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Gavin: Hello, welcome to the episode of The Lancet Voice. I'm Gavin Cleaver. 

Jessamy: Hello, my name's Jessamy Baganal. After what seems like months of special COVID 19 content, we're going to be returning to a more usual format of The Lancet Voice, where we provide you with broader health related topics, although of course COVID 19 content will inevitably also be presented.

In this episode, I talk with Calypso Chalkidu, who among other things is Director of Global Health and Development at Imperial College, and we discuss how a future COVID 19 vaccine might be able to be available to low and middle income countries. Rupa Sarkar, Editor in Chief of The Lancet Digital Health, discusses insulin pricing in the US with Professor Aaron Kesselheim.

And Helen Brooks, Senior Editor of The Lancet Rheumatology, discusses snake bites, access to antivenoms, and new developments in the field. 

Gavin: First, as Jessamy mentioned there, we're going to hear her talking with Kalypso Chokadu about COVID 19 vaccine access for low and middle income countries. 

Jessamy: Kalypso, perhaps you can tell us a little bit 

Kalipso: about where you work.

Sure, so I'm the director of global health policy at the Center for Global Development where I'm also a senior fellow. The Center for Global Development is a think tank and it has an office in the UK, another one in, in, in Washington, D. C. And amongst other things we do a lot of thinking on global health issues.

And so as part of that I have been working quite a bit recently with colleagues from other institutions on, a COVID vaccine. I'm also a professor of practice in global health at Imperial College School of Public Health. 

Jessamy: Brilliant. Perhaps you might be able to give a kind of slight summary roundup of where we are now in terms of vaccine accessibility for low and middle income countries and what some of the kind of deals and agreements are that are on the table 

Kalipso: at the moment.

First of all, we don't have a vaccine. And the issue of access, how important has to come after the development of one, though the way in which one is developed to some extent could determine access issues. So the whole of the planet different coalitions and partnerships.

Is trying to develop a vaccine. We've got about 180 odd candidates in the pipeline which could be split across seven or eight different buckets in terms of the way they would work, each one of them having a different mechanism, each one of the eight categories, a different mechanism for working.

And then in terms of the deals where we're seeing a lot of bilateral arrangements, between mostly high income countries and companies where countries such as the UK or the United States or China would China in the middle income bracket, but a very special country for different reasons would get, can, would contact a company, work with a company, a lot of the time a company the same country or more than one companies and make a deal.

Agree to buy an advanced purchase commitment, effectively agree to buy a number of doses of of a vaccine, which is yet to be developed but which this company is pushing down the pipelines developing testing. So there's a lot of that going on. And then we have some country coalitions coming together and doing something similar.

We have recently in fact, today the European commission announced any you wide. Arrangement where you countries coming together to again by a number of doses for their citizens before the vaccines are developed from a number of different companies. And also before that earlier this month, we had the Gavi vaccines alliance announced a similar arrangement with a particular emphasis on low income and lower middle income countries.

But a global vision and perspective and just to say that a lot of those bilaterals or indeed the EU deal a lot of these deals state that access for low income country, poor countries to the vaccine, a vaccine, which might well be developed in the context of Those arrangements would be somehow a short.

So president Trump, the U S administration said that they want to share a president. She in China said that if China finds a vaccine first, they would want to share. And the, you made it very clear that anything that gets developed will also be made available globally. And of course, Gabby. is very much the main financing instrument for a vaccine for poorer countries around the world.

Jessamy: And obviously, it's such a complex field, but in terms of some of the issues just with logistically, the infrastructure of how these vaccines might be shared when, as you mentioned, President Trump wants to be able to have, if they, if their vaccine works, to be able to share it.

How would that be instituted? What would that look like? 

Kalipso: That's a good question. Most of these deals are between payers, whether they're groups of payers or individual countries and companies are. Secrets. So for instance, just today I was looking at a UNICEF issued on behalf of Gavi and the coalition expression of interest call for expressions of interest to get companies to submit an interest in being part of the Gavi advanced market commitment but also promising that their data will be held in confidence, including pricing data.

So it's not clear what the arrangements would be. The closest, the more clarity is offered by the GAVI arrangement in relation to low income countries, but precisely because GAVI was set up to support immunization programs in poor countries around the world. The idea is that a certain number of doses would be set aside for poor countries, starting with perhaps the most vulnerable populations of frontline healthcare workers in these countries, depending on the number of doses that Gavi could secure.

