Search for tag: "genes"

Interviewer: With the power of computers behind them, scientists are solving the mysteries of undiagnosed diseases, 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. Aaron Quinlan, associate director of the USTAR Center for Genetic Discovery at the University of Utah. Dr. Quinlan, you recently had some really exciting results using technologies that your group developed. They may have helped solve a health mystery. This is about infants with a particular condition. What was going on?

Dr. Quinlan: We were studying infants with seizure disorders, and the genetic basis of those seizure disorders was unsolved.

Interviewer: So, the idea is that . . . I mean, obviously they had seizures, presumably pretty severe ones, but doctors didn't know what was causing it. So, there were about a dozen or cases, and you were able to possibly find the cause for most of them?

Dr. Quinlan: Yeah, for the majority, I guess 90% of the cases we have a pretty clear candidate that we feel strongly about, and in 9 or 10 of those cases, it's a mutation in a gene that is known to cause this phenotype but was not picked up via standard clinical diagnostic tests, and in a handful of other cases, we think we have discovered new genes that underlie this phenotype.

From a clinical perspective, there's a transition, certainly removing very rapidly from gene panel tests, where we only look at a very, very small subset of the genome to interrogate genes that we know cause a given disease phenotype to, I think, in the coming years, it will be a standard course of care to use exome or genome sequencing to do this diagnosis because it's so effective, and I think the clinicians that we were working with were very excited about the accuracy and the rapidity with which we could make these predictions.

Interviewer: The role of you and your group in this is that you've developed a computational tool called Gemini, and that's what led to these results. What is Gemini?

Dr. Quinlan: So, we used genome sequencing of both the infant and their parents to try and identify genetic mutations, essentially, that cause the disease phenotype in question, and this process requires a broad spectrum of computational methods, everything from rapidly and accurately processing the sequencing data to identifying genetic variants that exist in these families, and then finally to essentially get back to a needle in the haystack problem of what is the single genetic mutation that causes the phenotype and isolate that from the potentially millions of genetic variants that are benign but exist in these infant genomes.

So, the idea is that Gemini takes all the genetic variation that's observed in the genomes or exomes of all the individuals that you're studying, and it integrates all that genetic variation information with the extreme wealth of genome annotations and reference databases that we have. For instance, some people might be familiar with OMIM. It's a list of all the known mutations or genetic variants and genes that are associated with diseases.

Interviewer: Right, so keeping up with the pace of research, the pace of knowledge.

Dr. Quinlan: Right. It's an incredibly demanding problem because there's probably 50 to 60 reference databases that we try to use, and they're all evolving. They all have mistakes. Those mistakes are fixed, and you've gotta propagate those fixes to the mistakes as quickly as possible so that . . . what we're trying to do here is empower discovery for human genetics, and so, having the latest and greatest information, obviously, empowers that process.

Interviewer: So, is there somebody who's monitoring each of those databases and saying, "Oh, gotta update, gotta update, gotta update"?

Dr. Quinlan: Yeah, we have people in the lab who monitor that, but, believe me, the research community that uses this software, they monitor it as well.

Interviewer: And so, the real tricky part is that a lot of us have scads, you can give me the numbers, you know, scads of variations in our genome, and so that the problem is finding the one or ones that increase risk for a certain disease.

Dr. Quinlan: That's right. I mean, any two individuals differ by about 3,000,000 to 4,000,000 genetic variants. So, when you look at a family, do a whole genome sequencing of an entire family, you're going to find on the order of 3,000,000 to 10,000,000 genetic variants that you have to sift through. Now, many of those, admittedly, are very simple to ignore, especially for rare disease phenotypes. We typically focus on genetic variants that affect protein coating genes. But even when you do that, you're talking about on the order of 18,000 to 20,000 genetic variants that need to be considered, and so, we need to be able to do that in a quick and reproducible way, and we want to minimize false predictions, but I think even more concerning are real genetic variants that may be associated with the phenotype that you miss. So, we want to essentially find everything but don't over-predict.

