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Dr. Jones: Sex and Marriage. Is it an oxymoron? Two words in the same phrase that mean the opposite? Today on The Scope, we're going to talk about some surprising findings about romance in the long-term marriage. This is doctor Kirtly Jones, from the Department of Obstetrics and Gynecology at University of Utah Health Care 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: There's been a lot of recent dialogue about the end of sex after marriage. It's boring. We're too busy. The kids took it out of us. It just doesn't happen. This isn't just an overworked U.S. problem. On a survey of Japanese couples, it suggested that as many as 50% of married couples in Japan considered themselves in a sexless marriage. Sexless in the sex world, isn't really sexless. It means that the couple is having sex less than once a month. In real numbers, 34% of Japanese couples have sex less than once a month. Maybe the difference between the 34% in one survey and the 50% in the other is that some just forgot that they had sex because it was so unmemorable.

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Interviewer: New insights into the complexities of autism, up next on The Scope.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Julie Kiefer: My guest Dr. Ryan O'Connell, Professor in Pathology, was recently awarded the National Institutes of Health New Innovator Award for high risk, high impact research. So how did it feel to get the announcement of that award?

Dr. Ryan O'Connell: It felt great. It was very competitive, so you didn't know what to expect. It was very surprising to get the good news. It took a few minutes to set in, but once I realized that I was going to receive the award, I was incredibly grateful and excited.

Julie Kiefer: Your research concerns micro-RNAs. Can you explain what a micro-RNA is and what it does?

Dr. Ryan O'Connell: Sure. Micro-RNA is a small RNA that instead of encoding or producing a protein, the micro-RNA itself has a function within the cell. This function, at least the function that we understand the most, is to reduce the level of specific proteins in the cell.

Julie Kiefer: Have they been implicated in disease, as well?

Dr. Ryan O'Connell: Absolutely. Actually, that's where micro-RNAs were rediscovered, so to speak. They're found to be expressed at aberrant levels in certain types of cancers. That really started this whole wave of trying to understand what micro-RNAs are. Now we know that they are altered in disease states such as cancer, auto-immunity and cardiovascular disease. What happens is by their levels changing, the pathways that they control now become out of whack and that can really either cause or enhance disease states.

Julie Kiefer: The research that you're doing in association with this award involves actually regulating these regulators. Can you explain how you're doing that?

Dr. Ryan O'Connell: Micro-RNAs are clearly really important in driving cancer phenotypes, in driving auto-immunity and a lot of this knowledge has come from work that we've done in mice. I've become really interested in trying to move our studies into some human, pre-clinical models. For the grand proposal, the idea was to take this TALEN technology, which again is a molecular machine that can specifically alter precise locations in the human genome and delete genes in human cells, was to use this technology to be able to delete the micro-RNA genes that we know are important for disease. So we wanted to bridge the TALEN technology with our knowledge of what micro-RNAs can do and their role in cancer and auto-immunity.

Julie Kiefer: So in the lab you can genetically engineer the TALEN protein to edit specific sequences, then you introduce those TALEN proteins into the cell and they do their job.

Dr. Ryan O'Connell: That's right. So the TALEN can be designed to bind to any sequence of DNA, and then once bound, you can attach additional machinery that can actually delete precise pieces of the genome. Again, we wanted to use this to be able to delete segments of the micro-RNA genes that we study.

Julie Kiefer: So beyond validating what's already been done in mice, could this be a new type of therapy?

Dr. Ryan O'Connell: Exactly. In addition to seeing if our results really translate, I really believe this technology could be developed even further and used as a therapy. If you have, for example, a cancer that is dependent on the over-expression of a micro-RNA, can we now use the TALEN technology to reduce or eliminate the micro-RNA gene that's the driving force behind the disease.

Julie Kiefer: It's hard to imagine how this would actually work, and maybe that's work in progress. How would you actually get these TALENs into a person?

Dr. Ryan O'Connell: Right. We work with the hematopoietic system or the blood system or the blood system. The nice thing about working with that is that the hematopoietic stem cell has been well characterized. So we routinely can take a hematopoietic stem cell and reconstitute a persons entire blood system. This is done all the time, therapeutically. It's also true that it's possible to take the TALENs and to introduce these into the hematopoietic stem cell so that the TALEN could modify its target and then what we want to design it to do is modify the micro-RNA gene. Then we put these stem cells, potentially, into people, and then when the stem cell gives rise to the blood system, we can now create a blood system where we've removed the driving force of the disease.

