Womb transplant baby, and ancient seafarers
In the News podcast: the first baby is born in the UK to a woman with a transplanted uterus, and we speak to the surgeons responsible. Also, the best evidence yet the shingles vaccine can help reduce the risk of developing dementia; a drug that could make human blood deadly to mosquitoes. Then, we travel back in time 8,500 years to hear about the sea voyage of hunter gatherers to the Mediterranean island of Malta...
In this episode
01:05 - Woman with transplanted uterus gives birth
Woman with transplanted uterus gives birth
Richard Smith & Isabel Quiroga
She is just a few weeks old - but a baby girl called Amy has just made medical history. Born to 36-year-old Grace Davidson, Amy is the first child in the UK to be delivered from a transplanted uterus - which was a gift from Grace’s sister. Grace was born with a condition meaning she had no uterus of her own and therefore no prospect of natural pregnancy. The procedure is very risky, because it involves major surgery and intense immunosuppression, especially initially. This means the uterus can’t be left in situ indefinitely. It’s the culmination of decades of painstaking work by Richard Smith and his colleague Isabel Quiroga. They told Chris Smith how it happened…
Richard - This is a 25-year process whereby in the last four weeks we were very happily delivered a little baby, Amy Isabel, and she came from Britain's first transplanted uterus and the uterus had been donated by the recipient's sister called Amy. This is just fantastic, I have to say, for all of us. It's such a happy family and really great to see.
Chris - What was the reason for needing to do this, Richard?
Richard - All the people who are coming to us for potential transplants are people who either don't have a womb and most of those people have been born without a womb, so in this case the patient had MRKH, which is a syndrome whereby you're born with no womb.
Chris - But obviously no uterus means no prospect of a pregnancy and that's the problem you're seeking to solve here.
Richard - Yeah, that's absolutely right. So up until now the options for women were either to go down the route of surrogacy, which is country-dependent but there's also quite a lot of issues with surrogacy. The other option, of course, is adoption. Well, now we have this third option.
Chris - So talk us through, actually, before we bring Isabel in, who is your partner in crime in this, talk us through what the process involves to get a uterus from one woman into another and then culminate in a pregnancy.
Richard - I suppose the easiest way is to go back two years ago to when we did that transplant. Two sisters were admitted and there's the retrieval operation from Amy. It's a modified radical hysterectomy is the official term, so it's a long dissection, lasting about eight hours in fact. And then there's the implantation procedure that's led by Isabel. Isabel does the vessel hook-up and then I do the kind of genital tract anatomical hook-up with the vagina and the ligaments, etc.
Chris - Do you have the two patients in the same operating theatre side by side or are the two of you operating in adjacent theatres, Isabel? Where do you stand and when does this get handed on to you?
Isabel - We have two separate theatres. Due to infection control, you can't have two patients in the same operating room. So the way it happens, where we start the donor operation, when we are at a point in which the organ comes out, then it comes to a small operating room side table in which we can prepare the organ for implantation. With any organ, the most important thing to do once it comes out is to remove the blood. We don't want little clots within the vessel in the organ, so we flush all the blood out. Once we have the organ ready for transplant, then we can go with the organ to the other theatre, adjacent theatre. The recipient would have already been anaesthetised. The operation, getting the vessels ready, which are the vessels that are going to go and provide the blood supply, have already been made for us to join the uterus vessels onto. So the organ gets its blood supply from the recipient.
Chris - And do you see the thing, as soon as you take the clamps off, do you see the blood flow in and it go a beautiful red colour so you know you're in business? Is that how you know, right, we've got a good chance of this working?
Isabel - Absolutely. So all organs, when they're cold and when they're deprived of blood, have a pale colour. And so when the blood returns into the organ, you can see them changing colour.
Actually, when you do kidney transplants, that's absolutely amazing. It's one of the wonders of what we do. So it's very similar in the uterus and you see it changing colour and almost coming to life.
Chris - One of the things that was occurring to me, though, you are a transplant surgeon and you don't normally do uteruses. So how on earth did you get involved in this? And was it a steep learning curve to start doing uteruses?
