Shifting the paradigm of how we treat infections to one that promotes resilience and health.

 Interview image DD

I have been working with the SHIELD consortium now for a little over 1.5 years now. SHIELD is a universities of Sheffield, Edinburgh, Birmingham, and Newcastle led partnership to develop host defence therapeutics.

The coordinator of SHIELD, David Dockrell, is in my mind the perfect example of a translational researcher who is working at the intersection of basic science and clinical medicine. He is able to bring together big concepts that have the potential to really make a difference and at the same lead a team that is delivering the meticulous and sometimes tedious basic science.

Working to help moderate the interactions as I do in SHIELD has been an interesting experience that has stretched my mind. Just the number of acronyms that fly around in the dialogue is mind boggling. 

That said, what I have learned is that the work that was conceived and is now being conducted in SHIELD is very elegant and illustrates what I think the future of medicine will look like.

So, I asked, and David agreed to let me interview him. The full transcript is at the bottom of this post and a link to the podcast is here.

What follows is a short summary of the interview with some highlights and emphasis on some of what I think are the most important points.

Moving beyond the ‘blunt tool’ mindset

“I think our challenge is that we have had a mindset, and the mindset has been that infections are bad, that we need to use antimicrobials to knock out the pathogen, probably ignoring some of the other effects of the antimicrobials.”

I like to think that in the past with more simple concepts of disease it was little more than hopeful thinking that blunt treatments would be effective without undue secondary consequences. Take chemotherapy for example.  

As David points out we really now have the opportunity to move away from such approaches:

“Now, we're realising that there's a whole community structure of these bacteria, and there's a whole interaction between that community and health, and therefore we need to be more precise in how we target the pathogenic bacteria without altering the broader community. What we want to introduce is probably a more subtle change. And of course, that's something which our own bodies have been doing and do very effectively for most people.”

David describes this as promoting resilience and health, which is an interesting intersection of what one might describe as more holistic approaches and traditional, reductionist approaches.

I have always myself thought that scientists and clinicians for the most part understand, and want to take a more holistic approach, but such approaches are limited when we only understand a fraction of the biology that makes up the complexity of health and disease.

Those limitations are now beginning to be resolved as technology advances, making the paradigm shifts envisioned in SHIELD possible.  

“…what SHIELD is doing is trying to understand what are maybe the basis of some of these subtler perturbations using screening approaches to identify key responses involved in bacterial killing and confirming which are defective in patients at risk of infection.”

David spends more time in the interview delving into some of the approaches being used in SHIELD including some very interesting technology.

Shifting paradigms with consortia

In the second part of the interview, we talked about consortia and their role in medical research and innovation:

“The kind of examples that I'm most drawn to are some of the consortia that have really challenged paradigms, because I think that's what we're trying to do.”

He goes on to cite some of the consortia that formed around HIV research as examples of how consortia shifted paradigms. The biggest paradigm shift was perhaps that people became aware that HIV could be cured.

The reason consortia can make these kinds of paradigm shifts is because they bring together resources and technology:

“what a consortium with several different institutions and multiple principal investigators gives us is the ability to cover multiple different assays, multiple different validation platforms in one group”

An important point that we also discussed is that in order to make a difference, consortia have to involve multiple different types of stakeholders:

 “We have talked about what SHIELD aims to achieve, and we have talked about academia’s role in this research, but obviously, we need industry engagement to develop our findings, and we need to work with industry to make our findings relevant and potentially add value to some of the things that they may be working on. But in terms of other stakeholders, it's very important that something like SHIELD works with the public, with government, with funders. This is only possible through government funding and public support for scientific research.”

When I asked David my standard question: Why do you do what you do? his answer really put the importance of consortium based efforts like SHIELD into a global context:

“I do what I do because I think we need to challenge paradigms and find new ways of dealing with disease processes which affect all of the world's population, irrespective of where they live, irrespective of socioeconomic status.”

