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The Importance of World Hepatitis Day - Dr Joe Grove explains why World Hepatitis Day is so important, as one in 12 people worldwide are living with the disease...
Hepatitis in the Clinic - Professor David Adams explains the types of hepatitis, and how they are treated...
The Science of Hepatitis - Professor Jane McKeating takes us through the science of hepatitis, from it's discovery in the 1980s through to her groundbreaking work in Birmingham...
Living With Hepatitis - A Patent's Perspective Part 1 - The scientific developments by Professor McKeating’s team don’t just help us with treating the diseases; the more we understand the virus, the less fear we hold. This is especially true for those who are suffering from the disease...
Living With Hepatitis - A Patent's Perspective Part 2 - At the end of World Hepatitis Day, Jules - a hepatitis C patient for over 20 years - regarded the researchers as the unsung heroes of hepatitis treatment. I found out what had attracted him to the event in the first place...
Transcript of Interviews
The Importance of World Hepatitis Day
Dr Joe Grove
Ben - World Hepatitis Day was a global event dreamed up by the World Hepatitis alliance, the WHA. In addition to the amazing events held at Birmingham University, the WHA sourced support from former US president, Bill Clinton, and London mayor Boris Johnson, who voiced his support through Twitter. Birmingham University’s events saw researchers, students, members of parliament and patients and the media gather to hear about the importance of Hepatitis research. As well as exploring the latest scientific advances, we heard about the clinical implications and the opportunities for young doctors and PhD students. Dr Joe Grove organised the event and joined me afterwards to explain exactly what World Hepatitis Day is about.
Joe - World Hepatitis Day, like World AIDS Day, has the general goal of raising awareness of viral hepatitis internationally. It’s a little-known fact that one in twelve of the world’s population are living with chronic hepatitis, caused by the hepatitis B virus or the hepatitis C virus, however, the vast majority of those individuals don’t actually know they’re infected. However if people seek out treatment, they may be able to have a resolution of their illness. So it’s important that we raise awareness. And also people should be aware about how you can come into contact with these diseases and maybe change their lifestyle to avoid coming into contact.
Ben - One in twelve people seems awfully high, I mean, that’s hundreds of millions of people, surely?
Joe - Yeah, that’s five hundred million (500,000,000) people worldwide. Obviously, like a lot of diseases, for instance like HIV, the distribution varies across the globe. In the case of hepatitis C virus, if you’re looking at America, around 1-2% of the population; in the UK it’s somewhere just below 1%; however if you maybe go to areas such as Egypt where, due to poor sterilisation during a vaccination campaign, you could look at a prevalence of 40-50% of the population in certain areas infected with Hepatitis C.
Ben - So what do people do to put themselves at risk of contracting Hepatitis?
Joe - Both hepatitis B and hepatitis C are predominately blood-borne infections, so you come into contact through blood to blood contact. So, for instance with hepatitis C, before there was a decent screening regime, the vast majority of infections in the West were due to blood transfusions. So people receiving blood transfusions before 1989 would possibly have come into contact with HCV [Hepatitis C Virus]. Now, in the developed world, such as the UK, the majority of new infections occur via intravenous drug users. However, it is also possible to catch the disease via sharing your toothbrush or razor or other drug paraphernalia with somebody who may be infected. hepatitis B on the other hand, you can also catch through those modes of transmission, however it is also quite easy to catch hepatitis B via unprotected sex. So there are numerous routes of transmission, not dissimilar to HIV.
Ben - And what are you working on here in Birmingham?
Joe - So, specifically in Birmingham, we are looking at the way in which hepatitis C enters liver cells and we do this using the recently developed cell culture system. hepatitis C was discovered around 20 years ago and it has been only since about four years ago that we have been able to grow the virus in the lab. In having this full replication system, we can study the entry of the virus in cells. So we’ve been using different compounds and also looking at the effect of antibodies on whether or not the virus can infect cells. And also identifying and picking apart the receptors the virus uses to enter. Some of the most interesting work so far has been looking at the tricks that hepatitis C might use to evade the immune system. For instance, it’s becoming apparent that HCV can pass from one cell directly to another, so from one infected cell to an uninfected cell, feasibly within the liver. The advantage to a virus of doing this is that it does not come into contact with circulating antibodies. Antibodies can stick to viruses and neutralise them, make them ineffectual. So by transmitting directly between cells, the virus avoids this.
