Xenotransplantation

Covid jabs do affect women’s periods, but only to a minor degree and only temporarily and with no long-term impact; that’s the conclusion of a number of studies that were set up last year to investigate reports from some women of menstrual changes in the immediate wake of receiving covid vaccines. We reported last year that this investigation was underway, so it’s a pleasure to circle back and speak again with Imperial College’s Viki Male, who works on the interactions between the immune and reproductive systems. She explained what was going to happen. Now she’s here to tell Chris Smith what’s been found…

Vicki - As the vaccines were rolled out last year, particularly as they were rolled out to younger age groups, people started talking about noticing changes to their periods after they'd had the vaccine and quite a few reports about 35,000 by last autumn had been made to our vaccine safety monitor scheme, the yellow card, and the same sort of thing was happening in the United States of America as a result of which the national institutes of health put aside, um, 1.6, 7 million to do more research into this, to find out if there was a real link. And, um, some of those studies have now started to report,

Chris - How did they investigate?

Vicki - One of the NIH funded studies that reported just a couple of weeks ago, used data that people were inputting into a menstrual cycle tracking app. So this is really nice, because people are inputting their data in real time and also, these people were using the app to help track and control their fertility. So they were really motivated to put in correct data because it would have a real impact on them. There were about 4,000 people in this study of whom 2,400 were vaccinated and the rest acted as unvaccinated controls. After the first dose, they saw no effect on the subsequent period, but after the second dose, there was on average about half a day delay to the subsequent period. So a change, but a small one, and definitely very small compared to natural variation. But the people who really noticed something were those who had both doses in the same cycle. And of course this is something that doesn't happen in the UK because our inter-dose interval, but they had more than a two day delay on their next period. But it's really important to know that even these people who had a two-day delay on the period after they'd had both vaccines in the same cycle, their periods were back to normal within two months.

Chris - What about the other study?

Vicki - So there was another study in Norway, which looked at almost 6,000 people, all of whom had been vaccinated, and they asked them to recall their periods before and after the vaccine. They did notice that about seven and a half percent of people in an unvaccinated cycle would call their period heavier than usual. But about 13.5 percent of people in a vaccinated cycle would call their period heavier than usual. And that was a significant difference. So again, here we have, a change, which in this case is heavier than normal periods, but it's reasonably small compared to normal variation.

Chris - I suppose one very important comparison would be to say, well, what happened if a person in that sit duration actually caught COVID. What does that do to your menstrual cycle?

Vicki - Yes. I think this is also a really important point. So studies that have looked at how COVID affects the menstrual cycle haven't been designed in the same way as these, so we can't compare them exactly. But there have been two, which find that change in menstrual cycles after COVID is between 15 and 25% of people whodone caught COVID. So actually that's quite a large possibility that you'll experience a change if you get COVID.

Chris - Why do we think this is happening and should a person be worried about this?

Vicki - So neither of these studies have really done anything to address the potential mechanism, although as an immunologist, I do think it's quite interesting that you don't see anything after the first dose, but you do after the second dose. When something happens more the second time than the first time, that's so often a sign that the immune system is involved, which of course probably shouldn't be surprising here. Vaccines are designed to work with the immune system. So to me, that suggests that this is an immune mediated mechanism, and we do know that the immune system can crosstalk with sex hormones. And of course it's sex hormones that are driving the menstrual cycle. So that could be one way that this is happening. Another way that this could be happening is because we know that there's a really rich immune system in the lining of the uterus, which helps to control the buildup and the breakdown of the lining of the uterus. So it's possible that a big stimulation of the immune system could affect what's going on temporarily there too. These, to me, are the most likely hypotheses, but definitely in terms of the take home message, the changes that we are seeing are really small compared to natural variation. They reverse quite quickly. So I wouldn't want this to put anyone off getting their COVID vaccine.

Modern medicine has made transplant surgery much more successful now than it once was. Cambridge University transplant surgeon, Chris Watson, joins Adam Murphy to discuss the history of transplantation starting in the early 20th century...

Adam -  Let's take you right back to 1902. Hungarian Emerich Ullmann transplants the kidney of a dog into another dog. He later repeats the process and places the kidney of a goat into a dog - the first record of xeno transplantation; cross-species transplantation.