The points David makes in the interview underscore the important role consortia have in shifting paradigms and how that role is more important than ever as we seek to make more subtle ‘tweaks’ to complex systems.

The centres that make up SHIELD include:

Edinburgh Infectious Disease

Edinburgh Centre for Inflammation Research

Florey Institute, University of Sheffield

Imagine: Imaging Life, University of Sheffield

Newcastle University, Respiratory Medicine Research Group

University of Birmingham, Institute of Microbiology and Infection

You can find out more by listening to the interview, reading the transcript below, and by visiting the SHIELD website.

You can listen to the interview podcast here.

Transcript:

I'm very fortunate today to have David Dockrell. He is the chair of infection medicine at the Edinburgh Medical School. His interests lie in macrophages and in innate immunity, and really more specifically about how to protect healthy individuals from infection by optimizing the innate immunity. The idea is to limit reliance on antimicrobial therapy.

Now, I've known David for some time. We started off in the COPD MAP Consortium together, which was really working on COPD, and in fact the previous podcast from Ruth Tal-Singer was also in that same consortium. But more recently, I've been working with David in a consortium that he is leading called SHIELD. What SHIELD is really trying to do is develop host-defense therapeutics. It's a great example of going from bench all the way up with the ambitions into clinical implementation. I'll let David say a lot more about that, but you know, it's great to have you. Thank you, David. How are you today?

Yes. I'm well thanks, Scott. It is good to talk to you. As you've highlighted, SHIELD starts from the position that most people who have serious bacterial infection have this condition because part of their normal innate immune response to that infection fails. And we believe that while we're very good at classifying certain groups of individuals who are at risk because of extremes of age or because of certain medical conditions that they may have, we're less good at understanding exactly what molecular pathway is failing in these individuals, and how we can reconstitute that response to make them function more as the healthy, resilient population do. So, our consortium are really trying to identify the pathways which promote resilience and health, particularly in the lung but also at other tissue sites where infection occurs, and to try and prevent and modify the cause of these bacterial infections when they do happen.

In a way, can you then say that you're really kind of promoting wellness, as opposed to treating illness?

Yes. Very much so. We think that a lot of our focus medically and of course it's conditioned by diseases where we focus on the aberrant pathology, but in this case, we think that a lot of our focus needs to be on what promotes resilience and health for the healthy population and try and reconstitute that or get back to that state for the individuals who are susceptible or more susceptible to these diseases.

I want to back up a minute. I think that they had a good context there, but with that in mind, what you just described, I want to ask you a real simple question, which is why do you do what you do?

So I do what I do because I think we need to challenge paradigms and find new ways of dealing with disease processes which affect all of the world's population, irrespective of where they live, irrespective of socioeconomic status. I think these are problems which the whole global population face. And of course with regards to antimicrobial resistance, it is one of the current urgent medical threats which we face, and it's something which I believe we all have to try and address in our respective areas of research. So I think it is a perfect constellation of both a problem involving a disease process which affects everybody and a threat whose evolution affects everybody.

We've had antibiotics for a long time and it's one of our bigger successes in medicine, but why is it a challenge now to find new antibiotics?

I think our challenge is that we have had a mindset, and the mindset has been that infections are bad, that we need to use antimicrobials to knock out the pathogen, probably ignoring some of the other effects of the antimicrobials, and such as their broader effect on the beneficial commensal flora and the microbiome more generally, and therefore actually getting us to think more about how to prevent and how to modify these infections without such a reliance on antimicrobials is a step change. This has the knock-on affect of limiting the attractiveness of the traditional antimicrobial approach. A further challenge is that these traditional antimicrobial approaches have focused on a relatively limited set of targets and there has been limited identification of new antimicrobial targets. I think in medicine and in promoting health, it is these step changes which often are the most challenging, but ultimately should prove the most rewarding.

Would it be fair to even say that when we treat with antibiotics, you're sort of disrupting the normal homeostasis of the body? Is that the right way to think about it?