Ben - Birmingham seems to be at the forefront of a lot of Hepatitis research, what’s so special about Birmingham?
Joe - We’re in a very fortunate position here to have some excellent scientists and clinicians and a leading liver unit that carries out hundreds of transplants a year for a lot of HCV and HBV [Hepatitis B Virus] patients. With severe disease, a transplantation’s their only option. So, we have a lot of elements converging here in Birmingham, so it allows us to feed a basic scientific research into clinical results for patients. We also, here, have a dedicated clinical research facility.
Ben - And today’s been a wonderful day to show it all off.
Joe - Yeah, it’s been great. I think one of the moist valuable elements, really, is having representatives from the patient community come along. I think it’s important that there’s a communication between the different elements of viral hepatitis support throughout the UK so that we have the science going on, we have the clinical research and treatment; there’s also groups doing social work for people infected with the HCV, like the Hepatitis C Trust. The work they do offers patient support. And obviously there’s an increasingly large patient community. I think it’s good to foster relationships between these, and today has been a great opportunity to do that.
Ben - That was Dr Joe Grove explaining why he thought a World Hepatitis Day event was important and why Birmingham University was ideally suited. As well as forging relationships between the diverse groups that were attending the event, Dr Grove took us on a tour of the labs, showing us both the scientific and clinical research settings. This was a great opportunity to really understand the research in its proper context and a view behind closed doors for the Hepatitis patients who had come along.
Hepatitis in the Clinic
Professor David Adams
Ben - As part of World Hepatitis Day, we were taken on a tour of the scientific and clinical research facilities. This was a great opportunity to really understand the research in its proper context and a view behind closed doors for the Hepatitis patients who had come along. To understand more about clinical approaches to hepatitis, I spoke to Professor David Adams. David is a medical doctor as well as a Professor of hepatology and so ideally suited to explain how the scientific research impacts on clinical applications. David first explained the difference between the different kinds of Hepatitis.
David - There are four different types of hepatitis that we commonly see; called A, B, C and E. D is a rare virus, which is an obligate parasite of B. But to talk about the four main ones, A and E are similar in that they are both transmitted via the oral route, so they are particularly at risk where you have areas or poor sanitation. Both of those viruses predominately cause acute infection, which resolves without long-term sequelae. A very small proportion of patients may unfortunately develop a really severe Hepatitis and go into liver failure but the majority of patients recover and don’t have any chronic, persistent infection. That really sets those two viruses apart from hepatitis B and C , which can both be associated with chronic infection.
Hepatitis B, worldwide, is a huge problem in countries where it’s endemic, that is where the virus is always present in a high proportion of the population. It tends to be contracted by children in the neo-natal period. Those patients tend to develop long-term, persistent infection without a lot of liver damage but later on in life that can cause a slow progression to chronic hepatitis and cirrhosis and liver cancer, so that’s one of the main causes of cancer in the developing world. In the Western, developed world, hepatitis B is more usually contracted as an acute illness in adults, usually via sexual transmission, where it can present with an acute hepatitis that resolves but, in a proportion of patients, probably 20-30%, the virus persists and those patients become chronically infected and will need long-term follow-up and, possibly, treatment to prevent them going on to develop cirrhosis and liver cancer.
Hepatitis C is a different type of virus to hepatitis B. hepatitis B is a DNA virus, whereas hepatitis C is an RNA virus. It’s also contracted via the breaking of a body barrier such as a mucosal membrane or, particularly, blood and is usually contracted through contaminated blood products either by treatment in the developing world with unclean needles, or intravenous drug use in the developed world. And the problem with hepatitis C is that probably in about 80% of patients who are infected, they will not get rid of the virus. They may not even know they’ve been infected. The acute illness is usually very mild but 80% will go on to develop chronic infection and of those 80%, a proportion, probably 20-30%, over a long period of time will go on to develop scarring, cirrhosis, liver failure and liver cancer.
Ben - So hepatitis leads to liver damage which, in turn, can lead to liver cancer. What are our options for treating it once the damage is there?
