Transcript of conversation between Professor Stephen Baker and Dr Lara Marks, 18 November 2020

Stephen

I am Stephen Baker. I am a microbiologist, and I'm a Wellcome senior research fellowship holder based at Cambridge University. I've been here for almost a year and a half. Prior to this, I spent 12 years working, developing a programme of research around studying enteric diseases in Hoi Chi Minh city, Vietnam. And as a component of that work, we did a lot of development of understanding how bacteria move within populations, how they evolve, and also then how then they cause disease and how we can treat and prevent disease.

Probably the biggest takeaway message from that 12-year period is that from everything that we worked on, that everything became more drug resistant over that period…. When I started, actually, we produced a paper highlighting the emergence of multi drug resistant Shigella. And 12 years later, the year that I left, we wrote a paper describing the emergence of Shigella, which is resistant to all but one antimicrobial. And we'd actually watched that organism evolve over that whole period, I was there for 12 years.

Lara

You mentioned something called enteric diseases. Can you tell me what that is?

Stephen

Enteric diseases are infections that trigger diarrhoea and other symptoms in the gastrointestinal tract. So the focus of my work has been on bacteria, not exclusively, we have done some other things on viruses and also a little bit on parasites, but bacteria mainly, and these are bacteria that we happen to ingest, that stimulate rather unpleasant, either short term or prolonged diarrhoea by triggering an inflammatory response within the gut. This may not seem particularly important to those residing in the UK or Europe. But in low to middle-income countries, there is a huge burden of disease, an association with mortality in infants, and the vast majority are treated blindly with antimicrobial therapy, which, to some extent, we're not really sure whether that works or not. But in response, the organisms have become increasingly resistant to the drugs we use to treat. So we have a problem.

Lara

And you've seen an increase over the last few years.

Stephen

We've seen it dramatically increase over the last few years. And actually, I'm not the only one to have seen this. There are many other people working in this area, but actually witnessing it first-hand and watching that kind of evolution in real time, and not just on that organism, but also on a whole host of different organisms. Not just the ones that cause disease in the gut, but also ones that we see emerging and causing infections in the blood, and also in the lungs of people that are hospitalised.

It is very easy to think actually it's not really our problem, because this is occurring somewhere else. First of all that's not a particularly great attitude. But secondly, bacteria don't hold passports and they don't understand borders, we transmit and transpose these things all over all over the place.

This has been proven very nicely in the last 12 months with respect to COVID. Any organism that we identify that can live on the skin or in the lungs or in the gastrointestinal tract of somebody in Southeast Asia or South Asia can be in London within a 12-hour plane journey. So whether We like it or not, these problems are on a doorstep. And we have some responsibility to not only think about them, but also do something about it.

Lara

And why do you think resistance in the last few years? What do you think are the main factors?

Stephen

I think there's lots of factors why drug resistance is increasing. It's easy to say that it's purely to do with antimicrobial use. There's a lot of talk about antimicrobial misuse and antimicrobial misuse and animals and other things. Actually, the biggest driver is that it's a natural phenomenon. If you expose bacteria to chemicals which can kill them over a period of time, they will become resistant to them. We've known that for the last, you know, 80-90 years. So resistance is something that is largely inevitable.

Lara

But why is it increasing?

Stephen

There's various aspects to that. I think there probably is more exposure to drugs. In the places that I've worked in the past, antimicrobials are available in the community, you can get them without a need to go see a doctor, you don't need a prescription. There is also a lack of diagnostic testing. So people don't really get informed on what they have, because the diagnostic testing structure probably isn't up to scratch in these places. And it's easier and cheaper just to treat people with antibiotics.

But also, I think it's more complicated than that. I think there are probably feedback loops within these bacterial populations that once they become resistant, they're more prone to becoming resistant to other antimicrobials, too. So it's not purely just due to antimicrobial exposure, there are probably other things that interact with the bacteria in our gut, which makes them become more prone to becoming resistant to additional antimicrobials when they are resistant to one already. So I think there's lots of different complicated things that are all interacting together to make the problem worse.

Lara

And do you think also environmental things have affected it?