And then there would be certain allocation rules within country which would be, are being set out by WHO, but are not yet. public. Now, middle income countries or high income countries are paying for the vaccine themselves, whether through GAVI or other arrangements, do not have to adhere to any of these rules.

And even as part of the GAVI proposal, it's not clear how vaccines will be split, volumes will be split between low income countries or lower middle income. countries and perhaps high income or upper middle income countries were paying and decide to join the GAVI arrangement. So what proportion of doses would go to whom?

How do we sequence that? How do we influence that? That's not very clear. And it depends of course, also on how many doses we do get and how fast, that's another big question. 

Jessamy: And I guess we've been going on the assumption that for many of these big projects that they are scaling up very quickly to be able to produce, huge doses or huge amounts of these.

vaccines. But as you say that's not a sort of definite, what is it that needs to happen to try and clear up some of these issues? 

Kalipso: We, unfortunately things are not particularly transparent. So we, under normal circumstances in some countries, and I'll take the UK as an example we've got nights.

Now nice works together with companies as they bring things down the pipeline and works together with the European regulator, EMA and MHRA. They offer joint scientific advice. So way before products come to market, there is a process wrapped around. Assessing the value, discussing price, discussing populations, appropriate populations to target.

And then at the point at which an innovative drug, for instance hits the market, gets authorization. There's a lot of thinking that's happened. Of course, right now we're living in an emergency, extraordinary situation, an emergency. We don't have such a process when you could have repurposed and I suggest that we should have repurposed Health technology assessment process and early scientific advice process and still have time to do that Precisely to address the issues you highlight to be able to understand better And to convey a bit of trust, confidence to, to people outside who will end up will ask them to take this vaccine ultimately.

So they need to trust in the process followed. The first striking alone is not as reassuring. So it'd be nice to have a process wrapped around all of it. So we have bilateral deals. The UK government, AstraZeneca, the U. S. government with Pfizer, Moderna, a number of other mostly U. S. companies and AstraZeneca the Chinese government with a couple of state owned enterprises the European Union, a commission, and we'll see who they pick.

And as a result of fragmentation, multiple parallel books happening, and perhaps even a bidding war where you have companies going. from country to country and saying we haven't yet produced the vaccine, but we're very close. Would you pay us for 300 million doses, please? If you want to access, because the Americans that are already in, and you're going to be left without.

It's unfortunately not a good situation to be in. It's certainly non transparent and not particularly well managed. 

Jessamy: And are there other situations vaccines, vaccines. And infrastructure in place that we can learn from or piggyback on to. Obviously, it's a quick moving field and we're walking in the unknown, but are there areas that we can learn from to, to try and make this clearer and easier and potentially more equitable?

Kalipso: I think there are enough. I think, for worse, probably, obviously, because everybody wants to have a vaccine as soon as possible, but I suspect that this is not going to be a quick win I'm not particularly convinced that, say, by September we'll have tens of millions, hundreds of millions of doses of a successful vaccine to deploy, say, in this country or the United States.

So I think I think we have time. I think the, timelines of the most advanced products in terms of the clinical trials don't finish till late next year. And so I think what is worth doing is on top of all the existing deals payers, national governments who are pushing all of this with public money and as they should be given the nature of the problem ought to reflect a bit more.

On exactly the issues you flagged. So what? What are the rules of the game? What? What are we picking? Who is doing the picking on what criteria? What basis? What will happen if the winner doesn't come in market or the first product that we betted on actually is not as good as the second or third, but have already paid for the first.

How do you allocate within country? How do you allocate across countries? This is a global problem requires a global solution. It could be mutually beneficial to deprioritize certain populations within a country with the vaccine, prioritize citizens of other countries. So yeah, so just say, on one hand, we've got the bilaterals with countries such as the United Kingdom or the United States or China with their own state or enterprises and infrastructure.

And they have, they're making their own deals. And then we have blocks of countries, such as the European Commission, European Union again, making bilateral deals with companies about specific products not yet produced. And then you have Gavi, fending for the poorest countries, though the aspiration is, as they stated, a much more broad, but the idea is that subsidies and health financing support goes only to the poorest nations.

And then we have the middle, the missing middle, countries that perhaps have some ability to pay, they're not very poor, but where the world's poorest people live, where we're seeing some of the outbreaks of raging, you mentioned Latin America Latin American countries are not part of a a big block or that haven't yet made such a move as a block.

