China hides Covid data, the problem with pain

Maria Van Kerkhove leads the World Health Organisation’s work on emerging diseases. This week, prompted by the recent disclosure of previously unreleased information from Wuhan regarding the origin of Covid-19, she's written a stinging editorial in the journal Science in which she says, "Three weeks ago, the World Health Organization (WHO) learned that scientists in China possessed data on viral samples from Wuhan that had been gathered in January 2020, which should have been shared immediately, not 3 years later, with the global research community. The lack of data disclosure is simply inexcusable." Strong language. So what data does she mean, and what should our response be?

Maria - So there's data that was collected in the Wuhan seafood market. The data that became available contained molecular evidence. There were animals in fact sold at that market. Now, that was suspected, but it wasn't confirmed. But also, some of those animals that were sold at the market were susceptible to SARS CoV 2 infection. And what that means is that there were potential intermediate hosts. And for scientists like myself and public health professionals around the world, this is a really critical finding because these viruses sometimes pass through another animal that could be at that market. We call those intermediate hosts before they infect humans. And so the data provided more clues to suggest that there were intermediate hosts at that market. And that was new information.

Chris - How did the data come to light and where had it been in the meantime?

玛丽亚,由中国疾病预防控制中心,生成的数据and the data was submitted to GISAID, which is a platform that hosts information and data on sequences and what we call metadata. It's supplemental data that talks about the sample collection date, where those samples came from, just more information that was submitted to GISAID as part of research that was done by a group in China, which published a preprint last summer looking at the samples. And so the data existed, and the data collection, the sample collection date from those samples was January, 2020. And so the challenge that we have as a global community is that this information has existed for more than three years. And we would need this information to be shared so that it could be analysed. And that's the big story here. That's the real crux of it. And maybe you haven't heard me speak because I feel like I've been so blunt about this for so long, because this is not a game. This is about understanding how this pandemic - which has killed at least 7 million people, has disrupted every single one of our lives, has changed futures - we have to understand how this began. And data like this are critically important to be shared because by knowing this information, we take steps to mitigate, to prevent this from happening again, because unfortunately this will happen again.

Chris - The World Health Organization have performed one so far, analysis, back in 2020/21, of what is thought to have occurred to start the pandemic. Samples were requested then by the WHO and China resisted providing them and still have resisted providing them. Does this fall under that same mentality? There's something here where getting information from the source is proving very challenging. And if so, why?

玛丽亚,你指的是任务,place in January, February 2021 of international scientists and Chinese scientists to understand the origins. That was a mission specifically looking at the origins of SARS CoV 2. And they published a report in March 2021 outlining what they were able to determine. And within that report, there were a number of studies that were recommended that needed to be conducted. And it included samples at the market tracing the animals back, doing serology, which looks for evidence of past infection through antibodies of people who worked at the market within the animals themselves. And look, the start of any outbreak is incredibly challenging. And what you're majorly focused on right at the beginning is five questions. What is it? How is it spreading? What is the extent of infection? How far has it spread already? What disease does it cause and what do we do? And at the time, the cat was out of the bag so to speak; the virus was already spreading. And so a lot of the efforts early on were on putting out that fire, stopping human to human transmission, reducing the morbidity and mortality because we were seeing huge increases in deaths and hospitals were being overwhelmed. But in addition to that, there's always work that's done at that initial source or what you think is the initial source. We knew the market played a really important amplification role because most of the cases were associated with that market. So the market was closed, the market was disinfected. That was the right thing to do. But what also happens at that time is samples would be collected. Those samples were collected, we knew that was happening. That's where some of the early sequences were identified, as well as some of the early sequences from the patients. And the question is, what happened to that information? Were there studies that actually traced the animals that we now know were sold? Were these wildlife, were these domestic species? Was this legal trade or illegal trade? And that's not a blame question, it's just getting to these answers. Because we can't come away with this pandemic and say, we need better surveillance, we need better reporting. We need to actually know the exact drivers of this. Where did they come from in terms of the trade routes? What were the animal species that were there, the conditions by which they were raised, the conditions by which they were sold so that we could do better, we could prevent this from happening again. So a lot of those early days, that early work, I believe more was done. There's incredible scientific knowledge in China that this work maybe was done. And that's what we're questioning. We keep questioning has this work been done? And if so, that data needs to be shared immediately.

