A plant-based ointment recipe pulled from a 1,000-year-old manuscript is spiking excitement about what historical knowledge and traditional remedies can do to defuse the antibiotic crisis. At the same time, it’s highlighting how difficult it can be to move any compound—natural or synthetic, ancient or modern—from the lab bench to where it might do the most good.
You might have seen coverage of this: At the annual conference of the British Society for General Microbiology last week, a team of researchers from the University of Nottingham in England and Texas Tech University in the United States presented the results of their attempt to translate and manufacture an ointment described in a medieval manuscript held at the British Library. (The abstract doesn’t seem to be online, except within the conference program, so I snipped it and uploaded it to my Scribd account here.) The text, called Bald’s Leechbook, is in Anglo-Saxon; you can think of it as one of the earliest medical textbooks written in the West. The recipe is presented as a remedy for styes, pustular infections of an eyelash follicle that, in the pre-antibiotic era—and the 10th century was definitely pre-antibiotics—could cause blindness or even death if the infection spread to the nearby brain. It specifies garlic, leek, onion, honey, and bile from the digestive system of a slaughtered cow, and describes in detail how the potion should be made, by boiling up a solution in a brass vessel and fermenting it.
And, apparently, it works. The UK arm of the team translated the recipe, concocted it, and conducted initial tests on bacteria on culture plates. The US side tested it on infected tissue harvested from lab mice. In both settings, the potion killed MRSA, drug-resistant staph—and killed at higher rates than vancomycin, a last-ditch drug that medicine reserves for serious infections with that superbug.
“We were really surprised, and I was surprised,” Christina Lee, PhD, a medieval scholar on the team, confessed by phone. “I have always held up the idea of the pragmatic Middle Ages, that they had knowledge and method, but I was not sure whether that would hold up.”
One challenge, Lee said, was figuring out just how to make the recipe. First, plants growing now are not the same as then; the team chose modern varieties, making a best guess that the chemical components would be the same. Second, the recipe—like your grandmother’s prize pound cake, maybe—contained no proportions; just a list of ingredients, and instructions to brew and hold them. The team thought maybe equal amounts would work. And last, the recipe specified a “brazen vessel”; the group settled instead for adding strips of brass copper sulfate while the potion boiled.
Initial lab tests showed the concoction killed staph, while its individual ingredients, tested separately, did not. They turned to Kendra Rumbaugh, PhD, whose lab at Texas Tech University’s Health Sciences Center frequently conducts efficacy studies of new antimicrobial compounds. She tested it using lab mice, by creating a surgical incision, infecting it with staph, killing the mice and harvesting the tissue, and then soaking the infected tissue in the medieval concoction as well as a vancomycin solution and plain saline. In the tissue treated with the medieval compound, 90 percent of the staph died.
“Whereas vancomycin did, essentially, nothing,” she told me. “Now, ideally, if you have an agent and want to go to the (Food and Drug Administration), you want to see 99.99 percent killing. We would want to see better before moving into clinical trials.”
So what happened? The researchers admit: They are not yet sure. The team includes microbiologists, but not, at this point, biochemists; as they move forward into a second phase, they hope to recruit more collaborators. “Right now, this is a crude solution with a number of ingredients,” Rumbaugh said. “They will have to figure out what the active ingredient is.”
An almost-lost medieval recipe that works is marvelous, but is it practical—or even, really, new? I checked with several biochemists, who pointed out that looking for natural antibacterials is a longstanding research endeavor. (For instance: The medieval recipe contains garlic. Here, listed at the National Library of Medicine, are 354 papers going back to the 1940s examining allicin, an antibacterial compound in garlic.)
“It is exciting that this team were able to validate an ancient traditional remedy,” said Cassandra Quave, PhD, an ethnobotanist whose Emory University lab studies the antimicrobial properties of plant compounds. “It demonstrates that traditional medicine—which 80 percent of the world still uses—isn’t just old wives’ tales, but has science behind it. But the challenge of getting anything to market is the regulatory hurdles.” Despite its plant origin, she pointed out, this remedy or anything like it probably would not be eligible for approval as a dietary supplement, for which the rules are looser. If its discoverers assert a clinical effect, they likely would have to go to the FDA for investigational new-drug approval.
And FDA licensing requires much more detailed analysis than the researchers have done to date—essentially, taking the formula apart and then putting it back together, said David Kroll, PhD, a natural-products pharmacologist who writes the Take as Directed blogTake as Directed blog for Forbes. “What you normally do with a complex mixture is, extract out the fat-soluble and water-soluble compounds, separate the chemicals in each, and test them individually for the effect you are looking for—anti-staphylococcal activity, in this case,” he told me. “And then, if you are claiming synergy between the components, you have to put them back together, and test the results again. The mixture has to be highly defined, and highly reproducible.”
And then it has to be tested—in clinical trials, if the creators intend the compound to be licensed as an antibacterial. Complaints about the FDA’s requirements for clinical-trial design are legion (for the full story, try David Shlaes’ blog The Perfect StormDavid Shlaes’ blog The Perfect Storm); suffice it to say that highly capitalized pharma companies already consider clinical-trial requirements a major stumbling block in creating new antibiotics.
Quave and Kroll pointed out that 10 years ago, the FDA approved an accelerated, streamlined approval process for plant-based products, called the Botanical Drug Pathway. In the decade since, according to the blog Fierce Pharmablog Fierce Pharma, it has received more than 500 applications for plant-based medications—and approved two.
The tentative conclusion for now: In retrieving this almost-lost remedy from antiquity, the team that produced and tested this crude but fascinating medication faced significant challenges. But the hurdles they will have to leap, if they attempt to move it forward into a viable product, will be higher yet.