Stephen

Yeah, so we pump a lot of antimicrobials into the environment, both during manufacture, but also then through the use of agriculture, not only in animals, but also on vegetables and other things. We use them as a way to improve food yield. There are also other chemicals that circulate in the environments that are used as pesticides, and other things and bacteria survive in those environments, too.

So there may be some crosstalk between the use of different chemicals which allow them to become resistant to antibiotics simply by chance, because there is maybe some overlap in those environments about the way different chemicals interact, and they stimulate the same pathways. So organisms have to survive not only often within us, but also in different places. Anything that allows them a survival advantage, such as resistance to any chemical means that they're going to be propagated.

Lara

And when you came back to Cambridge, what did you decide to do?

Stephen

Moving away from somewhere, where you're on the forefront of what's going on, from a low middle income country puts you in a different position, when you enter back into the UK. It was quite clear that I wasn't going to be doing observational studies on children with enteric diseases in Cambridge. But then there are other expertise around and other interests. And I think that something I decided while I was actually in Vietnam I was moving towards something that's become probably a main feature of my work and was not only describing how drug resistant works, but also then doing something about it. And we’re trying to structure the group into three key areas to understand this.

I have examples of all of them that are either in press or close to being submitted for publication, one of which would be then a repurposing of antimicrobials. We have drugs that are available that have either been forgotten about or are used for different treatments that are not particularly commonly circulated. So I've been working with particular organisations to have access to compound libraries. We've done some work to identify different antibiotics that work in a different way that we can then repurpose for treating infections caused by bacteria that are resistant to a whole range of antibiotics. And we've had some success with that and that works and we're in the procedure now of trying to raise some money to do a clinical study to try and identify a new drug to treat extended drug resistance infections (XDR) in Pakistan, but also potentially in Southeast Asia.

Lara

Can you just explain what XDR is?

Stephen

XDR means extended drug resistance or extensively drug resistant. That's an organism that is resistant to all one or two different classes of antimicrobials. We've really run out of options to treat those particular types of infections, so we have to dig deep into chemical libraries to try and find things that have been forgotten about or just not used. And then try and reinvigorate interest in getting those manufactured so we can use them to treat these infections.

Lara

What drugs that you're trying?.

Stephen

There's some drugs that were kind of orphaned and forgotten about in the 1980s, that were no longer accelerated for whatever reason. It may have been the fact that at the time there were competing interests with other chemicals that had better activity, and so therefore they were not progressed. There are a few of those.

But also there are oral preparations of otherwise injectable drugs that are being used in more developed countries that are not available in developing countries. And the idea would be to provide access to those drugs so that we can use them orally rather than actually providing them as injectables, which means that if you don't have to go to hospital, you can provide them in an outpatient clinic. So it's not just about resistance, but also how we get around resistance and also then providing access to these drugs that people can use them when needed.

So that's one thing. I see it as a stopgap if we're going to change procedures to treat with different antimicrobials. It's inevitable that these organisms become resistant to these antimicrobials, so it depends how long we've got.

I don't see that as a long term option. So we're looking into other things, where we're trying to understand a little bit more about how we can then develop new generation vaccines.

Conventional bacterial vaccines work by linking a particular type of sugar, which is on the surface of the bacteria to a particular type of protein from another bacteria, which acts together, thus boosting the effect of the sugar in protecting somebody against a particular bacterial infection. What we're trying to do is keep the sugar that we know helps protect against the infection, but combine it with a different protein that may have a wider range, a host range to protect the individual against more bacteria. We're trying to develop this procedure now whereby we can identify the new proteins, but then also then combine these particular sugars and proteins together in a kind of mix and match setting. So we can then try and provide broader reactivity for bacterial vaccines.

And that's something we've only just started. The procedure is then to work out what happens when people are naturally infected, to look at the way our immune system sees the organism, or sees components of the organism. And then we try and then mimic that by identifying what that particular thing is, and then trying to make it into a vaccine. And hopefully, then we can trigger a similar type of protective immune response that you may get from a natural infection.

Lara

Presumably that takes a lot of understanding of the host and the pathogen relationship and the interaction between the two. Is that what you're discussing here?

