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Ashley's Biggest Takeaways

• Diggle and Harrison met in Oxford, where Harrison was finishing up her Ph.D. and Diggle was doing background research for his work studying evolutionary questions about quorum sensing.
• When Diggle began searching for a postdoc, Harrison, who had been conducting an independent fellowship at Oxford and studying social evolution, applied.
• The AncientBiotics Consortium is a group of experts from the sciences, arts and humanities, who are digging through medieval medical books in hopes of finding ancient solutions to today’s growing threat of antibiotic resistance.
• The group’s first undertaking was recreation and investigation of the antimicrobial properties of an ancient eyesalve described in Bald’s Leechbook, one of the earliest known medical textbooks, which contains recipes for medications, salves and treatments.
• The consortium found that the eyesalve was capable of killing MRSA, a discovery that generated a lot of media attention and sparked expanded research efforts.  
• The group brought data scientists and mathematicians into the consortium (work driven by Dr. Erin Connelly from the University of Warwick).
• Together, the researchers began scouring early modern and medieval texts and turning them into databases.
• The goal? To mathematically data mine these recipes see which ingredients were very often or non-randomly combined in ancient medical remedies.
• The group recently published work showing synergistic antimicrobial effects of acetic acid and honey.
• They are also working to pull out the active compounds from Bald’s eyesalve and make a synthetic cocktail that could be added to a wound dressings.

Featured Quotes:

Diggle: I'm a molecular biologist by trade. I did my Ph.D. in quorum sensing in Nottingham, the University of Nottingham in the U.K. And as I was getting to the end of my postdoc, having studied mechanisms of quorum sensing, I was kind of thinking, ‘Well, what am I going to do in the future?’ And I ended up kind of bumping into and meeting some evolutionary biologists, who are now at the University of Oxford, who started asking questions that we'd never really thought about, you know—they were more why questions? Not how does quorum sensing work? Why is it there, and what survival value does it give to the bacteria? And through that, we started asking some more evolutionary questions about quorum sensing. And that's kind of how I started my own group, I guess.

And at the same time, Freya, was working as a Ph.D., I think she was doing a Ph.D. in Oxford. And then then I had a postdoc job that came up, and I was very, very happy that she actually applied for it. And so she joined us at Nottingham, which was great.

Harrison: I think that Job was kind of pivotal in my career direction. I was still sort of deciding whether I was going to be a microbiologist or an evolutionary biologist. And so, when the job with Steve came up, it just looked perfect. And I think that that kind of crystallized everything. For me, that was where I learned to be a proper microbiologist.

The other project we started at that point, which was what became the AncientBiotics Consortium, was really a complete accident. We had been talking to Christina Lee, Ph.D., who was in the School of English at Nottingham, and we had this shared interest in the history of disease. Hers being a professional interest as a specialist in that area, and mine being a very passive interest as a microbiologist who also does some reenactments. And so I'd read a bit about medieval medicine as part of that. And Steve, I think you said before, one of the reasons you became a microbiologist is because you had this fascination with the Black Death and the plague.

Diggle: Yes, its my big big passion.

Harrison: Yeah, so you were quite happy for us to sort of take up this slightly mad idea of doing a collaboration with Christina, making some of these medieval recipes in the lab and seeing if they worked.

Harrison: We really thought this was going to be a couple of weeks side project—we'd get a pat on the head from colleagues for being interdisciplinary—but it wouldn't be a huge piece of science. And that's actually developed into something that really has become an interdisciplinary project.

Diggle: It's also a good point, I think, to step back a little bit and think about the fact that there are other people who've done some of this kind of work before. And I think it gets a lot of resistance, because the really interesting thing about our study was that it's the combination of ingredients that really has the impact, right. And this is a problem in trying to get funding for these kinds of things. Because people like to have single molecules, not combinations of ingredients, that just seems crazy.

But I think one of the most interesting things for me is—and this comes through talking with Christina, who is the humanities professor at Nottingham—I think we generally think that maybe cultures and societies over 1000 years ago, we tend to think of them as quite backwards. Right? And maybe what they were doing was just kind of, in the U.K., we call it quackery, you know—that they just did this kind of random stuff to just see what worked and what didn't work. But what's quite interesting, is that it's the combination [of ingredients] that works. Were they actually doing the scientific process of understanding 600 years before the scientific method really became established? And so, for me, that's one of the really interesting things of this, which now allows us to do what Freya said—asking “Well, why does it work?” You know, “What is it that actually works.” But there's a lot of interesting angles on this that are not just about finding a new therapy. It's all about understanding what our ancestors were doing and why they were doing it.

Harrison: Oh absolutely. You know, we don't fully understand how they were categorizing these ingredients or symptoms. What was driving them to make certain combinations? And this is something for the Humanities experts in the consortium. They're also thinking, “What does this tell us about knowledge transmission?” You know, was it a case where somebody in one place used ingredients A and B to treat a condition, and someone somewhere else used ingredients C and D. And when they exchanged each other's work, or heard about each other's work, they put all 4 together?

