Search for tag: "genetic"

Dr. Jones: If you knew that you had a gene that caused illness in your children, what are your choices? New research into editing genes in human embryos gives us some new choices and new dilemmas. This is Dr. Kirtly Jones from obstetrics and gynecology at University of Utah Health and this is The Scope.

Announcer: Covering all aspects of women's health, this is The Seven Domains of Women's Health with Dr. Kirtly Jones on The Scope.

Dr. Jones: Mutations in the genes we carry cause thousands of diseases. Some of the diseases are manageable and some are deadly. If we knew we had those genes and didn't want our biologic children to suffer those problems, what might be the choices?

Of course, you could toss the genetic dice and just hope that the next baby didn't have the disease. A lot of people do this. They can't afford other options, although the care of what might be a critically ill child has its own costs. Maybe they feel that the options of creating a child aren't in their hands. Maybe the disease they carry isn't life ending but is life limiting. They have to manage with this disease and they figure that the children will as well.

Okay, the next choice might be that you choose not to have biological children. Some people make that choice because the possible outcome of a child with a severe disease is too heartbreaking for them. They may adopt children or remain childless.

Another choice might be to use donor egg or donor sperm depending on whether the dad or the mom has the mutation and make a baby that way. Donor sperm are relatively inexpensive, donor eggs are not. Some people want their own biological children and may search for another path.

Genetic testing of early fetuses in the womb by collecting cells from around the fetus has allowed pregnant women and their partners to know if the fetus carries the abnormal gene. The couple can decide if they want to terminate the pregnancy. This was the only option until about 15 years ago for a couple to try to select a healthy pregnancy. Clearly, it can be heartbreaking for couples to terminate a wanted pregnancy but if they already had a child die from the disease, that option might be preferable.

About 15 years ago, pre-implantation genetic diagnosis became widely available in the U.S. Couples with a known genetic disease can have in vitro fertilization and their early zygotes, very early embryos, can be tested and only the healthy embryos placed in the uterus to hopefully implant and grow. The abnormal embryos can be discarded. In healthy fertile couples with genetic diseases, this technique can be very successful.

Now, this week a multinational group led by a team at Oregon Health Sciences University reported the first successful techniques in editing out a mutation in sperm from a man with genetic heart disease. They were careful and successful in creating what appears to be genetically normal embryos. Although the embryos weren't implanted and were discarded after testing, their new technique opens up new doors and asks some questions.

Wow, this reminds me of typing term papers 50 years ago on a typewriter. When you made a mistake on the page, you could use white out, but it looked bad. You had to start all over. Then came the electric typewriter which let you correct little errors but not big ones. Then magic happened, computers created word processing. You could cut and paste with a click. It would even tell you when you'd made a mistake. It completely transformed written document creation. That in mind, how did this Oregon team do it?

They used a gene editing technique kind of like word processing called CRISPR-Cas 9. A lot has been written about this genetic technique. You can watch it on YouTube, there are TED Talks. It was invented or perhaps we should say discovered by two women scientists, one from the U.S. and one from France.

The Oregon team put a little cool twist on this technique. They took the sperm from the man with a known mutation that causes heart failure, they added the sperm to donor eggs. After injecting the sperm into the egg, they added a molecule created in the lab to specifically cut out this abnormal gene from the sperm DNA. And the really cool part, the egg with the normal gene had natural gene repair mechanism that replaced the gene from the sperm that been cut out, with a copy of the normal gene from the egg. They even in the paper called it not "gene editing" but "gene repair."

The zygotes that were created with this technology were then tested and the majority of them were normal by genetic testing. Now, this was a very special kind of genetic problem. It came from the man and was carried in the sperm. The cutting and pasting happened very early after the sperm was added to the egg, waiting later after fertilization doesn't work as well. And other research teams using this technique in already fertilized eggs didn't find it worked as well. We don't know if this would work if the egg was carrying the mutation and that would be much harder to do as eggs are hard to get.

So why would a couple use this technique when it's perfected rather than other options we've already mentioned? Some people have philosophical or religious concerns about discarding embryos. This new technique isn't perfect and some abnormal embryos will still be created, so discarding embryos will still happen.

Should we do this just because we can? Maybe. Pre-implantation genetic diagnosis, the technique we can do now to replace only normal embryos is complicated but it works very well. You do need a bunch of embryos to make sure you have enough for some to be normal. Gene editing might allow for greater chance of getting normal embryos, if you don't make very many eggs.