They're not, certainly not, don't qualify for aid, and they're certainly probably not, most of them at least, not wealthy enough to entice. Companies like Pfizer, AstraZeneca, given that other big nations, such as the United States, are already in this space. These countries are left out.

Indonesia, the Philippines. It's not clear, India, it's not clear where they stand and whether they would qualify, whether the poorest amongst them would qualify for aid or not probably not. And then there's also populations, refugee populations, displaced populations.

And again, it's very difficult to see countries prioritizing those populations within the borders voluntarily perhaps. Depends especially if there's pressure on volumes and pressure from public opinion to vaccinate, frontline healthcare workers or vaccinate the workforce so that the economy can start again.

So there's lots of question marks and in the absence of a process, with clear criteria and engagement and, consultation, it's very hard to see how this can be resolved unfortunately. 

Jessamy: Yeah, it does seem very murky at the moment. As just on a sort of personal point of view, how do you see this playing 

Kalipso: really?

I don't know. I think you're right. It is completely unclear and I don't think governments and development partners have managed to repurpose and, take advantage of well established processes for Engaging industry in discussions on products that are coming down the pipeline.

So advanced market commitments have been around for a while. The idea that you can link those to value and you can move from an advanced purchase commitment where you're buying a product, not yet developed. And the fact in effect, you're betting on that, but moving from that on to creating a market for a product, not a specific product from specific company, but a product.

So multiple companies compete to produce it and then you reward them. This has been around for a while, it's nothing new, but it seems that panic stricken governments went ahead and started this sort of bidding war, and of course companies are already in the game, I think, understandably are taking advantage of this and are selling.

Ex ante, in advance millions of doses of products that haven't yet been proven. So how do we get ourselves out of this? We all, in parallel, we're seeing an attempt, a noble attempt by Gavi to fundraise. They went for two billion, which would not have bought that many doses.

They got about 500 million. Now 500 million would buy them a bit over a hundred million doses for a a vaccine that requires two shots and a hundred million, vaccinated hundred million people across low income and lower middle income countries is not enough. It's not going to make a big difference.

So not enough aid money pulled together, a lot of fragmented bilateral deals, possibility of double paying. So how do we get out of that? I think it's going to take a while for a successful candidate to come to market. And I think as perhaps less successful candidates that governments perhaps place their hopes on do come to market the questions will be asked as to, the decision process and plan B.

And I'm hoping that in, before that happens, some groups, perhaps the commission perhaps the UK government and others who have established mechanisms for engaging companies and discussing performance, discussing safety, discussing value for money decide to inject some of those elements into existing deals.

I think it's still, it's not too late to do that. And I think at some point we'll have to do it because unless you're extremely lucky and, a vaccine kind of comes down the pipeline immediately and we have the appropriate plans in place. and billions of doses get produced. That would be wonderful if that happened and we have lasting immunity.

But I somehow I don't, I'm not as optimistic. 

Gavin: So fascinating to hear from Calypso and you talking about that then Jessamy so much to think about in terms of a COVID vaccine, which of course everyone in the world is desperate for, but so many kind of Safeguards and things to put in place and things to think about as the development goes on to when we eventually do get to this point.

Fingers crossed where a vaccine is available that this, it does have this kind of equitable distribution. 

Jessamy: Yeah I suppose it's just like everything in COVID 19. It's so fast moving that there is this huge potential for sort of knee jerk reactions. And I think, one of Calypso's major points that really comes through from the interview is it's not too late.

It's not too late to start thinking about this in a more sort of systematic and Processed way, falling back on some of the things that we already have the existing infrastructure that we have available to assess vaccines and to think about how we're going to distribute them in a fair manner.

Gavin: Yes, it's absolutely vital. We've spoken so much over the last couple of months about the kind of inequitable effects of this disease. For there to be inequitable distribution of a vaccine at the end of this disease would be would be one final multiplier for that inequity. 

Jessamy: Yeah it's such a horrific kind of thought, really, and I think that, I just hope that, people are listening and that there are more voices out there who are trying to petition.

for this kind of, really thoughtful way of going about it now, so that we don't get ourselves in a situation where, half the world is in great danger, which ultimately means that we're all in great danger. 

Gavin: Next up, we're looking at insulin costs in the United States. You'll hear Dr.

Rupa Sarkar, Editor in Chief of the Lancet Digital Health. Speaking with Professor Aaron Kesselheim, a bioethicist and drug pricing expert, about the problems that diabetics in the US have accessing affordable insulin, what's happened recently, and what's being done currently. 