Chris W - They didn't get very good results from this. One of the problems was the technique of joining blood vessels hadn't really been sorted out. Carrel in France pioneered that.

Adam - 31 years later, Yurii Voronoy from Ukraine took what was learned and carried out the first human transplant. However, having used a cadaver that had been deceased for a few days prior to the procedure, the patient soon ran into complications, which we have learned from since then.

Chris W - Nowadays, when we take organs out, we flush them with an ice-cold preservation solution, then we can keep kidneys for 24-36 hours and get good results. We can keep livers for 12 hours. Hearts are even more sensitive - we can keep hearts for probably four hours.

Adam - Back then, it wasn't really clear where a renal transplant should go.

Chris W - When Ullmann did his goat into dog, he put it into the scruff of the neck of a dog, as there is lot of spare flesh there. He could put a kidney in. Voronoy put it into the thigh of a patient.The benefit of the thigh was the blood vessels are very superficial and you can watch how much urine it produces, because you can bring the urine to the tube that drains urine from the kidney out onto the surface of the leg, and you can watch the urine drip down. Of course, that's not a very long-lasting solution because you get infection going back up into the kidney.

Adam - Yurii's patient only survived two days and it wouldn't be until the early 1950s when Rene Kuss, Charles Dubost and Marceau Servelle carried out a series of renal transplants that some components of the procedure we know today would begin to fall into place.

Chris W - At that time, the French were using kidneys from donors that had been guillotined, and these were criminals who had been sentenced to death and then their kidneys were removed. Having got fresh kidneys and implanted them, they still had a problem that the kidneys didn't work. They worked for a few hours and then they failed. What they hadn't appreciated was this process that we call rejection. This is something that had been identified as a possible problem back during the war years by a scientist called Peter Medawar. So rejection was clearly a problem that had to be overcome. But rather overcome it, the next pioneer was a gentleman called Joseph Murray working in Boston in the States and he had some identical twins - one of whom had kidney failure, one of whom was fit and well. Given that they're identical, there was no immunological difference between them, so he was able to take a kidney from one twin and put it into the next twin. That continued until the sixties, where chemical immunosuppression was started to be used, pioneered by a surgeon in my own hospital here, Sir Roy Calne, who's long since retired, but he developed both azathioprine and cyclosporine as immunosuppressants, which is what allowed transplantation to take off and allowed us to do successful livers, hearts, lungs, as well as getting good results from kidneys.

Adam - So success. But then as now, Sir Roy Calne couldn't find enough donors for the number of patients sitting on that waiting list.

Chris W - Currently, we've got around about 6,000 people waiting for an organ of some type in the UK. Four and a half thousand adults are waiting for a kidney. There are 100 children waiting for kidney, 250 waiting for a lung, 300 waiting for a heart, and about 600 waiting for a liver transplant. We do about 4,000 transplants a year. If you're waiting for kidney, then you can wait and be kept reasonably healthy on dialysis. If you are waiting for a liver, or a heart, or a lung, then you don't have long to wait before you become too sick. So there is a significant mortality, a significant rate of dying, in patients while they're waiting. That's about 10% if you're on the liver transplant waiting list, and as high 25% if you're waiting for a lung transplant.

Adam - If you do receive your transplant, your life is still dictated by your new organ.

Chris W - On immunosuppression, you need to take tablets daily for as long as the transplants last or in the case of a heart, lung or liver, for the rest of your life. Those tablets have their own side effects and they also have adverse effects. So being immunosuppressed puts you more at risk of infections and being immunosuppressed also makes you more at risk of certain sorts of cancer, particularly cancers where there may be a viral aetiology.

Adam - As you can imagine for those with vulnerable immune systems, the last two years have caused even more disruption, having to shield consistently from the coronavirus. On top of this, both the number of donors and transplantations carried out have decreased by a third as a result of the pandemic.

Chris W - If you remember, most of the ICU beds were full of patients with COVID. We weren't sure whether COVID would be spread to patients having a transplant - the likelihood is we thought it could be. And therefore, the last thing we want to do is to give a viral infection to someone and then start them on immunosuppression. The other problem was many of these transplants require patients to go into an intensive care unit for a short period afterwards - livers, hearts or lungs do for example - and there were no intensive care unit beds. So of the 23 kidney transplant programs in the UK, 21 closed for a period of time during that first lockdown, when COVID was really severe.

