Search for tag: "genetics"

It sounds strange, but I hear a lot of old wives' tales about children and their hair. We'll tease out the truth on these hair tales on today's Scope.

Parents often tell me that they shave their baby's head because it will make their hair grow in thicker. Unfortunately, that's not true, and all you'll have is a bald baby. Hair texture and growth rate are determined by genetics, and the only time a person's hair will change is if they've had chemotherapy.

Then there's the opposite. If you cut a baby's hair before their first birthday, it will give them bad hair. No, got to stick with genetics on this one, not the timing of your baby's first haircut.

Another one is that eating carrots or the heels or crusts of bread will make your child's hair curly. If only this one was true. Again, back to genetics. Eating healthy food will make your hair look good, but it has nothing to do with curls. There is one positive truth about eating the crusts of bread though. It actually contains eight times the anti-oxidants of any other part of the bread.

Then there's the thought that you should wash your child's hair until it squeaks, hence getting it squeaky clean. Forget this one. Shampooing your child's hair until it squeaks strips the hair shafts of natural oils and can make it dry and frizzy. Stick to lathering just once and rinsing thoroughly with a shampoo that is made for children and it is safe if it gets into their eyes, which you know it will.

Finally, there's the old wives' tale about how if your baby comes out with a full head of hair that would explain all the heartburn you had during pregnancy. Surprisingly, researchers have found this one to be true in some cases, although they're not really quite sure how. Wasn't the case for me, I had bad heartburn and two bald babies. So this one too, really, should be taken with a grain of salt.

And if your child has no hair, that's okay, as long as they're not over the age of, say one or two, and don't have any evidence of any hair formation. If that's the case, then you'll want to talk to your pediatrician.

updated: April 12, 2021
originally published: March 6, 2017

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

Announcer: Health tips, medical news, research and more for a happier, healthier life. From University of Utah Health Sciences, this is The Scope.

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.

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Interviewer: The Will Smith movie "Concussion" focuses on a condition called Chronic Traumatic Encephalopathy. Dr. Colby Hansen is from the University of Utah Orthopedic Center Concussion Clinic. Dr. Hansen, tell me about this condition.

Dr. Hansen: Well, I think in general there's still so much for us as a scientific community and as a medical community to understand about this entity that is highlighted in the movie, chronic traumatic encephalopathy. I mean, it seems pretty clear that trauma is a common denominator, but we don't know to what degree genetics may play into this, to what degree other types of issues may play into it, either mental health disorders or whatnot. We don't know at what amount of exposure to trauma people are put at risk. Just frankly, there's a lot to tease out before we start being over-reactionary and pulling the plug on sports and things of that nature.

Interviewer: The condition that they're talking about in the movie, what exactly is that?

Dr. Hansen: Chronic traumatic encephalopathy is really a diagnosis that can only be made postmortem or after death by autopsy. What some of these researchers are seeing are abnormal collections of clumps of protein called tau that has also been linked to other degenerative diseases like Alzheimer's dementia. They've seen these under the microscope of some of these former athletes, and there's really no denying that they've seen this. So now they're in a phase of trying to characterize are there maybe certain areas of the brain where you get this kind of collection more than others, to what degree does this correlate with known behaviors or symptoms that the patient was experiencing while they were alive, and then ultimately trying to make the link back to the sport or the activity that they were engaged in. People would generally feel or believe that not every football player who progressed through to the NFL has this disorder, so who does and who doesn't and what are the differentiating factors between who does and who doesn't.

Interviewer: Do people that don't play football develop this disease?

Dr. Hansen: At least in terms of the case series, the group at Boston led by Dr. Ann McKee, who's a neuro pathologist there, has studied the most brains and they are not exclusively football players. This disorder was originally described many, many years ago, many decades ago, in boxers, and was termed Dementia Pugilistica which literally means "boxer's dementia." We would assume that the common denominator is trauma, but we don't know much beyond that. How much trauma, at what age the trauma occurred, there's even a lot of debate now not in just concussions, but just the repeated impacts that don't necessarily produce a clear, observable concussion.

At the end of the day there is so much for us to learn, to understand, about not only the impacts of a single concussion and how is the best way to manage it, how is the best way to assess it, but of course the long-term ramifications of concussions and repeated concussions in the health of our athletes and anybody who's active.

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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: Stepping out of the Ivory Tower and into the arms of the patient community. 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. Gabrielle Kardon, Associate Professor of Human Genetics at the University of Utah. Dr. Kardon you were in Washington D.C. last week, what were you doing there?