Rupa: So it's Professor Aaron Kesselheim, and you're a professor of medicine at Harvard Medical School and a faculty member in the Division of Pharmacoepidemiology and Pharmacoeconomics.

in the Department of Medicine. Thank you. So can you give us a bit of background on the prevalence of patients with diabetes in the U. S. and why insulin prices are problematic? 

Aaron: Diabetes is extremely common in the United States and the incidence of type 2 diabetes has been in, has been increasing over the past few decades.

As the United States has struggled with an epidemic of obesity. And as the population has has overall aged those are both increasing age and obesity and unhealthy lifestyles are. Contributors to risks of type 2 diabetes in particular.

Diabetes is extremely common in the United States, and it's been increasing. And insulin is obviously one of the mainstays of therapy. And in particular, there are oral medications that are useful, but you know for type 1 diabetes in particular insulin is essential and you know for some patients with type 2 diabetes they get to the point where the oral medicines aren't effective enough and some And some will require insulin as well.

Or else they can be at risk of really substantial morbidity cardiovascular disease, kidney disease, eye disease and even mortality. 

Rupa: There have been reports that the price of insulin in the U. S. are becoming exorbitant, forcing patients to even turn to websites like Craiglist for their insulin.

This has had knock on effects, as patients can get the drug without the supervision of a doctor. And there have been stories of patients who have required emergency care because of severe blood sugar highs and lows after self dosing. with drugs from Craigslist or Walmart and even dying as a result. Can you talk more about why insulin pricing is so high and is becoming so inaccessible to people in the U.

S.? 

Aaron: Insulin pricing is a major problem. The fundamental reason why insulin prices have been able to increase so to such high levels in the United States and why insulin is so expensive is because in the United States, we allow pharmaceutical manufacturers to charge whatever they want and without any substantial restrictions on it.

And and insulin is a brand, a branded product. There are different kinds of insulin and different formulations of insulin. But there are no generic versions of insulin despite the fact that that insulin itself was, discovered. Very famously a hundred years ago and insulin the insulin that we now take has changed over time but it, the insulin that we now take hasn't really changed that much in the last few decades despite that insulin remains a brand name product and in the United States pharmaceutical manufacturers are able to charge whatever they want for their brand name products and because of the various fractured buyers market where there are public payers that buy that cover prescription drug insurance and private payers that, that, that have prescription drug insurance it makes it really, it makes it challenging for individual payers to negotiate against the pharmaceutical manufacturers.

And there are, basically three main pharmaceutical manufacturers that make insulin in the United States, and they don't really compete against each other on price. And because, price is so unregulated in the United States for a product like insulin, which is an essential medicine that patients need to survive, and that therefore pharmaceutical insurance plans must cover it has allowed the pharmaceutical manufacturers to continue to raise the price multiple percent year over year way above way above inflation and because there's no competition from generic manufacturers, despite the fact that the drug is very old and because branding manufacturers don't compete against each other on price in a lot of cases it has led to a all of these different factors together have led to a situation where the price of insulin has increased substantially year over year, that's led to more out of pocket costs that patients have to pay and that's led to what you were talking about, where People are having to turn to the, the black market or the gray market to try to supplement or to try to get insulin or try to supplement insulin or they've been, hoarding insulin leftover from previous prescriptions as ways of trying to deal with it.

Rupa: In March this year, it was reported that things were changing in the U. S. If drug companies and insurers agree to participate, the Trump administration proposes limiting insulin costs to 35 a month for some older Americans. And since then, Eli Lilly has announced capping most of its insulin to 35 per month to help ease the fin on diabetics who might be facing financial challenges due to the coronavirus outbreak.

Have you seen these measures and do you think that this is enough? 

Aaron: A lot of the measures that you're talking about and other measures that other states in the United States have have passed relate to out of pocket costs from insulin. And this is potentially something that is relatively unique to the United States, as opposed to other countries around the world, where the cost of a medicine both relates to the amount of money that, that a pharmaceutical insurance company will pay and then the pharmaceutical insurance company will have a, some out of pocket costs that they've contracted for patients to pay.

And so what all of these measures do is they limit the out of pocket costs that individuals pay, but they don't necessarily limit The total cost to which includes the cost that the insurance company will pay and, ultimately the cost of the insurance company will pay maybe much higher than the out of pocket cost and ultimately that ends up getting, translated into increasing premiums or, cost of healthcare for everybody across the insurance across that insurance market.

