Professor Alice Roberts, University of Birmingham & Emily Noel, University of Sheffield
One method being used by scientists to investigate the heart, and heart problems, is by looking at how they form in the first place. This is its embryological development. Birmingham Universityís Alice Roberts is a clinical anatomist and sheís just written a book on the subject...
Alice - Embryology is largely just how a single cell, a single fertilised egg develops into a baby. So you look at how cells proliferate. And thereís this wonderful process of origami where new tissues form and they fold in on themselves and some of itís quite destructive as well, so you get cell death occurring to separate the fingers for example. Or particularly relevant to the cardiovascular system where you get rods of tissue forming and cell death in the middle producing little tubes which will later be blood vessel.
So when you look at the development of the heart embryologically, you see that it basically forms as a contractile vessel and then it loops around and it has to undergo this process of septation. So you get, essentially, little partitions appearing in the heart, which set it up so that at the moment of birth, it can suddenly go from supporting a single circulation to supporting a double circulation which you need if youíre an air breathing animal, which you suddenly become when youíre born. Up until that point you haven't been using your lungs to breathe air and instead youíve been getting your oxygen from the placenta which enters the heart in a completely different way.
So embryology helps us understand the function of the heart during the antenatal period, so in that nine months when you're in your motherís womb. But also, actually, it has real relevance for understanding congenital heart defects as well. Because a lot of the problems that we see in babies hearts are because of something going slightly wrong with what is actually a very complex process in the embryo.
Chris - Alice Roberts. And also studying how the heart develops is Sheffield University's Emily Noel.
Emily - Weíre trying to understand how babies are born with certain heart defects. So, why theyíre born with holes in their heart, arteries that donít connect up properly, and we try and understand what genes make these process happen normally and why they go wrong.
Chris - How common are these abnormalities?
Emily - These abnormalities are the most common birth defect that there is, at least 1% of live births. Often these are sorts of defects that need to be corrected immediately postpartum and, quite often, even if you have surgical correction of these defects, individuals can end up with lifelong complications as well.
Chris - How are you trying to get to the bottom of why they happen?
Emily - We use embryological models - things like mouse or things like zebrafish to try and understand how your heart develops normally. Understanding how an organ develops normally is very important for being able to understand then what goes wrong. So we try and identify which genes are important for normal development and then we can systematically try to understand why these genes are important.
Chris - It is complicated but can you explain, for the likes of me, how does a heart develop and when?
Emily - The heart develops very early during embryonic development. So, in humans, your heart will have developed already by around four or five weeks after fertilisation, and the heart usually starts off as a very simple tube. This tube then undergoes quite a complex folding event, which is very important for making sure that your chambers line up properly, all your veins and arteries form properly, and it this sort of process of folding that weíre very interested in and, if this process goes wrong, why you end up with defects.
Chris - So one tube bends itself into a series of wiggles, I suppose, and that gives you the sequence of chambers that the adult heart has?
Emily - Yes, thatís correct. So one tube forms initially and this tube is already sort of roughly divided into what will become and atrium and what will become a ventricle.Those are the different chambers of the heart and then this tube will undergo two bending events which will mean that your atrium and your ventricle are going to be in the proper place in the adult heart, and that the sceptre between them can form properly.
Chris - Those are the walls?
Emily - Yes. Those are the walls of the heart which will separate your atrium and your ventricles.
Chris - And youíre asking, well that must be obeying genetic instructions to form, so which genes are controlling it and, therefore, if it goes wrong, which genes must be going wrong?
Emily - Absolutely. So we look at all of these different aspects and say OK, what are the genes required for each of these processes and, if we don't have these genes, why doesnít the heart develop normally.
Chris - You make it sound very simple, but Iím sure it's not or you wouldnít be doing the research you're doing. How do you do that?
Emily - In my lab we use zebrafish embryos. We can either specifically knock down genes that we know are important in people and say OK, if we lose this gene in a zebrafish embryo, does itís heart not loop properly, and if itís heart doesnít loop properly, why doesnít it loop properly? And the other approach we can take is just to look in general at zebrafish that we know have heart defects and say OK, which genes have caused these defects?
Chris - You talk about fish though. How relevant is a fish to me as a human? Iím not a fish obviously.
Emily - No, of course.
Chris - Despite appearances may be deceptive.
Emily - Absolutely. Zebrafish hearts when it begins to form is very similar to the human heart. So it starts off as a tube and it undergoes looping events that are important for making sure that the chambers are lined properly. The zebrafish heart actually only has two chambers compared to the human heart, which obviously has four, but certainly these early processes of heart development are very similar. We know that a lot of the genes that govern this process are also very similar.
Chris - Once someone has been born with one of these problems, why is helpful you saying well we know which gene is was that caused that?
Emily - So there are a number of reasons why we try and understand genetically what causes congenital heart disease. One of those reasons is something as simple as genetic counselling. People who have these problems, they want to know why they they have congenital heart diseases. Information is very powerful and also itís very important that we can provide good advice to these people if they want to go on and have families of their own. So whether theyíre likely to pass these malformations onto their children too. The second thing is that if we know thereís going to be a familial sort of genetic component to their heart disease that we can keep an eye on in pregnancies as they progress, and make sure that if there is going to be a need for surgical intervention, then that can happen as soon as itís pertinent to do so.
Chris - Some people also say, if we understand how the heart develops, we might be in a position to kickstart it into regrowing itself when it goes wrong and forming healthy tissue again in the context of disease.
Emily - Yep. And I think thatís a particularly pertinent point when it comes to things like heart regeneration. So the zebrafish is capable of regenerating itís heart after itís had damage done to it and there is increasing evidence that, actually, embryonic genetic programmes are reinitiated in our hearts as it undergoes regeneration in the zebrafish. So being able to understand why these pathways are driving heart development may actually help us understand how we can activate regeneration in adults who have undergone things like a heart attack.