Interviewer: I imagine you spend a good part of your day in front of a computer screen. I'm wondering do you think about how this sequence of letters you have in front of you is actually a real person.

Dr. Quinlan: Yeah. Admittedly, I am fairly disconnected. I'm a genetic researcher that spends 12 to 15 hours a day in front of a computer, and I'm not a clinician, so, I don't interact with patients on a day-to-day basis. However, I mean, that is our motivation here, is, you know, that was the main reason I moved my lab from the University of Virginia to the University of Utah was to have that connection.

We have a very nice interaction between researchers and clinicians here at the U, and I think it really helps to bring home the reality of these cases. We meet with the doctors who actually work with these patients, and when you understand their plight both in terms of the diagnostic odyssey and also the impact on these families, both in the short and long term, it makes it very real.

I would like to be able to provide a resource to try and solve rare disorders in Utah, nationally, and not only retrospectively for families that are sort of pursuing this diagnostic odyssey, but also to have a system where this can be done in real time in collaboration with clinicians in our hospital and other hospitals so that when there's an infant that comes through the NICU or there's some pediatric genetic disorder that is perplexing, we have a system in place where we can sequence the genomes and actually bring our tools to bear on solving that problem quickly and as accurately as possible.

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: A glimpse in Utah's storied history in the field of genetics. 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. You know, something that is lore here at The University of Utah is this Alta meeting. Can you talk about what that meeting and why it was so important?

Dr. Gesteland: So I came in 1978 in August and I was busy setting up my lab when The Department of Biology had a department retreat up at Alta. And they had two guest speakers, David Botstein and Ron Davis and Marc Skolnick, who was here at the time, was also at that meeting. And there was a discussion about the possibility of using these DNA markers that are variable from person to person as a way to do a mapping of genes and humans.

Ray White, who was not at the meeting but was at The University of Massachusetts, had done experiments in fruit flies discovering these highly variable pieces of DNA and shown that you could really use these to localize where genes might be on the Drosophila genome. So the discussion that went on at Alta was could this same kind of technology be developed for humans. And at the end of that meeting Botstein and Davis, whom I had known well from earlier years, stopped by my lab as I was setting it up and they were just full of excitement and enthusiasm.

They got up to the whiteboard and were drawing pictures of how it would work and how many markers it would take to map human genes, but it was very clear that that was likely to be a real turning point. Then subsequently Ray White was involved in that conversation and the four of them published a monumental paper that really changed the way human genetics was done.

Interviewer: So the technology is restriction fragment length polymorphism (RFLP), what did that allow scientists to do that they couldn't do before?

Dr. Gesteland: Before doing human genetics was tough going. So what this allowed you to do was to link a particular piece of DNA to a region of a chromosome from a family that had a particular disease within that family. That would give you an address in a town for where that gene might be. It didn't know what street it was on or what house it might be in, but it gave you a town to begin to look among. So if you could then begin to sort through larger fragments of random pieces of DNA from humans and find a much larger piece that has that one variable piece you're interested in to get you closer and closer to the gene of interest that you're really trying to find. Closer to the street, closer to the house where that gene really resides.

Interviewer: And that's the objective in the end to find that gene, that culprit, of the disease.

Dr. Gesteland: That's right. So you could for the first time have a physical association of something you could have in your hand to a real gene and giving you access to what the mutation might be in the family to cause the disease. A monumental turning point.

Interviewer: Was it embraced by the scientific community or did people start using that right away or...

Dr. Gesteland: That really caught on very quickly. There are places all over the world that immediately launched into that general approach. So there was a big, almost a race, to put markers all over the human genome. One of the fundamental things that made that a more sensible approach world wide was an effort that Ray White and Jean-Marc Lalouel here arranged with the genetic research lab in Paris to settle on a set of some 50 families whose DNA would be made available to anybody interested in mapping human genes.