Yes. It is using a very blunt instrument to introduce a change in a specific population of bacteria. I think our concept of what constitutes a particular infectious disease is changing. We used to think very much that with one aberrant pathogen caused the infection and the target was to remove that one aberrant pathogen. And of course a lot of that arose because we had relatively imprecise microbiologic tools which just identified the predominant pathogen rather than the larger global community. Now, we're realizing that there's a whole community structure of these bacteria, and there's a whole interaction between that community and health, and therefore we need to be more precise in how we target the pathogenic bacteria without altering the broader community. What we want to introduce is probably a more subtle change. And of course that's something which our own bodies have been doing and do very effectively for most people.

So it's trying to go back to that idea of using what's worked, and using what's worked is essentially a tweak to a balance of different microorganisms rather than coming in with something that tries to knock out broad populations, including the pathogen, and will then have unforeseen consequences to health.

The other side of this, I just add, is of course the microorganisms keep evolving, and therefore the selective pressure we introduce with the antimicrobials means the therapy itself is self-limited, and our ability to keep generating new antimicrobials is challenged. We have a limited pipeline. So we need to come up with completely different solutions to broaden our defence portfolio.

Yes. Well, it's very interesting that you put it in those terms. Are there examples already where such tweaks have an impact? Or is this something that still needs a lot of proof of concept work?

I think it needs quite a lot of proof of concept work. I think there are examples, and potentially we could highlight for example situations where individuals are born with single gene defects that affect their immune system. And an example would be chronic granulomatous disease, where their neutrophils will be less efficient at generating reactive oxygen species to the NADPH oxidase system, and in that setting for example, we can try and prevent infections by giving interferon gamma such as cytokine to try and stimulate and prevent some of the consequences of that gene defect. I think what we're talking about is probably a next stage, which is dealing with less dramatic perturbations and probably with quite subtle interventions.

I think that weaves nicely into SHIELD. How is SHIELD sort of going to try to move that needle, or move things forward?

I think what SHIELD is trying to do is it is trying to understand what are maybe the basis of some of these subtler perturbations using screening approaches to identify key responses involved in bacterial killing and confirming which are defective in patients at risk of infection. We have tremendous advances which, in the scientific community, we can take advantage of in terms of genetic manipulation of cells, particularly with methodologies such as the CRISPR/Cas9 technologies, and we're trying to use these using primary cells and to identify what particular components contribute to the ability to kill bacteria.

But beyond that I think one of our big challenges, and it's been a big challenge for the community as a whole, is that when we perform screens or when we identify targets, that we validate those in appropriate models, and that includes validating them with primary human cells. It includes working with patient groups and with samples in patient groups. And potentially it also involves imaging responses in vivo in people. Therefore, I think one of the things that SHIELD will try and do, and is doing, is bringing together a group of individuals with a group of different methodologies so that we can have a very broad portfolio of assays that can validate the relevance of particular targets that we identify, and that will be both in relevant model systems but also very importantly in people.

I think there's a lot there. But I wanted to take a minute and kind of maybe expand on a couple of those things that I know are interesting, for example, can you kind of explain in some ways how SHIELD is doing the screening, right? Like a concept some of the listeners don't quite understand, but I think some of the things are quite interesting, what you're doing in SHIELD.

Yeah. Basically, our focus is particularly on microbicidal killing mechanisms, and particularly in macrophages, as you've alluded to earlier. We are performing screens of both the early stages of bacterial killing, by which I mean killing mechanisms that happen in the time period two to four hours after bacterial challenge, and then a rather more delayed period of bacterial killing that happens in the region of 12 to 16 hours. And that's the time when we the think the outcome of many infections are decided, if there isn't the ability to clear the residual pathogens that haven't been killed by the first wave of killing.

