Episode 10: We All Need Therapy, Including Mums and Unborn Babies

Transcript

Speakers:

Host - Olivia

Guest – Prof Anna David

 

00:00:02 Olivia Moir 

Hello everyone and welcome back to it all starts here. I am, your host, Olivia Moir, and we are back here today for our final episode of season one. I'm so excited, today we are going to be diving into the field of prenatal therapy with none other than Professor Anna David, Director of the EGA Institute for Women's Health here at UCL. Her teaching and research roles at the institute include professor of obstetrics and maternal fetal medicine, and she leads the research of the prenatal therapy group. She also has clinical roles as a consultant in obstetrics and maternal fetal medicine at UCLH, here in London. I have had the pleasure of getting to know more about her research whilst completing my masters project in the prenatal therapy group over the last year and I absolutely cannot wait to dive more into the details of her work with you all today. 

So with that being said, let's get right into things and maybe hear a little bit about where this all started for you and how you landed in the field of maternal field medicine. 

00:01:08 Prof Anna David 

Well, Olivia, thank you very much for inviting me to do the podcast. I'm really excited to have a chat with you and congratulations on getting through your masters with flying colours, fantastic.  

How did it all start for me? I suppose it all started really when I was a medical student. And I remember having the opportunity to go and travel in India with a friend of mine and we went to work in a hospital on the Nepalese Indian border in Bihar, which was a very deprived area. 

And it was just a wonderful opportunity to go and experience life in India. Life in the hospital. And because I was a woman, they said, would you like to come and do some work in our labour ward? We were there for about three or four months. So I ended up delivering my first baby in India when I was a third year medical student, which was quite an experience and I became fascinated by the fact that women are just amazing when they're pregnant. You know, a woman can be really ill in pregnancy, in labour we saw women who had severe preeclampsia, so severe, high blood pressure and very edematous. And then they'd have their baby. They'd be safely looked after, and then you see them the next morning and they're up and about and they look completely different. And they're looking after this baby. And I just thought, wow, you know, women and pregnancy, it's an amazing. It's an amazing thing.  

And so that's, yeah, so that's where I delivered my first baby. Where I I got my interest in obstetrics, in pregnancy and maternal fetal medicine, and then when I qualified, I decided to go into obstetrics and gynecology. And I did quite a lot of scanning early on, so in my days off or in time off after a sort of night on call, I used to go to the ultrasound department and, you know, put this scan on and just have a look around and you learn so much just by doing an ultrasound and actually having a look at that baby before they're born. 

And so, you know, I go and see the babies on the special care baby unit after birth, and I'm a bit like, that's my baby that I've looked after. You know, I've seen them on ultrasound and they're like a, they're like a separate person, but they're all part of this whole, you know, pregnancy journey and so that's that's how I got into this area. 

00:03:33 Olivia Moir 

I love that. That's such a lovely story and I love the element of travel in there. It's always, I think so cool when you can experience like the practice of medicine in different places, that's amazing. So I mean, thinking more into this prenatal therapy route and field as we kind of explore that today, there's going to be some talk about the research and then of course, the clinical applications of this. But maybe we could start with why this field is so important and its own sort of unique field. 

00:04:06 Prof Anna David 

Well, I think pregnancy and prenatal therapy is absolutely vital to society because you know in pregnancy you are basically developing the next generation and the fetus, the baby, the unborn baby is going to become the children and the adults that are going to develop society and become the the future, and they themselves are going to have children. And so we know a lot about the fact that the environment before you're born, the one in your mother's womb really dictates how you're going to develop later on, and what your health is going to be like. So if you have a healthy pregnancy, if your mum has a healthy pregnancy, you come out with a good weight on about the 85th centile and on time, you know, after 37 weeks of pregnancy, you are much less likely to have diabetes, hypertension, stroke, cardiac disease, dementia. All of those things later in life. But if you are in an environment, if you're intra-euterine environment is stressed: so if you are small, if you're not getting enough nutrients, if you're born too early, if you're born too big, if you're exposed to a lot of sugar because your mum actually develops diabetes in pregnancy, then you are more likely to develop diabetes later on in life, as well as high blood pressure, dementia, cardiac disease, all of these things. But we don't really think about this in this holistic way. But it's very clear that our population health absolutely critically depends on how pregnancy occurs and the big issue we have at the moment is that we don't really have any drugs for pregnancy. 