Isabel - Well, the story of how I got involved is a long one, but basically Richard and his team were interested in doing transplant from diseased donors. And I lead one of the retrieval centres in the UK. They just asked for some advice on how to get into the world of retrieval and it just developed into this true partnership. I have to say that I was initially quite reluctant. I couldn't see the need for this operation. I kept worrying about the risks. But it was only when I met the first patient and I heard the pain and what she had gone through that I understood the need for this operation. And obviously, I have changed my mind completely. And I'm a true believer in that this is a very worthwhile cause.
Chris - You must be delighted to hear that, Richard. You've got a fan. But you come in and do the final sort of close up and do the genital anatomy to make sure that's correct. Having got the organ in situ now, and it looks like things are going well, talk us through what happens in the days, weeks, months after that.
Richard - OK, so there's really close monitoring going on. We're doing cervical biopsies to look for rejection on a weekly basis at the start. We're doing Doppler flow ultrasound studies to look at blood flow within the muscle of the uterus. That's called the myometrium.
Chris - And how long do you allow before you're comfortable to say, right, I think we're ready to try to get a baby in here now?
Richard - So the minimum for that is six months. But there's various other factors that are brought into that. And certainly in this first case, we actually ran that process out to just over a year.
Chris - And when you decide that the time is right and it's safe to initiate a pregnancy, where do the embryos that you're going to implant, where do they come from?
Richard - So they've all been created pre-transplant and they're all in cold storage. And depending on age, they've all been pre-implantation genetic tested, meaning that we know that those embryos are genetically normal. And that's one of the conditions to being able to come into the trial.
Chris - And how many embryos do you put in?
Richard - One at a time only.
Chris - You go one at a time. And then how is the baby actually delivered? How do you decide when to deliver the baby and how?
Richard - So the pregnancy is monitored as per any other pregnancy. But there's a big issue for these women with a transplanted uterus that the uterus itself has no nerve supply so that they can't feel contractions. So obviously, we were monitoring that very closely. The delivery itself is performed by caesarean section. The baby was delivered really beautifully, I have to say. And the baby cried within seconds of emerging into this world, which obviously for obstetricians is a marvellous noise, that's for sure. And for mum and dad, even more marvellous.
Chris - Indeed. And at that point, does the uterus stay in and can you have more babies or does it have to come out?
Richard - No. So the women have got a choice at this point. You can either have a completion hysterectomy six months post delivery. We're certainly not in the business of removing the uterus at the time of caesarean section. Or you can go on and have one more baby. And once you've had one more, you can then have your completion hysterectomy six months after that. And the purpose of that is to restrict the time the uterus is in to a maximum of five years.
Chris - Were you both there for the delivery? Or did you only get to see... So you actually were there when the baby came out?
Richard - We were assisting at the delivery.
Chris - So you're like surrogate parents almost in this. It must have been an amazing moment, though, because that's 25 years of hard graft it's taken for you to get to this point.
Richard - Yeah, there were a lot of tears shed, actually. I mean, I'm not often rendered speechless, but that day I was really very, very moving.
Chris - Bet you never thought this was how your career was going to go, Isabel, when you thought I'm going to be a kidney transplant surgeon and end up making babies.
Isabel - Yes, it's totally a true new experience. As you say, I'm not often in a delivery room or seeing babies being born. So it was truly something very, very different and wonderful, actually.
10:22 - Shingles vaccine reduces risk of dementia
Shingles vaccine reduces risk of dementia
Pascal Geldsetzer, Stanford University
Scientists who have been tracking cases of dementia in Welsh adults have uncovered strong evidence that having the shingles vaccine - which blocks the chicken pox virus from periodically returning as an excruciatingly painful blistering rash, which is much more common as we get older - also significantly reduces the risk of developing Alzheimer’s Disease. The study relied on the fact that, in 2013, shingles vaccination began to be offered routinely to adults who were over 70 but under 80. And this meant that there were some people who were nearly identical in age and most other risk factors, but differed only in terms of whether they got the jab. This was an ideal random sample, which ultimately showed that people who received Zostavax were up to 20% less likely to be diagnosed with dementia in the seven year follow up period than those who didn’t have the jab. Pascal Geldsetzer at Stanford University carried out the research…
Pascal - What we want to show that a new vaccine or new medication works is a randomised clinical trial. So we may take say a thousand study participants and throw a coin and assign them that way to a vaccine group or no vaccine group. And the power of this is that we know these are really good comparison groups because all that's different for them is whether the coin landed on heads or tails. In the case of Wales we have a very similar situation in the way in which they wrote out the shingles vaccine program. So specifically they said if you had your 80th birthday just prior to the start date of the program you were ineligible and you remained ineligible for life. Well if you had it just after you were eligible. And so we see that just a one week's difference in age across this cutoff means your probability of getting the vaccine suddenly jumps from zero percent to 50 percent. So again we've got really good comparison groups those who are just eligible and those who are just ineligible who must be similar to each other because all that's different for them is whether they were born just a few days earlier or a few days later. And this is what's so unique and different about our study and why our findings I think are so exciting.