These so called families were normal families, not with any particular disease or phenotype, but all the people doing genetic mapping around the world agreed to use this set and that greatly simplified the worldwide understanding because everybody was working on the same material.

Interviewer: So what's an example of the useful information they were able to get from these set families?

Dr. Gesteland: One of the early ones was cystic fibrosis. A group here collected cystic fibrotic families and ran these highly variable sequences libraries against these families and found a connection to chromosome 7 and ultimately found the gene that's responsible for almost all cases of cystic fibrosis. So that was an early one. Neurofibromatosis, cancer, was a second one that came along quite quickly and then the list went on and on.

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

Interviewer: New insights into the complexities of 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: A recent report published in the journal Nature shows how incredibly complex autism is. Here to talk with me about the findings and what they mean is Dr. Hilary Coon, an author on the paper and research professor at the University of Utah. Dr. Coon, what did you find in this study?

Dr. Coon: Well, this study involved a lot more data and human subjects than pretty much any other study that we've done so far. In this study, we greatly increased our knowledge of genes with definitive evidence for association with autism risk. Now we're up to about 30 of those. Probably about 70 more are very likely to be associated with risk. But the other thing that we did was just look at the number of occurrences of mutations in these genes, we can make an estimate that there are probably over a thousand genes that are actually associated with risk. So, many, many genes out there that we have not yet identified.

Interviewer: I mean, this just shows how complicated autism is. Was that surprising to you?

Dr. Coon: No, not at all. So when we started out doing this kind of work decades ago, people were hoping that this would be a disorder that was maybe a few genes and as studies progressed it became okay maybe a dozen, maybe 20. The more we study this, the more complicated it becomes which isn't probably all that surprising considering this is something that has to do with the brain which is a very complicated organ.

Interviewer: What implications do these findings have for genetic testing?

Dr. Coon: Well, certainly genetic testing is hopefully something that we'll identify, make early identification so that parents can get their kids into treatment earlier. Of course, the problem that a study like this brings about is that we know that there are many, many genes that wouldn't be on a genetic test because we simply don't know what they are yet. And, in addition, the genes that are on there have variable degrees of association with risk. So, for example, you might see a mutation in a person, assume that that's a risk mutation and define that that person may get autism where as they may need 5, 6, 10 other factors in order to actually get the diagnosis. So, our knowledge of the inner play between different risk factors is also so far very limited.

Interviewer: So at this stage, genetic testing couldn't definitively point out every person who may get autism or who may not get autism. This is actually kind of similar to other complicated conditions out there.

Dr. Coon: I kind of think about this as the way we conceptualize risk for something like heart disease or obesity where we all kind of know that yeah, there are genetic factors out there, but if you have any particular risk factor it doesn't necessarily mean that you'll get a diagnosis. So while the risk factors are important, and maybe knowing about them are important, then that would lead to some preventative measures. The way that we have of defining risk is far from complete.

Interviewer: In the report in the journal Nature you also looked at what types of genes are risk factors for autism. What did you find there?

Dr. Coon: Yeah, so one of the things that the big studies are trying to do because this looks so complicated is to take the risk mutations, look at those genes, and try to group those genes into biological pathways just to try to make the problem a little more simple. And one of the biological pathways that appears to be very important is genes that control synapses. So these are the communications that occur between nerve cells and that certainly makes some intuitive sense.
Another one, another pathway where there are several genes involved is in genes that work to control genetic expression during development. So, it's possible that for example if the child might have a mutation in one or more of these genes that then they're more vulnerable, for example, to particular environmental hits that may happen during development. So, that's a really interesting gene pathway to sort of becoming to the fore, it brings up possibilities for studying all kinds of genetic and environmental interactions.

Interviewer: I think one thing that strikes me about those different classes of genes that are hit is that they all are sort of at top of a cascade of effects. I mean, if you impact how a synapse is made or if you impact how genes are turned on or turned off, that's going to have a lot of consequences down stream of that.