Of course many people worry about a slippery slope of creating people with specific genes for certain traits, height, smarts, eye color. But the same kinds of arguments were put forth when any genetic testing of fetuses or embryos was first attempted. So this technology is not ready for general clinical use at this time. It's amazing that they could cut out the abnormal gene from the sperm and the eggs' DNA repair could create a new healthy gene. If the technology gets better, and it will, it'll be available somewhere in the world and some people will use it. So stay tuned and thanks for joining us on The Scope.

Announcer: Want The Scope delivered straight to your inbox? Enter your email address at thescoperadio.com and click "Sign Me Up!" for updates of our latest episodes. The Scope Radio is a production of University of Utah Health Sciences.

Interviewer: Someone who is thin can end up with diabetes. And yet an obese person may be surprisingly healthy. Why is that? We'll talk about research today that addresses that question.

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. Scott Summers and Dr. Bhagirath Chaurasia, in Nutrition and Integrative Physiology at the University of Utah College of Health.

You know, I thought one way we could start talking about this is that this type of research has a personal connection for you. If we're talking about thin people who get diabetes, which is kind of not the stereotype, that's something that you've faced in your own life. Not with you personally but with a family member?

Dr. Summers: Yeah. I was 14 years old when my father, somewhat precipitously, developed diabetes. He was 38. He was a fairly athletic individual. And to be honest, after he got diagnosed, he became sort of an exercise addict, and this was the way he would control his diabetes.

But despite all of his efforts and the fact that he was incredible fit and won countless road races, his diabetes worsened and became quite severe. So that was sort of the impetus for me to study diabetes in my career.

Interviewer: Right. So that profile is a surprise, right? Because what's more typical?

Dr. Summers: Yeah, he's an unusual diabetic, but he's not the only one. There's actually a fair number of people that can develop diabetes. We have kids that develop it, a classic type 2 when they're obese and we have adults that develop diabetes when they're thin. I think, actually, what we're learning is that distinction of type 1 and type 2 is much muddier than we realized and there's a lot of types in-between.

Interviewer: So often I think of diabetes as being a problem with the body's management of sugar. It turns out that's part of it. But what you two are looking at is the role of fats in diabetes and maybe it's sort of a mismanagement of the way fats are stored?

Dr. Summers: Yeah, I think so. I think the issue is really what's the type of fat, right? So fat has a lot of different terms, right? Sometimes when we're referring to fat we mean the tissue and sometimes we actually mean the food we're eating. But at the end of the day when fat is eaten, it's converted into something called fatty acids which are then taken up into cells and then they're restored in fat tissue as something called triglycerides.

Ceramides is another way that those fatty acids get metabolized. Instead of getting stored effectively or burned for heat, they sort of spill over into this and they conjugate with a certain protein derivative, protein metabolite. So it's just this different type of fat and metabolite that accumulates and it seems to have a whole series of actions that really are almost part of a universal stress response and a lot of the damage they do seems to be relevant to most of the diseases associated with obesity.

Interviewer: And do we have any idea why one person might be more able to store the fat as triglycerides versus going into that ceramide pathway?

Dr. Summers: Not as much as we need to. No, we really don't. When fat makes the decision to either be stored, burned, or go to ceramides there are some regulatory factors. We know that inflammation, infections will drive it into the ceramide pathway. We know that cortisol stress will.

We don't know as much about the dietary component as we should. We know ceramides are made from saturated fat and a certain type of protein that's a conjugation of those two. We don't as much as one would think about how much you eat, whether that influences it or not. And there may be a genetic component, too. About 20% of Utahans have a mutation in a ceramide synthesizing gene and those that do tend to have diabetes or hyperglycemia.

So I think there are a lot of factors that are driving it and we're trying to . . . that's sort of the holy grail of our research is to figure out those two questions - how ceramide works and what's driving its synthesis.

Dr. Chaurasia: Yeah, and that's exactly the next steps that we are following onto.

Interviewer: So you did some research in mice. What did that work show you? You had too many ceramides in mice.

Dr. Chaurasia: So what we showed is that if you delete out one of the initial enzymes required for ceramide synthesis, specifically in the adipose tissue, these animals tend to be more insulin sensitive. They tend to burn more calories and they tend to deplete out what we call the bad fat, white fat, into something called brown fat which actually turns them to other [inaudble 00:04:30] fat, actually and which allows them to burn more calories. And that's why we think that these animals are much more skinny and much more metabolically healthy.

