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Molecular genetics in twin studies
Professor Louis Keith, MD: “Good morning ladies and gentlemen, viewers of the OBGYN.net. My name is Louis Keith and as many of the viewers who watch regularly know I’m an identical twin and have been involved in twin studies and on this network for many years. I’m Professor of Obstetrics and Gynaecology at Northwestern University and I’d like to introduce the gentleman to my right, who is Dr. Andreas Busjahn, who got his degree in genetic epidemiology at the Humboldt University here in Berlin, and at the Volhard Clinic after that. He did post-doctoral work in molecular genetics and genetic epidemiology at the University of Indiana with Professor Richard Rose. Dr. Busjahn has started a new company here in Berlin and it is that, which I would like you to talk about among other things this morning, Andreas. But let me tell our viewers what the plan of this interview is. We want to talk about genetics and the issue of zygosity; second, we want to talk about conventional twin studies that most of our viewers have read, either in my book or your articles or in the literature versus the studies in molecular genetics. And then I want you to tell us about your company and its unique outlook on molecular genetic studies and how they can help, not only patients and myself and other twins like me, but industry in general. So with that roadmap Andreas, would you start?” Andreas Busjahn, PhD: “As you mentioned the first issue is the zygosity testing and as you may know the basis of doing twin studies is always to compare similarity within monozygotic twins and fraternal or dizygotic twins. So first of all you have to define who is monozygotic and who is dizygotic. And you can do this by just looking at the twins and looking at their similarity, which is what most groups would do in the beginning, for instance by using a questionnaire, but of course there is an error rate because sometimes fraternal twins look pretty much alike, like ordinary siblings do, and sometimes monozygotic twins have some striking differences on the outside. So there are other ways to do this. We propose to use molecular markers to test whether two twins are identical in their DNA or whether there are differences.” Professor Louis Keith, MD: “When you use the term molecular marker, would you define that for our audience because most of us have heard about DNA tests but how does the term “DNA test” differ from the term “a molecular marker”?” Andreas Busjahn, PhD: “Any DNA test is based on markers. The markers can be totally different things. We use the same approach as the FBI or any other police organisation would use if they test if two samples are actually identical, because that is exactly what we test when we look for zygosity. So we have two samples, one from each twin, and there are several parts of the DNA that have no coding meaning so it’s not a gene, it’s just the part of the DNA with a big variability and you can use these stretches of DNA as some sort of house numbers, so to say. If two people or two samples are identical on seven or ten or 15 of these markers then you can be rather sure that they are identical. So the security we can get as the error rate is way below 0.1%.” Professor Louis Keith, MD: “You know you used a very interesting term there, that is “house numbers” as the markers because in the test that you did of my brother and myself, and we saw the result, these were numbered little squiggles, N266, 304 whatever it happens to be. But I like the term “house numbers”, because in reality when we as non-geneticists think of the whole genome and all of the squiggles and all of the things that it contains I think the idea of having a number of sequences of house markers is very attractive, at least for simplistic ways. From that discussion of markers and zygosity issue why don’t you tell us how there’s a difference between all of these studies with genetic markers and the conventional ones in more detail. Just a little bit so we can see a contrast.” Andreas Busjahn, PhD: “If you compare the very old-fashioned way of just looking on the outside appearance of twins to test whether they are monozygotic or not it is quite obvious that there are several issues that are coming from the environment that can make even monozygotic twins quite different. If they have a very different life-style, one being very active the other rather being on the couch-potato side you would expect them to look different once they reach a certain age. And especially the older the twins are the more dissimilarities you would expect even in monozygotic twins, while the DNA is rather stable. So even if you have very old twins, even up to their 90s or older, the DNA is still stable enough to test for being identical or non-identical.” Professor Louis Keith, MD: “So correct me if I’m wrong, but are some of these environmental changes what is commonly called the post-zygotic mutation?” Andreas Busjahn, PhD: “No, when I talked about environment that was more based really on life-style issues that would show on the outside. But of course the DNA, although being very stable, is not 100% identical between old-age and younger age because we are all collecting more and more mutations during our life cycle.” Professor Louis Keith, MD: “And those are the post-zygotic mutations?” Andreas Busjahn, PhD: “And that would be post-zygotic mutations.” Professor Louis Keith, MD: “In other words you collected and I collected just by virtue of our aging, is that correct?” Andreas Busjahn, PhD: “Right. The older the twins are the more likely it is that there are some changes even in the DNA but that usually would not apply to the kind of markers we are using so you wouldn’t expect variations in those markers but there would be other kinds of changes.” Professor Louis Keith, MD: “Well yesterday, when we were talking you were telling me about a project that you are involved in here in Europe, where you are going to collect cord blood to keep it for future