David - Once the damage has been done and the patient has got cirrhosis and end-stage liver disease, either in the form of liver failure or, as you say, the development of liver cancer, then we don’t really have any medical options and the only option is liver transplantation. There are several problems with liver transplantation; one being that there is a shortage of donors, so there’s a waiting time and there aren’t enough donors for the number of recipients we would like to transplant. The second problem is the transplant doesn’t, unfortunately, get rid of the virus because the virus seems to hide in other sites in the body, we’re not quite sure where, but almost invariably after the transplant the liver gets re-infected with the virus so the recurrent infection and recurrent hepatitis disease is a real problem. Many of these patients will end up needing to be re-transplanted because the disease has recurred. As far as liver cancer is concerned, transplantation is a problem because we know that we can only successfully transplant somebody with liver cancer if we catch the cancer early enough. Once it’s grown beyond a few centimetres in diameter we know from experience that after the transplant the cancer will rapidly come back. So it’s very important that patients with cirrhosis, with end stage liver disease, are screened. We have blood tests and ultrasound scans that we can do to screen for liver cancer and if we pick it up in early stage then get them, if appropriate, onto a transplant waiting list as soon as possible so we can transplant them before the cancer has spread too far. But it’s going to be important in the future to combine transplantation with drugs that prevent the replication of the virus and the re-infection of the liver with the virus and this has been very effectively done nowadays in hepatitis B so that hepatitis B infection was a contra-indication to liver transplantation because the patients all got re-infected and died. Now, actually, with antiviral therapies, which are very effective, it’s one of the best indications for liver transplantation. So hopefully we’ll be saying this about hepatitis C infection in the future.
Ben - So what are our current treatment options?
David - So the current treatments are based around interferon, which is a naturally occurring antiviral factor produced by the patient’s own body when infected by a virus. Particularly a form of interferon called pegylated interferon, which means it’s linked to a chemical which makes it last longer in the body than it would otherwise. And that’s given by injection and that’s combined with a drug called ribavirin, which has some weak anti-viral properties but seems to work very well in combination with interferon. So those are the current, standard treatments and there are a range of new treatments coming into clinical trials at the moment. We hope that these will come into clinical practise in the future but our mainstay at the moment is interferon and ribavirin.
Ben - Interferon works by encouraging the body’s own defences to kill off infected cells. What are the side-effects?
David - The side effects are really, pretty much, that it makes you feel like you’ve got flu because when you get flu it’s interferon that’s released, so patients can get headaches and feel agitated. One particular side effect which can be really quite profound is depression. Many people, when they get a bad viral infection, such as influenza, do feel profoundly depressed before, during and after the infection so some patients just can’t cope with the interferon because of the effect it has on their mental well-being. The side-effects tend to go off with time and they can be treated but they’re not inconsiderable and some patients just can’t tolerate it and have to stop treatment early.
Ben - So killing off infected cells with interferon seems a bit like taking a hammer to the problem. Are there no more subtle ways around it? Can we stop the virus replicating or can we stop it getting into cells in the first place?
David - Well that’s the aim of the new generation of drugs, to be much more specific and to tackle different parts of the hepatitis C machinery that blocks its ability to reproduce or, as you say, even better than that, that’s blocks its ability to actually get into the cells. Those drugs are potentially very exciting and some of the early trials look very promising, but as with all antiviral drugs, one of the concerns is always that the virus will mutate and become resistant to these agents, so we need to look out for that very carefully. And at the moment none of these drugs are licensed for routine use; they’re all still at the trial stage but I think the next few years is going to be an exciting time for new therapies.
Ben - That was Professor David Adams, who’s confident that we’ll see developments in hepatitis therapies in the next few years.
The Science of Hepatitis
Professor Jane McKeating
Ben - Any new therapies will ultimately descend from a greater understanding of the science of hepatitis. So I met with Professor Jane McKeating, who is head of the hepatitis C Research Group at Birmingham University. Her lab has been responsible for some groundbreaking hepatitis C discoveries, although the disease itself was only discovered relatively recently.
Jane - So hepatitis C was discovered about 20 years ago by Michael Houghton and his colleagues at Chiron.
Ben - And since it was first discovered how much have we found out about it?
Jane - Oh my gosh, a lot! Over the last twenty years there have been huge, really big, jumps, I would say. This doesn’t happen very often but in the hepatitis C field there have been jumps over the last twenty years from discovering the viral genome, to then showing that that virus was capable of actually infecting animals and causing hepatitis, then was the ability to grow the virus in the laboratory and that immediately led to the development of new antiviral therapeutics so I think that really it’s a textbook of showing how good basic science can lead to rally big strides forward in understanding a human disease.