Interviewer: Okay. And those are the ones where they had less ceramides?

Dr. Chaurasia: Those are the ones where we have less ceramides. And also we found in both the mouse cellular models as was the human cellular models is that if you treat them with increasing concentrations of ceramides, they tend to down-regulate, the expression levels of certain genes which are required for browning and increasing energy expenditure.

Interviewer: Which is actually helpful?

Dr. Chaurasia: Which is helpful, exactly.

Interviewer: Yeah, because it takes that away from white fat which is the more toxic fat.

Dr. Chaurasia: Exactly. Yeah.

Interviewer: Okay. Are you looking into ways to maybe manipulate those pathways to see if that can be used to treat diabetes?

Dr. Summers: Yeah, absolutely. So we've known before that if you treat with . . . there are drugs that you can give to mice but not to people and if you give that to them it prevents diabetes, it prevents fatty liver disease, it prevents hypertension, and cardiomyopathies, and things.

And so we're trying. You know, a part of our lab is trying to develop new drugs that will mimic that. We're testing some natural products that actually are out there that people can eat that might be able to deplete ceramides. And we're looking at dietary interventions, as well. Or we'd like to at some point, at least, look at dietary interventions to see if we can try and modulate this in addition to looking at the genetic components.

Interviewer: And so you think interfering with the ceramide pathway has a potential to help a lot of people?

Dr. Summers: I do. I mean, we've been working on it for a long time now. So it's been 15 years plus.

Interviewer: You're pretty motivated.

Dr. Summers: So, yeah, I'm still a believer at this point. You know, there are a number of things that can prevent diabetes in mice. So the fact that we can do it with this is there are other people that can do it, as well. And turning that into an effective therapy, I'm rather convinced ceramides can contribute to the development of diabetes.

Whether we can actually target that safely in a person is unclear because the reality is ceramides are actually . . . they do good things, too. So it's only when they get above a certain threshold that they become toxic. So can we titrate them in a person? Can we get them to make just, you know, not too little, not too much and remain healthy, is going to be a challenge for us.

But this is what we're trying to do and what I believe passionately we should do.

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

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

Lynn: My name is Lynn Jorde. I'm the Chairman of the Department of Human Genetics at the University of Utah School of Medicine. I'm here today with Dr. Eric Green, who is the director of the National Human Genome Research Institute.

So, we've heard a lot about the ever decreasing cost of genome sequencing, about a million fold in the last decade. Does this mean that everyone should be sequenced? Or if not, who should be sequenced?

Dr. Green: So from a research perspective, I think there's great power in getting tremendous amounts of data from as many people as possible and using this in very robust ways to try to understand many aspects of health and disease. I think your question though, is aimed more at, "Should everybody get their genome sequenced as part of their medical care?" I'm not sure we're quite there yet. That might be where we are eventually, but just because we have the technical capabilities of doing that, I think we're far away from knowing what to do with that information in a clinical context to say that this should be sort of used for everybody. Rather, I think it's most useful now in very discreet areas where there's clear evidence that having genomic information will be helpful to that patient.

Lynn: Some critics have said that the Human Genome Project, of which you and many of us have been a part, hasn't really delivered on one of the original promises to revolutionize medicine. How would you respond to that?

Dr. Green: When the Genome Project ended 13 years ago, there was incredible celebration. In fact, many of use were euphoric about having achieved the goals that were set out for the Genome Project. I think in our exuberance lots of promises were made and lots of claims were made to have this was going to revolutionize this, that and the other and lead to great medical advances. I think much of that exuberance might have been over interpreted as meaning those advances were going to take place quickly.

There was no reason to believe it was going to happen that quickly. Actually, if you look back in the history of bio-medical research, there is usually periods measured in decades between very basic discoveries, such as the discovery of antibiotics, the discovery of the basic biochemistry of cholesterol metabolism and the actual changes in medical practice that led to advances in medicine. Decades. Here we are only 13 years in to having information about our genome available to us. So we've not seen the revolution, that I think will eventually come. I think for that we've been criticized.

I think we just have to take a step back, recognize that we're 13 years in. There's some vivid examples where genomics has had a profound effect on medicine, but they're the earliest examples. Even in aggregate those don't represent a revolution, but they're highly illustrative of what is coming.