Chris - The World Health Organisation, though, came under criticism for almost singing from China's song sheet at the beginning. And people said, "you allowed a sort of puppet show to play out when that investigation went through because people were whisked in a stage managed way from one venue to another. And these sorts of samples and these sorts of data that were being requested, can we see some sewage samples or some blood samples from across China to try to gauge the spread?" Those sorts of samples have still not been provided. One does wonder what else is there that could be shared and should be. Why are China so resistant to giving even organisations like the WHO access to this to help prevent the next pandemic?

玛丽亚——是的,我认为有一些重写of history here. Because you know what we were saying publicly, what we were saying to China, what we were saying to all of our member states, what we were saying behind closed doors, there were excessive requests for information on the cases that were known on the extent of infection, on the case definitions, on the testing that was being done, on the samples that were collected from humans, from animals, from wherever it could be. And these were requested repeatedly. As WHO, a lot of people think we can just parachute into any country we want, walk in the front door and say give us the samples. We don't have the power to go into countries and collect those samples ourselves and walk out with that. You know, that suitcase with those biohazard stickers on it that people see in the movies - that doesn't happen. And listen, I'm just as frustrated as all of you on why we don't have this access. We work all channels, scientific channels, technical channels, diplomatic channels. Again, this is not a game. We're not playing around here and saying, you know what? It would be nice to have access to this information. We need access to this information so that we can do better the next time.

Chris - One of the things that people do find very frustrating internationally is that China has form in this area, because it was even with another coronavirus that they did a similar sort of thing 20 years ago, when the first SARS emerged. There's evidence that that was circulating. And we believe China knew it was circulating for maybe six months before they told the rest of the world. It then escaped the bounds of China and there were thousands of cases. There were nearly a thousand deaths because of that. People criticised China and said, you need to be more transparent. Here we are 20 years later, and history is repeating itself now. Now we returned to the question that we really first began to address here, which is why is there this reticence to be more open? Why not share this data unless, as some claim, there's something to hide?

玛丽亚-我的意思是除了健康问题。我think it relates to the other questions that you were asking. What are the incentives to share? And more importantly, what are the disincentives to share? Now, we're focusing right now on China, but we do have challenges with reporting information from many countries. We have outbreaks that are occurring of other pathogens over the last couple of years, over the last year in particular. And we have challenges of getting information from countries. This is a problem and a challenge that we must face, and we must work on the incentives and the disincentives. I can talk to you about why it is important for this information to be shared, why the world needs to be vigilant, why we need to act faster, why it is so much better to prevent something from happening than to try to control it and end it once it has started spreading. And I can talk to you about the financial implications and that it's much better to spend a million dollars or a billion dollars on pandemic preparedness rather than the trillions of dollars that we are spending right now on the response and on the economic impact of Covid 19. I can talk to you about governance. I could talk to you about responsibility and accountability. What I can't do is force countries to adhere to this. I do think this is why something like a pandemic accord is so important. It's a promise that we will do better, that governments will do better, that everybody has a responsibility and a collective responsibility to do better. Because forget these borders that we have within our countries. These viruses, these pathogens don't respect borders. We live in a completely interconnected world where a virus that passes from an animal to a human or passes - let's say it was a breach in biosafety or biosecurity - into humans. Once it's efficiently transmitting within humans, it can go from one part of the world to the completely opposite part of the world in 24 to 48 hours. That's why everything that we've done for Covid 19 in terms of surveillance, sequencing, improved diagnostics, sharing of information, better data management systems, better analytics, has to be maintained. Because if we dismantle these systems and say, oh, we'll just scale them up for the next time, we're living in a fantasy world. This will happen again. But we have not addressed, and we have not moved forward on this issue of transparency and sharing. And frankly, I'm very concerned that we're almost in a worse situation than we were before this pandemic began. And that is because of the politicisation. That is because no one wants to find that next pandemic virus. No one wants to be blamed for this. But collectively, as a species, we all need to be working together on this.

How widespread is the problem of persistent pain? Speaking with Chris Smith, Alan Fayaz is a consultant in anaesthesia and pain medicine at the University College London Hospital…

Alan - Well there is actually a very specific definition for pain. It's been marked out by the International Association for the Study of Pain. And they say that pain is fundamentally an unpleasant sensory and emotional experience, but an experience that is associated with actual or potential tissue damage. So that's the other factor. So when you break that down, it can't be pleasant. It has to be unpleasant. It's a sensory experience, but there is an emotional component to it and that's what differentiates pain from other unpleasant sensations. For example, smelling a bad smell or eating bad food or listening to bad music, those are unpleasant. But because of the strong emotional component to it, that's what differentiates pain. Finally, it is usually in the context of some perceived threat, but that threat doesn't have to be necessarily visible. So I don't have to see a broken bone to believe that you have pain. It's just that it's in the context of that tissue damage that it happens.