So I think what we will provide is by looking at a number of time points, we will able to look at the host response more broadly. It is harder to genetically modify the neutrophils, but we are able to use a variety of other approaches, using targets that are important to macrophages and testing these in neutrophils. And there are of course model systems in which we can manipulate myeloid cells more broadly that obviously we can test the relevance on neutrophilic inflammation. So that enables us to move from macrophage screens in isolation to responses in inflammation in general in model systems where the neutrophils may be the predominant myeloid cell exerting the selective pressure on the pathogen.

I mean, the idea, if I can just maybe just paraphrase it in a simple way, is to improve the performance of the macrophages, right?

Yes. We think that for many tissue sites infections, such as infections in the lung, but not necessarily restricted to the lung, the first encounter with a number of bacteria is with the tissue macrophage. This is happening in all of us probably all of the time. And mostly that outcome is in favour of the host and in favour of the healthy individual. And those bacteria are effectively cleared.

When individuals make the transition from that stage to one of disease, by which I mean an established infection where there is a significant level of inflammation and therefore potentially symptoms and signs we recognize clinically, when that happens, it is because those initial host defences which we're focusing on  in the tissue macrophage, but obviously also including some humoral elements and soluble factors that are released in particular tissues, and also those involving nonprofessional phagocytes like epithelial cells fail. But when that transition has been passed, we then move to a state where we need to recruit inflammatory cells, the principle of which is the neutrophils required to kill the bacteria, but there are other inflammatory cells including recruited inflammatory monocytes that become macrophages in tissue. So the function of these cells together, and their ability to kill bacteria then becomes critical to the outcome of the early disease. So we're interested both in what's preventing infection at the level of macrophages (and related responses) and in the early steps of the established infection to look at points at which we can increase killing to modify outcome.

You also mentioned imaging in humans. I think that's a very interesting concept. I know some of the work is quite fascinating. Can you explain some of that, how that's going to have an impact?

I think we think about imaging on different scales. And by imaging I mean imaging of cells so that we are better able to understand the factors that need to be produced or produced in the relevant location within the cell. So super-resolution microscopy approaches give us the ability, an unparalleled ability which we haven't previously had, to not only test if a critical factor which is needed in microbicidal is produced, but also to determine is it produced in the right place. That means adjacent to where the bacteria are and able to kill the bacteria, rather than maybe have some of the harmful consequence for the cell, or more broadly for the tissues around that cell.

But we're not just focused on individual cells in isolation in the lab. We're also interested in how those cells are functioning in the body, and using some of these sort of developments in imaging aligned to diagnostic capabilities, particularly around fiber optics and bronchoscopy, it is now becoming possible to image the same immune cells in tissues like the lung and try and start to identify their interactions with bacteria and potentially some of the molecules that they produce.

When I said at the beginning that really what we need to do is recalibrate or tweak the host response so that we more effectively combat the infection, clearly we're not talking about an extreme example of turning a switch on or off, we're talking about shifting something by maybe quite a modest amount to calibrate the individual's response and understanding where an individual is on that spectrum so that we can effectively recalibrate them, needs good ways of measuring that response. And we think that the imaging modalities which can be aligned to technologies like bronchoscopy, and other endoscopic procedures may be an effective way at giving us that capability so that we can personalize an individuals treatment.

An interesting point I want to bring up here, because if you look at other fields besides medicine, one of the impacts of technology is enabling more personalized tools or technology usage. I think in a way what you're saying this is also driving us towards personalized medicine. Is that the right way to think about it?

Yes, absolutely. I think the challenge is, going back to the point that I made, this is not something that's a binary on-off switch. It's not, for example, an occluded blood vessel that needs to be opened up. It's not a population of malignant cells that all need to be killed. This is something where there is potentially a balance with a number of different bacteria but some harmful bacteria, and we need to kill off those harmful bacteria or at the least kill off those harmful bacteria when they get to a location where they need to be removed, such as the distal airway or other areas where we may normally have very small numbers of bacteria. Another example would probably be the bladder.