analyses, doing the markers here and then checking it later on. Why don’t you tell our viewers something about that?” Andreas Busjahn, PhD: “The main idea of sampling newborn twins with all the prenatal data and perinatal data and cord blood and placenta tissue is to address all these questions, what is going prenatally? When we talk about environment we always think of whatever happens to us once we are born. But of course we have an environment even before we are born which is quite important but we have no idea what it is really doing to us so we try to figure out what is going on prenatally. There is another very important issue, even monozygotic twins, although they are identical if it comes to genes, may have a striking difference because they might share the placenta or they might have different placentas so they might actually share the blood supply. And it’s possible that there is a big difference between those monozygotic twins, who have one placenta, and those who have different placentas and so they don’t share a blood supply. But that is a question that can only be answered during pregnancy and after delivery right away. There is no way of going back later on. So the idea of that registry is to get this kind of crucial information and then later on to test if that has a bearing on health.” Professor Louis Keith, MD: “Doesn’t that take us into your new company because it’s called, if I remember correctly, “HealthTwiSt” and you made that name Health Twin…say it again.” Andreas Busjahn, PhD: “It’s Health Twin Studies.” Professor Louis Keith, MD: “Health Twin Studies, so “Health TwiSt” it’s a perfect contraction. Tell us about “Health TwiSt” and what made you decide to start it and what you think it will offer, not only to twins but more importantly yesterday when you were describing it to me you said that this had a potential to revolutionise the way long-term studies are done.” Andreas Busjahn, PhD: “I think most people know the basic idea of the twin studies. You look at the similarity of monozygotic twins for a given trait and the similarity in dizygotic twins, and whenever monozygotic twins are more alike than dizygotic twins you know that genes are playing a role and you can actually estimate how much of the percentage is due to genetic influences, this is called heritability, and how much is due to environmental issues. If you look at blood pressure 50%-60% can be explained by genetic variation and the remaining part by the environment. If you look at body weight, it’s even stronger the influence of genes, it’s more than 80% probably. Now this is the very old-fashioned, conventional way of using twins to see whether a trait is genetic or not. But now think of a single gene that you are interested in. For such a single gene people might have the same variant from the parents or they might have different variants. By applying the same logic you can now compare dizygotic twins, who are identical for that single gene, who have just one different copy of that single gene, and who have totally different copies of that gene. So now you have three groups of dizygotic twins who are either like monozygotic, like dizygotic, or like unrelated people. So comparing these three groups gives you a good estimate on how strong is the influence of that single gene. And the importance of doing that in twins is if you think of the genes and the environment as a big orchestra and you try to figure out the meaning of a single small instrument and everybody is playing a different tune there’s no chance of hearing the influence of that single instrument. But as dizygotic twins share 50% of their genes and a lot of their environment, this background noise is dramatically reduced. So they are playing more or less the same tune and now you have a good chance of hearing the difference, even in a small flute.” Professor Louis Keith, MD: “How exactly do you see the potential for what you just said for industry to capitalise? Because you know as well as I do that in recent months there has been a lot of talk about a declining number of drugs coming to the market, for let us say hypertension or obesity, because of the long-term cost involved with testing it. Where will the twins and your company come into this?” Andreas Busjahn, PhD: “Now we all know this huge promise of the human genome project that it is going to revolutionise the medicine; that we will have personalised medicine, and that by using genetics we’ll find new targets, new therapeutic pathways, because this is what we really need. We don’t need just small changes in existing medications, we need more systematic therapies that are causal instead of symptomatic, is that the term?” Professor Louis Keith, MD: “Yes, symptomatic.” Andreas Busjahn, PhD: “So what we want to do is, we want to switch from the current symptomatic therapy to a more causal therapy. The idea of using genetics is to find the real causes of things like hypertension. Now this is done mostly in animal studies. So based on the idea that mice and men share about 98% of their genes, it is conceivable to see that if you knock out a gene in a mouse and it changes blood pressure this might lead to a new target for medication. But now we know that although we are playing with the same LEGO blocks as mice as we have the same genes we are using this in a completely different way. So before you start to develop a substance based on animal research it is a good idea to test the relevance of that gene in humans. And as twins are the most informative sample you can have we propose to use functional genetics, molecular genetics in twins at very early stages of drug development to select those targets that will have the greatest potential.” Professor Louis Keith, MD: “Well, thank you very much. That’s very interesting and I hope to hear as time progresses further progress reports perhaps on the OBGYN.net or off the OBGYN.net, but I wish you every success with your new company.” Andreas Busjahn, PhD: “Thank you very much.”
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