Risky research: making diseases more deadly

Along with the more common side effects of getting a COVID jab, like a sore arm or fatigue, some women have reported a change to their periods, ranging from starting early or late, bleeding more heavily, or skipping it all together. Now, some scientists are now calling for a closer look at what might be going on, including Viki Male who’s from Imperial College London and spoke to Eva Higginbotham about how, and why, this might be happening...

Viki - A lot of people, and back in September it was just a little bit over 30,000 people, have reported that they've noticed a change to their period happening shortly after the vaccine, but the changes that people are reporting have been mixed. The most common one is your period being later than usual, and the next most common one is it being heavier than usual, but some other people have noticed other things like skipping your period altogether, or perhaps their period being lighter than usual. The way that this data is collected, we can't actually know for sure if these are changes that are being caused by the vaccine, or if they are natural changes or variations to the menstrual cycle that just happened after people have got the vaccine and so they've made a connection and made a report. I think what is very important to say is that most people who are reporting this find that their period goes back to normal within a month or two. So this is not a long-term change. And, also, we know from other evidence that the vaccines don't have any impact on female fertility.

Eva - Are people reporting this relating to all the different kinds of vaccines that are available in the UK? So Pfizer and AstraZeneca, for example, or is it just one vaccine type?

Viki - Yeah, so it's actually all the vaccines that are available in the UK. And, in my research, I sometimes talk to people who are being vaccinated in other countries as well, and people are also saying this in connection with other vaccines. So what that tells us is that if there is a link between being vaccinated and having a change to your period, which to be clear, we don't know yet, it tells us that it's not, for example, any particular ingredient of one kind of vaccine. That suggests to me that if there is a link it's probably to do with the immune system being activated. And, in support of this idea, we do have some evidence that some other vaccines like the HPV vaccine can be linked with changes in periods. And we do also have evidence that other things that activate your immune system, like COVID itself, for example, in about a quarter of people who have periods, who get COVID, they'll find that there's a change to their period. So all of this does link into the idea that there could be something going on that could be mediated by the immune system.

Eva - Do you have any thoughts on what that mechanism could be? How could the immune system affect your menstrual cycle?

Viki - Well, I think that there are two biologically plausible ways that this could happen. The first is that we know that the immune system can affect reproductive hormones and indeed reproductive hormones can affect the immune system. Being vaccinated could perhaps slightly alter the levels of sex hormones, and sex hormones are what's driving your periods. So if they're changed, you might find your periods coming perhaps a little bit later. The other possibility is that we know that the lining of the uterus is really rich in immune cells, and this is actually what I work on in my day job, and these immune cells have a role in the build-up and the breakdown of the lining of your uterus. And so we could imagine that if we activate these cells, which the vaccine might do, because it gives your immune system a broad, activatory stimulus, this could perhaps slightly change the way that they're acting to build up and break down the lining of the uterus. And that would in turn have a knock-on effect on when, or perhaps how heavily, you bleed.

Eva - And what sort of studies do you think need to be done to figure this all out?

Viki - Well, ideally we would have asked people - solicited this information - in the clinical trials, because if in the clinical trials we'd said to everyone who has periods, "did you notice a change to your periods?", we would have the comparison between the people who got the vaccine and the people who got the placebo, or the other vaccines, depending on the kind of trial. And that would have told us for sure if there was a link here. What we're now trying to do a little bit is play catch up. So one approach to this that I'm really excited about is tapping in to the data that we can get from menstrual cycle tracking apps, where people have tracked their cycles over many years. We know what's normal for them, and then asking them to log when they get the vaccine, and then we can see a change. And, if there is a change, how common is it? Once we've got that data, I think we'll be able to say with quite lot of certainty, whether this is really linked or whether it's just something that people happen to be noticing and making the connection.

Eva - Is it common in clinical trials to ask people if whatever the treatment, or vaccine, or whatever it's for, has had an effect on the menstrual cycle?

Viki - As far as I know, it's never been done in vaccine trials, and that's partly, I suspect, because so many vaccine trials are done on children, because with most vaccines we're developing them to protect children or to protect people as soon as we can, which usually means giving the vaccine to them as children. So I think this is one of the reasons that we haven't usually thought about this before in vaccine trials. But what I hope we'll take forward from this is that, actually, this is probably the sort of thing that we should solicit, because it's the kind of thing that people are interested in, and do worry about.