So I think, when we look back at the history of genomics, say 10, 20, 30 years from now, I think that will be the fair time to assess whether or not our claims that were made when the Genome Project ended, were accurate or not. It's just too soon to do it now.

Lynn: So we're seeing investigations now, of all sorts of traits. The genetics of IQ, people claim to have found genes that influence things like aggressive behavior, anxiety. This gets pretty controversial. Are there areas that should be off limits, at least off limits to NIH funding?

Dr. Green: Absolutely. People get very uncomfortable with some of these ideas of doing genomic studies to better understand the basis for IQ, for aggression, various other attributes. It's also controversial scientifically, so before we even think about whether or not we want to limit this, I do want to put some reality on this. I think most scientists would agree that getting an accurate assessment of intelligence is not simple. Getting an accurate assessment of behavior is not simple. I think it is scientifically controversial whether we can even make major gains in this by doing these studies. So I think that really has to temper our enthusiasm for it. But then, of course, there's the ethical and societal implications of this. Are people going to be comfortable with it?

I think we need to be very cautious. When we are going to use these new tools of genomics, especially at this early stage, to prioritize things that are going to have great societal benefit. There's so many major medical challenges, disease areas, that will benefit from using these tools first and foremost, those are the areas that should be prioritized and I think that's where we should be putting our energies. At the same time, we should be very careful looking at what some of these other studies that might be envisioned, how they'll be perceived and how practical they are. I think they're going to end up being a low priority. In some cases, one might imagine doing some studies, along those lines. I just don't think they're going to be at a very high priority.

There's a lot of controversy of whether they'll be successful. It just doesn't seem to be the thing to be emphasizing right now. So, my enthusiasm level is low. I think in general people are making decisions about where money is going are going to deprioritize them. I'm not sure I want to say there should be a ban, but there should be careful scrutiny put on these. Research dollars are precious and we need to go to things that are more practical, and things that will have a higher impact on human health and disease.

Lynn: Over the past two years there's been quite a lot of controversy about patenting human genes. So, how does patenting, or not, affect scientists and consumers? Could it affect interests on the part of the private sector in investing and genetic and genomic research?

Dr. Green: There's not simple answers. The whole intellectual property construct and the ability to get patents and protecting people's advances are very important for the private sector and their ability to invest in things and feel comfortable that they will get a return on investment and so forth.

On the other hand, there's something a little special about the human genome. It is very basic, fundamental to humankind. It is our blueprint and the potential to have fundamental information about our blueprint be used. And a fast note, any day we be restricted makes many people uncomfortable. I think one of the things genomics has done, and its sort of cultural values associated with data sharing, is making as many things available to everybody, freely, widely. I think has served us very well. I think the fundamentals of understanding how the genome works in human genes and so forth, having no restrictions on their use, I think is very, very important.

There's a vision associated with using information about one's genome to tailor their medical care. I think many of us get very uncomfortable if in the process of doing so, if too many patents were laid down they would look like tollbooths across the double helix. Every single time we would go to one to analyze one part of someone's genome, we would have to pay a toll, and that would greatly hinder advances.

So, I think many of us have taken a position that it's so basic, that information, that just raw information, which is easy to get about the human genome and about genes, should sort of be off limits for patenting. Now, if you use that information you come up with a great intellectual advance and you design things around it and you come up with something that is more than just the basic fundamental information, yes, that should probably be fair game for patenting, for getting intellectual property and so forth. I think it's that raw information about genes that has made many people uncomfortable and have said that should be off limits for patenting.

Lynn: A big part of this then is the public understanding of traits, of what it means when we say a gene is associated with a trait. This gets us to the question of genomic literacy. What can we do to increase genomic literacy among the public so that they will better understand these kinds of issues?

Dr. Green: Genomics is a relatively young discipline. It's only been around a little over a quarter century. We are fortunate that it's been wildly successful. I think we're all very proud of that, but that's actually created a bit of a challenge for us. The challenge is that this field of science is finding it's way into medicine faster than any of us could have anticipated.

As a result of that, we have some complicated concepts, but also some basic language of genomics that it's finding its way into medical care. Yet, most people don't necessarily know the basics of this. They haven't been given the opportunity to learn it. Many of the healthcare professionals weren't taught this when they were in school. So this is happening so fast and furious that our ability to educate the public, educate healthcare professionals, is lagging behind.