Chris S - Chris Watson and interestingly, before the turn of the century, traffic accidents accounted for the majority of donors. But with improved road safety, these days donors are increasingly middle aged individuals who have died of other common conditions.

Scientists are trying to develop ways to grow replacement human organs in the laboratory, whilst others are developing ways to increase the numbers of donor organs that are fit to be transplanted. But, in the meantime, researchers are turning to animals, particularly pigs, as one way to address the shortfall. Chris Smith and Adam Murphy find out more... 

Megan (01:05) - We all have antibodies that recognise pig cells, and those are called natural antibodies. That doesn't exist against other human tissues and cells unless we've had some prior exposure. There are also other parts of the immune system, like the T-cell response, that exist for any foreign tissue or organ that is quite strong against xenographs. And finally, there are what we call innate immune responses from cell types that we call natural killer cells and macrophages that are particularly powerful against xenographs.

Chris (01:48) - So what happens, Megan, if we put just a piece of animal tissue, an animal organ, into a human and we just let the immune system do what it does normally without any kind of drug control or anything.

Megan - Well, if there was no drug control, and say it was a pig organ, and no genetic modifications had been performed, then antibodies in our circulation would immediately bind to the cells lining the blood vessels of that pig organ, and that anti antibody binding would initiate a very dramatic process called hyperacute rejection. Within minutes to hours, those blood vessels would be clotted off and the organ would not have any blood flowing to it and it would die. There were some transplant done initially with non-human primates and these same dramatic antibody effects didn't happen in those combinations. But, of course, there are many problems with using non-human primates as an organ source: some of them are endangered species, there are ethical problems with using them, and there are many infectious risks associated with using non-human primates - so that's pretty much been discounted. The pig, on the other hand, is closer to being the right size, especially if you use miniature pigs which we have in our centre, and they have similar physiology to humans and the risks are actually much more manageable.

Chris - How have you therefore sought to overcome what the immune system naturally wants to do to foreign tissue like that from a pig?

Megan - Our approach really began with the development of nuclear transfer techniques with the famous sheep Dolly back around the turn of the century. In the early 2000s, we and another group were able to use that approach to "knock out" of the pig genome the gene that creates a critical enzyme that creates a critical target that is seen by the vast majority of those natural antibodies that bind to the cells lining the blood vessels. By making this early genetic modification to eliminate this enzyme, we eliminated that target on the endothelial cells of the pig - that was a big step. Our group is working on inducing immune tolerance, not only the ones that are targets of antibodies, but also the targets of T-cells and natural killer cells.

Chris - So, in essence, you are both blinding the immune system to the presence of the new tissue because you have removed from it targets that it would normally regard as hostile, and at the same time you then introduce the new material to the immune system saying, "no, this is friend not foe." How do you persuade the immune system that this is friend not foe?

Megan - Well, we have two methods: one involves removing, from the recipient, the organ that produces T lymphocytes - that organ is called the thymus - and putting in the thymus from the pig. So, in that pig thymus, the T lymphocytes learn that the pig, as well as the human recipient, are both self.

Chris - Can I throw a spanner in the works and say, if you're putting pig tissue in, even if it's a thymus, how do you stop the thymus being rejected before it persuades the immune system it's all right,

Megan - Good question. You have to eliminate the T lymphocytes that are already there in the body so that you're starting with a clean slate.

Chris - I'm with you. And what was the second step.

Megan - With the second approach, we can actually educate the B-cells as well as the T-cells to think that anything on that pig is self so that these lesser targets of antibodies are no longer targeted because the B-cells that see those targets get tolerized as well.

Chris - Obviously the long term goal is we grow new organs for people tailor-made to them, or at least compatible with them, and we don't need to dip into animal reservoirs to solve our problem. But, in the near term, do you think that this has legs, this approach? Using very physiologically similar animals like pigs?

Megan - I do - I think it has legs. I think that bioengineering is making great progress and stem cell biology is making great progress, but the complexity of making a functioning organ from scaffold and cells has not yet been surmounted. It's going to work one day, but that day is quite far off. By that time we may have worked out tolerance to pig organs so well that that will be routine and that will solve the problem.