Biomedical researchers often want to keep animal organs alive outside of the body to study them, just like how you’d keep an organ transplant alive before it goes into a patient. But those organs need oxygen to survive. Right now, the solution is to keep the organ in a bath with bubbles of oxygen. But a team at LMU Munich have another solution that sounds like it’s come straight out of science fiction. To keep their tadpole brains alive long enough to study how the nervous system works, they’ve injected algae cells into the blood vessels in the brain. When illuminated, the algae produce oxygen, which is fed directly to the surrounding brain cells, as Sally Le Page heard from Hans Straka...

Hans - The brain of all animals need an awful large amount of oxygen. Now, what we were interested is how can we actually understand how much energy a brain needs to perform its function? And our idea was why not directly use the oxygen, which is produced by plants and recruit it to provide the energy for the functional brain. Of course, we cannot plant the tree into the brain. So we had to go to a smaller version, which are algae. Algae are green plants at a single cell level. So these algae produce oxygen, just like a tree produces oxygen. Now, by inserting these algae into the brain, we thought we would have the capacity to directly produce the oxygen inside the brain, which can then be recruited by all the nerve cells in the brain.

Sally - So the air that I breathe, obviously I need oxygen to survive, the oxygen comes from trees and algae anyway, and you're like, why don't we short circuit that, why don't we cut out the middleman and just stick the photosynthesis right next to where the oxygen is being used?

Hans  - Exactly. That was the basic idea because it's faster. In our study, we injected algae into the blood vessels of a tadpole. We are working on these animals after euthanizing them and isolating the brain from these animals. And afterwards measured the production of oxygen upon illumination of the tissue.

Sally - You've got these tadpole brain tissues. You've got them floating around in this little bubble bath of nutrients, oxygen, and now you've inserted algae into their brains. What happened?

Hans - As soon as you turn on the light and shine the light on the tissue, the algae you start to produce your oxygen to such an amount that you all of a sudden can measure a considerable amount of oxygen, even inside the brain. Now, when you turn off the light, it goes down to zero again, because first the algae don't produce oxygen anymore, and the brain is starting to consume all the oxygen that the algae have produced actually.

Sally - And does that mean that if you wanted to, you could turn the light up and down on a demo switch and really fine tune control how much oxygen the brain is getting?

Hans - Exactly. That is what we, what we so to speak have done because we have repeatedly turned the light on and off and saw that the nerve cells start firing. And then they stopped firing when we shut down the light and then restart the firing, when we turn on the light. So we could really drive the brain activity by shining a particular amount of light.

Sally - And now we know it's theoretically possible. In the distant future, looking through your crystal ball, can you imagine human treatments where we might start injecting algae into humans to increase oxygen in parts of their bodies?

Hans - In theory, I could imagine something like that, but I mean, I could imagine a lot of things on the long run, as you have been used together with fibroblasts to heal skin wounds, because the oxygen which the algae produce actually helps closing the wounds. So on the external surface, this is already employed. Well, why not employing it internally as well.

Chris Smith spoke with flu expert and virologist at the University of Glasgow, Ed Hutchinson about researchers creating a form of avian flu that could possibly spread between humans...

Ed - So there was this huge question hanging over the influenza field. We knew that influenza was very good at jumping from birds into humans, because that was where previous pandemics had come from. We knew there was this really nasty strain of highly pathogenic H5N1, avian influenza as it was called, that was quite often making people very sick, but we didn't know whether that had pandemic potential. And it wasn't at all obvious how you could, using sort of standard methods, address that question. And then at this conference Ron Fouchier, who is one of the world's most highly respected flu researchers, stood up and basically said, well, we've answered the question. We took a strain of H5N1 influenza virus, we gave it a little bit of a head start knowing what adaptations it would normally take getting used to growing in mammals, and in a very secure facility, we looked to see if it could become transmissible in ferrets and it could. And instantly that answered the question. From that point on, we knew that H5N1, at least in principle, could become a pandemic virus, and it was therefore entirely legitimate to monitor H5N1 strains and to put a lot of effort into making sure that never happened.

Chris - Well we've actually got a clip of Ron Fouchier at that conference where he announced he'd been doing the work. So let's have a listen to how he described his findings...

