As I understand it, you use the Utah Population Database. Can you describe that resource?

Nicki: Yeah. It's actually an amazing resource, one of the reasons why I'm here in Utah. The two key factors that I'm using for my multiple myeloma resource are, one, the genealogy. In other words, kind of how people and their parents and their grandparents are all linked together in genealogical records. There's about two-and-a-half million people who we know at least three generations of their genealogy in the UPDB. We have that back to the pioneers.
Then what we have on top of that is a mandated Utah Cancer Registry. The cancer registry has been in place since the late '60s and every cancer that's diagnosed or treated primary cancer in the state of Utah goes into that registry. If you can imagine looking in front of you at a genealogy, like an enormous family tree, and then throwing cancer diagnoses on there, suddenly you can just see these constellations of cancers.

Based on that, without asking anybody to recall their family history, we can identify these families which look extremely powerful to be able to study and then through a mechanism that's in place at the Utah Cancer Registry, because of course I don't know who these people are, I can say here's a family I would really like to study. Then they invite those people. They say, "Nicky Camp at the university would like you to be part of one of her studies." If they say, "Yeah, that sounds great," then we get their contact details and we invite them into the study.

Discover how the research of today will affect you tomorrow. The Science and Research Show is on the Scope.