Chris - How did you follow the people up and for how long?
Pascal - The beauty of the National Health Service in the UK is that it's a single provider, single payer health care system. So we see people in our data no matter which general practitioner they visit and we've been following them up for seven years in our primary follow up period and just see the strong strong protective signal for dementia.
Chris - Right so the people who got vaccinated were at much lower risk of dementia then?
Pascal - Absolutely. So our best estimate is a 20 percent reduction in new dementia diagnoses from shingles vaccination over the seven-year period which is a large effect size, much larger than for existing pharmacological tools. And because this is a readily available, inexpensive, one-off, safe intervention, I think this really has important implications for population health, dementia care and also research into what actually causes dementia.
Chris - What do you think the mechanism is? Do you think it's all centred on chickenpox, the virus itself, or do you think that the vaccine is doing something else and there's something else, nothing to do with the virus, might be having an effect on the nervous system? Can you get at that?
Pascal - I think there are two broad mechanisms that could be at play here and they're not mutually exclusive. So one of them is a chickenpox virus specific mechanism where the virus hibernates in your nervous system for life is in this constant interplay with the immune system and that causes some sort of inflammation process which through the shingles vaccine is reduced and that has benefits for dementia. The other mechanism is a virus independent mechanism which is a broader activation of the immune system, a boost to the immune system if you like, which is known to happen with many vaccines and particularly with this life attenuated vaccine that we have been studying and that these broader immune mechanisms have benefits for the development of dementia and Alzheimer's disease.
Chris - One way to get at that last point you made would be if you took a group of people who were having a vaccine but it wasn't the shingles vaccine and follow them up. So has anyone done that or do you have that sort of data where you could see they're also having something stimulating their immune system, nothing to do with chickenpox or shingles and they also have dementia or not?
Pascal - Absolutely, I think this is an important research agenda. However, this runs into this fundamental limitation that we have with most of these studies that all we can do is compare those who get the vaccine to those who don't get the vaccine and we know that people who go get vaccinated are very different to those who don't. They have got different health behaviors, different health characteristics, different dietary behaviors, physical activity levels, etc. And so those are not good comparison groups and becomes very hard to control for these variables because we usually don't measure them, don't have them in electronic health record data and that's why this shingles vaccination program is such a unique opportunity to get at cause and effect.
Chris - What's the best age for vaccination to stop shingles is one question but what's the best age for vaccination to stop dementia might be a totally different one and it might be that if you'd intervened at 70 not 80 you'd see an even bigger effect.
Pascal - Absolutely, yes, that's something that we can't address in our particular research but it's something that we would love to look at in future research.
Chris - What would your advice be then? Do you think that off the back of this you've got enough evidence to say to people ‘look for heaven's sake do not eschew the shingles vaccine because this might not just stop you getting shingles it might also stop you getting dementia?’
Pascal - Absolutely, we know that shingles vaccination has benefits for shingles prevention and so this knowledge that there may be an additional dementia benefit I think only provides additional motivation. However, I think really to convince the public health and medical community that this is a true cause and effect and should be a recommended approach for dementia prevention or delay I think for that we need a true randomised clinical trial on the effect of shingles vaccination on dementia and cognition and that's what I'm currently putting all my effort and energy into as our next research step and hoping for funds from private foundations and philanthropy to be able to get such a project off the ground.