Dr. Kardon: The purpose of the whole trip to D.C. was to go with these families who are all affected by congenital diaphragmatic hernias. So this is a common birth defect that affects about 1 in 3,000 children, and to rally support from the House and Senate for increased funding for NIH, in particular for birth defects and CDH.

Interviewer: Could you have imagined doing this a year ago?

Dr. Kardon: Well maybe a year ago, but five years ago I wouldn't have. What we were able to find is that the connective tissue, which is basically the matrix that's surrounding the muscle and hooking the muscle to the tendon was regulating everything about development of the diaphragm's muscle. It controlled normal development, and that actually mutations in the connective tissue were the cause of this very common birth defect.

At first it was it's just a really interesting scientific questions and then over the years as we started to make progress and we realized that actually maybe we could gain some serious insights, then I was very interested in connecting with the families. In part just because you get interested in it and you want to know really what is the situation if you have CDH. And then in part because it turns out the family members have lots of information that they don't realize that they have that gives you incredible insight into the birth defect.

Interviewer: Is it fair to say that this intersection with this disease has totally refocused, at least part of your lab?

Dr. Kardon: Yes. I had always worked on limb development and limb defects, but now more than half the lab is working on the diaphragm.

Interviewer: You have mentioned that they have information that has helped you. What kind of information?

Dr. Kardon: So for instance, I was talking to parents in D.C. and there were at least two parents who were talking about CDH babies in which also in that baby was not only this diaphragmatic hernia, but they had a cleft palate. And it turns out that there are developmental processes that are very strongly linked between the two and so to see them repeatedly in the same patient gives you some insight into the science behind it, so that was something that was really interesting.

Interviewer: Do you think that you've been able to give something back to them? Do you talk to them about your science and do they understand it?

Dr. Kardon: Right. Actually, I think there's one way that was sort of surprising that I think maybe had the most impact on them. There's an enormous variability in the single diagnosis and for the families that's really hard. So it is really hard to be the parent of a child who dies and meet up and see a parent of a kid who also has the same defect, but looks completely normal. And I think that's very difficult, I think it's difficult to be a cohesive group when there's such different outcomes.

So I think the thing that I could contribute to that conversation is to tell them that there are good genetic reasons as to why there's such variability and in fact this is one of the real scientific conundrums about the defect is that there are many ways to get a hernia. And in part some of those ways to get it involves this de novo mutations that arise in the kids and when and where those mutations arise really affects the outcome. And so that when as a parent, as a pregnant mother, you're diagnosed at 20 weeks with the CDH, you have absolutely no idea what's going to happen when your baby is born.

Interviewer: So it's not their fault.

Dr. Kardon: It's not their fault and it's very different from let's say, people who have Duchenne muscular dystrophy, where they're all pretty... there's some uniformity to the disease. There's a pretty general progression. There is not any uniformity in CDH, which makes it really difficult.

Interviewer: Do you think they take comfort? Some people have taken comfort in knowing that?

Dr. Kardon: I don't know, it's hard to know. This is my first sort of serious interaction with patients... sorry, with parents of patients and with patients, and some of the parents it was pretty raw. There were parents who were at this meeting who have lost their baby only a month ago. So they're in a tough place.

Interviewer: Yeah. Obviously this turned into kind of an emotional investment, as well as a time investment. I don't know, what does that mean for you?

Dr. Kardon: I don't know. I make a pretty serious commitment to do the science, and that commitment means that I'm taking time away from my family, and so I would hope that what I'm doing should be something that's important and makes an impact on someone. And so it's helpful to see who that would make a difference to. And I really am still a basic scientist. But it's kind of hard when you're working in this direction and you can see that there are hints that you may be able to do something in terms of therapy and it feels like it's a challenge, it's kind of this puzzle, "Why wouldn't you do it?" We could actually do some clinical trials using mice, now wouldn't that be really interesting?

Interviewer: Is there anything that you can think of that you want to make sure to get across?

Dr. Kardon: I guess the one thing it's really that scientists sometimes shy away from interacting with the patients of the families and it seems a shame, it seems like you can learn so much from them. They have an enormous amount of knowledge that they don't even realize that they have about the disease. It's just buried in them, funny little observations that they have made. And you come in there with a completely different set of eyes and talk to them, and they'll say something and you'll go, "Wait, wait, say that again. What is it? What happened here?" And you learn a huge amount from them, so I think it's really worth while.

Announcer: Interesting, informative, and all in the name of better health. This is the Scope Health Science's Radio.