Ben - And through the understanding that we’ve developed, we’ve already been able to wipe out hepatitis C from blood transfusions but we still don’t have a working vaccine or a treatment that we know will wipe it out. How far away do you think these might be?
Jane - Let’s say that currently the accepted therapy is an interferon/ribavirin combination. Now in some viral genotypes that’s quite a good therapy and we’re getting about a 70% response rate. When we say response rate, those individuals are now, clinically, cured. We can’t detect the virus in the blood anymore; we can’t detect it in the liver. We would hope that within the next five years that we will see a huge battery of new therapeutics coming on line, will be routinely used, targeting the viral enzymes. And I think that we’ll envisage that in five years time, we’ll start to be at a stage where we are with HIV; in that you will give tailored drug therapies so that you want to give the best possible combination of therapeutics to an individual that respond to the virus they’re infected with. That’s maybe more in the ten year window but, certainly, there will be a real change over the next five years.
Ben - So how does it initially get into the liver?
Jane - We envisage that it will be blood-borne and that most things naturally will migrate to the liver. Firstly it will come into contact with the sinusoidal endothelial cells. Now they are interesting as they express a number of the receptors which we think the virus engages but they’re not permissive to viral infection. And so we think that they may be important for, maybe, antigen uptake; that they may be important for tolerising the immune response that may be initiated in the liver; we then get movement of the virus into the hepatocytes. That’s the primary cell-type within the liver where the virus is replicating. At the moment we know that there are four molecules we believe are important. The first two molecules were CD81 and scavenger receptor B1, which is important for cholesterol metabolism. Now both of those molecules, I think we could safely say, could be classified as receptors in that they interact with the virus. We then have two other molecules; claudin-1 and occludin, which are members of the tight-junction protein family, which, so far, may actually be a facilitator of entry in that they are required but they may not interact with the virus directly. So we have these four molecules which, interestingly, are expressed in other places of the body but it’s how these four molecules work in a very unique way to the hepatocyte that we are currently trying to understand in how that’s taking it into the virus and we are looking for antibodies and small receptor mimics that can actually target these molecules and, therefore, prevent entry.
Ben - And how does it get from one liver cell to the next one, does it have to go via the blood again?
Jane - That’s a good question, something that we’re working on quite actively at the moment. It looks now that that there are two pathways. Particle assembly is essential and you can get release from one liver cell and re-infection from the cell-free particle route which is the traditional way and that’s dependent on all the receptors I’ve just described. Or the more recent data we’re finding is that the virus seems to move through cell-cell junctions and, therefore, is resistant to complement and antibodies that you will find in the peripheral blood.
Ben - Many different viruses are also good at hiding from the immune system. Does hepatitis do the same thing?
Jane - Yeah, we published earlier this year that hepatitis C virus can actually internalise into B cells and we’ve also documented it going into T cells, very much akin to what’s been published for the HIV, that you can actually move around the body and hijack a B cell and that B cell doesn’t support the replication of the virus but it can deliver it to a hepatocyte. The fact that I said earlier that the virus actually utilises tight-junction proteins; these proteins are actually very important for maintaining epithelial cell barrier function and the hepatocytes of the liver form very tight barriers and what we find is that when they become infected that barrier breaks down and you get a reorganisation of localisation of tight junction proteins which, interestingly, allows lymphocytes to get into areas of the liver where hepatocytes are, which we would perceive may actually promote the fact that the virus is actually internalising into a B cell and for that B cell to then deliver the virus to a hepatocyte, so it’s quite a neat trick.
Ben - So the virus infects a cell and then not only primes that cell to allow that cell to pass the virus to neighbouring cells of the same type but also actually encourages immune system components in that it can then infect to use as a vehicle...
Jane - Yeah, that’s pretty new information, yeah, from what we are seeing at the moment. What we don’t know as yet, is that a route that you could actually use to infect host to host as well. But we know it is a blood-borne virus, whether the blood is actually within a cell or in a cell-free form and whether being within a B cell actually maintains the virus half-life is an interesting thought and we are literally doing those experiments at the moment.
Ben - You’ve mentioned HIV which has obviously had an amazing outpouring of resources and a great deal of study. Can we learn from the research that’s gone into HIV, ways to avoid the resistance that’s been seen in HIV?
