The antibiotics hidden in medieval recipes

While the practice of medicine looked very different in the Middle Ages compared to today, people living in the medieval era and throughout history wrote down recipes for treating different kinds of illnesses. In a unique collaboration between microbiologists and science historians, researchers reconstruct historical treatments to see if they might make effective modern-day antibiotics. So far, many have shown promise.

Host: Stephanie DeMarco, PhD, Associate Editor, Team Lead

Guests:

Joel Klein, The Huntington Library

Freya Harrison, University of Warwick

Steve Diggle, Georgia Institute of Technology

Christina Lee, University of Nottingham

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Photos from Stephanie DeMarco's visit

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Transcript

Stephanie DeMarco: Hello everyone! Welcome back to DDN Dialogues. I’m your host, Stephanie DeMarco.

Today’s story starts with a cold. Whenever I start to feel a scratchiness at the back of my throat or if I’ve got a bad case of the sniffles, I turn on the kettle to assemble my get-well-soon remedy. Into the mug of boiling water, I put a spoonful of apple cider vinegar and a generous glob of honey. My fiancé introduced me to this concoction as something that his mom always made for him when he was sick, but people have been using this combination of vinegar and honey since ancient times. They called it oxymel, and everyone from Hippocrates in ancient Greece to physicians in medieval Persia and beyond used it to treat all sorts of ailments, but most of all, infections.

The ancients, it turns out, may have been on to something. In today’s episode, we’re going back in time to medieval and early modern England. There, we’ll explore what medicine looked like during the Middle Ages, an old treatment for an eye stye, and finally, how looking back at historical texts led to an exciting new discovery about oxymel as a potential modern-day antibiotic.

The medieval and early modern period in England spanned a tumultuous few hundred years. It started in the late 5^th century, through the Renaissance, and to about the end of the 17^th century. This was, of course, the age of knights and kings, but it was also a time when a toothache could turn deadly. People living during this time were very familiar with infectious diseases. From 1346 to 1353, the Black Death killed about half of the population of Western Europe. It, in fact, is still the most fatal pandemic in recorded history. While the medieval period was absolutely a scary time to be alive, medical care was available. 

Joel Klein: You definitely did have academically trained physicians. You had city physicians, who many of them did receive some kind of formal training, but there were all sorts of other practitioners. You had herbalists and people selling quack cures. It was a very complicated place to be practicing medicine.

DeMarco: That’s Joel Klein. He’s a curator for the History of Medicine and Allied Sciences at The Huntington Library.

Klein: In the Middle Ages and the early modern period, there are still many folk traditions. You do have the rise of new empirical modes of thinking, but your main, say diagnostic modes in early medieval and early modern medicine would have been taking the pulse and checking a person's urine. That's not to say that's the only thing that they did, but those were two of the primary practices that you would use to diagnose patients.

With that said, though, there's a lot that is in early medicine that's just as you would expect from common sense. So, one of the individuals that I work on has a treatise on medicine related to pregnancy and childbirth, and the rearing of children, and 90 percent of what you read in this book from the early 17^th century is exactly what childcare manuals still say today. Make sure that the child is fed, and that you change them often, and you can treat the rash with this particular salve, that kind of thing. 

One of the main things I like to challenge as a historian is the idea that everyone in history was stupid. They certainly weren't. They didn't have access to some of the modern things that we have. And science is always changing, and medicine is always changing. It's really hard to make sense of the world around you, especially working in that period. There's just a lot of tradition.

DeMarco: Many of these traditions and medical recipes that doctors of the time used were handwritten and bound into books. I met up with Klein at The Huntington Library, and he showed me some of these medieval and early modern medical texts.

Klein: This is a modern binding of a medieval manuscript. You can see it has various titles here, but medical recipes, very ancient on vellum, so vellum is animal skin. It's a series of medical recipes, and really, it's a series of things to do for particular problems. So, this is from England. They say about the year 1400, but probably a little earlier than that. And here at the very end, it has the signature of an individual Symon Wysbech, “studens in iure canonico,” so that means “student in canon law.” And he was paid by this wealthy individual to copy all of these different medical recipes into one particular text, so that wealthier individual could have all of these different medical recipes at hand in the household. It's written in Middle English, and you can see the text is not particularly easy to read to modern eyes. 

DeMarco to Klein: No!

Klein: But you've got here, say a recipe for hot gout, toothache. There are some charms in here. The staunching of the blood, so how to stop blood from a wound. Dropsy, I mean, you name it, you can probably find it in here. “For him that is spitting blood.” That's a fun one. So, it has mostly herbal remedies. Do you want to see this other book that I have? 

DeMarco to Klein: Sure, yeah, that’d be great.