So we need to effectively kill those bacteria that get to the wrong location or start to invade a tissue. And to do that, we need to calibrate the individual's response so that they function effectively. Their resident defences clear the first few bacteria and these have to be cleared without generating excessive inflammatory responses that might damage surrounding tissues.

Much of the morbidity and mortality that we associate with bacterial infections comes because of a dis-regulated and aberrant inflammatory response, not necessarily because of failure to kill bacteria. The issue is that you kill at too great an inflammatory cost. So a big concept of what we're trying to do is ensure that we kill at the early stage with cells that can kill with minimal induction of inflammation and minimal requirement to recruit some of the other inflammatory cells that may equally be effective at killing but may do so at the cost of more bystander tissue injury.

Yeah. I think that's a great point that I think a lot of people don't understand or appreciate and I remember clinically, whenever you had someone with a bad infection, sepsis or something, the riskiest time is when you first started the antibiotics because that's when things are going to go bad. I think that's really interesting. Now, as you know, it takes about 17 years to go from research finding to clinical implementation, which is a long time, but how is SHIELD trying to reduce that gap? And who needs to be engaged now in SHIELD and in the future to make that happen?

Yes, I think the things that we need to achieve in SHIELD are that we need to change paradigms, and by changing the paradigm, introducing the idea that we need to recalibrate or modulate the host response and add an alternative to antimicrobials, is a concept we need to sell. Now, clearly there is some quite fundamental biology going on in the screens which will identify targets which ultimately we hope to find ways of modulating with pharmaceutical agents and ultimately identify hits that could be taken forward as therapies. That's clearly a long-term undertaking, as you said. However, within SHIELD, we also have candidates that various members in the consortia have identified. We can take those forward as proof of concept in model systems and potentially with therapies, that repurpose drugs in many cases, to show proof of concept that this approach can work.

But ultimately one of the most immediate things that we can do and we are aiming to do is engage in clinical trials with therapies, particularly cytokine-based therapies that can modulate some of the key host responses that we've identified. These are agents that have already shown promise in preliminary studies in the clinic as potentially being able to modify hard clinical outcomes. And if we can show that they modify some of the targets that we are interested in, and in the context of existing or planned clinical trials, embed some of our assays, I think that will give another very important element that will show that host-based therapy is realistic.

The other key thing which I think SHIELD can do to accelerate the research in this area is by establishing assays and model systems, and  join these up with with imaging approaches to join up the different elements in the pipeline required to validate new therapies that we might develop or that other colleagues might develop. So essentially thinking of a staged validation platform that can help us move the most promising targets from cell biology and model systems into clinical trials. I think joining up those different platforms can help accelerate that translation.

Do you think you could do this on your own, or as a consortium, an important piece of that? I mean, what ways does the consortium really help you to meet those ambitious goals?

I think individually, no one investigator has the bandwidth to cover all these different areas of what consortium level funding. And what a consortium with several different institutions and multiple principal investigators gives us is the ability to cover multiple different assays, multiple different validation platforms in one group. Beyond that, it also forms a focus. It shows a number of like-minded individuals working together, and it shows an effective academic focus to bring in and draw in partners, other stakeholders, particularly in industry. As we develop particular targets, or as they have particular targets, that they might want to get additional validation on, we can work together to try and accelerate the development of some of these

So industry partners are a key partner in this. Obviously, the first stage, as you've alluded to, is setting up our assays and our capabilities, but pretty much from the next year or so in our work, the engagement with industry will be very important. And then obviously moving forward the capacity to take forward the clinical trials, which I've alluded to, are only possible because of industry partners. So those trials are being planned with input from industry partners. Obviously, when we get to the point of having some targets that we would want to take forward, we would have to be working with industry partners who have interest in developing them from that point.

What's the best example of a high-performing, successful consortium that you know of? And why would you say that was so?