Jane - I trained as a HIV [researcher], this is where I did my PhD and studies so I think there’s a huge amount we can learn from HIV. We certainly can see it’s an RNA virus so we immediately with a multi-drug therapy we will see resistance patterns. And we know we are going to resistance patterns in hepatitis C treatments, so I think it’s set the stage, we know we are going to have to go with combination therapy, and HIV is leading the way on tailored therapies so there is much we can learn and we mustn’t reinvent the wheel.
Ben - So what’s the next step for you and your team here at Birmingham?
Jane - The next step. We’re really still trying to understand the viral entry process. Why does the virus only really infect the hepatocyte and, importantly, how we can design studies to understand the pathology? How does the virus get into the liver but, more importantly, does the virus itself cause the damage to the liver or is it the immune infiltration that is actually causing the damage? Now, classically for many years, hepatitis is seen to be something where the damage is driven by the immune system. But that was before we had a virus in a lab which we could grow and a virologist can’t really do much in the lab until we have a virus. So now that we have one we are beginning to see that the virus is contributing to the pathology also so I think we really want o understand those interactions and how the virus can modulate the lymphocyte recruitment and movement into the liver.
Ben - So as we discover more about the hepatitis C virus we are learning more about how it evades and takes advantage of our immune system. Although we’ve only had twenty years to study the virus, the science has come on in leaps and bounds and many potential routes for clinical development lie ahead of us. That was Professor Jane McKeating.
Living With Hepatitis - A Patent's Perspective Part 1
Ben - The scientific developments by Professor McKeating’s team don’t just help us with treating the diseases; the more we understand the virus, the less fear we hold. This is especially true for those who are suffering from the disease. So I spoke to Wendy to find out what brought her to the World Hepatitis Day event.
Wendy - Well, I had hepatitis C for approximately twenty years. I had treatment five years ago and I’ve been clean ever since, you know, clear of the virus should I say. And I have a lot to do with the Hepatitis C Trust; I go to conferences, I’ve helped set-up a Hepatitis C support group, and they just invited me along today so I thought it would be a really good opportunity to see how the other side works, really, and what progress there is and what new things are going to come about to help people with the virus.
Ben - We’ve heard today that in the course of the last twenty years there have been some very dramatic leaps forward in the understanding the science of hepatitis C. As someone who suffers from the virus, do you appreciate being told all the nitty-gritty; is it helpful for you to know some of this deep science?
Wendy - Yeah, I think so. Twenty years ago, when I was first diagnosed, they phoned me up and said I needed to come to the liver unit because I had this hepatitis C virus. I phoned my dad and I told him and he said I think it’s something to do with AIDS. That was my first thought. For my first three years I was back and forth from the liver unit and twenty years ago they didn’t really tell you a lot. I didn’t really understand what it was, anything about it, so I walked away and forgot about it, basically because I didn’t know the implications of it. So for five to seven years I walked around forgetting that I’d got this virus because I didn’t really know anything about it; maybe it’s I didn’t want to know, I don’t know but I think not enough was said to me to understand. They may have told me but on my first appointment I didn’t really have a clue what they were on about so I think people really need to know because it gives them more of an understanding as to the seriousness of it and the implications of having it long-term. I think the media are getting better with it now but I still don’t think it’s enough to let people to know how serious it is.
Ben - So you would support World Hepatitis Day from both a personal and professional view.
Wendy - Oh, absolutely, absolutely. I work for a drugs service. We have approximately 800 clients. We recognise that approximately 25% of those have got the hepatitis C virus and we haven’t even tested all of them. It’s just so scary because of the amount of clients that are walking around that don’t know that they’ve got it, that could be infecting other people that haven’t got it, and I just think it’s really scary and I don’t think they understand. The majority of people that you talk to will say “oh, that’s that thing that kills you, isn’t it?” Well no, not necessarily, but left untreated it will really have a detrimental effect on your health in the long-term. They just don’t really understand.
Ben - And having just had a tour of the research facilities here do you think you’ll encourage more people, both healthy and people who have hepatitis, to actually get involved in the research?