17:57 - Safe human drug can poison mosquitoes
Safe human drug can poison mosquitoes
Alvaro Acosta Serrano & Ghaith Aljayyoussi
But first, dog and cat owners may well be familiar with treatments you can administer to your pets that means their blood becomes toxic to fleas, keeping them flea-free for a period of time. Well scientists have discovered that a drug called nitisinone can do a similar thing for human blood and render it toxic to mosquitoes! The research suggests mosquito populations could be controlled this way to prevent them from transmitting diseases like malaria. Alvaro Acosta Serrano and Ghaith Aljayyoussi are the brains behind the research…
Alvaro - We were studying the one specific metabolic pathway of an amino acid that is important, it's called tyrosine. And what happens is that when tyrosine that comes from blood, when these insects take what we call a blood meal, so this is important for the nutrition, for reproduction, etc. So these insects, like a mosquito, they need to degrade or metabolise several components from blood, including tyrosine. And when we use this drug that is called nitisinone that is currently used to treat humans that are born with rare genetic diseases, when a mosquito takes a blood meal with that drug, then what happens is that dies because it blocks the metabolism of tyrosine, suggesting that is essential for mosquitoes to survive. So we were looking into the biology of this, but then realised that that could be a potential way to stop transmission of disease like malaria in endemic areas in Africa.
Chris - So Ghaith, how did you take that forward? Then you had the observation that there is a drug, it's already used, it does appear to pass from the blood of a person into a mosquito, where it's lethal for the mosquito. Sounds terrific, an opportunity for us to get our own back on mosquitoes. But how did you actually take this forward in a proper research way to uncover what the potential was?
Ghaith - So the idea basically was that once a person takes that drug, it's going to circulate in the bloodstream. And when the mosquito bites that person, it's going to take part of that drug, which is in the bloodstream, and it will give its effect, which is going to be a poison for the mosquito. So my job here was to kind of guess what kind of concentrations and drug levels will be in the blood after someone takes it. For example, if somebody takes a tablet of nitisinone, what are the blood levels going to be after a few hours, after a week, or after a month? And to be able to do that, we use something called pharmacokinetic simulations from what we know about the drug. And we can simulate what will happen to a person that will take that drug. And we will know what the blood levels will be at various time points. And from that, we can guess that if somebody takes that drug and a mosquito bites them, say after a week, how much drug will be there for the mosquito to take? And will that amount of drug be enough to kill the mosquito? We know this information from what we call in vitro studies, where we feed blood that has nitisinone in it to different mosquitoes at different levels, and we see what level kills the mosquito. And we connect the simulation to what we know about the toxicity of that drug to mosquitoes. And then we can guess exactly how effective that drug is going to be. How much does a person need to take? And for how long will it be effective in killing mosquitoes?
Chris - And the critical thing is, it's got to kill the mosquito, but not kill the person. So is it possible in order to get enough of the drug into the person to kill a mosquito, but without harming the taker, the user?
Ghaith - Well, the beauty about nitisinone is that it has already been used for a long time for treating other diseases. So we know what levels are safe for the human. So we didn't need to do any kind of fancy toxicology studies. And we are sure that this is going to be safe because numerous studies have been done proving that a dose of X is going to be absolutely safe for the human.
Chris - What happens next then, Alvaro?
Alvaro - Well, what happened is that by serendipity, while we were doing this study at the Liverpool School of Tropical Medicine a couple of years ago, we found out that the Liverpool Royal Hospital, which is only two blocks from the Liverpool School of Tropical Medicine, they were conducting trials with nitisinone on patients who are born with another condition in the tyrosine metabolism pathway in humans. So they were on nitisinone and they had a great experience already working with nitisinone for about a decade or more. So they were excited to hear that we were working with mosquitoes and that nitisinone was killing mosquitoes. We were excited that they were working with patients. So we joined forces and we managed to get blood from these volunteers that were on nitisinone. And that helped us to perfect all the pharmacological modelling that Ghaith was referring to. And it's very different to say that we test the drug mixed with blood and give it to mosquitoes in the lab than using a blood where nitisinone has been taken up by a human and it's been metabolised. So that was the more realistic scenario into the possibilities.
Chris - In those studies then, were you basically presenting the mosquitoes with a surrogate arm to feed from, which had that patient blood plus drug in it, which enabled you to then test directly what effect does this have on the mosquito?