As a result of that, this becomes very important when patients go to see their healthcare professionals and now will start hearing, in some context, about genomics. They don't really understand those words, they don't understand that language. If the patients don't understand it, they're going to go home and talk to their family. They may not understand it. They talk to their friends, they may not understand it.

So we have a societal responsibility to increase literacy about basic language of genomics, because that is a language that will increasingly be used by healthcare professionals, as part of patient care. It's not anybody's fault that we find ourselves in this situation. We're victims of our own success. We've been successful scientifically and now we need to sort of redouble our efforts to think about how to raise genomic literacy more broadly across society.

Lynn: Looking forward to the next decade, the next two decades, what excites you the most about genomic medicine?

Dr. Green: I think what excites me more than anything is the optimism that I have that what is going to transpire over the next decade is going to be significantly greater than what has transpired over the even last decade or the last two decades. I think we're so much more poised to accelerate progress than we ever have been in the last 25 years of genomics.

So, what I anticipate, what I'm excited about, is on multiple, multiple fronts, multiple areas, whether it's cancer, whether it's rare disease, whether it's infectious disease, whether it's in thinking about how to prescribe medications in a more precise and rational way, it just seems in so many areas, the progress I anticipate over the next ten years, I actually believe will be even more remarkable than what I've seen. Yet, I've been shocked by how much we have seen medical applications of genomics begin to be realized on a timeframe that I simply would not have predicted when I got involved in this field initially. I'm even more excited about the next generation of biodmedical researchers and healthcare professionals who I think are going to be the ones that are going to truly realize genomic medicine.

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

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.

Dr. Jones: Cancer in humans is a result of bad luck, bad genes or bad behavior, or a combination of the three. You can't change your luck or your genes, but let's talk about behavior. This is Dr. Kirtly Jones from Obstetrics and Gynecology at the University of Utah Health Care and this is "Cancer and Bad Behavior" on The Scope.

Announcer: Covering all aspects of women's health, this is "The Seven Domains of Women's Health" with Dr. Kirtly Jones on The Scope.

Dr. Jones: It's been said that the risk of getting cancer is about one-third chance, one-third your genetic predisposition, and one-third your behavior. Now, you can argue about those rough fractions and some would add another one-third environmental factors, but oops, that's four-thirds. But anyway, cancers are us.

There is a gene that helps prevent cancer called p-53. Elephants rarely get cancers. Now, they don't smoke and they don't get sexually transmitted diseases that we know about. Anyway, they have 20 pairs of p-53 and we all have one pair. People who inherit a faulty copy of that one and only p-53 gene have a 90% chance of getting cancer in their lifetime.

Those of us who have our normal one pair have about 25% chance of dying from cancer in our lifetime. So cancers are us. It's how we evolved and one of the many reasons we are different from elephants. But does that mean there's nothing you can do about getting cancer? I said cancer was one-third bad luck, one-third genes and one-third bad behavior, and let's throw in the environmental risk into that group.

Of course, most cancers are a combination of several of these factors, but what cancers are more likely to be influenced by behavior and what can we do? The poster child for bad behavior causing cancer is lung cancer and cigarette smoking, or exposure to secondhand smoke.

In developing countries where women don't smoke cigarettes, they do smoke the irritating small hydrocarbon molecules involved in cooking over wood fires in an enclosed area, small house or a hut. Some of this is bad behavior that can be changed. Cigarette smoking, either directly or with secondhand smoke, can be changed and we are changing by helping different cooking tools for women in poor countries. We can do something about this.

Of course, some lung cancers are generic and some are bad luck. There's an increased risk of lung cancer with radon exposure, but you can check the radon in your house and the basement easily by calling your health department. And if your radon levels are elevated, you can put a little fan in your basement, an easy behavioral change.

While we're on smoking, we can talk about oral cancers and esophageal cancer, which are increased in smokers and smokeless tobacco products. We might as well throw an alcohol, which is a risk factor for oral cancers as well. Of course, we all know the people who smoked or chewed all their lives and didn't get cancer, and that's where luck comes in or maybe these people had some elephant genes.

Now, cervical, rectal and oral cancers are related to sex and smoking. The two together are particularly risky. The sex part is that these cancers are related to the HPV virus, which is transmitted sexually. So if you never smoke and you never had any kind of sex, you won't get these cancers.

"Wait," you say, "No sex ever?" Well, it's hard to know if your partner or partners have HPV and it's hard to choose a life with no sexual contact ever, although some people do. But you can be careful. Limit your numbers of sexual partners. Practice safer sex with condoms and have your parents get you the HPV vaccine when you're 13 to lower your risk.