So there's only been two drugs ever which have been licensed for use in pregnancy and pregnancy conditions are affecting a high proportion of of women who are pregnant. So things like preeclampsia, high blood pressure in pregnancy, swelling, that kind of thing, probably affects up to about 5%. So that's one in 20 women preterm birth. So that's delivering a baby before 37 weeks, affects at least 10% in the UK and and and higher in other countries. Fetal growth problems where the babies doesn't grow as well contributes highly to still birth and also contributes to babies being born small. And there's this concept which recently developed in a Lancet series called the small vulnerable newborn or SVN. 

Of where if you're born small, if you're born preterm, we know that you're much likely to have problems later on in life, but we don't have any drugs to be able to treat these conditions. We have no treatment for preeclampsia. We have no good treatment to prevent preterm birth, and we have no good treatment that can make the baby grow more in the womb. And we're not very good at predicting who's going to get these treatments? It's getting better. But but we're not very good at predicting and preventing them. People are now starting to use low-dose aspirin in women who are thought to be at increased risk of preeclampsia. And that does reduce the risk if you take it early enough in pregnancy. But of course people have felt that pregnant women are a sort of vulnerable population and they and we shouldn't be giving them drugs, but that's probably the opposite of what we should be doing. We should be throwing money into researching how we can improve outcomes for pregnancy for babies, because actually they are the future generation and if we don't get it right for them, our health population health is going to suffer later. 

00:07:45 Olivia Moir 

Yeah, absolutely. And I mean just outlined so many of the key concepts. So while I think like with my masters, you know, I hadn't done a lot of research and studying necessarily in the clinical applications when it comes to pregnancy and you know as I mentioned to you before, I think when you think of treating the pregnant woman and you talk about the applications of drugs and you know what that could look like in clinic. At first you're like, well, yeah, I mean, it's so risky like the they're carrying a baby. So, you know, maybe we don't play around with that, but that's like, that's the first thought. And then once you hear you know everything else in the counter arguments to this, including the fact that pregnant women suffer from all the same conditions that non pregnant women and other people suffer from. It's like, well, of course, there needs to be research that goes into drugs during pregnancy, and we can't just be treating them as if they aren't pregnant because there is another person growing inside of them. 

It's just so interesting to sort of, you know, from a research perspective, investigate all the different effects that can happen in terms of your development as the baby, but also as the mother carrying a child in pregnancy and and sort of like how that as a condition can, you know, affect the different things. 

00:09:03 Prof Anna David 

I think it's really important what you're saying is that when you start thinking about it, you you sort of have this sort of realization that we're going about it all wrong. Clearly, we have to make sure that any drugs that we develop, any trials that we do in pregnant women are completely safe or are as safe as we can make them. And of course, a lot of the the reason why women of reproductive age or pregnant women were excluded from clinical trials came from very sensible advice that, that that came from this the the sort of thalidomide issue that that, you know in the 1950s, 60s, 70s where women were given thalidomide to prevent miscarriage. But actually it it wasn't done in a very well controlled way and and and the safety data wasn't there. Although actually when you look back at some of that animal evidence, there was some evidence of of harm and particularly in high doses to the sort of development of the fetus and so because of that following that women were routinely excluded from clinical trials or and women of reproductive age were routinely excluded. Actually, probably about, you know, one in one in five women of reproductive age are going to get pregnant. So that means you end up excluding everybody. And so you're really only developing drugs for half of the population. And of course I think it's got to be done really carefully and there there is there are moves to do this.  

We are now developing a working group to think about how they can include pregnant women and lactating people into drug development and I think that's a really good move. We are seeing some some change and of course during COVID you know there was this whole thing about ohh well we shouldn't vaccinate pregnant women because we don't know if it's harmful or we don't know if it's safe. One of the big trials of different drugs for COVID was the recovery trial, and when it opened, it didn't didn't initially include pregnant women in the clinical trial, but very quickly after there was a big move to say no. Look, you know, pregnant women are very vulnerable. We need to include them and they were subsequently included in the clinical trials, and that basically showed that giving steroids for women who had severe COVID was safe. But what ended up happening was when the vaccines were developing initially, we didn't know whether it was safe in pregnancy because they hadn't been tested out in pregnant women and at the height of the pandemic, certainly in the UK, around one in five women who were one in five adults admitted to the intensive care unit, and the 2nd wave were pregnant women. And you know that that's a huge statistic. And these women were really ill. They were ventilated for many, many months. We saw them at my hospital and and that was all because when the drugs were developed, when the vaccines were developed, were pregnant, women were not routinely included and and also people were concerned about how the sort of spin was put out about the safety of this vaccination. Rather than saying we don't have any evidence to show harm, there was we don't have any evidence. 