And so ultimately people do pay that, if the, okay. The price of the insurance company stays high, but they just don't pay it as directly with respect to the out of pocket costs. So I do think measures that cap out of pocket costs in the ways that you're describing that have been, implemented by certain states in the United States and have been proposed by the Trump administration and have been proposed by certain manufacturers, those may help relieve the immediate problems that some people have in coming up with these out of pocket costs but it doesn't relieve the greater issue of increasing drug spending on insulin.

Which is again, an old product that is for which there really hasn't been, a lot of innovation in the insulin market in the last few decades. That's, of note. And so it doesn't really change the issue of extremely high prices for insulin overall, although it does offer a measure of relief to patients.

with respect to their out of pocket costs. 

Rupa: That's very interesting. So are you saying that this announcement of capping insulin costs isn't actually going to impact those who most need it, those who are on Medicare, for example? 

Aaron: No, I think it, I think, again, I think it'll impact them, but it'll impact them in a limited way.

It'll impact their the out of pocket costs that when they go to the pharmacy. To pick up their insulin they pay and that's a really important thing. However, what it doesn't do is it doesn't necessarily you know reduce the overall spending on insulin and the impact of the high prices overall because You know the out of pocket cost is just one fraction of the overall cost of the product The rest of the cost is paid for by the insurance company and then that ends up getting reflected in healthcare premiums overall So I don't think it'll change the overall Healthcare system spending on insulin in the large sense, but I do think it can have an important impact on out of pocket cost.

And so it's a partial solution that it may fix some, some issues in the short term, but doesn't really change. But the issue in the long run or in the broad sense, of 

Rupa: course, and that is very important, not only for insulin accessibility in the U. S. But globally, the prevalence of diabetes is rising, especially in low middle income countries.

And there is a need for low cost insulin to meet the demand in these countries. I believe last year the WHO launched the insulin pre qualification program to boost access to diabetes treatment in these regions. Now, you are an expert in bioethics related to costs, availability, and use of prescription drugs, both in the US and in resource poor settings.

So I'm interested in your insight on the future of insulin availability in low middle income 

Aaron: countries. The, to the extent that the price of insulin has been a, really important issue for a lot of people with diabetes in the United States, a much more substantial issue in other countries where there are a lot more poor people and just less resources overall.

At the government level to try to help ensure that people get the medications that they need. I really think what we need to be doing is trying to build capacity in, in local settings around the world for low cost manufacturing of insulin. And not just relying on, the three major multinational companies to be able to provide adequate supply.

And I think that what the prequalification program that you're talking about is an effort to do is to try to, provide pathways for. High quality local production of insulin that can then be made available at at cost or at a, small amount over cost of production to, to benefit the local local populations.

And so I think we really, the impact of high drug prices is magnified in these settings. And we, as a. In the global health community, I think we really do need to pay attention to how to address this. And one way to do that is by better emphasizing developing local production of these products in a safe and high quality way.

Rupa: So insulin is a critical drug for huge populations who suffer from diabetes around the world. And I think at the moment, I don't go a sentence without mentioning the current situation that we're in. And I don't think we can avoid talking about COVID 19. So changing tack a little bit. Obviously the world is anticipating a drug, a vaccine to, to treat COVID 19.

What lessons can we learn from the issues surrounding insulin pricing and availability to help determine the price for this critical drug for COVID 19? 

Aaron: That's a really good question. I think that one of the lessons is not to leave drug pricing and drug pricing issues up to the manufacturer of the product, because if you do that, then manufacturers, will be driven by trying to meet the demands of their shareholders and we'll try to extract the maximum amount that they can.

And in the case of insulin there, there were, it, the various organizations that are trying to encourage appropriate care for people with diabetes, who realized have realized relatively late in the game that, that they, they don't have a lot of leverage over the over the price of the product.

And thinking about issues relating to pricing and and supply up front before we get to the point where there's a product and, there's a massive demand for it and not enough demand or too high of a price to meet that demand is important. And so I think we need to think about how to set principles ahead of time about prices and not just leave and not just leave those kinds of decisions up to the companies.

And if we do that, I think we will try to come up with fair ways to price products and to try to make them available and to try to You know, come up with systems for ensuring that there is adequate supply and adequate manufacturers of a product and, then try to make sure that it can be disseminated.