Dr. Coon: Right, so the other thing to keep in mind though, again is, okay, say you have a mutation that's in a synaptic pathway, the brain is amazingly complex in that there are a lot of compensatory mechanisms. So you might have some sort of defect but as humans we have many ways of sort of getting around those particular defects. So, you're right, this cascade effect is probably hugely important.
But again, any one mutation may not put you over the edge as far as risk. It may take that mutation plus a number of other more subtle mutations that mean that maybe your compensatory mechanisms don't work as well or maybe that one environmental hit that occurred at a particular time in development was way more important than it would be for the next individual. But if you weren't exposed to that you'd be fine.

Interviewer: Do these findings also suggest something about autism itself, what autism is?

Dr. Coon: You know, this is maybe the way we used to think about mental retardation as being all one entity and now we know that even X-linked mental retardation there's dozen of different very specific syndromes. So, it's likely that autism is hundreds of different disorders and we lump them all together simply because we don't understand enough to be able to split them out.
There are some particular syndromes that have been very specifically identified, like rett syndrome, that result in autistic behaviors and a diagnosis of autism that they are very well characterized. And we know their genetic mutation. So that kind of thing is sort of like picking away at the iceberg, getting at one particular rare syndrome after another.

Interviewer: So how do you plan to untangle all of this? What is the future of this type of research?

Dr. Coon: Well, okay, there's a huge place for the large consortium studies. Really, with that kind of collaborative research you start to be able to have enough individuals that are participating, enough samples, enough people working on the problem together just to begin to make sense of it, begin to see patterns in the results. So that is an absolutely crucial part of this.
We're kind of lucky in Utah in that I think we have another part to play that's important and that maybe can't be done in many other places in the world and that is simply with our really big amazing families here. The families that participate are just incredibly unique in that they'll come in over and over and over, they will agree to be tested in multiple different ways so that we can start trying to figure out sort of the specificities of their traits that they're carrying in their family.

And because we have families with 3, 4, 5, sometimes 10 individuals in just one nuclear family, we can really see how these particular genetic mutations occur together with very specific traits and characteristics. We can look at their certain historical information and try to figure out if there were any other environmental exposures, we can look at all of their medical history and try to figure out exactly what some of these mutations might mean.

Interviewer: So something you just mentioned is the autism sequencing consortium and that you're part of that and that's who published the paper. I actually find it really interesting that you're referred to as autism sequencing consortium instead of your individual names and institutions.

Dr. Coon: You bring up a really good point. This is a collaboration of over I think, 37 different institutions and hundreds of scientists working on this. And everybody on this consortium is so concerned with making progress, scientific progress, much more concerned than their own careers or their own making their name in the world, right?
So, the authors actually agreed to simply list as the "author" of this paper being the consortium and then give a link to a website that lists all the consortium members. It's a really nice thing to be able to see the evolution of scientific work going towards this very collaborative collegial type of consortium where everybody's really working together to try to solve a very important problem.

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

Interviewer: I think we've all realized that smoking while you're pregnant is bad for your baby, but it could be worse than you thought. We'll examine that 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: When a child's in the womb, it's very sensitive to the environment it's subjected to, and the consequences of that environment can really have a long-term effect for the baby afterwards. That's according to new research from Lisa Joss-Moore. She's a PhD. and also an associate professor in the Division of Neonatology at the University of Utah. Tell me about your research and what you found out.

Dr. Joss-Moore: Well, we're interested in how early life events, like maternal tobacco smoke, can have a life-long influence on the development of disease. What we do in our lab is we look at early insults, for example, maternal tobacco smoke. What we do is we have an animal model where we introduce tobacco smoke just like it would be if it were a pregnant woman smoking. We give the same amount of tobacco smoke that you would see in an active smoker, and we only give that tobacco smoke exposure during the fetal period.
During the post-natal period, there's no further exposure, and what happens in the long-term is that the model animal developed Type 2 diabetes, obesity, insulin resistance, and various kinds of lung deficiencies. What we're focusing on in this particular study is the effect of prenatal smoke exposure on the development of lung disease. So this is like if you were a human baby, this means that your mom smoked while she was pregnant, but then you had no other exposures after you were born. What's very interesting and somewhat disturbing is that we have shown that if you have that early exposure, you can grow up to develop insulin resistance, Type 2 diabetes, obesity, and changes in your lung structure and function.