Doctors at the University of Maryland Medical School saw in the new year in style just over a month ago, when they pulled off a world first: the trasnplantation of a pig's heart into a man. Dr Mohiuddin, director of the university's cardiac transplant program, spoke to Chris Smith...

Chris - How's the patient doing, Muhammad?

Muhammad - The patient is doing reasonably well. The progress is slow, but it's according to the plan. The transplanted heart is doing excellent; it's not showing any signs of rejection. We did a biopsy yesterday and it came out very clean, which means that there are no signs of rejection.

Chris - Backtracking slightly, tell us a bit about this patient and why he ended up in the situation where he needed a pig heart.

Muhammad - This patient was admitted to our hospital two months before the transplantation. His heart has gone through failure and our heart failure team determined that he was not a candidate for a human transplant, mostly because of his noncompliance: he has not taken good care of himself and has never taken medicine or gone to the doctor. And, for the last two months, he was also on a machine, the ECMO machine, that serves as an artificial heart. So, this patient was denied of a heart transplant from a human, not only from our institution, but from several other institutions.

Chris - And, for that reason, he was willing to accept the risk that would've gone along with having a pig transplant. How was that even broached? Presumably he didn't bring this up. Did someone on your team say, "Well, look, we are working on this. Would you like to try it?"

Muhammad - Yes. He has shown motivation to live. He always asked if he could get a human heart. We offered to him, "We are doing an experimental procedure where, in our baboon models, we have shown good results of a pig heart with 10 genes surviving for a long period of time. We would like to test it in you if you allow?" And he agreed to it.

Chris - When you do the procedure, is it very similar to the way we currently do human heart transplants where we recover the organ from the donor, it's then rapidly brought to where the recipient is, and then just literally plumbed in: you take the old one out and put the new one in.

Muhammad - The procedure is exactly the same. If you didn't know what was underneath the drapes you would think that there was another human donating the heart. But, in this case, there was a little bit of a difference: the heart that was taken out from the pig was put into this perfusion machine, where it was perfused with a special fluid while taking it to the human where it was put in. There was some disparity between the heart sizes, but that was adjusted by the expert team of surgeons we have.

Chris - Is the heart the right size? Because in my experience having done this sort of work myself in the past, it's very important to get a heart that's not too big or not too small for the size of the patient because otherwise you're asking too much of it or basically trying to cram something that's too big into something that's not designed to fit it. How do you overcome that?

Muhammad - Since this patient had this condition which causes the heart to dilate - when we opened his chest, his heart was found to be a little bigger than the pig heart - the surgeons that performed the surgery, including my partner, Bartley Griffith, were able to adjust that difference and the heart worked perfectly.

Chris - And how are you keeping the patient well? How are you controlling the immune response? Because the heart you've used, and we've heard from Megan and George about how it's been manipulated to make sure it's friendly to the immune system and doesn't pose an infection risk, but obviously there's the patient's own immune system to contend with. How do you make sure that the heart isn't attacked by the patient's immune?

Muhammad - We are using immunosuppression, but to a very minimal amount. My work has targeted a pathway that prevents the crosstalk between the B-cells and T-cells and, as Megan described, both are very important components in attacking the graft. So, with this antibody that blocks that crosstalk, we have been able to get good results in our nonhuman primate model, and it's translating very well in this patient also.

Chris - It was more than a month ago, now, and the person is still doing okay. You must be very buoyed up by this?

Muhammad - Of course. I mean, this is like a dream come true.

Chris - If you can do hearts, does this mean then that pretty much any organ in that pig could be transplanted; the kidneys, the liver, other things that we really struggle to provide for patients?

Muhammad - Of course. That's why we use the 10 gene pig. Another group in Alabama and New York will be using kidneys from similar pigs and trying to do a kidney transplant. The same pig can be used for liver and other organ transplants. One pig for all organs.

Chris - Muhammad, thank you very much, and we wish you luck with the rest of the research. That Muhammad Mohiuddin. Isn't that an amazing outcome? And I hope we have brought you full circle here, listening to this programme this week, where we've started with transplantation over a hundred years ago, to the situation where we are now able to move organs from other animals into humans and they don't get rejected. It's incredible.