Alvaro - That's correct. And that allowed us to determine what we call the mosquito side effect, which means that what concentration is able to kill mosquitoes and more importantly predict what the concentration of the drug a person can take in order to see for how many days or weeks the drug will remain active, killing mosquitoes and other blood sucker insects as well.
Chris - So Ghaith, when you got hold of that data, which basically enabled you to test some of the things you'd already predicted, but then also make further predictions, what does the picture look like? Is this going to be theoretically possible to control mosquito endemic areas with this strategy?
Ghaith - Well, when we got the clinical data, it confirmed our predictions. And based on that, we knew that through more kind of epidemiological modelling, a number of people in the community that nitisinone will indeed have a significant effect on killing the mosquitoes in this malaria endemic community. And we've also compared it to another drug called Ivermectin, which has the same effect on mosquitoes where it's poisonous. And we found out that because of the properties of nitisinone is going to hang around in the bloodstream for a longer period of time at a high enough concentration that it will kill the mosquitoes for a longer time. So the answer to your question is yes, and we think it will outperform other drugs as well in that context.
Chris - And to be clear, of course, what it's not doing is stopping the person who gets bitten getting malaria potentially, but it does then rein in the population. So it works because lots of people poison lots of mosquitoes, which overall brings down the mosquito population, therefore reducing transmission rates.
Ghaith - That's correct. And that's why some of the ideas of applying this kind of treatment is that for all the people who will take nitisinone, they could take prophylactic drugs that protect you from malaria as well. So the drug that protects you from malaria will take care of not getting malaria, and at the same time, you will be able to kill the mosquitoes in the community. So you get two in one with one visit to a doctor.
25:23 - Hunter-gatherers embarked on epic sea voyage to Malta
Hunter-gatherers embarked on epic sea voyage to Malta
Eleanor Scerri, Max Planck Institute of Geoanthropology
Until recently, archaeologists believed that the Mediterranean island of Malta was out of reach for humans before the invention of boats and the emergence of farming. But now new research suggests that hunter-gatherers were making sea crossings of at least 100 kilometres to reach the island 8,500 years ago - a full millennium before farming became mainstream. I’ve been speaking with Eleanor Scerri at the Max Planck Institute of Geoanthropology. She went to Malta in anticipation of studying how later human arrivals might have affected the balance of nature but discovered by accident that we’d been there a lot longer than anyone had realised. And this tells us that we must have been adept seafarers by a much earlier time than had been appreciated previously…
Eleanor - We went to this beautiful site which is a doline and that means it's a collapsed cave so it's essentially a big hole in the ground and at the northwestern edge of the cave there's this overhang and it's nice and it's dry and it's a rock shelter and it's exactly the sort of place where you'd want to camp. So we thought it was an excellent place to try to see where we might find evidence of the first people to arrive on Malta which we assumed would be farmers and as we dug through our trenches we found the usual sequence. We went through the Bronze Age, we went through the Temple Period, went through the Neolithic and it didn't stop. The pottery and the domesticated animals dropped off and then we just started finding stone tools and deer and tortoises and fish that were obviously cooked. But this was all at a much deeper level which suggested it was older and you just didn't seem to be like anything that had been discovered in Maltese archaeology before. So I started to have my suspicion then that we were uncovering something unusual but it wasn't until all the radiocarbon dates started coming in a few months later that it started to confirm that we were indeed piecing together a picture of something that we never expected to find.
Chris - So how old were these remains and when does that therefore point to their being people on Malta from?
Eleanor - Well we knew the first farmers had arrived around 7,500 years ago that is and this is in keeping with what we know about the spread of farming in the central Mediterranean and so that gives us a useful benchmark. And our results suggested that people were on Malta at least a thousand years before so 8,500 years ago and possibly even earlier, possibly even up to around 9,000 years ago and the archaeology reflects that. There's no evidence of domesticated plants, there's no evidence of domesticated animals and the way these people are behaving in their subsistence strategies, foods they're eating, the diversity of their diet, it's completely different to anything we see in later farming communities on Malta.
Chris - Some interesting questions surface then don't they? How did they get there? If it's an island they must have known at that time then about quite complex seafaring because it's not easy to get to Malta. The nearest land is, what, Sicily 100 kilometres or more away?