Julie Kiefer: So you would add these TALEN proteins into the stem cells outside of the body and then reintroduce them through transfusion or something like that.

Dr. Ryan O'Connell: That's one approach, right. That's correct.

Julie Kiefer: Okay.

Dr. Ryan O'Connell: You could also, if you wanted to prevent auto-immunity, instead of going through the stem cell you could take the T-lymphocyte, which is the causing force of the auto-immune disease, and introduce the TALEN into the T-cell outside of the body and then also infuse the T-cells back in as another alternative.

Julie Kiefer: That's really fascinating. It's like a radically new type of therapy. What's interesting is that the TALEN protein comes from plants, right?

Dr. Ryan O'Connell: That's right.

Julie Kiefer: So you'd be introducing a plant gene...

Dr. Ryan O'Connell: It's from a plant pathogen, a bacteria.

Julie Kiefer: A plant pathogen? Okay. So you'd be introducing that foreign gene into humans and that would be carrying out essentially genetic engineering in human cells. How do you think people will receive that?

Dr. Ryan O'Connell: Although the TALEN proteins basically were first identified in the plant bacterial pathogen, the amino acids that the TALENs are actually comprised of are the same nucleic acids that are found in human cells already. We would basically just be introducing a specific new type of protein, again comprised of the same kind of molecules that are already in our cells, and stringing those together in a specific way were we could enable the function of the TALEN, which is the genome editing, to occur.

Julie Kiefer: So you don't foresee the media taking this out of proportion and saying there's genetic engineering in humans? There's such a phobia of that in our food.

Dr. Ryan O'Connell: Right. I think if people can understand the specifics of what we're doing here, I don't think they'll be concerned. Were not going to be transferring microbes or entire organisms into people. We're simply taking a design that's found in these particular bacteria and then using that design in these particular molecules and re-engineering it so that it can be useful in our cells.

Julie Kiefer: When I think of different types of therapies, another one that comes to mind is the magic bullet, which are antibodies that target specific disease cells. How does this technology compare to that?

Dr. Ryan O'Connell: Antibodies are very useful to eliminate cells that are dangerous or causing disease. They can also be used to deliver cargo to specific cell types. So antibodies absolutely have their place, but antibodies do not have the ability to get inside the cell and correct genes that have become mutated and that are the causing force or the foundation of the disease that's happening in people. Whereas with the TALEN, it's a completely different concept. The TALEN again is a molecular machine, that if we can design it correctly and deliver it properly to the right cells, can actually go in and fix problems and mistakes in your DNA sequence and in so doing, can fix the foundation and the cause of the disease that the person is suffering from.

Julie Kiefer: Why do you believe in this research? What's motivated you to take this path?

Dr. Ryan O'Connell: I do think that at the end of the day, it's pretty clear that genetics plays a huge role in most types of human disease. I think in many cases we're beginning to understand the nature of the types of variations in gene sequence and mutations that occur and how those result in the problems that a lot of us face. So I think while a lot of therapies are more band-aids to try to treat the symptoms of a disease, I do believe that through genome editing and hitting the most important genes, which I believe include micro-RNAs, we can actually fix the cause of disorders that happen. It's applicable not only to cancer, but to auto-immunity, cardiovascular disease and just about any disease that we face as people.

Julie Kiefer: What else can you use TALENs for, besides combating different disease?

Dr. Ryan O'Connell: If you want to get creative, it's possible that one day once we understand things a whole lot better that we could use genome editing to change any trait that a person might have by being able to make precise alterations to the relevant genes that control different traits that we have.

Julie Kiefer: Wow.

Dr. Ryan O'Connell: This is pie in the sky stuff at this point.

Julie Kiefer: Yeah. Sure.

Dr. Ryan O'Connell: But I think everything starts with an idea and then you work hard and you try to overcome the obstacles. I think there's a lot of demonstration of ideas turn into discoveries that turn into everyday therapies and things that we can use to better our lives.

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