Stephen

Yeah, it does. And I think that we've done some of that on a relatively superficial level. What we've done has been to take convalescent serum from the blood of people that have been exposed to these particular pathogens, and then mine out antibodies, which is what we think is important for triggering the right type of immune response to the vaccine. And then we work out what components or what bits of the bacteria those antibodies bind to, and whether those antibodies actually do anything, i.e. they have some function, so we can identify how they work. [The idea is] if we give somebody that component of that bacteria, we hope it would trigger a similar antibody response, which will then have some function to prevent infection.

Lara

Right. So that's the new generation of vaccines that you're looking at.

Stephenl

Yeah. It's a way really of creating a more kind of mix and match platform for the way we then choose and select different proteins and different sugars and stick them together to try and have a wider range. Rather than focusing on one individual organism we might be able to protect against a whole subspecies or a whole species or potentially a genus of bacteria, depending on how they work.

Lara

And would that help with different strains of bacteria, as happens with evolution?

Stephen

Yeah, correct. What we hope is by having a broader range of organisms that we can target, then that may also then limit potential escapes over a period of time, the bacteria may then change the outside of their structure to avoid the immune system. That's the immune responses triggered by the vaccine. By having perhaps a broader scope of the way the vaccine may work, and the organisms may target that also may limit escape from people being immunised in the future. So not only make it protect against the range of organisms, it may also then have more longevity as well.

Lara

So that's one arm that you're looking at. What other ideas are you working on?

Stephen

The third arm is the one that's probably I'm most excited about. And this is the development of antibodies.

So following on from my description of what we were trying to do with vaccine development we take the bacterial cells and understand the components of the bacterial cell that are recognised by the immune system. Now, if we then take these components themselves, they may form the particular components of a vaccine. But also, then, if the vaccine is then mediating an antibody response, which binds to that particular protein, we can then theoretically just provide that antibody.

What we're now working on within our own group in collaboration with companies that can help us do this, is to try and identify a mechanism to actually work out what the targets are, but also to produce antibodies that we think they can treat drug resistant infections.

The concept would be, you enter a hospital in country X with a particular infection, to which there are no antimicrobials available, because it's resistant to all of them, then we would then treat that individual with a therapeutic antibody, which means you provide potentially almost instant immunity to that particular infection, it could activate prophylactic protection. You could protect somebody by giving somebody a particular injection of an antibody. So if they were going into a particular hospital where there was a risk of infection, you could then pre-empt and prevent them getting infected, potentially, by giving them almost immediate immunity. Or you could also treat infection in the same way by when you identify that bacteria, you could give someone that specific antibody and then treat the infection by triggering an immune response inside them to then deal with infection, which they might not be able to do themselves.

Lara

Have you already created some antibodies in that way?

Stephen

Yes, we have. So we're using a relatively new approach, which I can't tell you about right now. But what we're looking at is a way to then generate a thorough antibody map of the surface of an organism, picking out not only the proteins, but also the antibodies that bind to these proteins. We have them manufactured, which means that somebody actually purifies them and makes them for us.

And then we screen them against a whole different panel of organisms. What we do then, is using a high powered complex microscope, we image a whole plate of different organisms and measure not only where the antibodies are binding on the bacterial surface, but also the amount of antibody which is binding on the bacterial surface. And that allows us to work out what the potential thing that we're binding to, but also the actual ability of that particular antibody to cover the surface in bacteria.

Now, the idea with that is multifaceted. What we're hoping is we can identify an antibody which triggers a cascade of an immune response, which allows them the immune system, essentially to smash a hole through the surface of the bacterial cell that's killing the bacteria. So what we're trying to do is identify a particular antibody complex that allows us to then kill the bacteria using the immune system of the infected individual. Now this may seem like Star Trek, but we know that it works for viral infections. And there are these antibodies that are becoming licenced and available for various things. We've seen only in the last few days, these RNA vaccines become available, which is a different technology, but also fairly like Star Trek. [It shows the] ability of using the individual's own biological system to trigger something that can then either prevent or treat an infection.