Eleanor - Looking at Sicily for example that's about 85 kilometres away as the crow flies but it would have been like a longer distance by sea if you take into account you know even in the past ships prioritised departure from the Gulf of Gela in south-central Sicily because the currents would take you to Malta. So 100 kilometres seafaring at night so it takes you beyond what's possible to paddle through in daylight hours even if you're looking at quite fast paddling say between three to four kilometres an hour probably more likely something between one and two kilometres an hour. So it's a phenomenal distance and Malta and Sicily are not mutually visible, the islands are only mutually visible on a clear day from a vantage point. So they would have had to have knowledge of sea marks, they would have had to have knowledge of the stars and navigation at night and a whole host of really sophisticated maritime skills to be able to make such frankly an epic journey.
Chris - Is it possible that this was a handful of people who actually were not very good seafarers got blown off course and got lucky to get to Malta and then they were marooned there and well that became their new home or have you got evidence that there were people coming and going there was there was some evidence of people flux which argues it was regarded as as a place to get to a destination.
Eleanor - Yes I think we can infer that so the archaeology suggests people were there for centuries you know although it's a very small island I don't think people would have been able to survive there for centuries if they were just cut off both in terms of the regular population size that you would need to keep a population going over centuries without becoming completely inbred and also not over exploiting the resources available on the island. And we know for example that Malta had its own species of indigenous deer. I think this deer would have been completely wiped out if people had limited access and they couldn't come on and off the island and so we think this by inference suggests that people were actually coming and going.
Chris - Do we know what sort of boats they would have had?
Eleanor - This is a trickier question so from the Mesolithic in northern Europe we know that hunter gatherers used dugout canoes so this is where you get a single big tree trunk and you can follow it out and we also know in the Mediterranean region that some of the very earliest farmers were also using dugout canoes so it's likely that they were using something like this.
Chris - This then pushes back the time when we think we began to master the waves. Is that really one of the big take-homes from this study?
Eleanor - Yes it is I think by any standard this is a seminal voyage in human history it's among the sort of top human endeavours I think when it comes to seafaring in human history. This raises the question where else did they go and was there a strongly connected maritime Mesolithic world that we're only just starting to understand then?
31:29 - How do animals react to shifting magnetic fields?
How do animals react to shifting magnetic fields?
James Tytko asked Miriam Liedvogel, professor of ornithology, to help find the answer...
James - The best supported ideas include the presence of a tiny compass needle of magnetic iron oxide in the beaks of some birds. Or there's the radical pair hypothesis, which explains magnetoreception with quantum mechanics. Mirjam Liedvogel is director of the Institute of Avian Research in Germany.
Miriam - You can think of the Earth's magnetic field as a giant bar magnet. So there is a north pole and a south pole, and the intensity is highest at the poles. And then it gradually decreases towards the equator. And another feature that the Earth's magnetic field, because its spheric orientation, also provides is a difference in the inclination angle. So the angle of this vector, how it enters the Earth's surface, changes. So it's perpendicular at the poles, and it is almost horizontal to the Earth's surface at the magnetic equator. So for birds, we know the inclination is the feature they are using. So they don't care about polarity, actually.
James - Due to turbulence in the flow of molten metal in the Earth's core, which generates the magnetic field, it can be susceptible to changes in intensity. Magnetic poles can wander, for example. The north pole has moved from Canada to near Siberia over the past century. So how do migratory animals react to this turbulence?
Miriam - Yeah, so it's a good question. And we don't know exactly how they do it, but we know that they can cope with fluctuation. I mean, there's daily fluctuation in intensity, also probably inclination. It's not a static entity. It's also not so that they exclusively rely on magnetic cues. So for their migratory journeys, for example, if it's a night migratory bird, the magnetic field is an extremely reliable cue. It's ubiquitously present. But night migrants also use star patterns or the rotational center of the sky or the starry sky. I mean, some other animals use the Milky Way or any other sort of celestial cues to orient as well. And they integrate this information into a very robust navigation program. So if one cue is absent or gives funny signals that doesn't really make sense for what the animal knows it should do, then it can also just say, OK, well, I rely or I prioritise some other cue.
James - Animals really are master navigators, orienting themselves using the sun, the stars, other cues besides the multiple modalities of magnetoreception, potentially also working in tandem, as we've described today.
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