Wendy - Yeah, definitely, you know it’s just about raising awareness from my point and coming to places like this and having tours and speaking to clinical directors and research students, it gives more people an insight and I’m excited now because I know that there’s more research being done and they’re becoming more better treatments for people; if they have more treatments for people then there’s a better success because, at the moment, a lot of people are failing the treatment because of the side effects because they just can’t manage it so, if we can make that easier for people then more people can get treated. I mean, we can’t treat 50% of our clients that I work with because of their chaotic lifestyles, the support network they don’t have and the vulnerability. We couldn’t contemplate putting them on treatment because they’d fail because of the extent of the side effects that it has on people, you know, we need to be looking at making it easier for people to have treatment.
Ben - Wendy’s position, not only a former patient but actively working with hepatitis patients in the community, highlights one of the benefits of World Hepatitis Day. It’s a unique opportunity for researchers and clinicians to communicate with patients and that means that everyone can benefit.
Living With Hepatitis - A Patent's Perspective Part 2
At the end of the day, Jules regarded the researchers as the unsung heroes of hepatitis treatment but I found out what had attracted him to the event in the first place.
Jules - For more awareness about hepatitis C and to see what goes on on the other side, which I found very interesting. Because I think the research people are the sort of the unsung heroes, shall we say.
Ben - And, you actually suffer from hepatitis C, how long have you been suffering?
Jukes - 25 years, 26 years, I’m not really sure.
Ben - And in that time, as we’ve seen today, there’ve been some huge advances but still, relatively little is known and it’s great that we have opportunities like this. And do you think more people should find out about the clinical research and the science behind it?
Jules - I think so, yeah, because people aren’t so scared of what’s going down. Because a lot of people are ignorant, shall we say, of what’s hepatitis C and the causes and the facts and people think you can catch it by holding hands with somebody who’s got it and that’s not the case. And this sort of thing brings awareness from both sides.
Ben - And obviously it’s very much in your interest as well as in the public’s interest that we find new treatments and new cures
Jules - Well, without a cure I’d be dead. If you get it and you don’t get treated, somewhere along the line you’re going to die and that’s as easy as...
Ben - So how have you been treated for hepatitis?
Jules - I’ve had liver biopsies, I’ve had the early stage interferon when it was first under development, I had to give myself three injections a week and lots of tablets and that wasn’t very nice. That failed. Then a few years later I took a second course of interferon for 18 months, which was pegylated so I had to have only one injection a week. That wasn’t quite so bad but still not pleasant. And I’ve got twenty weeks left, now, of my third course of interferon, so far so good. You can have nothing in your body and then all of a sudden the treatment stops and it’s back and they’ve got to give you something else. But you know you’ve just got to keep trying and trying. You’ve got to be a pretty clean liver, just keep yourself focussed and that’s all you can do isn’t it?
Ben - And it’s also very important that people get tested, as you said there’s a lot of stigma. There’s even stigma about having a test.
Jules - Well, if they’ve ever had tattoos, shared a needle or anything else then they should have a test because you never know. You could be walking around thinking you’re happy as Larry, sound as a pound but, unbeknownst to you, you’ve got this virus inside your body that won’t really do anything for ten, fifteen, twenty years and then it’ll hit you like a tonne of bricks.
Ben - And in that time not only are you becoming more ill but also you’re quite likely to be passing it on.
Jules - Well, this is the one. If you’re aware yourself. Say you’re in an intravenous drug-taking clique, if you’ve got it, all your friends’ll have it and nobody’ll know. It’s just an ignorance thing isn’t it?
Ben - Do you think that the fear of the treatment and it’s side effects is something that keeps people from being tested?
Jules - Perhaps, but I don’t think people realise about the treatment. I think the initial stages, a liver biopsy, that’s sounds very scary to a lot of people, you know, they won’t even go there. But once you’ve had the liver biopsy, that’s the easy bit, shall we say. The treatment’s not pleasant, but you know you’ve just got to grin and bear it. Because, like I say, it’s either take it or don’t take it. It’s live or die, so where do you go?
Ben - So what do you think is going to be the future both from your perspective as someone who is looking for ways to control and treat the hepatitis but also what do you think based on what you’ve seen today is going to be the next step?
Jules - Well, I think the next step is going to be amazing. The technology is coming on in leaps and bounds, the researchers, they’re getting there. What I’ve seen today has shown to me that they’re making massive leaps and advances in the discovery of this virus and, you know, how to combat it which is very tricky. It’s a cuckoo in the nest isn’t it; do you know what I mean?
Ben - And that cuckoo in the nest may yet be flushed out.