Ron - We borrowed evidence from a previous pandemic, when avian viruses changed and caused infections in humans. And some of the changes that occured in those pandemic viruses we have introduced by genetic manipulation into an H5N1 virus. And that H5N1 virus now replicates in the upper respiratory tract of mammals. Now that virus has many of the hallmarks of a pandemic virus but we found initially that it was still not transmitted. It was very surprising. And so what we did then was to put it into a mammal and let the virus adapt to the mammal for a few rounds and then take that virus and then that virus will become transmissible. And so by intelligent experiments we were able to introduce three mutations into the virus that were necessary, and then because we didn't know the rest of it, we let the mammals do the rest of the story and they accumulated two or three additional mutations. And those five or six mutations are enough to make this virus transmissible.

Chris - Ron Fouchier speaking to me back in 2011. So Ed, interestingly in that instance, they did it by effectively encouraging the virus to change in its natural way. They weren't actually tinkering with it genetically. Other scientists have done things slightly differently by taking samples that actually came out of the permafrost, for example, of people who were victims of the 1918 Spanish flu and they've recreated the 1918 Spanish flu. Was that with the same aim in mind? To try to understand what it takes for a virus, not just to be flu, but to be a really nasty flu?

Ed - So that was a separate study, one which took place slightly sooner, but actually raised a lot of the same concerns because you've created something which didn't exist before which is potentially dangerous. That experiment there was not answering the question, "could this virus become a pandemic?" Because we knew it did. The 1918 influenza, the great influenza as it is sometimes called, is still by most measures, even today, the worst pandemic we have a record of, but at the time we didn't know why that was so dangerous. So once again, working in a very, very controlled way, the researchers were able to bring back from the dead this virus and work out what had made it so dangerous so that we could protect ourselves against similar viruses in the future. You kind of hope that the first thing to be brought back from extinction would be something a bit more cuddly or exciting, but actually it did turn out to be this virus.

Chris - One of the most deadly diseases we've ever encountered! Did it deliver in the respect that the aim was laudable, as you've said, to try to understand whether these things can become pandemics and what it takes for them to do that, or how do they cause severe disease, are we better endowed with knowledge about flu biology and its threat that it poses to us because of these experiments?

Ed - Sure. So I think, the two studies are separate, but if we look at the H5N1 study, so this question of "could H5N1 influenza viruses adapt to humans?" There were two types of answers you could get from that study - there's a specific answer and a general answer. The specific answers are what kind of changes would the virus need to gain in order to start becoming an efficient mammal virus rather than an efficient bird virus, and we got some answers out of that, and some answers which we'd never known about before. But influenza is a complicated machine and you can fine tune it in many different ways. So although we learned some of the ways in which influenza could adapt to humans, we didn't spot all of them. And indeed the next part of it which came along, which was in 2009, blindsided us because it tweaked a whole set of different features of virus which hadn't cropped up in this study. So it showed us some specific features, some things to watch out for, but it didn't highlight all of the possible ways in which this very changeable virus could adapt to humans. But in general terms, it answered the question definitively "can highly pathogenic H5N1 influenza viruses adapt to become transmissible in mammals?" And the answer was very, very clearly yes, because they showed that it happened and that's an unambiguous answer.

Chris - Are there any ways that scientists could have arrived at the same point with that knowledge in hand without having to do this research, this gain of function research, to create potentially extremely devastatingly dangerous pathogens?

Ed - It's very hard to see how that general question could have been answered in any other way. However, this study published a huge amount of focus on how these studies can be carried out and what people have put a lot of effort into since is to work out ways to do these things even more safely. So we already had very good secure labs, but, for example, there are now ways to break the virus at the same time as you fix it in other ways to ensure that, even if you generate something which is better in some respects, it's not going to be capable of thriving in the outside world.

High-security labs use equipment and procedures to protect themselves and the wider public. But of course, anywhere there are humans, there’s the possibility of human error, and laboratories are no exception. Alison Young is an investigative reporter and Professor of Journalism at the University of Missouri. She specialises in mistakes and errors in biosafety. Sally Le Page asked her what can go wrong in these high-security labs...