In a fast way to the people who need it. So I think that will require organization and coordination among public health authorities and local governments. I think it would require local production of these products in the same way that we were talking about with respect to insulin.

And I think it will require cooperation between the public and private sectors. In, in responding to this unprecedented global emergency. 

Jessamy: It's funny, isn't it? Because the thing about insulin pricing in the States is it just creeps up on you and does just seem to represent, the larger failings of health care in the United States.

And I know that the Lancet Diabetes and Endocrinology published a letter a couple of years ago. And, They discuss these three major pharma companies, Eli Lilly, Norva Nordisk, and Sanofi. And they, they contribute 99 percent of all of the insulin to the states. And that point, I think, about, not letting pharmaceutical companies purely dictate the price is such an important one and kind of links into our discussion with Calypso earlier about, really having proper regulations and a proper system to well regulate these things.

Gavin: Yeah, I think it really shows the kind of thing that can happen when when you don't have strong legislation in place. As I said in the interview, ideally you'll want some kind of. Generic insulin production in place, but there are so many different barriers to, to the production of generic insulin in the United States.

You can see that it's one of those things where it just, it doesn't have to be like this. And yeah, it's really important to relate it back to what what Calypso was talking about before that like you said, these structures have to be in place. So we end up with a system where, in this case.

One in every four Americans, according to an article in JAMA recently, are actually cutting back on insulin, which is not a situation anyone would want to be in. 

Jessamy: Exactly. What's so scandalous about this is, this is a completely essential medicine for everybody who needs to take it.

It's not something like, aspirin or paracetamol where, yes, it might be preventative for things in the future. This is an immediate that needs to be taken by patients to keep them safe and healthy. And it's what's so incredibly scary and tragic about it is that patients Require this on a daily basis and that they mustn't be rationing this because the health consequences of that are enormous 

Gavin: It's just such a difficult situation for people at the whims of this pricing to be at and you know as was highlighted in that interview the price of Insulin has gone up rapidly in the last few years far above inflation and it's I think it's to be hoped that some form of far reaching price control or solution to this can be found in the next few years before this situation gets any worse.

Now, of course, mentioned in that interview were several kind of stopgap solutions of a price cap on insulin and so forth, but the problem with the U. S. system, as was said in the interview, is that the costs of that to the insurance company will just feed back into wider costs to the individual.

Finally for this episode, Senior Editor of The Lancet Rheumatology, Dr. Helen Brooks, speaks with two experts on the treatment of snakebite, to talk about advancements in the field for this under reported problem. 

Helen: The burden of death and disability caused by snakebite is huge. Data from the World Health Organization show that around 5 million people are bitten by snakes each year, up to 138 million.

Thousand of these people will die, and around 400,000 are left with permanent physical disabilities or disfigurements. We treat snake bite with anti-venom designed to treat one snake species, which rarely works against another. Less than half the anti-venom needed is currently produced worldwide and many are ineffective, unaffordable, or cause serious side effects.

Those most affected live in some of the world's poorest communities and investment into snake boat. Research is low. Some more ways to research snake venom are sorely needed. Earlier this year, long before lockdown, a paper was published in Cell that provides a new way for us to research snake venom and for us to look for antivenoms.

The researchers cultured cells in vitro, which they'd taken from snake glands. As the cells grew, they organised into structures called organoids that seemed to mimic the snake venom gland structure and to produce toxins that we would expect to see in snake venom. This exciting new development in organoid technology may open up new ways to study snake glands and the toxins they produce without the need to catch quite so many snakes.

I'm joined by Professor Nick Casewell from the Liverpool School of Tropical Medicine, who investigates the composition of snake venom and is researching strategies to develop new snakebite therapies. Hi Nick, thank you for joining us. 

Speaker 6: Hi Helen, thanks for having me. 

Helen: Could you tell us about the current problems that we face when trying to treat snakebite?

Speaker 6: Yeah, so snakebite is A World Health Organization listed neglected tropical disease, and it affects millions of people every single year. We think probably around 140, 000 people die from snakebite every year, mostly in the tropical regions of the world. One of the major challenges we face with trying to tackle snakebite is that there are a number of different snakes that cause this problem.

And their venoms all differ too. And that means that we have to try and inhibit the toxins that are in the venoms of lots of different species of snakes with our therapies. The other challenges that we face are that most of the people who are bitten by snakes are rural people. agricultural workers, and they're usually impoverished.