And so some people did you know, volunteer to have have testing vaccine COVID vaccines in pregnancy.  

And in fact, when you ask pregnant women whether they'll take part in clinical trials, they will say, yes, we had a great experience at UCLH of testing out one of the vaccines. And we had a massive response, we put out the information out on our electronic patient records and said would you like to take part in this trial? 

And we were overwhelmed with people saying yes, I'd love to take part. So I think it's a real myth. Pregnant women understand. Not everybody wants to take part in a clinical trial, but they are willing to participate if you if they feel that you're taking their care, can you know sensibly and you're trying to do it as safe as possible. 

00:13:05 Olivia Moir 

Which I believe is probably the most important opinion. If if being led by a healthcare practitioner. 

00:13:14 Olivia Moir 

Yeah, well, one of the issues with safety and pregnancy clinical trials is that we haven't until recently had the vocabulary to describe safety properly. So the work that I've been doing is has been developing a treatment for fetal growth restriction, which is a a condition where the fetus doesn't grow very well in the womb and we're trying to develop a drug that will help that. 

And that was some of the stuff that you worked on in your project. 

What we discovered while we were doing this is, is that we didn't have the right terminology to describe safety aspects in clinical trials. So when you do a clinical trial of a drug, you want to measure safety, you want to measure what are called ‘adverse events’. These are things that happen. They might be due to the drug, they might be due to the intervention, or there might just be something as part of the disease. 

When we had a look at in about 2015,2016, at what terminology there was out there to describe maternal adverse events and fetal adverse events there was very little there was about two or three for the fetus. You were either very small or you were sadly dead. You were still born. And so we just didn't have the right terminology. 

So we went about and we asked colleagues and people in all the different areas, the pharmaceutical industry, neonatologists obstetricians, fetal medicine, fetal surgeon people just to think through. We developed a completely new terminology which describes maternal adverse events, fetal adverse events.  

And now we can actually, if we're giving a drug, we can now measure what effect it might have on a fetus, what effect it might have on the mum. And so we can come up with some grading and it helps you develop doses. So if you want to try a new drug and you want to escalate from low dose to middle dose to high dose, you now have some way of framing the escalation process, but this has not been done before, this is completely new. And it's been adopted by meddra, the medical dictionary regulator activity, and it's also been very much welcomed by all the the regulators. So FDA, European Medicines Agency MHR, A and all of that. So I think it you know there's definitely things moving in this process, but it just takes a long time and I think we just need to keep going with it. 

00:15:33 Olivia Moir 

Yes, absolutely. Yeah. That's, uh. You laid that out really well. And I think focusing in more on sort of now the research of and behind in terms of prenatal therapy. I mean, as we said, it's lacking maybe the clinical applications and you know I think research we can always have more, but there is lots that's going on right now.  

And and so I think when we're thinking about the different types of research going on, what are people investigating and sort of the applications of this, because oftentimes I think you know, our research is led by the clinical applications. So what are the different areas or maybe types of prenatal therapies if you were going to describe them. 

00:16:17 Prof Anna David 

So I think there's quite a lot of work that's going on in terms of placental problems. So for example fetal growth restriction, which we're looking at, we're trying to develop a a therapy based around increasing blood flow to the, to the uterus, which we think is one of the underlying problems. 

There's quite a lot of teams that are working on prevention of stillbirth, so one of the the disease is one of the conditions that can affect the placenta are inflammatory disorders where for some reason the mum appears to mount an immune response to the placenta and these women have recurrent stillbirth. 

And so some work that's been done at the Institute is looking at trying to use anti-rejection drugs to actually prevent that coming and that that that seems to be going quite well. There's also teams in the US that are looking at treating preeclampsia. So preeclampsia is a condition where you get high blood pressure and protein in the urine, and as I said, it affects about one in 20 women and are often more severe in the first pregnancy. The difficulty he has is it’s very difficult to predict whether it's gonna happen and it can come on quite quickly. And it's all to do with an imbalance in the sort of angiogenic so sort of proteins that are involved in vasodilatation - dilation of the blood vessels. And so what a team is doing is looking to see if they can drop down and this imbalance. Rebalance things to try to delay delivery for, you know, maybe a few days or a few weeks. So yeah, there's lots of. There's lots of things that are ongoing, but it's quite a challenge because you've got to really make sure that you know the natural history of the condition that you're treating: so you know how does preeclampsia actually develop and how quickly do people get ill? What are the outcomes? And and then you've got to develop your drug. You've gotta test it out. And of course, you're not gonna test it out in women first of all, you're gonna test it out in preclinical animal models. 