The kind of examples that I'm most drawn to are some of the consortia that have really challenged paradigms, because I think that's what we're trying to do in therapy here. So for example I'm particularly drawn to examples like those that have been developed around HIV therapy, so for example thinking of the shock and cure strategy of waking up dormant immune cells that may contain an important residual HIV reservoir, try and kill those cells, so that ultimately there isn't a latent reservoir in long-term memory cells that may reactivate.

So within the UK, an example of that would be the Cherub consortium that's been developed with NIHR funding. Now clearly it's one example of several initiatives, and for example in the United States there's are big NIH and other consortia, as there are in Europe. In this area and one other example would be one that's been developed through researchers in Boston and Oregon.

And I would highlight these not because they have changed the particular therapy yet or solved that problem, but because they have used innovation and they have changed the way that the scientific and medical community and the public think about the problem. And they have made people aware of the idea that HIV could be cured. Now clearly, there's a lot of work to do before we get to that point, but they've changed I think very effectively the paradigm. They've addressed the agenda scientifically and also in the community.

Other such examples I'd highlight some of the working for example of TB resistance. And again a relatively recently funded initiative, which has joint Wellcome and MRC funding in the UK, is the CRyPTIC initiative, and there are many others addressing multidrug-resistant TB. So I'm very much drawn to these sort of consortia that are really changing the mindset and the paradigm. I think that's really the model that we need to approach in SHIELD.

It's interesting you mentioned HIV, because when you look at HIV, the speed in the end that the medical community and society responded to that and to get it to a point where it was treatable was really quite impressive. I saw a presentation and did some looking into this from the patient-stakeholder standpoint because the patient-stakeholder group in HIV who had been very active and very engaged with this, so it's been really a great example. And your point about paradigm shifting is great.

I want to just end with one last question. Is there anything else that you want to bring up or highlight in this that we didn't talk about?

We have talked about what SHIELD aims to achieve, and we have talked about academias role in this research, but obviously, we need industry engagement to develop our findings, and we need to work with industry to make our findings relevant and potentially add value to some of the things that they may be working on. But in terms of other stakeholders, it's very important that something like SHIELD works with the public, with government, with funders. This is only possible through government funding and public support for scientific research.

I think there's a very important debate which we're keen to engage in which is to raise the importance of public and state funding for research in academia to enable us to tackle these issues. And clearly, the public and their elected representatives have a lot of choices and there are a lot of priorities that need to be addressed. So it's important that we keep having that debate.

There are clearly many aspects of this in terms of antimicrobial resistance which are affected by that public debate, including the public's perception of when they should use antimicrobials. But equally, it's very important to have that debate to emphasize the importance of the funding to conduct research on this topic, and also the importance not just for what we do in any one country, but how we address this as a global problem, because we must address all potential sources of highly-resistant pathogens and make our research relevant in all these sources. So we've got to address this in a very joined up way as a global community. And it's really important that we find solutions and approaches that work around the world.

If someone wants to find out more about SHIELD or about the work you do, how should they do that?

Well, we have a website for SHIELD. We also have a number of publications which have started to come out supported by SHIELD work, and some of those details can be found on our website. Also, the investigators in SHIELD are listed there, and you can see the range of other engagement activities we are engaged in, including the activities that the members are involved in through their own personal webpages and that gives, I think, an idea of the range and depth of activities we're engaged in.

Great. What I'll do, I'll put the website in the notes. So anybody who's listening to this, you come to the post, you can see the website. Thank you for coming on. I think it's been very interesting. I learned a lot. Again, thanks a lot.

Okay. Thank you, Scott. It was fun talking to you. And thank you for the interest in the consortium.

Scott Wagers

"The Consortium Whisperer" Physician and researcher who has spent the last 12 years engaged in developing biomedical R&D consortia, as well as designing and supporting the delivery of consortium based projects.

No matter who you are, you can, and you should innovate through consortia. They are the only way to make a big difference to the future of medicine. Want to find out how? Get in touch.