And this means that often it takes these victims many hours to get to a health facility where they may be able to receive treatment. And many times, there may be no treatment there for them in any event. And this leads to a huge number of deaths, but also a great burden of disability on some of these already heavily impoverished people.

Helen: So how do we currently produce antivenom? 

Speaker 6: So at the moment we use quite an arcane technology for treating snakebite. Antivenoms, as they're known as, are made by immunizing animals, mostly sheep or horses, with sub toxic doses of venom. And over a period of time, these animals produce antibodies against the snake venoms that you've injected them with.

And we can harvest those antibodies and then use them as medicines to treat snakebite victims. So we take the antibodies, formulate them, purify them, clean them up a little bit, and we will then inject them intravenously into victims in hospitals. But these therapies have a number of deficiencies with them.

Firstly, we're using animal proteins as a cure and that means that we have a, quite a high incidence of adverse reactions because obviously these proteins are not recognized as being self by our bodies. The other problems we face relate again. to venom variation, this idea that different toxins found in different snake species differ.

And so a therapy is only going to be as effective against the snakes that you actually use to generate that anti venom because it won't recognize or neutralize toxins from different snake species because the antibodies obviously won't recognize them. And so that has led to quite a fragmented market where we have to use different therapeutic products in different parts of the world to treat Bites by different snake species and if you keep in mind that for a clinician working in sub saharan Africa It may not be very obvious which snake has bitten a particular patient or how best to treat that individual 

Helen: How did your team get involved and contribute to the organoid study?

Speaker 6: So I was put in touch with the group leading this study at the Laboratory of Hands Clavers via one of my existing collaborators Frank Lonk, and he asked if I'd be interested in getting involved with trying to help the team characterize what the Organoids they produced were actually secreting and whether we could identify Venom toxins consistent with those we might expect to find in a snake itself rather than venom gland organoids And so when I heard about this project, I thought it was obviously fascinating, but very exciting as well for the field because of the potential opportunities this technology would enable us to do moving forward.

And so our group really then engaged quite heavily in the study to try and understand what the toxins that these organoids were producing were, how similar or different they might be compared to the venom of the snake species that these organoids were derived from. And also whether the toxins that were being produced were recognised by antivenoms and what they actually do as well.

Helen 

Gavin: also spoke with Professor Hans Cleavers. 

Helen: So I'm joined by Professor Hans Cleavers who works at the Hubert Institute. He's a pioneer of organoid technology and was the lead author of that study. Thank you very much for joining me, Hans. 

Gavin: Hello. 

Helen: So you have made many models of different organs in the past, such as the intestines.

Could you briefly explain what these organoids are and what their advantages are as a tool to study the biology of a particular organ? 

Speaker 8: Yeah, so we developed organoid technology by chance. We had been looking for the stem cells of the lining, the interior lining of the gut, the epithelium, knowing that they are the most active stem cells, if you would ever find them.

And that happened about 12, 30 years ago. They're at the base of the crypts of Lieberkuhn. And once we had them marked in mice originally, and later in humans, We found out indeed, they're extremely active in the gut. We then tried to rebuild the system in, in vitro, in the lab using a set of growth factors that we knew were important in the gut.

The original intent was really to make more stem cells out of them, but much to our surprise, these stem cells, when you take 'em out of the body of a mouse or a human being, they make mini versions. Of the gut with every cell type that we knew existed in in real life also exists in these mini guts, these organoids and also we even found some new cell types that we didn't know existed in real life in these mini guts and later confirmed that they are present in a real, so they really are miniature versions of normal human orbits.

And we then, after we did the gut, we found out that this would be done for almost every internal organ of human body. 

Helen: But this is the first time I believe that you've made organoids from non mammalian cells. So could you tell us a little bit about what inspired you and your team to try and culture snake stem cells?

Speaker 8: The reason that we in the end try to grow non mammalian tissue, in this case, snake tissue, was really, I think initiated by three PhD students who who were a little bit bored with getting, coming up with new protocols for prostate or breast tissue or lung or ovary or, and they were thinking apparently over a beer, what would be the most iconic organ of a vertebrate?

And they thought that was the snake venom plant. And so they set out to do this. I don't think they really have thought this through very deeply because we are using the human growth factors that sometimes work for mouse, not always. But they definitely have never been tested for snake cells.

But essentially when you take human growth factors. and snake cells from a venom gland, but also from a snake liver or snake pancreas, for instance, you make many organs that represent the snake venom gland or the snake liver. So apparently these growth factors, they don't care about the evolutionary distance between humans and snakes.

