Pompeii DNA, and a black hole feeding faster than it should

A vaccine trial - called the Nova-301 trial - has just launched across the world to find out if we can protect people against norovirus. The stomach bug is rife at the moment across the Northern hemisphere. It causes millions of cases of diarrhoea and vomiting each year, and it spreads like wildfire, partly because each infected person has enough virus leaving their body, upwards and downwards to potentially infect the entire world population. And it doesn’t only hit hospital wards and schools - but also national growth. So, how might a vaccine help? Well it’s being made by Moderna, one of the companies behind the Covid jabs used during the pandemic, and it’s based on the same sort of technology: the mRNA message coding for parts of the virus that the immune system can react to is injected and hopefully primes a protective response. Dorset GP Dr Patrick Moore is the chief investigator on the study…

Patrick - Norovirus is also known as the winter vomiting bug. It tends to cause severe nausea and vomiting with diarrhoea that lasts about one to three days.

Chris - And how much does this cost the economy, do we think?

Patrick -
If you look at the effect on the NHS, so how much does it cost to give patients who have norovirus the treatment, it's about a hundred million pounds per year. But when you take into account other financial factors, such as lost earnings for example, it's probably estimated around 300 million pounds a year.

Chris - Goodness, it's a lot isn't it? There must be millions of cases to reach that sort of figure. It must be running into the millions of cases per year.

Patrick - Globally, we have about 685 million cases a year. In the UK it's about 4 million.

Chris - There's certainly big numbers. And at the moment there is no way to prevent them apart from infection control and keeping out of the way of people who've got it, presumably?

Patrick - That's correct. So the only treatment is actually supportive. So it's oral rehydration or intravenous rehydration, which is usually a hospital admission.

Chris - And how easy is it to catch?

Patrick - This is one of the most transmissible viruses that we have, actually. It is extremely easy to catch it. So it's either aerosol, someone's vomiting in the same room, or it's what they call faecal oral.

Chris - What's the strategy that's being taken then to try to prevent people catching it?

Patrick - So we're looking to see if we can vaccinate against this virus. It's quite a difficult virus to vaccinate against because there are so many different genotypes and genogroups. So norovirus is actually a family of viruses. And actually if you look at all of the viruses that are out there, there's 10 genotypes. And in those genotypes there's 49 genogroups.

Chris - So presumably you could catch one and make it a response to that, but then if you caught a related one a bit later on, you would have fewer defences against that and you become ill again. So it's pretty tricky to stop it.

Patrick - Yeah, correct. I mean, not all of those viruses circulate within humans, but there are certain viruses that are more popular in humans, and that's what the vaccine is trying to protect against. So they've taken three of those viruses and they've produced a vaccine to protect against those three common viruses that we have in humans.

Chris - And what's the nature of the trial you're doing? How does it run? Who's the Guinea pig effectively and what's the nature of the vaccine?

Patrick - So this is what they call a Phase 3 trial. We have been through the earlier phases. The Phase 1 and the Phase 2 trials have shown a good safety profile and also that the bodies produce a good antibody response to the vaccine. We're looking to recruit in the UK about 2,500 participants from about 27 NHS sites. It's quite a large trial and it's what they call a double blind randomised control trial, which basically means that nobody knows whether you get the active vaccine or whether you get a sort of a saline vaccine. And what we do then is we then measure the efficacy, so how well the vaccine works.

Chris - Presumably you'll be looking at the people you vaccinate to see what the rates of natural infection are then and seeing if you get fewer of those infections in the people who've got the real deal versus the saline placebo. And if you do, then you can argue it seems to be protecting people.

Patrick - That's exactly how it works. Yeah. And obviously we'll be measuring and monitoring the safety profile of the vaccine as well and whether it's tolerated well and ensure that our participants are safe.

Chris - How long are you going to follow the participants up for?

Patrick - Trials are running for two years. We vaccinate our participants. We then do a two year follow up. So in that time we'll look to see how well the antibody response is there for, but also we'll then be measuring whether there are any cases of gastroenteritis which are caused by Norovirus. And that will give us our efficacy endpoint.

Chris - And going forward, let's assume that you do get the result we're all hoping you do and this does work. How is it going to be used?

Patrick - That's a decision for the regulatory authorities to decide how it's being used. But certainly from a medical GP perspective, we do have a significant burden in hospitals and care homes, not just with the residents but also the staff as well. They have a lot of time off work and a lot of pressure on the NHS over the winter months. Ultimately, I see that as the main benefit.

Chris - Would it join the ranks of the annual flu and possibly Covid vaccines that we give people? Given that this does seem to have a seasonality to it, it becomes more common in winter and less so the rest of the year. So it would make sense to kind of front load the system or anticipate when someone's going to come into hospital, give them a dose of this before they come in with enough lead time, obviously, so that they're less likely to succumb when they're in.