Chris - And if we pick an average person off the street, what fraction of people at any moment in time will say they've got pain?

艾伦,是有区别的剧烈的疼痛,which is pain that essentially makes sense for which there is an evolutionary basis. This is a signal from the outside world to your brain warning you that you've injured yourself. And then there's chronic pain, which is pain that's been present for the period of greater than three months. And that's no longer functional because the function of pain is to warn you, allow you to rest, distract you from the other day-to-day activities so that your body can heal and recover. But at three months, we would assume that all the healing and recovery that a body can do has happened. So at this point, we considered the pain to be dysfunctional and that's often the point at which we would call it chronic pain. And in the UK our study from 2016 suggested that somewhere in the region of between a third and half of the adult population experienced chronic pain at any one period of time.

Chris - And who does it happen to? If we look at that proportion and we ask are there any common factors or recurring factors, do you see any trends?

Alan - There are some trends. Certainly with age, there are trends. So a tendency to be more common the older you get. So when we look at populations over the age of 75, approximately two in three older adults will experience pain and a little less common if you're younger. But in some studies, some population studies in the UK as many years, one in three people under 45 years of age. So that you know, what we would consider the working population at the very least, experience chronic pain as well. But certainly a trend towards increasing likelihood of chronic pain the older you get and perhaps a little bit more common in females than it is in males. And certainly more common if there are coexisting conditions such as depression, anxiety, and social circumstances that have an impact as well. So if you are poorer, if you've had less opportunities for education, if you are unemployed, you are more likely to experience chronic pain than if you were not.

Chris - I've seen patients who say that they are very, very susceptible to pain. Is there any evidence that pain can run in families or some people are genetically more susceptible to experiencing pain in a more pronounced way acutely,

Alan - Almost certainly there is a biological component that drives pain. We know for example, that in general females, contrary to common perception, have a lower biological pain threshold than males do. But again, even when we look at that, there are psycho behavioral societal factors that may be causing that, that may be driving, that might not just be genetics, it might not just be the sex of the patient. Going back to the definition of pain, it's a sensory and emotional experience. So we know the brain is involved in all forms of pain. I'm not just talking about complex, problematic, dysfunctional, chronic pain. I'm even talking about pain in the context of injury. What we think, what we believe, what we understand has a huge impact on what we feel and the way we feel it with very different experiences. And that's why there is a strong emotional component to pain that I think genetics, it's not enough to explain the variations across the population and within an individual.

Chris - And presumably that emotional top-down control and role that's being played in pain must underpin some aspects of what, what we dub the placebo or even the nocebo effect where you expect something to happen. And so it does.

Alan - Absolutely. Absolutely. So there is a kind of therapeutic value to it. There is also potential therapeutic harm, but it extends beyond that. It is really why we focused not just on a biological approach to managing pain, but understanding the importance of sociological psychological approaches to modulating pain and really the importance of being sensitive to the environment and the context and the person's beliefs and fears. And anxieties and how they can impact on pain. Think about body aches from going to the gym. You go to the gym, you work out the next day, your body aches. But invariably you feel good about it. It's a nice feeling. You almost pack yourself on the back and you celebrate it and you go out. But if you have the flu or if you have a cold, it's almost exactly the same sensation. It's almost exactly the same feeling you have in your muscles. But certainly if you're me, you're sort of very catastrophic about it. You feel very miserable, you feel down, you take to your bed. Two very different responses to essentially the same stimulus. And again, this is reinforcing the idea of what does our belief about what's causing this, whether it's true or not, how does that drive what we feel and how can we harness this therapeutically.

Chances are, almost half of you listening to this programme right now are feeling pain you’ve been enduring for 3 months or more, and that means you’re experiencing “chronic pain”. And as Alan told us earlier, this seems to be associated with some kind of change in the way parts of the nervous system’s pain network behave. And our next guest, Kings College London neuropharmacologist Peter McNaughton, thinks he knows why: he’s discovered that chronic pain signals are triggered by a special ion channel or “pore” on the affected nerve cells. This turns on in chronic pain states and activates the affected nerve, producing incessant pain signals. The good news is that if he blocks it, at least in experimental animals, the pain is blocked too. He told Chris how it works…

Peter - Now, something that I often tell my students is they can conduct an experiment on pain and the only equipment they need is a brick and their toe. If they drop the brick on their toe, that's acute pain. The next day their toe is red, swollen, and throbbing. And that is inflammatory pain with a lot of inflammatory mediators having been released to make the pain worse. And if after three months their pain is still present, then that's chronic pain.