Alison - There are a variety of things that can go wrong and that have gone wrong. I have spent most of the last more than ten years reporting on accidents that have occurred at some of the world's most elite labs, places like the National Institutes of Health. Obviously viruses and bacteria don't just walk out on their own. The ways that they can potentially get out usually has to do with human error or riding out on human beings.

Alison - And we had a situation at the Centers for Disease Control and Prevention, where a scientist at the CDC in 2014 was preparing a specimen of what was a benign strain of avian influenza to send for research at another government lab. The problem was that they had used some bad safety practices and prepared the specimen at the same time they were also preparing specimens with a very deadly strain of avian influenza. So they send off the specimen to this other lab and the scientists who are working with it, didn't realize that they were working with this deadly strain of influenza until the chickens in their research study all unexpectedly died. In that case, we got lucky. Those researchers just happened to, as a matter of course, be working with a higher level of protection, but they were not required to for the kind of experiment that they were doing.

Sally - Is it possible to do this research in a way that is 100% safe?

Alison - Everything is subject to human error. These labs are designed with redundant safety systems, but at the end of the day, it's human beings that are operating within them. In the United States, there are only a subset of laboratories that come under actual true regulation. Every year, just in that subset of labs, there are a hundred serious incidents every single year where a person working in a lab has been exposed to some sort of select agent pathogen.

Sally - So that doesn't mean that there are a hundred instances where the virus or bacteria has escaped. It's where there is a chance that the researcher has been infected.

Alison - Exactly. I mean, the good news in all of this is the number of those incidents where the person who is working with the pathogen actually becomes infected is relatively low. And even lower still are the number of times where a laboratory accident has resulted in infections out in the wider community, but those kinds of incidents have happened.

Sally - Can you give us an example?

Alison - Sure. I mean, there are three really prominent examples of this. In the UK in Pirbright in 2007, at a large animal research and vaccine manufacturing facility, they had what was literally a lab leak, where they were working with Foot and Mouth Disease virus to make vaccines. And they had leaky drainage pipes that had corroded and not been maintained. And ultimately there were herds of cattle that were on nearby farms that became infected, and there were 600 cattle that needed to be culled in that case.

Sally - Animal and human pathogens and diseases have their different categorisations, but Foot and Mouth is at the top of the animal diseases. It only is worked on in the most secure facilities and this is happening in the UK, and yet somehow it still managed to escape.

Alison - It really is one of the ones that is held out there as being an example of what can happen, even when you know you were working with one of the most dangerous pathogens out there. We also had, you know, obviously the pandemic has everyone thinking about SARS coronaviruses and when the first SARS virus emerged, after that epidemic was contained in the summer of 2003, there was a series of lab accidents where workers who were unaware that they'd become exposed in their laboratories, went out and were out and about in public until they developed symptoms. So they didn't even know a lab accident had occurred until after they became ill.

Alison - And then lastly, we'll also say that, when we think about the larger consequences of a lab accident on the world, there was sort of a global epidemic that is believed to have involved a non-natural occurrence of a virus. And so this is in 1977, the re-emergence of an H1N1 influenza virus. This was a strain that when scientists studied, it looked like it had been frozen in time from 1950, the last time that it had been seen. And it's widely viewed that it was either some form of a laboratory accident or some sort of a vaccine trial that had a mishap. So these kinds of things where the pathogen gets out and affects the wider community are relatively rare, but they have happened. And the concern that is being expressed when it comes to gain of function research by scientists and some members of the public is that they may be rare, but there's the potential for devastating consequences.

Sally - If human error is inevitable and there is always going to be the chance, however small, that there could be an accident, in your view, having reported on this for the last few decades, do you think that all of this research should just be stopped? Is it just too hot to handle? Too risky to do anything with?

Alison - As a journalist, it's not my place to say either way, but that is part of the important debate that is playing out right now. There are those who believe that this research is vitally important to developing various treatments and understanding where the next pandemic may come from. But there are those who believe that the risks are not worth whatever the benefits are. And I think that it's an important debate that all of us need to be paying attention to.

Sally - And who does get to decide on whether the risks of this research outweigh the benefits.

Alison - That is an outstanding question. And that's one of the things that's out there for debate. When it comes to very risky research, there are some mechanisms in place for some layers of approval, but questions have been raised in the United States about whether those structures are adequate to ensure sufficient oversight.