Lara

So it's a bit like the new vaccines for COVID, the mRNA vaccines, the idea is that you give something to someone that would then let the body trigger the immune response.

Stephen

Completely correct. Yeah. And also, then there are issues thinking, well, these are alien to us, because they're being manufactured. But antibodies are completely and utterly natural. We have them in our blood all the time against a whole range of different things. All we're doing is working out how we make those things and what they're against. And then we can then manufacture them to be exactly the same as our own antibody, just binding to the things that we're particularly interested in.

Lara

So the technology that you're developing, could be used for a host of different bacteria, that it wouldn't just be one specific bacteria?

Stephen

That's something that we don't know. We are working with very focused projects on specific bacteria at the moment and we have some initial positive results. So it looks like that the system works and that we can, in a laboratory at least, trigger an appropriate type of response from those antibodies. And also, we think that those antibodies bind against a range of different bacteria across a kind of like different genetic space. Not all bacteria, but the same within the same species, they're variable. But we think we can get antibodies that bind across a large proportion of bacteria in a specific species. What we don't know as yet is if there is a magic antibody out there, that will then bind to a whole range of different pathogens that we can just use in one go. That seems unlikely given what we know about that to a diversity, but it's not impossible. And if we can come up with the right targets, then actually, there's nothing stopping us giving a combination of different antibodies together that would then cross or cover a whole range of different potential functions.

Lara

What you're describing is very exciting. What are the major challenges you see going forward in realising this ambition?

Stephen

This is new technology, and the industry, and also, the field of antimicrobials is still very much focused on small molecules, because of the way that we understand that they work. We know the procedure for how they've been developed. And we also know we can make them at low cost. And generally they will have some useful timeline. That window is diminishing whether we want to admit it or not.

Then there is a decreasing interest from industry about developing new antimicrobials for various reasons. And also, as we've shown beautifully through the last 75 years of bacterial and human evolution, that this is not a long term solution. We get some more longevity out of antibiotics if we use them appropriately. But we're clearly not very good at that either.

As a kind of optimistic pessimist, I would say that, it seems like antibiotics are pretty much a done deal for humanity and will be in the next 50 years. At the current trajectory it would be difficult to see how we could stop or revert the position we've got ourselves in unless something magical comes along that can change this in the next 20 or 30 years. It doesn't seem like antimicrobials are going to be a good long term bet. So we do need to start thinking about alternatives.

This type of technology that I've been talking about has been successfully used for other indications. It's being developed now for other viral infections. There are therapeutic antibodies that are becoming available for COVID, which theoretically work. There are some precedents for antibodies that work against bacteria in the gut. There's an antibody that's licenced for Clostridium difficile, which causes hospital acquired enteric infections. But then there's a big move into this type of technology for cancer treatments, and also then for immune deficiencies and other things.

So this is a technology that's being used. What we're trying to do then is use this technology and apply it to understanding how we can develop new therapeutics for drug resistant bacteria. And it's a challenge for sure, because bacteria even though they're very small and theoretically they are actually very complicated. So just because we have an antibody against one bacteria, that doesn't mean it's going to work for a whole host of different other things. So we have to understand exactly how that bacteria works, we have to understand exactly what antibodies bind to, we have to understand exactly what it's doing, what it can't do, and whether it can induce any degree of response within the human that's hopefully going to prevent an infection or treat an infection, and hopefully not make it worse.

Lara

And I know that monoclonal antibodies are used to treat cancer and autoimmune disorders, and those have been very expensive. How do you see this becoming affordable as drugs for low to middle income countries?

Stephen

Okay, yeah, this is a big argument. Part of the standoff and not moving forward in this area has been the expense. Pharmaceutical companies don't see infectious diseases as a big money making area. And I kind of understand that, but that doesn't mean we shouldn't do it, I think there is a need for it.

So two things, there is a huge markup on manufacturing costs of monoclonal antibodies. And there are ways to make them cheaper by essentially crowdsourcing resources and other things to get the cells that express those antibodies into a specific pipeline for manufacturing. We can make that cheaper.