Klein: I just happen to have this pulled. It's a 17^th century herbal. A Generall Historie of Plantes by John Gerard. It's one of the most important of the herbals published in England. It's over 1000 pages long, and it does have these beautiful woodcut illustrations of literally thousands of plants. This also is full of medical information. So, how are these particular plants used to treat various diseases? Oh, this is a fun one! Foxglove, which of course is still used today, digitalis. It can be poisonous, but it's actually because there are certain compounds in it which go to the heart. It is used as a medicine for various ills related to the heart and the circulatory system.

This says, let's see: Foxe glove boiled in water or wine, and drunken, doth cut and consume the thicke toughness of a grosse and slimie flegme and naughtie humours; it openith also the stopping of the liver, spleene, and milt, and of other inward parts. 

So, and it's fun for me being at The Huntington because we of course, still have Foxglove digitalis growing in the gardens. When I give tours, and sometimes I do give tours of the herb garden, a lot of people ask for actual medical advice, and I say, it's not my domain. There are people out there who work in actual pharmacy and medicine, who are reconstructing early recipes from books like this to see what modern applications they might have.

DeMarco: In fact, there is a group of researchers that includes both science historians as well as microbiologists, and they call their interdisciplinary collaboration the AncientBiotics team. Their goal is to look for historical recipes that might serve as old-but-new treatments for modern day conditions, and it all started with a microbiologist and her love for medieval reenactments.

Freya Harrison: I'm Freya Harrison, and I'm a reader in microbiology at the University of Warwick. In my spare time, one of my main hobbies is historical reenactment, so I started to learn sword fighting about 20 years ago, and then got very interested in early medieval history as a part of that. I'd kind of done a bit of reading just for fun about historical medicine. Towards the end of my PhD, I came across a humanities research article from Michael Drout in the US, where he and some colleagues had tried reconstructing some early medieval remedies and testing them. And I thought, well that's really cool, you know, filed that away, the idea that people were doing that. And then several years later, when I moved to the University of Nottingham, I got talking to Christina Lee and Erin Connolly, who are both on the humanities side of research, and are both very much interested in the history of disease, of disability, and of medicine and science. And it was really through conversations with them where this idea emerged of, you know, why don't we do this? We've got a good combination of humanities and science skills here. Let's see if we can identify some of these remedies that might make sense from a natural products perspective, make them in the lab, see if they do anything. And at the time, I was a postdoc in Steve Diggle's lab. And he's also a bit of a history nerd, so he was very keen on getting involved in this.

Steve Diggle: So, Freya came to me and said, “Can we make this?” And I said, “Sure, sounds like fun!” 

DeMarco: That’s Steve Diggle, who is now at the Georgia Institute of Technology. The first remedy they decided to recreate came from a 1,000-year-old Anglo-Saxon medical text called Bald’s Leechbook.

Diggle: The recipe was to deal with a wen, which translates to a lump on the eye, which is probably a stye if we think of it in modern terms, and they're usually caused by Staphylococcus aureus.

DeMarco: The recipe directed them to crush together garlic and a historical plant called cropleac. They would then need to combine that with wine and cow bile, and let the mixture sit in a brass or bronze container for nine days. But even with so few ingredients, Christina Lee, a science historian at the University of Nottingham, explained that recreating this recipe was no easy task.

Christina Lee: There is one ingredient, cropleac, which is an allium species. Nobody is completely sure, you know, as to what it is, or what exact we should be looking at.

DeMarco: The researchers ended up substituting an onion and a leek for the mysterious cropleac, but even with this swap, modern day allium plants are likely very different from ones that grew in the Middle Ages.

Harrison: And if you think how much selective breeding has happened of vegetables, we're not going to know, is the chemical makeup of this exactly the same as it was, you know, 1000 years ago? It could be very, very different.

Lee: Even if you're thinking about the plants, do you use them fresh? What about the winter? Do you use them dried? Some of these remedies require animal parts, so for example, we have pigs bladders, and you can't just kind of go, “Well, you know, this person is very sick. Let me you know sort of slaughter a pig.” So, are there people who are keeping this? Is there an economy? Today, if you're doing drug discovery, you know exactly where to order from.

Diggle: They have bull-ox gall in the recipe, and so that's bile from a cow's stomach. Obviously, we weren't going to get bile from a cow's stomach, but you can buy ox gall from chemical companies like Sigma. So, you can mimic it, but then what concentrations do you use? I think Freya had a conversation with the Sigma rep on the phone and trying to figure out what approximate concentration of bile you would find in a cow's stomach. 