Chris - And looking at what underpins each of those different elements with the acute pain that's physically activating pain nerve cells, because you've done damage with the brick and the intermediate inflammatory pain is because you've done damage to tissue, which has now released loads of chemicals, which are winding up the nerve cells. And then three months later, if you've done serious damage, that's when something's rewired because everything else has got better or gone away. But something physically has to be rewired to keep that pain state running.

Peter - Yes, acute pain, we made some large advances in that in the last 20 years or so, you activate these ion channels as they are in the membranes of the nerve cells, which fires off action potentials which go up to consciousness and say, ouch. Your description of inflammatory pain was pretty good as well. There are a whole slew of different chemicals that are released by inflammation that generate inflammatory pain, and mostly they're not acting on the same ion channels as I spoke a moment ago. The work in my own lab has shown that a different ion channel called HCN2 generates an inward current that causes firing of action potentials, which say pain, pain, pain. Now the view about 20 years or so ago was that, in chronic pain, something different happens because what often happens is that the inflammatory phase subsides and it looks as though it's healed, yet the patient is still in pain. So the rationale was that there had been plastic changes in the spinal cord so that the pain, in a sense, had moved inwards and become a pain memory in the spinal cord. I'm not saying that point of view is wrong, but there's increasing evidence nowadays that pain nerve fibers continue to fire even in chronic pain states. So something is causing them to continue to fire even though apparently the site of the injury has healed up.

克里斯,我想接下来的问题是我们所有的试验ence pain every day, whether it's tripping over a stone or standing on something or touching the hot cooker, but we don't all develop chronic pain off the back of it. So why is it that some people do get into these pain states and quite commonly in the population, but it's not as common as our everyday experience of acute pain and thank goodness it's not.

Peter - Well, there's typically a pathology of some sort that's driving it. Another example would be rheumatoid arthritis. Patients that suffer from these types of arthritis suffer continuous pain in their joints. So I think there's pretty obvious pathology which is damaged to the joints. Work in my own group has shown that once again, it's these HCN2 ion channels which are driving the pain.

Chris - Is sort of a summary then of that something, we don't know exactly what, but something triggers that particular channel or pore in these pain nerve cells to either become more active or you get more of them. And so the nerve cell becomes more active than it should be. It should have a sort of baseline level of activity and the presence and activity of that poor means it's more active than it ought to be.

Peter - Yes, exactly. Although the baseline activity should be zero because, as I'm sitting here, I feel no pain whatsoever. So, presumably none of my ion channels are active and there are no action potentials, nerve signals that are going up to my consciousness.

Chris - Are those ion channels just sitting there doing nothing normally then and something's turning them on or has something changed in the nerve cell that it now produces those ion channels, those pores and puts them in the nerve ready to make these abhorrent signals?

Peter - As far as we know, it's the first of the two. The ion channels are there all the time. They're silent, they're there to detect pain. Normally you don't have pain, but if pain occurs, they produce the inward current and produce the activity in the pain sensitive nerves.

Chris - So what's turning them on then?

Peter - Well, what's turning them on? Inflammatory mediators. There's one that's very well known to pharmacologists called prostaglandin E2, A chemical that drugs like aspirin and ibuprofen act to reduce the other class of analgesics. The opiates act more centrally on the transmission of the pain signal at the first synapse in the spinal cord. And they're wonderful, wonderful painkillers, but they come with a side-effect burden, which, I'm sure everybody's aware of. Addiction, death as a result from overdose.

Chris - But if one talks to patients themselves, they'll say that 'nothing touches this doc. I take all these pills and I've still got the pain'. Now, is that just because they've taken so many tablets that their pain has outstripped the ability of the tablets to control it? Or is the mechanism different that we are now short of shutting the pain stable door after the pain horse has bolted?

Peter - Well, the work from my lab really shows that it's this HCN2 ion channel, which is critical in triggering long-term pain. And the channel can be driven by inflammatory mediators or possibly changes in the internal ambience of the nerve fibre, which switches on these channels as well. But it seems that these channels are extremely important in generating chronic pain. And one of the things that my lab's been trying to do is to develop blockers for this HCN2 ion channel, which in animals at least, these blockers deliver wonderful analgesia. So we're hoping to develop blockers which could go into use as more effective painkillers with fewer side effects. That's the hope, at least.