Interviewer: Wow. So it goes way beyond just lungs?

Dr. Joss-Moore: It goes way beyond just lungs.

Interviewer: Yeah.

Dr. Joss-Moore: We focus on the lung and the other aspects in our lab. One of the things that we have learned about the lung, which was previously characterized mildly, but we're studying to understand the mechanisms now is that when you have these fetal exposure to tobacco smoke, your lung changes in terms of its molecular composition. It changes in terms of its structure, and mostly importantly, it changes in terms of its function.

Interviewer: So it's a different lung than somebody that hasn't been exposed?

Dr. Joss-Moore: Correct.

Interviewer: Wow.

Dr. Joss-Moore: Correct. And while these studies are ongoing, we expect that this new lung, this different lung, is actually much more sensitive to damage from subsequent insults, such as a Salt Lake inversion or exposure to tobacco smoke. Should that individual grow up to become a smoker themselves, their lungs are going to be much at risk of damage than had they have never had the in-utero exposure.

Interviewer: Is that because the fetus is still developing, and it's somehow changing the way that genes are doing what the genes do?

Dr. Joss-Moore: That's exactly what we found. We looked at various pathways. One of the pathways that we're particularly fond of involves signaling from fatty acids, particularly omega-3 fatty acids. The downstream targets of some of those signaling includes epigenetic modifying molecules, and what happens when you mess up those epigenetic pathways, you change the gene expression program. When you change gene expression in an organ that's developing, the result is that you develop a slightly different organ than you would've had otherwise.

Interviewer: So the analogy would be that your genes are these little machines that are manufacturing the parts, and if something isn't manufactured properly, you get a part that's not what you expect?

Dr. Joss-Moore: Exactly. If you live in an extraordinarily clean environment, and you have no other insults on your lungs, maybe you get to be an old person before you notice. Sadly, that's not the case. We have a lot of other lung irritants that we're exposed to, and we expect that what you would see is a more rapid onset of damage. There are studies that link early tobacco and nicotine exposure to the development of asthma, hypersensitivity of the airways, and other lung disorders.
What we're trying to do in my lab is really trying to understand some of the mechanisms by which this early exposure produces these changes. We want to understand the mechanisms because once we do we can really begin to develop targeted interventions that may make a difference.

Interviewer: Gotcha. And understanding, too, that it would mean that you would hurt something else when you're trying to . . .

Dr. Joss-Moore: Exactly. Because the population that we're really looking at is newborn infants, there's a lot of development going on. While we may have something that's really good for the lungs, it might mess up the kidneys, for example. So one of the reasons why we focus on what we do in an animal model is that it gives us the ability to use our intervention, and one of our interventions involves an omega-3 fatty acid DHA. We can look at the effect on the organ that we care about in this case, which is the lung, but at the same time we could look at other organs, such as the brain and the kidney, and we can make sure that our treatment that's helping the lung is not hurting any of those other organs.

Interviewer: Yeah. So what's the big take-away from this research for the average person?

Dr. Joss-Moore: Well, the first thing is that it's very important to realize that these early life exposures really do have long-term effects on the fetus.

Interviewer: Would you describe them as profound?

Dr. Joss-Moore: Yes. Absolutely. There's a big body of evidence now that's really identified that. The general field is known as the developmental origins of health and disease, and the idea that if you have toxic insults, like, for example, tobacco smoke, there's other maternal conditions such as hypertension that can really change the way a fetus develops. Some of those consequences in the fetus may not be felt until later on in life. But if we can understand what's causing them, it's going to allow us to intervene and perhaps prevent some of those diseases from developing later on.