Liver cancers and hepatitis B and C. The most common kind of liver cancer, hepatocellular carcinoma, has about 80% association with hepatitis B and C. You can get hepatitis B and C from blood and sexual exposure. We screen our blood supply for these viruses, but people who do injected drugs and share needles are at risk.

You can also get these viruses passed down from your mom. Hepatitis B is more likely to be passed on to your baby than C, but there are good vaccines for hepatitis B and babies of moms with hepatitis B can get special treatment at birth to decrease their risk. Again, you have to be careful with your needles and your sex.

Now, skin cancers are related to sun exposure. Sixty-five percent to 85% of melanomas, the most deadly kind of skin cancer, are related to sun exposure. Ninety percent of non-melanoma basal cell and squamous cell cancers are related to sun exposure. Well, we evolved in the sun and sunshine is good for us in many ways, but there's too much of a good thing. So sun block from the time you're a kid will very substantially decrease the risk of common skin cancers as well as melanoma.

And you won't get wrinkled. Just think about how smooth the skin is on your tummy and how wrinkled it is on your hands and the face.Well, those of us over 60, we never had our tummies hanging out in the sun. And remember that you almost never get skin cancers on your tummy.

These are just a few and those are the easiest targets for behavior of change. A paper in the scientific journal Nature from January 2016 looked at the risks of cancer contributed by external factors, not genes or bad luck. The title was "Substantial Contribution of External Risk-Factors to Cancer Development." I would suggest that all the Scope listeners look it up and read it, but the math was much too hard for me and it made me a little dizzy.

So you can get the gist of it by scanning it or from this little podcast. The biggest risk for starting those bad behaviors that can lead to cancers are in young people, those who start smoking, have sex without protection and lay out in the sun. And you can tell your kids about these risks and they probably won't listen to you. But you can make sunscreen a habit for your kids from infancy. You can model good behavior by not smoking inside or outside your house, and you can get your kids vaccinated against HPV and hepatitis B. And then, you can wish for good luck or good genes, and thanks for listening to The Scope.

Announcer: thescoperadio.com is University of Utah Health Sciences Radio. If you like what you heard, be sure to get our latest content by following us on Facebook. Just click on the Facebook icon at thescoperadio.com.

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.

Announcer: TheScopeRadio.com is University of Utah Health Sciences Radio. If you like what you heard, be sure to get our latest content by following us on Facebook. Just click on the Facebook icon at TheScopeRadio.com.

Jamie:

Interviewer:

Interviewer: DNA tells the story of a 40 million year long battle between primates and deadly pathogens. 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: Post-doctoral fellow Matt Barber and Nels Elde, assistant professor of human genetics at the University of Utah, published a paper in the journal Science, documenting an incredible battle for survival between infectious bacteria and primates that has been raging for 40 million years. I'm joined today by Dr. Barber.

Why do you think knowing this story is important?

Dr. Barber: Well, when we think today about emerging resistance of bacteria to antibiotics and we're sort of losing our arsenal of drugs and therapies that we can use against some of these pathogens, and so understanding these sort of new weapons we can use against them I think is really important

Interviewer: I think we're all familiar with the immune responses that our bodies normally mount to fight off infections-- we sneeze, we have to blow our nose. But your story focuses on a different type of response.

Dr. Barber: Right, so what we're talking about here is often referred to as nutritional immunity, so the idea here is that, primarily it's been focused on iron. So iron is an essential nutrient not just for us but for also cellular microbes that inhabit our bodies: so bacteria, fungi, all these guys. So one sort of passive means of immunity is to effectively starve bacteria of nutrient iron. So iron in our body is almost entirely bound by chaperone proteins or other factors that effectively hide this nutrient from potential invading pathogens.

Interviewer: And scientists have actually known about this nutritional immunity for a long time, but I think what your story does is show how important it really is.

Dr. Barber: So what our story is really telling is that really, for at least the last 40 million years of primate evolution and probably in human populations today, is that this battle for iron between bacteria and primates has been a determining factor for our survival as a species.

Interviewer: So how did you go about figuring this out? What was your first clue that this was important?

Dr. Barber: So our story primarily focuses on a primate gene called transferrin. So this is a protein that floats around our blood steams, and it's been known for the last 50 years as the iron transporter in our bodies. So transferrin in the bloodstream binds free iron, transports it throughout the body and delivers it to our cells. But it turns out transferrin is also an abundant source of iron for pathogens.

