Search for tag: "dna"

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: Searching DNA for clues to the cause of death, 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. Marty Tristani-Firouzi, a pediatric cardiologist at the University of Utah. Paint me the scene here, a child dies unexpectedly, which is a horrible situation in any case. But, if it's not clear why the child died, what's typically done to find the cause of death?

Dr. Firouzi: There is an investigation at the scene to try and understand the circumstances of the death. A lot of infants that die, and fall into the category of sudden infant death syndrome may have certain situations with sleeping on a mattress which isn't firm, or somehow they became smothered, someone rolled on top of them. That sort of a thing would identify a cause of death. But more commonly, an autopsy is required. And the autopsy then rules out unknown cancers. It can also reveal trauma that would be a non-accidental death. Frequently, the autopsy ends up being negative. And then we get back to the situation where the family is told, "We really don't know why your child died."

Interviewer: There must be a presumption that the heart is the cause for the many of these sudden deaths. Is that true?

Dr. Firouzi: That is true. And I think the literature supports that as a general assumption. It's such a profound event. The heart is so crucial in maintaining our survival. And we know that arrhythmias can cause sudden death. In patients that are known to have specific diseases, some of them will suffer a sudden cardiac death. And so by excluding the pathology, by saying these are autopsy-negative sudden deaths, in the young, I think the majority of clinicians in the country would presume they were arrhythmic until proven otherwise

Interviewer: Part of what you're doing, is kind of getting beyond the traditional autopsy. Why is it not enough?

Dr. Firouzi: If the heart looks normal structurally, even under histology, the heart can look completely normal and yet these individuals can have died of an arrhythmic death and have other family members. And so . . .

Interviewer: So a heart arrhythmia . . .

Dr. Firouzi: A heart arrhythmia where the heart beats too fast or too slow and that results in sudden death. So the term "molecular autopsy" refers to the ability to do DNA analysis of the deceased victim and that really goes the step beyond the traditional histological autopsy.

Interviewer: What can the DNA tell you?

Dr. Firouzi: The hope is to perform genetic analysis of the deceased individual and identify either known variants and known genes that cause inherited arrhythmias or novel genes that we haven't yet associated with arrhythmic risks. And our hope is that we can find this in deceased individual and then sequence the first-degree relatives and find out whether other family members carry that damaging variant.

Interviewer: Why is it important to know the cause of death? I mean, it's something that's already happened so it just for peace of mind or are there other reasons as well?

Dr. Firouzi: Sure, that's a great question. A lot of families want to know why so that they can have some sense of closure. But I think more importantly is whether other family members are at risk. So for the arrhythmic types of death, many times these arrhythmias run in the family and the family may not know that. And this sort of sentinel finding of sudden can occur in these types of inherited arrhythmias. And the question then is who else in that family is at risk of dying suddenly? And this is a very difficult thing for families to process because they're in this grieving process and then finally they're told that maybe they have something in their family and maybe their other children will have the same demise.

Interviewer: So even if this one child dies at a very young age, there could be older members of the family that are still at risk?

Dr. Firouzi: Absolutely. That is exactly right.

Interviewer: So what exactly are you looking for in the DNA?

Dr. Firouzi: There are specific families of arrhythmias. The most common and probably the most well recognized is the family of long Q-T syndrome, of which there are up to twelve genes that have been implicated in long Q-T syndrome. What we see, at least in Long Q-T syndrome and a lot of other inherited arrhythmias, there are other family members that carry that disease variant. And they may be normal. They may have normal electrocardiograms if we put them under stress, like an exercise stress test. Sometimes they will behave normally as well.

But if we further stress them by giving them a medication and testing whether they have electrocardiographic findings, sometimes under those more extreme circumstances, we can uncover the clinical phenotype that is consistent with the disease. And so the key part of this is not just to do the DNA analysis on the deceased, but to do a clinical analysis and a DNA analysis on the first-degree relatives.

Interviewer: And you had mentioned too that a part of this whole initiative is discovery as well. I mean, there are some genetic variants that we know about, but there are probably a lot we don't know about.

Dr. Firouzi: Yes, absolutely. So there have been a few studies that have used this concept of the molecular autopsy where they go through sequentially and look at a series of individuals that had died suddenly. And in maybe 20% of those sudden death victims, you can find a variant in a known gene that is known to cause arrhythmia disorders and sudden death.

But the majority don't have a simple variant. And the fact that they died from an arrhythmic death, presumably, would suggest that indeed they have some genetic disorder and that variant may lie outside the coding region, which outside the exome in the whole genome space in some area that has not been well characterized. And the majority of DNA has not been characterized.

The other part of the discovery is can we find variants in this what was thought to be desert landscape of the genome, which actually probably plays an important role in the regulation of the ion channels that we know cause these sudden death disorders.

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

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.