Harrison: Sometimes they do give you amounts, or they might say, take as much as a peppercorn of this or an eggshell full of that. Or they might say, use equal amounts of this and that, but a lot of the time, they're not using that. And that kind of ties in, I think, with those books being working manuals. If you were giving someone a recipe who did a lot of baking, you might say, you know, make a basic sponge mix. You wouldn't need to give them the details because you'd assume they knew it. It's a basic bit of knowledge for them.

We're certainly not saying that when we make these reconstructions in the lab, we will make exactly what a historical physician made. We don't have a time machine; we can't do that. But we can try and get as sensible an interpretation as possible by working with people who have that specialty.

DeMarco: In the end, the team put together the best reconstruction they could and tested their concoction against in vitro biofilm cultures of Staph aureus and in mice with chronic methicillin resistant staph infections.

Diggle: And It killed Staph aureus cells really quite well, but also you couldn't drop an individual ingredient out of the recipe. It had to have all the ingredients for it to really work.

Harrison: We were incredibly lucky in that basically, the first remedy we tried was very promising. So, we absolutely lucked out there, and that gave us the impetus to keep doing this kind of work. 

DeMarco: Harrison has continued working with the AncientBiotics team. Recently she and Connolly built off of what they learned from their stye treatment reconstruction, and this time, they zeroed in on oxymel. While vinegar and honey, the two ingredients that make up oxymel, are commonly found in the kitchen pantry, they both individually have medical uses as well.

Harrison: Acetic acid is in clinical use for treating infected wounds, primarily burn wounds. Medical grade honey of various kinds is a very established treatment for infected wounds. No one puts them together. And then, you speak to someone like Erin who says, “Well, this idea of mixing vinegar and honey and making oxymel, this is something that is in medicine across a broad range of history, across a wide range of geography. If you look around the Mediterranean in the Near East, every kind of source you look at, people have started to put these two things together. And it gives you that new insight of, “Oh, well, why haven't we tried doing this?” As microbiologists know, we're all about combination therapies. Here's one that seems to have some historical backing that we've just not tried.

DeMarco: Honey and vinegar may seem like simple ingredients, but they both contain many different natural products that researchers think could be giving them their antimicrobial effects.

Harrison: The use of honey in modern medicine is quite telling. Honey is antimicrobial for several different reasons. It's got several modes of action, several targets, and nobody has made a synthetic honey. So, we know manuka honey is working through osmotic activity, through the presence of methylglyoxal, potentially through B-defensins. Not one of those single things alone has become a clinical agent. You need that kind of slightly raw, mixed ingredient. 

DeMarco: While vinegar consists primarily of acetic acid and water, it also contains various natural products depending on its starting material. For example, vinegars made from red wine will have different natural products in them compared to those made from apple cider.

Harrison: We know pure acetic acid has this excellent, clinically useful antibacterial activity at very, very low concentrations, and what we wanted to know was when you see antimicrobial activity of a vinegar, is that purely because of its acetic acid content, or are there other things in at least some vinegars which modulate that effect? And if we were to find that a vinegar was more powerful than just its acetic acid content, that could give us a clue that there's a natural product in that vinegar that we could extract and combine with acetic acid to get potentially a better clinical effect.

The second hypotheses was then the next level of complexity. And that was: What happens when you put acetic acid or a whole vinegar together with honey? Again, do you get something that has better activity? And does it have a broader spectrum of activity? By putting two agents together, you can kill more bugs? More kinds of bugs? Or is it a quantitatively different level of activities?

DeMarco: So, the researchers set out to test the microbe-killing properties of different vinegars and a modern-day equivalent of the ancient oxymel.

Harrison: We had a very long list of vinegars we were potentially interested in, which we had to whittle down for the paper, and this really came through conversations with Erin. We looked at the range of vinegars that would have been used in some of these texts based on where they were written. Sometimes they specified types, but sometimes we just saw where in the world were they written, and what would people have been making vinegar from?

So, we decided that most places would turn wine into vinegar, so we could try red and white wine vinegar. A lot of places make some kind of cider, so an apple cider vinegar will be useful. And then, if we look at some of these uses of oxymel coming from the eastern Mediterranean or the Middle East, then things like date vinegar or pomegranate vinegar would be quite interesting as well. Erin would tell you that pomegranates are really interesting from a historical medicine perspective because there's a lot of pomegranate products, so including the vinegar was interesting.

DeMarco: Most intriguing to Harrison and her team was that when they looked at the complexity of the different vinegars in their study, they saw that pomegranate vinegar contained many more compounds than the others. They then put two different pomegranate vinegars, red wine vinegars, and pure acetic acid to the test. They measured how well each of them disrupted Pseudomonas aeruginosa or Staph aureus biofilms in a synthetic wound model.