So you need to decide which is the best model to test it out in and there are not that many, and then you've got to do some toxicology studies. These are very expensive. They have to be done in in a proper laboratory process according to good laboratory practice. And they are analyzed a lot by the regulators. And there are traditional types of toxicology studies that are done in particular animal models like rats and rabbits. And then once you know that, you then have to do your clinical trial. And so you've gotta try and come up with the right inclusion criteria for your clinical trial, which is often the most severely affected women, and where you are most in equipoise about what might be the risk, but what potentially might be the benefit if your drug actually works. So then you set up your clinical trial and if it's a first in human drug, you might be recruiting one patient at a time.  

So: 

Recruiting a patient. 

Giving them the intervention. I won't call it a treatment. Giving them the intervention because you don't know if it's the first in human drug, whether that drug is actually gonna work. So it's not a treatment, it's an intervention. 

Giving him that intervention and then looking at the outcome of that one pregnancy and you might want to wait a couple of weeks after babies born to check the baby's OK and then recruiting the next patient.  

If you've got to do, you know, 12-15 women like that, it is gonna take you two or three years to get to the end of your trial, but that is probably the only way that it's safe to test out a first in human drug, so we've gotta do it like that. And of course, very expensive. You've gotta make your drug to very high quality, reproducible manufacture. You've gotta have people who will be, you know, data safety, monitoring board and ethics review and really careful collection of all the data, all the risks, all the things that the patient might report, all the things to do with the baby. 

So yeah, it's really expensive. And so it's not really surprising that it's not done very commonly, but that's no reason not to do it. 

00:20:39 Olivia Moir 

Absolutely. Yeah. So in terms of the different research you've outlined the different types that are being focused on around the world. But what is something that or your research in particular, what are you focusing in on right now? 

00:20:52 Prof Anna David 

So in terms of what what I'm currently working on, my main research in prenatal therapy is trying to develop a treatment for fetal growth restriction, which is where the fetus is really small and and effectively stops growing before birth. 

We know it affects probably about one in ten pregnancies, but it's a very common cause of still birth and the baby doesn't necessarily need to be very small to be affected. So we have some babies that are, you know, relatively normal size, you know, perhaps 25th percentile for example, but actually they're the ones that have the problem and having a  still birth later in pregnancy.  

But the the point with developing a new drug is because it's quite risky, you end up focusing on the most severely affected cases where the outcome for the baby could be really bad and potentially your therapy might improve it. So it's it's a big balance. So we've been focusing on the most severely affected, the most early onset fetal growth problems. Those babies that end up being very small, less than the third centile. So on a sort of population of one to 100, it would be the bottom three out of that 100 the population. 

And what we've been focusing on is trying to increase the blood supply to the womb so we know that commonly what happens is that the placenta cells early in pregnancy normally invade the blood supply to the uterus. The uterine arteries, and they strip out of this muscular layer of the vessel out from these  blood vessels and basically open up these vessels and a create a very low pressure, high flow circulation. So your blood supply goes from being in the uterine artery is about 50 mls per minute to about 500 mls per minute by halfway through pregnancy. It's an amazing, amazing transformation and it just happens like that, very early in pregnancy are all to do with the hormones that we have, progesterone, estrogen and also due to a key protein called vascular endothelial growth factor or VEGF, it protects vessels, it causes new vessels to grow, it dilates vessels. 

And in FGR, we know there's an imbalance in this VGF availability in the circulation. It's not the only reason why people get small babies.  

So we know the maternal heart cardiovascular system is very important as well. So so it it's it's about how healthy you are when you get pregnant as well as your risk of having umm heart disease and sort of vascular problems. 