Helen: I thought it was very interesting that they had to culture the organoids at a lower temperature. And did you think that was perhaps, was, were they inspired by the fact that snakes are cold blooded? 

Speaker 8: Yeah. So they realize that snakes are cold blooded. So that was one thing they had also saw through very well.

And so they grow them anywhere between 25 or 28 degrees centigrade. And when you warm them up to 37, which would be the normal temperature for us, for human cells they no longer grow. So that was a smart of them to really try this out. It's really the only big difference between growing human mini organs and growing snake mini organs.

Helen: Great. What are your next plans to investigate with these organoids? 

Speaker 8: Yeah, so using the snake venom gland organoids we discovered a number of things that were not known. For instance, nobody really knew what different cell types there are in a snake venom gland. It turns out that what I didn't know but read up is that snake venom contains many different venomous components, 20, 30, 40 different components that can do very different things.

And the venom is only there to allow a snake to stop its prey from running away. Now, there are many ways by which you can do this and snake venom is extremely creative and basically triggers all of these different ways. So it can paralyze, it can lower blood pressure, it can make the prey unconscious by wearing on the brain, et cetera, et cetera.

So we found out that first of all, the different components of the venom are made by different cell types in the venom gland. And we also found the stem cells. In the venom blend, very basic question that we have always been interested in to learn more about stem cells. Turns out that they very closely resemble the stem cells that we knew from mammals.

So the particular biomarkers, LGR5 is one that we discovered that marks essentially all stem cells in the adult human body, we believe. And we found the very same equivalent in the snake. Snake LGR5 is a fantastic biomarker for snake stem cells. 

Helen: So you're planning to capture some more different snake types to model their organoids as well.

Speaker 8: Yeah, we hooked up with a number of real snake venom scientists from the UK, from the U. S. Also with Freek Fonke here in Holland, who is a biologist and a snake venom expert, but also is a very public personality. He is always on television, he has these children's programs where he He chases down crocodiles and snakes and explains the biology of these beautiful organisms.

So we know that we've done about 10 different snakes in all cases. We could easily grow The venom glands now because every snake makes his own venom with 10, 20, 10, 20, 30 different components we will probably extend Building this biobank for multiple reasons. One would be many of these snakes are threatened species.

So if you have them in a biobank, we only need one sample for one snake from a particular species. And because we can grow this forever, we have the DNA. We can do the genome of that snake, almost no snake species. has been analyzed at the level of its genome. We have the live cells. We have the production platform.

So for making the venomous components, to study the venom, but also to use them to raise antibodies to raise anti serum for snakes, which is a big challenge. But also these components are very good candidates for new drugs. They will affect blood glucose. But pressure they will affect how muscles are by nerves.

They can. They have lots of effects on the central nervous system on the brain. All of these, we believe hold great promise to develop new drugs and affect about 10 drugs. Current currently available drugs come from or inspired by Snake venom components. 

Gavin: So I think it's really fascinating to talk about snakebite.

And it's one of those things that just doesn't get much mention. 

Jessamy: It's a huge burden of disease. We published a study in 2018, the vulnerability to snakebite. Snake bite of enemy, a global mapping of hotspots by Joshua Long bottom and etal. And essentially that is a great paper that shows the geographical distribution of these vulnerable populations who are, for the most part, more than an hour away from some kind of healthcare system where they might be able to get anti-venom.

Are at risk of snake bite from the 270 odd different snake species in the world. That sort of population is about 96 million. 96 million people who, or 92. 6 million, sorry, people who are living within these sort of very vulnerable geographies. And it's a problem which is so difficult to solve, because it's so bound with the general infrastructure of that country.

Whether you've got road transport, whether you've got a health system, whether you're able to get anti venom from one place to the next, whether you're able to tell which snake has bitten you in the first place, it's an extremely complex problem with so many different sort of cogs to the issue that it's hard to see a way forward and I guess that's what I really liked about that interview was this concept of using these small molecules and sort of things from metal chelation, which could be a bridging therapy.

So you would be able to take that having got a snake bite and it would give you a bit of extra time to be able to get to a health centre and decide which anti venom you might need. 

Gavin: Thanks so much for listening to this bumper episode of the Lancer Voice. We'll be back in two weeks with more stories from the world of health, science and research.

You can subscribe to us wherever you usually get your podcasts. See you next time.