Patrick - Yeah, I mean that's a good idea. But I suppose there's two things to sort of understand first, which we'll be looking at in the trial. So the first thing is how long does immunity last? We don't know that yet. And it could be that it lasts for a year. It could be that it lasts longer. And then the second thing is how much is the virus changing? How is it evolving? We don't know whether that vaccine will be effective in subsequent years. So again, that is something that we need to be looking at with this study.

In 79 AD, a huge eruption of Mount Vesuvius destroyed the ancient city of Pompeii. It covered everything in a layer of ash, and, in the process, preserved some of the bodies of the people who lived there. Visitors can see plaster casts made in the late 1800s of some of these remains. And, incredibly, when those casts were recently taken for restoration, a team of scientists were able to extract DNA from the remains of the 2000 year old victims encased within some of them. But while the bodies are certainly authentic Vesuvius victims, the genetic analysis has also pulled the rug from under some of the more romantic narratives that historians have woven previously about the bodies. Alissa Mittnik at the Max Planck Institute for Evolutionary Anthropology is one of the team behind the work…

Alissa - Notoriously, DNA preservation is not very good over long-term in warm climates such as the Mediterranean. Then of course the extreme heat of the Vesuvius eruption might have also contributed to the destruction of DNA. So first of all, we just wanted to see, would we be able to retrieve authentic ancient DNA, and then we really wanted to test some of these popular narratives that had been projected onto some of the individuals from which casts had been made in the past.

Chris - I think I've seen those casts, because I've been to both Pompeii and Herculaneum. It's a very striking place isn't it? But these are the plaster casts of the victims. They were made decades ago, weren't they, some of those plaster casts?

Alissa - Yes, so the method was first developed in the 19th century and since then over a hundred casts have been made. They would find some kind of cavity in this compacted ash sediment and then pour plaster in and then excavate that, and see what it actually was. A human that died there, an animal perhaps? That's quite interesting to think about what actually happened to the bones inside that cavity. So the soft tissue was decaying and the skeletal elements remained and they kind of followed gravity and fell down in this cavity. Then the actual pouring of the plaster would have moved around the bone some more. So what we were working with was, 86 of the plaster cast were undergoing reconstruction at that time, a restoration because they had been damaged in the past during the second World War. So at some of the points in the plaster, we could actually see inside the cast and we could see the bones that were embedded in the plaster. That's where we could take samples for our DNA study.

Chris - Do you get good quality DNA out of that, even nearly 2000 years later?

Alissa - It was difficult. So we sampled a total of 14 individuals, and in the end we only got usable analysable data for five of them. Then we also have to make sure that this is not any modern contamination that was introduced by any of the researchers, the archaeologists or anthropologists, that had been working with these casts in the past.

Chris - Some of them were probing the site even several hundred years ago, weren't they? People became interested in the Pompeian site. So how do you know this really is authentic Roman or Roman era DNA?

Alissa - There are some in silico methods, so by analysing the genetic sequencing data that we get, we can check for certain characteristics that are typical for old DNA. We do have somewhat a picture of what we could expect perhaps for general patterns of ancestry during the Roman era. There has been a big study done on the city of Rome during that time period, and what we found was that, what we see in Pompeii is quite similar.

Chris - Can this begin to give us some insights into the kinds of people who were in Pompeii?

Alissa - Yes, that was part of the analysis we did. So, we looked at different parts of the genome, the nuclear genome that is inherited both from the mother and the father, and then the mitochondrial genome that is inherited only from the mother's side. We compare that to populations around the world, both modern day populations as well as contemporaneous populations, where there has already been ancient DNA published. We related the individuals from Pompeii to see who they were most close to. That gave us some information about who their most recent ancestors could have been, and from which region of the world they originated.

Chris - What emerged then, because Pompei was an interesting place, wasn't it? It was a very rich Roman town. There were a lot of what we in the modern era would call posh people living there, very well moneyed, educated. They also had a large number of people working for them who would've been less so. Does that get reflected potentially in what you see in the DNA?

Alissa - During the Roman imperial era there's a real explosion of genetic diversity, and there's also a greater influence from the Eastern Mediterranean regions like Aegean, Anatolia, the Levant. Although Pompeii is a much smaller town, we do see the same pattern. So there is a large genetic diversity and we see this more Eastern Mediterranean genetic influence. Of course, this could be because these people were indeed themselves migrants from that region or their parents or grandparents were. The surprising thing was that in some of the cases that we studied, the DNA infected did not agree with some of these narratives that had been popularly spread. For example, we were looking at this group of four individuals from the house of the golden bracelet. These were two adults and two small children, and one of the adults was cradling one of the children on their lap. They were traditionally interpreted as being a mother and her child, and the other adult was the father of this group, and there was a second child, so a nuclear family.

Alissa - What we found is that, in fact, all four of these individuals were males. They were also genetically distinct from each other. When we look at their ancestry, although we can't create any definitive new story for these people, we don't know exactly who they were, and how they were related to each other. But it just shows us that maybe the first idea that comes to mind, the most intuitive or the most dramatic, is not the accurate one. We have to keep open mind. I was quite happy to be able to contribute to these people's story and maybe bring their truth a bit closer to us.