Diggle: It's a similar idea to when people like using phage, right, they will use phage cocktails because somebody said this phage works, and this phage works if we combine them.

Harrison: Yeah, and combination antibiotic therapy. I mean, wasn't it just last year colistin became no longer recommended to be used on its own and should only be used in combination?

Diggle: I think it's worthwhile pointing out that wounds were probably a real issue for people back evolved years ago, because people not only went to battle and things like that, but also a lot of people worked the fields, and they worked very hard jobs. I don't think it was an easy life, certainly not to be working class, back in those days. Often you were almost owned by a wealthy landowner, and you worked for them. And I would imagine that wound infections were extremely common. So, it was something that they were dealing with all the time. And they used to do things like dry horse feces, and things like that and put them on wound. There's lots of different avenues to explore.

Harrison: We've literally just submitted a preprint on Monday—just put that up on bioRxiv. So, working with Erin Connelly again, one of the things that she has really stressed is this really common usage of vinegar and honey—across many time periods and many cultures. You find the use of vinegar, the use of honey and the combination of vinegar and honey.

And so, Erin and I were discussing that this is very interesting because medical grade honey isn't very common in clinical use. It's fantastic for treating infected wounds, particularly diabetic ulcers—an indication it's used a lot for in the U.K. And acetic acid is also in clinical use, at least in the U.K., for burn wound infections. So about 30% of U.K. burn centers will use acetic acid-soaked dressings if you've got a Pseudomonas infected burn wound. And nobody seems to have put these together.

So, we had 2 thoughts. Firstly, do some vinegars contain other compounds that might add to or synergize with the activity of acetic acid—coming back to this idea of multiple ingredients in synergy—and secondly, what happens when you put acetic acid and honey, or vinegar and honey, together? And we found that there are some vinegars, particularly pomegranate vinegars, that are much more antimicrobial than you would predict just from their acetic acid content alone. And that's testing against P. aeruginosa and S. aureus in biofilm models in the lab.

Harrison: So Bald was the name of a person who, we think, lived around the year 1000 and commissioned a medical book or elite book to be written. And one of the remedies in this book is for a lump in your eye, which we think you could interpret as a stye—that'd be the most common kind of lump you'd get in your eye, right? So, an infection of an eyelash follicle. In the eyesalve remedy, the recipe says that you take garlic and a second Allium species, which we couldn't unambiguously translate. You pound them together in a mortar and pestle, and then add wine and cow's bile. And you leave this mixture for 9 days and nights in a brass or bronze pots. And at the end of that 9 days, you strain out the lumps, and you're left with a sticky liquid, which you're supposed to put in the patient's eye with a feather.

And this remedy was really, really interesting because garlic and Allium have been very well studied for potential antimicrobial compounds (things like allicin). And they do have quite good antimicrobial/anti-biofilm/anti-quorum sensing activity, at least in in vitro models. But they haven't translated through into clinical use. And then the wine and the cow's bile would also be expected to have antimicrobial effects. So, you're combining 4 things that we know from the lab can kill bacteria—at least in a test tube—and then you put them in this brass or bronze pot. So, you're potentially leaching copper salts into that mixture as well, which should give you another source of activity. So, we thought, “Yeah, this just looks such a good recipe to test from a microbiological point of view.” And if it is for a stye, then most of them are caused by S. aureus, so we've got a good candidate bug to test it against. We know the kind of bacteria that cause these sorts of infections. Steve, Steve was all for giving this a go in his lab.

Diggle: And the big fun thing was that it actually worked. But it's not just a bleach that kills everything. It was pretty efficient against S. aureus. And I think it was with Kendra Rumbaugh in Texas Tech that we worked with. She did some animal work for us, but she also has a synthetic wound model where she can put a consortium of different species in together, like enterococcus, pseudomonas, Staph. And when she mixed them together and added the eyesalve, it was just taking out the Staph. The other [microbes] weren’t as affected, which was interesting.

Diggle: I think that is the real take home from what I was saying is really be open minded, to working with people from different disciplines if there's a natural fit. Working with somebody who's an expert in another field, they can really help explain why these things are happening in a way that you couldn't do on your own in a really clear and effective way. So, be open minded. Having any kind of multidisciplinary angles gives you some unique insights that other people aren't getting.

Links for the Episode:

• A 1,000-Year-Old Antimicrobial Remedy with Antistaphylococcal Activity.
• Medieval medicine: the return to maggots and leeches to treat ailments.
• A case study of the Ancientbiotics collaboration.
• Phase 1 safety trial of a natural product cocktail with antibacterial activity in human volunteers.
• Sweet and sour synergy: exploring the antibacterial and antibiofilm activity of acetic acid and vinegar combined with medical-grade honeys.

Let us know what you thought about this episode by tweeting at us @ASMicrobiology or leaving a comment on facebook.com/asmfan.

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