And and So what we're trying to do is improve the availability of this protein in the uterine arteries and what we've demonstrated is that we can do this using something called gene therapy. The gene therapy is where you give a vector, it can be just genetic material or we're currently using a modified virus a little bit like the the vaccine, one of the vaccines that was for COVID, it's a modified adenovirus. It contains the VEGF protein and that modified virus very quickly gets taken up into the blood vessels and then that VEGF protein is expressed, you get increased levels of it locally and that causes the vessels to dilate, to reduce their contraction and we get new vessel formation. And so it's been a long journey and it's taken us. I remember the first time we thought about this idea was back in 2005. So it's a long way and we've gone, you know very methodically through. We've done some animal studies demonstrating that it improves growth in babies, fetuses, pups that are small and growth restricted and and we've done safety studies, we've done reproductive toxicology studies. We've asked patients, would you consider taking this therapy and yes, some of them would. We've looked at the bioethics, the legal situation of giving mums gene therapy and pregnancy and there are no barriers to it. We've done a natural history study of this condition to try and work out: If you see somebody with a very small fetus who is most likely to have a potentially bad outcome, who is going to deliver by 28 weeks because their babies effectively stopped growing? And then what are the outcomes for that baby? And what are the outcomes for that mum, so that we know really clearly what happens in the untreated population and we can then see whether there's a difference if we give the drug: Does it cause any harm? Does it cause any benefit?  

And at the moment we are doing the final stage of testing out in a preclinical model to show that our clinical drug is safe and effective and then if that if that works out, if that's OK, has good results, we'll then be applying for more funding to do the definitive first in human clinical trial. 

00:25:53 Prof Anna David 

But you know, it's taken a long time. We've done a lot of development along the way. We've optimized how we look after women and we've developed this new terminology that I was talking about. It's been really exciting. It's very frustrating. You have to be quite determined and think well you know, OK, that set back. You know, when COVID happened, it was a bit like, ohh, no. We're gonna have to delay it for a bit because we, you know, we couldn't get the funding. We couldn't start the studies and and you just have to go and say well you know I am seeing women in my clinic every week that have this problem and we can't currently do anything about it. 

But I think talking to women, the the fact that we are trying is really very positive and very helpful. They find that really meaningful. 

00:26:42 Olivia Moir 

Absolutely. Absolutely. And it's so it's so impressive to say the least. And I just wanted to quickly mention the VEGF protein that you're focusing on. So vascular endothelial growth factor. Why was that the one that you had chosen to hone in on for your research. 

00:27:02 Prof Anna David 

I think it's because it's well known that this VEGF protein has lower levels in women that have fetal growth problems and there's a reduced availability of the VEGF and also in preeclampsia as well we know that there's reduced availability, what appears to happen is that there's a soluble receptor which circulates in the blood and it mops up the available VEGF. And so there's an imbalance in its receptor and the available VEGF. And it's that imbalance that causes all the problems. t's possible that this may improve outcomes in preeclampsia. It might delay the onset of preeclampsia, but I think the VEGF knowledge came really from work that was done in the sort of 1990s early 2000s, about what is the underlying cause of fetal growth problems, placental problems. 

And so, without that really essential biology and investigation into it, we're never going to get down the the way of developing therapies. So you know, along the way, the group that I'm working with, the team, we're looking at different proteins. So we're looking at proteins, there is one that is called Apelin, which I think that was the one that you were looking at in your research. And we're looking at different proteins. People are looking at insulin growth factor, IGF, for example. Which might be a potential target or placental growth factor. I think what we really need to have is more investment in actual the biology, the pathology, the Physiology of pregnancy, because only by doing that we're really gonna understand how the diseases occur. 

And then we'll be able to provide drug targets around which we can, you know, develop some kind of new therapeutics. 

00:28:57 Olivia Moir 

Yeah. Going back to sort of the clinical applications of this, I mean you mentioned that right now in clinic kind of what keeps you going maybe with the research is the knowledge of there's not a treatment right now that's available in terms of the different conditions that can happen that would require prenatal therapy, but what would it look like in terms of what is being practiced currently in clinic for prenatal therapy? 

00:29:28 Prof Anna David 

Well, at the moment there's very little, I think much of it is around risk prediction, so much of it is around they're taking a really good history, working out if there's a family history of preeclampsia or fetal growth problems, checking the mum's blood pressure, it's very clear that there are good risk calculators. If you examine the woman early on. So if you do their blood pressure, if you measure the blood supply to the uterine arteries, there are very good algorithms now. I mean, one provided by the fetal medicine foundation at Kings, which identifies women at high risk of preeclampsia early onset preeclampsia and then saying, look, take low dose aspirin, which we've been using for many, many years, you know, 30-40 years low dose aspirin, 150 milligrams once a day.  

