The Public Accounts Committee today held its session with Dr Rachel Glover as part of its inquiry into the use of genomic sequencing in response to a pandemic in the Isle of Man. This is the first of four articles covering their marathon three hour evidence session. 

PAC line up;

Juan Watterson MHK – Speaker – Chair (JW)

Lawrie Hooper MHK – Vice Chair (LH)

Jane Poole-Wilson MLC (JPW)

Chris Robertshaw MHK (CR)

Julie Edge MHK (JE)

FEAT: Dr Glover (Dr G – lovely voice, she should consider audio books)

JPW: Welcome Dr G. Tell us about the purpose of genomic sequencing?

Dr G: It’s been around for about 25 years. Sequence means that we read the DNA or RNA letter of organisms. It’s not a new technique, it’s been around a while. 

For virus testing and pathogens it means we can see how the virus is evolving over time. 

Strains  = a distinct number of mutations. People who have been infected from the same source can be linked. It’s really useful. 

JPW: You talk about how it can be used in the context of pathogens, what do you think about the different approaches taken by different countries? HQ says it isn’t part of the immediate response to the crisis yet, Jersey has said a local lab for sequencing should be developed as we transition to living with the virus?

Dr G: In March 2020 the UK Gov formed COG UK which set up a network of labs who could provide tech and expertise to sequence viral genomics from Covid to see the variation in viruses circulating in the country. It was essentially an academic surveillance tool that builds on previous work. Previously it’s been used for Ebola and when Covid became a big pandemic, we had the expertise available to us in the UK to do so. It also helps us track variants that are coming into the country and where they’re going but this is only a broad stroke approach. It can be used for looking back but in the UK we used it on a real time basis. We developed a system to test bacteria around sandwich factories in the UK which was used to track any spread of bacteria around food production, this is the same principle for tracking virus from patient to patient. Covid is just under 30,000 letters long made up of RNA, if you think of that as a book chapter with paragraphs then in a virus that is a gene which creates a protein that has a job. For example the spike protein in Covid is what allows it to go into a cell and attach itself to us. But if that changes by just one letter then that can change the way that protein behaves and what it means, like changing cat to cut. That can change the way the protein behaves so it could make it more transmissible for example. Unlike DNA which is double stranded, RNA is single stranded and that means it can change a lot easier.  Viruses are like terrorists, they invade and want to reproduce themselves and break out. There are silenced RNA changes which don’t change the structure of the protein but others do. When the typos occur and the RNA changes, it creates lineages. 

Over the last 12 months scientists have tried to explain the changes as it passes through millions of people, so the lineage in the UK is different to Brazil. Those lineages are a result of the changes that are made. It is essentially a range of changes made in specific locations. New changes crop up all the time and when that happens there is a split. The most well known split now is what is known as the Kent variant. The reason different countries are working in different ways is down to the politics. 

The UK was well placed as it had genomic scientists to just start the process, other countries didn’t jump on it, USA has the capability to do it but they haven’t done that much because Trump wasn’t keen on it. Wales has been sequencing as much as possible and they have been looking at variants introduced to Wales which has led to border rule changes such as banning people from going in and out of Wales and it was genomics which informed the politics. My experience with UK gov was to use it in a practical sense rather than academic sense, I’ve spent most of my career in applied science. The next step is from academic to practical use for small outbreaks and filling in unknown links.

JPW: Huge amount of information. Thank you. A very helpful insight. Some follow up questions – you talked about the letters changing, how often does it happen?

Dr G: Don’t have a specific number, I can probably get a paper for you on it though. Mutation is random. We can estimate but not a hard and fast rule. You can get at least one maybe two different across the 30k letters within the householder. 

A superspreader event would mean a lot of people with the same strain. We would expect at least one or two per transmission.

JPW: You talked about the silent mutation?

Dr G: Can get you a paper on that too. RNA letters mutate faster than the impact on the amino acid. Mutations can happen and have no effect. Lineages happen when the amino acid changes. 

The way mutations can happen – they can occur in the same place, independently in different lineages. 

JW – From a lay person’s perspective, if three of us test positive, say myself, my wife and someone at work, could genomics be used to say where I got it from? 

Dr G: Lineage is a blunt tool so it can tell us all of you have the same lineage but that’s it. But when you start to look at specific amino acids and RNA changes then you gain more info, like zooming in with a high res camera. The actual RNA letters are the highest resolution you can get and if you add all of that together and recognise that there will be changes even within household transmission then you can map the spread more accurately. Using those models, you can effectively track who gave it to who. That has been possible since about 2016, it has been done for transmission studies in the UK and beyond but often this is done in very high risk areas such as a kidney dialysis ward in Scotland and before Covid it was used to track MRSA in a maternity unit. Even though people will be the same variant, you can also show people being part of a separate cluster. 

LH: You’ve talked about realtime turnaround – what do you mean by it?

Dr G: However long it physically takes. In the past it has taken up to a week. Advances in technology over the last few years means we can prepare the sample and do it quickly. Liverpool has a five day turnaround. In an outbreak situation, I still would jump in with both feet and try to do it as quickly as possible and to get the best results possible. Five days, when it can be done in 24 hours is real time sequencing. 

LH: There is a lot of info out there about it, different places are giving different timescales, Wales says two days.

Dr G: We could speed it up here because we are small and more agile.

LH: You mentioned we’re six months away from real time high resolution sequencing, could we do that tomorrow if we wanted? What we’re doing by signing up to Liverpool is saying we’ll get there eventually.