So we sequenced the transferrin gene from 21 related primate species. So this represents about 40 million years of primate evolution. And then we can use statistical analyses to say, "Are the actual amino acids in this protein rapidly evolving across different species?" And it turns out 16 of the 18 amino acids that we identified were all in this C-lobe of transferrin which really suggested that there was something interesting happening in that part of the gene.

Interviewer: One of the most striking things to me in your paper is this picture of the bacterial protein reaching for iron that is being bound by the transferrin protein, and where these mutations happen is right at that interface, it's like, "Wow, we've got to protect this one spot."

Dr. Barber: Right. So when we have this signature of rapid evolution that leads to the question of what's driving it. Why do we see this at all? And we have some information from the literature that bacteria that steal iron from transferrin, they encode these surface proteins, these receptors called TBPA. This is a receptor that is used by several important human pathogens, so nicera meningitis which is the positive agent of meningococcal disease.

Haemophilus influenzae is a pathogen, if you have kids, they've probably received the Hib vaccine, so this is a potent pediatric pathogen, as well as neisseria gonorrhea which is the causing agent of gonorrhea. So a lot of these important human bacterial pathogens utilize TBPA receptors. What we saw was that, when we mapped the sites that were rapidly evolving in transferrin, all 16 of those sites in the C-lobe under selection were interacting with TBPA.

Interviewer: So you know that these mutations accumulate in one particular spot, and so how do you know that they're really important?

Dr. Barber: I think that the strength of the study came from merging that evolutionary approach and using it as a guide for an experimental biochemical approach. And so what I did was purified transferrin proteins from several different primates. So, for example, we made a single mutation that represents one of the few changes between human and chimpanzee transferrin and that single amino acid, which is also under selection when we look across all primate lineage, that single amino acid was able to block this interaction. So this suggests this is functional genetic differences between humans and chimps, presumably related to bacterial immunity.

Interviewer: You can make some of the mutations you saw in these different primates, you can make them in the lab and show that they actually had an effect.

Dr. Barber: Yes. Exactly.

Interviewer: That must have been kind of a "Eureka" moment for you.

Dr. Barber: That was one of my favorite experiments I've probably ever done in my scientific career.

Interviewer: And of course bacteria aren't going to take this lying down, right?

Dr. Barber: Right. And if we look at the genes for this transferrin receptor, TBPA, across many different bacterial pathogens, it turns out that they also show these signatures of rapid evolution, and it's specifically in the interface of the protein that binds to transferrin. So, this is sort of what we think is seeing the flip side of the arms race from the bacterial perspective.

Interviewer: This story still plays out in the DNA of people alive today.

Dr. Barber: Exactly. Turns out that actually for several decades we've known about variation in the transferrin gene in humans. And so there's a variant of the gene that's called C2. It turns out that the C2 transferrin variant is very abundant. In a room of a hundred people, several people are going to have at least one copy of this gene. And the C2 variant comes down to a single polymorphism, a single amino acid change in transferrin.

And what's really interesting is that C2 transferrin cannot be bound by a receptor from haemophilus influenzae, but it could from some of the neisseria pathogens, like gonorrhea. And so, this was also the start of appreciating some of the underlying genetic variation on the side of the bacteria, that some could not see this human variant and some didn't care.

Interviewer: And I think it's fair to say that if you were just to look at the human DNA sequence, you wouldn't necessarily appreciate kind of the history of what has been going on.

Dr. Barber: That's right. And again, that's maybe another reason why this hasn't been picked up before is that, if we consider studies of human genetic variation we're looking on time scales of maybe thousands or tens of thousands of years. And when we look back, there's potentially no strong signatures of rapid evolution in transferrin within humans, to separate the fact that we see variability. Whereas if we overlay that with 40 million years of primate evolution that we can look at and understand, this sort of gives us a broader perspective on what might be driving some of these interesting changes.

Interviewer: And do you think if we were to do a similar analysis, that our DNA might have other stories to tell?

Dr. Barber: Absolutely. Some other work that I'm doing in the lab is applying the same approach to think about asthma susceptibilities. So for example, people have looked at genes that are different between humans that relate to the ability to develop asthma. And many of these genes are involved in immunity, and if we again look instead of within human populations, if we look across primates, many of these genes appear to be rapidly evolving. So I think this is the tip of the iceberg.

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