Interviewer: So could you actually make a lung that wasn't made properly the first time right, years after the fact?

Dr. Joss-Moore: Well, I don't know about years, but we know that we can correct a number of the molecular, structural, and functional findings that we found. So that's very exciting for us to continue down that path and see how long those effects remain in place. We're hoping that they're permanent.

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. Who your parents are matter. Dr. Christopher Gregg, a professor in neurobiology and anatomy, is researching patterns of inheritance that long-term effects on behavior and the development of mental health disorders. Dr. Gregg, what motivates your work?

Dr. Christopher Gregg: The cost of mental health in society, mental health issues, are unbelievable. Unbelievable. Most of the people in prisons, most of the people that are homeless, most of the people that are struggling to get by in life are suffering from some mental health issue.

Addiction, all of these problems are brain related and behavior related. At the moment, most of the pharmaceutical companies are pulling money out because the brain is so hard to figure out. It's so hard to find targets and it's so hard to find effective ways to influence behaviors in a predicable manner.

So in my mind, I think because we think we are able to decode these pathways in the brain, I think we have a very unique place in the field. I think we have a real opportunity to make a difference.

Interviewer: You're interested in how behavior is inherited?

Dr. Christopher Gregg: When people think about behavior I think they think a lot about the factors in their environment. So you might think about what role your parents played in your upbringing, what are your socioeconomic circumstances, what sorts of stresses and pressures do you have in your life, and so you think about the behaviors that you have or maybe why a particular disorder or addiction or some stress or anxiety disorder might emerge and you might think about those issues.

But, in fact, it looks like most psychiatric disorders are strongly influenced by your genes. So as a consequence, we have focused an enormous amount of effort in our research program in trying to define the genes that influence specific behaviors.

Interviewer: So why is that interesting to you?

Dr. Christopher Gregg: We had known before that there were these rare examples of genes called imprinted genes that exclusively express the copy you get from your father or exclusively express the copy you get from your mother, but people didn't have any way to study them in a kind of unbiased manner. So we set about to find all of these imprinting effects in the genome.

The bigger vision continues to be a general interest in finding antagonistic pathways in the brain. So when you think about many behaviors or different physiological states, they're opposing. You can be hungry or you can be satiated. You can be anxious or you can be calm. You can be social or you can be antisocial.

Naively, we thought maybe we could kind of decode the genome into the genes that push you down one path versus the genes that push you down the other path.

Interviewer: Why did you look into that in the first place?

Dr. Christopher Gregg: There was a theory proposed several years ago by an evolutionary biologist named David Higg. David proposed that there would be a conflict between mothers and fathers in placental mammals. The reason was that mothers are the only ones that make a metabolic investment by supplying nutrients through the placenta or through the nursing through lactation and fathers don't make any investment.
David predicted that mothers would evolve mechanisms that make the offspring less demanding and fathers would evolve mechanisms that make the offspring more demanding so they grow bigger, consume more resources, and outcompete the offspring for mother and father.

Interviewer: So how do you think how genes are expressed in the brain might fit Higg's hypothesis?

Dr. Christopher Gregg: We think the weaning period is sort of a major point of conflict because this is the period when offspring develop behavioral traits that are required for them to be independent from the mother. They become independent in terms of being able to find their own food. They have changes to anxiety and exploratory behaviors, changes to learning and cognition. Those changes have a major impact on the mother. The faster and more effectively that the offspring transition to being independent the less the demand on the mother's resources.

Interviewer: A lot of your work focuses on genes that regulate brain function or behavior and whether they're inherited from your mother or your father.

Dr. Christopher Gregg: The researchers in my lab have spent time developing technologies that allow us to study the expression of genes you get from your mother and compare them to the expressions of genes you get from your father. We find there are a lot of really interesting differences.

What's particularly compelling about some of those differences is that they seem to be particularly enriched in the brain. So we looked at differences in the expression of genes from maternally and paternally inherited chromosomes in the liver, in the muscle, and now in two brain regions, and in the developing brain and we find there are a lot of differences in the developing brain and in the adult brain but not very many differences in the liver and in the muscle. The chromosomes you get from your mother and the chromosomes you get from your father are used differently in the brain.