Theoretically, as it stands today, at cost, you could probably make a gram of monoclonal antibody for less than $100. But the prices are astronomical. So $100 is still a lot if you think about it for a gram of particular treatments. So we'd have to make it cheaper than that. But that is with every current manufacturer that we have doing this at whatever scale they're doing.

The science is there, there is no reason why, with some investment we can make this procedure cheaper. I agree that $100 for a gram of antibodies is expensive. And it's not as cost effective giving someone a broad spectrum antimicrobial, I agree. But that is in 2020, when we don't know what the targets are. I think that actually, once we know we can start rolling this technology out, it will naturally become cheaper, as have computers, mobile phones, televisions, electric cars, everything that once it becomes an accepted technology.

Lara

And what about administering them because so far, we know that they have to be given intravenously? Are you looking at how they would be administered?

Stephen

There are different things you can do with them. So for bacteria that cause problems in the gut, then there are mechanisms to get them into the gut. So we can use them to then target infections that I would be interested in the gastrointestinal tract. You can give them intravenously into patients with bloodstream infections, and that's probably the most efficient way of getting them into somebody that obviously has a bacteria in their blood. But if they have a lung infection, there's nothing stopping us coming up with methodologies for nebulising them or other things [to get them] into the lungs. So again, as there is a potential mechanism to make them cheaper there would be the ability to target the way we deliver them. And we can do clever things with all kinds of medications to get them into the right place. So intravenous is probably the most feasible way for systemic infection, but there's nothing stopping us from wrapping them up in different ways and delivering them in different parts of the body.

Lara

You've been pretty thorough. Is there anything else that you feel that we've missed out that you would like to add?

Stephen

No, I don't think so. I think I have talked about quite a lot of this stuff that we've got going on, I do think, even if it's not antibodies that becomes the next big thing. I do think we do need some thought and investment in developing new approaches, new technologies for how we then treat and prevent drug resistant infections. We have got a little bit overly blasé about the potential utility of using antibiotics. And even if I am wrong, and it's not a doomsday scenario with antibiotics, having additional armoury for us to treat or prevent infections has to be essential.

I mean, we've unfortunately learned a very, very harsh lesson this year, in how quick new infections can enter human populations and have a fairly devastating human and economic impact. It would seem prudent then that we need to invest in different ways to not only understand how these things work, but how we can prevent them. And as you can see various technologies, antibodies, RNA vaccines, adenovirus vaccines have accelerated this year. We're all discussing these things, and there has been some use of these technologies in the past, but they've accelerated beyond belief in the last nine months. There's really nothing stopping us doing this apart from a willingness really to get on with it and someone to pay for it.

I hope that if we are at the point, we can take some things forward, that it's not at the point where we've really waited too long. And we start having kind of global outbreaks of multi drug resistant organisms in hospitals, but we don't really have an alternative to treat, because we haven't spent enough investment now in trying to come up with ways to prevent the infections.

Lara

Do you think there's a more willingness to invest in this stuff now as a result of COVID? Do you think that the way forward might actually be a bit easier because of?

Stephen

Yeah, it's an interesting question, isn't it? You would hope so. I think that actually lots of these technologies will move forward, given the fact that they've gone through this bottleneck now. So yeah, so there's a kind of technological bottleneck, I guess, and also, then there is a licensure bottleneck that these things have gone through showing that they work and people begin to trust technology. So that's good.

Will they accelerate financially? It's difficult to say. We tend to have very short memories. So maybe, maybe not. I think that if you're asking me now, and I was sitting on a government advisory panel, apart from trying to maybe sound like feathering my own nest a little bit, but I do think that a mechanism for getting the economy back on track would be to invest in some of these technologies. And then for the UK, and as we enter this period of being post Brexit, post COVID, that we could use some of these platforms to start becoming a leader in kind of global healthcare. I think that that would be sensible. I think that over the next few months there are going to be enormous technological advances, and also a return on financial returns on some of these investments in vaccines and the antibody area. And I think it would make an enormous sense now to invest in them, and try to develop that as a platform over the next five to 10 years.

Lara

That's been great. Steve, thank you so much. That's been very informative.

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