Dr G: Not exactly, it’s based on priorities, for Liverpool theyr’e looking at the whole of the north west, we could look at high resolution data differently. I imagine in a few months in the UK they will sequence everybody in each outbreak because that’s where the priority will be but right now its on which isolates are we seeing coming in from Brazil and what is the main variant in the UK. It could be six months or later if there is a fourth wave.

LH: So we could do it quicker because we’re smaller?

Dr G: Yes, we could have been doing this first and mapped the outbreak and got a scientific paper out based on the Isle of Man, but it would’ve been nice to see the Isle of man at the forefront of science. 

LH: DHSC says genomics wouldn’t help due to missing links in the chain?

DR G: My experience is that it can absolutely fill in the links. Four/five years ago there was an outbreak in Ebola in West Africa, effectively it can hide and then infect someone else. A couple of months ago there was a small outbreak again and because so much genomic sequencing was done in 2014/15 they were able to see it was exactly the same variant as five years ago. That is rare but it was how they could track down the index patient who had been harbouring it for five years. It will be interesting how the COG UK data for the island eventually is open access, which for some reason isn’t, someone like myself will be able to look at the sequencing and determine if we are looking at two outbreaks or whether it was just one that festered in the background. I don’t know the answer to that now but genomics could tell us. While they only rely on looking at the lineage, they are looking at the blunt end of the tool. It will be interesting to see these results come out.

LH: We keep being told it’s the unknown cases causing issues, but you’re saying quick could solve that?

Dr G: If we had on island sequencing and the jungle drums are saying it could happen, then they’d still only get the same results as five day testing but the further analysis is what shows the data. You need to use two separate labs to do the sequencing and the covid testing so as to avoid cross contamination. Guernsey is currently setting this up because the issues can occur in a pathology lab. The lab was keen to put machines close together, but on island sequencing needs more thought than just having the machine.

LH: From my perspective it seems like we’re missing a tool, it’s no silver bullet, but it does seem to provide additional info for everything else that we’re asking for such as missing link. We’ve been told by gov that the possibility of using sequencing to link clusters doesn’t exist.

Dr G: There is nobody in gov or DHSC who understands it to a high enough degree. I know they are taking advice from Liverpool but their explanations will be academic ones and what is being done with the data, not what is possible with it. This could connect the dots and if it works on just one case then it’s worth it. The data we have so far is blunt tool data, if I had the sequencing then I could do it but I don’t have the data.

JE: A lot of today has been informative but alarming. Following on from sequencing, Public Health has told us that links can usually be found using the standard epidemiology approach, they don’t think you can split it beyond the Kent variant.

Dr G: If they don’t get any data beyond what variant it is, then they won’t get any further info on that, they need to look at the mutations below the RNA itself. As I understand it, there isn’t anyone in gov who can analyse that data. The team I worked in, there were about 10 of us in the UK doing it for their gov, so the island wouldn’t have that. It is frustrating to hear the gov say that but that is because it is the advice they are receiving.

JE: If you had input, do you feel it would have helped with lockdown periods or identifying sites which they’ve stopped doing, would it be beneficial?

Dr G: I can’t comment on why they won’t name sites, maybe it was because there were so many it was unhelpful but having the ability to test anyone and everyone who wants would be very helpful as it would identify cases you wouldn’t have picked up. I’ve rowed with people about symptoms, I know of people who said they had a cold and then their partner tests positive. The Isle of Man is following European guidelines but they are only just seeing the impact of the Kent variant so they haven’t updated it yet. I think they will update that list and we’ll be behind the curve. It comes back to what I said, knowing what variant you have got should change how you manage the outbreak. It’s about using every tool in your arsenal and that includes opening up the symptoms list to encourage people to get tested. Genomics may help to close missing links but you need to test people to get the sequencing.

JE: Border opening, what contributing could genomics give for opening the borders and preventing future lockdowns?

Dr G: It isn’t quite quick enough yet, if we could do it in five minutes we’d be laughing but we’re limited by physics. In regards to testing at the border there are possibilities there. I’ve previously joked we could test on the Ben-my-Chree. I think we’re getting to the point where vaccinating is more important than testing for opening of borders. We could even possibly open up more than we already have now.

Dr G: I think they have to continue with genomic sequencing because the Brazil variant is on the horizon which puts the vax strategy at risk. Genomics doesn’t have to be the only way, if you know the variant then there would be a real time PCR that could test for a variant after someone tests positive. Knowing what variant you have coming in is very important because if the variant blows through the vaccine programme then the problems begin again, that isn’t limited to the Isle of Man of course it’s a worldwide issue. 

JPW: Been fascinating. You said we could sequence on island, if we did, could we feed in to the Liverpool lab for the UK sequencing?

Dr G: Yes. Only info that the UK labs need are the meta data and RNA. All they want is date they were sampled, their gender and fast half of a postcode, it is not correct that the island can’t feed into the process. Birmingham and Exeter have said the same too.

JPW: Any accreditation we’d need?

Dr G: No, I asked that specifically because they say my lab doesn’t meet standard and Liverpool said all you need is the right equipment and follow the right protocols. Howard said my company wasn’t good enough. I spoke to Liverpool and they said I could do it from my lab. The issue comes down to funding, nobody on island can get funding because it is a UK funding system so it comes back to having to be funded on island.

JPW: As I understand it, there is no cost to enter into the UK research but ironically it sounds like the cost of not doing it could be greater?

Dr G: Yes when I said I’d do it for free, it would cost my company thousands but I wanted to do it.

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