Interviewer: Were you surprised to find that? Did you actually think it would turn out that way?

Dr. Christopher Gregg: We were very surprised. We continue to be surprise as we discover more and more things as we're doing this work. Now what I think is important to recognize is the implications of our study for human disease are that if you inherit mutations from your mother versus your father in these genes, it will have different effects on you.

Imagine you did a mutation in a particular gene that's imprinted and you inherent that mutation from your father. If you don't express the copy that you get from your father because there's a bias to express to copy that you get from your mother because it's a maternally expressed imprinting, then that mutation is not going to have such a deleterious effect on you. On the other hand, if you inherited that same mutation from your mother for that gene, then the effect is expected to be much stronger because there's no other healthy copy to buffer the effect.

Interviewer: So the idea is that one day, if you find that a susceptibility to being autistic is more likely to come from your mother, then the healthcare system can come up with a way to test for that?

Dr. Christopher Gregg: We already are able to analyze the genome sequence of a patient and we're able to analyze a genome sequence of that patient's parents. We can determine whether a mutation has been inherited from a mother or a father and by looking at that mutation, as well as many other mutations in an individual's genome, we think that we'll be able to infer whether that person is at risk for developing psychiatric disorders at later stages in life.

Interviewer: Are there some genes that you found that might suggest this antagonistic control, where one side has the opposite function of the other and that might be connected to a behavior?

Dr. Christopher Gregg: In very preliminary work we think we have defined antagonistic gene pathways that regulate anxiety and maybe risk for panic disorders.

Interviewer: So what's the next step to take that work?

Dr. Christopher Gregg: I think we have a very clear path ahead of use. We're going to define these pathways that are antagonistic and make you less or more anxious, for example. Then we have developed software in the lab that builds on those insights to find how those pathways intersect with known drugged pathways and our goal is to develop novel therapeutics and novel therapeutic strategies by leveraging that insight.

Then on the diagnostic side, by finding novel pathways that influence anxiety we can more accurately identify individuals that are at risk for developing an anxiety disorder.

The greater vision of the work in the lab is to define all of the sort of these functionally antagonistic pathways in the brain that drive different aspects of behavior and to develop a panel of markers that will help diagnose susceptibility for aberrant motivated behaviors and to develop novel therapeutics that modulate these pathways so that you can treat people that have problems with addiction, anxiety, social behaviors, eating disorders, these types of things.

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 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."

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

We like stories, we like storylines. When I write a paper, I always write it in terms of a story. Not because that's the way life is, but because that's the way we think. When we started gene targeting what it does is inactivate one gene at a time. No story is one gene. It's always the interaction of many genes together that has a beginning, a middle, and an end.

My end is always understanding. I'm excited when all of a sudden I understand something that I didn't understand before. And that is what makes science exciting, when you know all of a sudden, you see something that nobody else has seen before. My feeling is always push, push, push understanding. Push basic research and translation will automatically follow.

Science is interesting because it entails almost two completely opposite skills. One is flights of imagination. You have to think about things that don't exist and why they don't exist. It's that kind of mentality that allows you to jump into areas where the solutions aren't clear, that they look impossible. You simply have to extend yourself into them and then make it possible. On the other hand, if you want experiments to work, you have to work extremely diligently and pay attention to detail which is a completely opposite skill. A successful scientist has to have both.

Each one of us sees the world from our own eyes because of our training and because of our experiences, and everybody else is seeing it from slightly different eyes. I think the cross mashing of that is where new things can arise.

If you want to really be innovative, you're almost working at the edge of science fiction because at that point people are willing to have flights of imagination. One of the aphorisms that I was raised on, "The difficult we do right away, the impossible takes a little longer." It takes the same amount of effort to work on big questions as little questions. So why not work on big questions?