But you have to start it early. You have to start it by 16 weeks, other otherwise it's not going to be effective though, once you've, once you've got a small baby, there is no treatment that can make that baby grow more. So we just have to monitor them really carefully. So we would see them every one or two weeks to check how the baby's growing, what is the blood supply in that baby? How is the blood flow in the baby's cord in the baby's liver, in the baby's brain. And that tells us how the baby's doing, the fetal well-being and then we have to time the delivery really well so that it's not too late that we miss the boat and that either the baby has sort of critical heart failure, or sadly dies. Or we deliver them too early. 

00:31:03 Prof Anna David 

The neonatologists are very good at looking after babies that we give them, particularly if they're small and they help with their feeding early. Around the time of delivery, we can improve the outcome for the baby by two things. We can give them magnesium sulfate to the mum and intravenous infusion of magnesium sulfate to the mother, which reduces the risk for the baby having a fit after birth. 

And we can also give the mum an injection of steroids to injections of steroids, which the steroids crossover, the placenta and cause premature release of a protein in the baby's lungs called surfactant, which means when the baby takes a breath, the lungs work better, so we can very carefully time delivery. We can give these very short term treatments around the time of birth. We gotta make sure that we deliver them carefully. That might mean having a caesarean section for example, rather than putting them through a labour which might be stressful for the baby. And then delivering them in good condition. Delayed cord clamping so, making sure the baby gets a blood transfusion from the placenta, which improves the neonatal outcome, and then making sure they're well fed, kept warm after birth.  

But that's it. I mean, that's that's all we can do. Very frustrating. We've gotta make sure we have all these things lined up this package of care available and hopefully at some point in the future we will have some interventions which we can start delivering when we find the babies very small, we can start doing something which will delay us having to deliver the baby, or perhaps, you know, make  the baby grow better in, in later in pregnancy. But that's what we can do at the moment. 

00:32:42 

I mean you say that's all, but it's it's so impressive. Everything that is done. I mean, obviously as you said, it would be really wonderful to see everything that comes out of this field and that's kind of where I was going next in terms of what you hope to see, you know in the future in the next 5 to 10 years. But it is so impressive everything that you guys are already doing to help with intervening in these types of conditions and pregnancy. 

00:33:10 Prof Anna David 

So I think what I’d hope to see is potentially that we might be able to improve the diagnosis in these conditions. 

So that there's a variety of things that cause babies to be small or mums to get preeclampsia or or women to the liver pre term, and I think you know, throwing the new genetic techniques at is going to be really important. So looking at genomics, looking at, for example, whole genome sequencing identifying whether there's a variety of genes variations in genes that contribute to this, it's not gonna be on gene. It's gonna be a risk score based on a variety of genes or a number of genes. And so we might be able to then say to people look, you're at increased risk of this of of having a small baby. 

Let's get you really healthy beforehand. Stop drinking. Stop smoking, get fit, lose weight, be, you know, be more healthy and then take low dose aspirin before 16 weeks or perhaps earlier in pregnancy. Take progesterone to reduce the risk of preterm birth, for example. And then you will have a better outcome. So I think actually having access to the the genetics should improve, will allow us a a bit more information about what's happening with the placenta, what's happening with the mum, what's happening with the, the sort of the whole mum and fetal-placental unit.  

So there is there is opportunity there. It's gonna take large numbers of people to contribute their data and I think people do want to do that. But then of course, all the sort of analysis is gonna be quite complex. It's not gonna give us a, you know, a silver bullet which will really, you know, treat everybody.  

But I think being able to split out why is the baby small? Is it a genetic problem? Is it a problem with the placenta itself? Is it a problem with the tcardiovascular system? Is it problem with your proteins, for example angiogenic proteins? Is it a few things which we can then pick off and and tackle and actually improve the outcome?  

So yeah that that's my hope in the next 5 to 10 years that we will have a little bit more information about that. 

00:35:32 Olivia Moir 

I love that. I love that, especially coming from a genetics background. I completely agree. I think it was imaging to start us all off that really set off everyone in terms of finding out more and then this kind of going hand in hand with the imaging I think is the genetics and it's all just kind of coming together to show the whole kind of picture and story of what's going on inside.  

So this has been so wonderful and I have learned so much yet again from you. So thank you so much for that. And it's been such a pleasure having you on the. 

00:36:04 Prof Anna David 

Oh, pleasure Olivia. Great to speak to you.