Harrison: The pomegranate vinegars were massively more powerful than just the acetic acid. So, the most antimicrobial vinegar was a pomegranate vinegar in our study, and it had the lowest acetic acid content, and when you work out the minimum concentration that clears a biofilm, and if you then turn that into an equivalent acetic acid concentration, I mean, it's tiny, the amount of pomegranate vinegar you need. It's having effects where pure acetic acid would just be too dilute to do anything.

DeMarco: The team then tested whether combining vinegars with two different types of medicinal grade honey had a synergistic effect when used to treat a biofilm infected wound.

Harrison: Combining just the pure acetic acid with one of the manuka-based medical grade honeys, we were really going from a half log drop in the number of viable biofilm cells to going to a kind of three to four log drop, which is at the level where you start to think this might be clinically relevant. And then, we looked at two different pomegranate vinegars, and they were quite different in their effects. And one of them did seem to have a stronger synergy with the manuka honey as the pure acetic acid did, so we do need to have a look at this in a lot more detail.

DeMarco: With these positive results, Harrison and her team are eager to test these vinegar and honey combinations against biofilms made up of multiple bacterial species, including different clinical isolates that infect chronic wounds.

Harrison: The other thing that was exciting was talking to clinical colleagues and just sort of verifying and saying, like, “No one's doing this, right? Surely someone's thought of this before?” And people saying “No, this is fairly novel, the idea of combining the acetic acid and the honey,” and seeing how excited the clinicians were and how straightforward they thought it would be to take this into a clinical trial was really, really exciting.

DeMarco: In fact, Harrison and her colleagues have their sights set on the clinic already.

Harrison: We're going through the process now of working with the university hospital to go through the process of seeking ethical approval to see if we're allowed to start this work. And, you know, you're talking about a patient group who are faced with some pretty horrible consequences with these infections. You know, you do get non-healing wound infections, particularly in people who have underlying conditions like diabetes, that can be effectively untreatable. People with diabetes can get these small lesions on their feet or their lower legs that become nonhealing ulcers, and they can become infected, and unfortunately for a small but appreciable percentage of these people, these infections are completely antibiotic resistant. And sadly, people end up having to have an amputation to prevent that infection spreading to their bone or to their blood or triggering sepsis. So, anything we can do to get another treatment on the market, or to get an improved treatment on the market will be a massive, massive plus for these patients.

DeMarco: The researchers plan to start with the combination of pure acetic acid and medical grade honey, and then perhaps based on future research into the natural products found in pomegranate vinegar they might incorporate other compounds.

Harrison: The other thing about this combination as well is that both medical honey and acetic acid are quite painful treatments for patients. So, honey has quite a strong osmotic effect, which can be quite painful, and it has a fairly low pH as well, and the acetic acid obviously is a weak acid. So, even if we find that by combining these treatments, we get the same effect, but at a lower dose or for a shorter treatment, we might be making treatment a bit more bearable.

DeMarco: While Harrison is excited to begin testing this treatment in people, she did emphasize that this acetic acid and honey combination therapy is still firmly at the stage of laboratory testing.

Harrison: We're certainly not saying if you've got a non-healing wound, then mix up some vinegar and some honey. Don't try this at home!

DeMarco: While a modern day oxymel for infected wounds is still in early stages of development, the research from the AncientBiotics team has shown that historical texts may certainly be an untapped source of potential therapeutics.

Harrison: Now, my lab is very much split half and half. There's people doing the work on how bacteria form biofilms and how they become antibiotic tolerant, and then I've also got people who are looking at these remedies and testing them. I just would not have predicted this kind of thing would happen seven, eight years ago when we started looking at that first remedy, but it's really grown, and people are really interested in it.

I've always been a bit of a magpie when it comes to the work I do. I've had a lot of tangents in my career, and this has been a perfect example of something that's just new and interesting and cool. It involves talking to people and having conversations and being a bit creative and doing things differently. And that has been really, really exciting.

DeMarco: That’s it for this episode of DDN Dialogues. I’d like to thank Joel Klein, Freya Harrison, Steve Diggle, and Christina Lee for talking with me, and thanks to all of you for listening! Thanks also to Joel Klein for showing me medieval and early modern medical texts in The Huntington Library’s collection. Until next time, I’m your host Stephanie DeMarco.

This episode of DDN Dialogues was reported, written, and produced by me with additional audio editing by Jessica Smart. To never miss an episode, subscribe to DDN Dialogues wherever you get your podcasts. And if you like the show, please rate us five stars and leave a review on your favorite podcasting platform. And if you know someone who you think might like the show, please share it with them! If you’d like to get in touch, you can send me an email at sdemarco@drugdiscoverynews.com.

And, who knows, maybe the next great antibiotic has already been discovered, and it’s hidden inside a centuries-old manuscript, just waiting for someone to find it.