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Medieval medical books could hold the recipe for new antibiotics

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A recipe for an eyesalve from ‘Bald’s Leechbook.’
© The British Library Board (Royal MS 12 D xvii)

Erin Connelly, University of Pennsylvania

For a long time, medieval medicine has been dismissed as irrelevant. This time period is popularly referred to as the “Dark Ages,” which erroneously suggests that it was unenlightened by science or reason. However, some medievalists and scientists are now looking back to history for clues to inform the search for new antibiotics. The Conversation

The evolution of antibiotic-resistant microbes means that it is always necessary to find new drugs to battle microbes that are no longer treatable with current antibiotics. But progress in finding new antibiotics is slow. The drug discovery pipeline is currently stalled. An estimated 700,000 people around the world die annually from drug-resistant infections. If the situation does not change, it is estimated that such infections will kill 10 million people per year by 2050.

I am part of the Ancientbiotics team, a group of medievalists, microbiologists, medicinal chemists, parasitologists, pharmacists and data scientists from multiple universities and countries. We believe that answers to the antibiotic crisis could be found in medical history. With the aid of modern technologies, we hope to unravel how premodern physicians treated infection and whether their cures really worked.

To that end, we are compiling a database of medieval medical recipes. By revealing patterns in medieval medical practice, our database could inform future laboratory research into the materials used to treat infection in the past. To our knowledge, this is the first attempt to create a medieval medicines database in this manner and for this purpose.

Bald’s eyesalve

In 2015, our team published a pilot study on a 1,000-year old recipe called Bald’s eyesalve from “Bald’s Leechbook,” an Old English medical text. The eyesalve was to be used against a “wen,” which may be translated as a sty, or an infection of the eyelash follicle.

Human white blood cells (in blue) take on Staphylococcus aureus bacteria.
Frank DeLeo, National Institute of Allergy and Infectious Diseases

A common cause of modern styes is the bacterium Staphylococcus aureus. Methicillin-resistant Staphylococcus aureus (or MRSA) is resistant to many current antibiotics. Staph and MRSA infections are responsible for a variety of severe and chronic infections, including wound infections, sepsis and pneumonia.

Bald’s eyesalve contains wine, garlic, an Allium species (such as leek or onion) and oxgall. The recipe states that, after the ingredients have been mixed together, they must stand in a brass vessel for nine nights before use.

In our study, this recipe turned out to be a potent antistaphylococcal agent, which repeatedly killed established S. aureus biofilms – a sticky matrix of bacteria adhered to a surface – in an in vitro infection model. It also killed MRSA in mouse chronic wound models.

Medieval methods

Premodern European medicine has been poorly studied for its clinical potential, compared with traditional pharmacopeias of other parts of the world. Our research also raises questions about medieval medical practitioners. Today, the word “medieval” is used as a derogatory term, indicating cruel behavior, ignorance or backwards thinking. This perpetuates the myth that the period is unworthy of study.

During our eyesalve study, chemist Tu Youyou was awarded the Nobel Prize in Physiology or Medicine for her discovery of a new therapy for malaria after searching over 2,000 recipes from ancient Chinese literature on herbal medicine. Is another “silver bullet” for microbial infection hidden within medieval European medical literature?

Certainly, there are medieval superstitions and treatments that we would not replicate today, such as purging a patient’s body of pathogenic humors. However, our work suggests that there could be a methodology behind the medicines of medieval practitioners, informed by a long tradition of observation and experimentation.

One key finding was that following the steps exactly as specified by the Bald’s eyesalve recipe – including waiting nine days before use – was crucial for its efficacy. Are the results of this medieval recipe representative of others that treat infection? Were practitioners selecting and combining materials following some “scientific” methodology for producing biologically active cocktails?

Further research may show that some medieval medicines were more than placebos or palliative aids, but actual “ancientbiotics” used long before the modern science of infection control. This idea underlies our current study on the medieval medical text, “Lylye of Medicynes.”

A medieval medicines database

The “Lylye of Medicynes” is a 15th-century Middle English translation of the Latin “Lilium medicinae,” first completed in 1305. It is a translation of the major work of a significant medieval physician, Bernard of Gordon. His “Lilium medicinae” was translated and printed continuously over many centuries, until at least the late 17th century.

The text contains a wealth of medical recipes. In the Middle English translation, there are 360 recipes – clearly indicated with Rx in the text – and many thousands more ingredient names.

As a doctoral student, I prepared the first-ever edition of the “Lylye of Medicynes” and compared the recipes against four extant Latin copies of the “Lilium medicinae.” This involved faithfully copying the Middle English text from the medieval manuscript, then editing that text for a modern reader, such as adding modern punctuation and correcting scribal errors. The “Lylye of Medicynes” is 245 folios, which equates to 600 pages of word-processed text.

I loaded the Middle English names of ingredients into a database, along with translations into modern equivalents, juxtaposed with relationships to recipe and disease. It is very time-consuming to format medieval data for processing with modern technologies. It also takes time to translate medieval medical ingredients into modern equivalents, due in part to multiple synonyms as well as variations in modern scientific nomenclature for plants. This information has to be verified across many sources.

With our database, we aim to find combinations of ingredients that occur repeatedly and are specifically used to treat infectious diseases. To achieve this, we are employing some common tools of data science, such as network analysis, a mathematical method to examine the relationships between entries. Our team will then examine how these patterns may help us to use medieval texts as inspiration for lab tests of candidate “ancientbiotic” recipes.

Word cloud from the Lylye of Medicynes.
Erin Connelly

In March, we tested a small portion of the database to ensure that the method we developed was appropriate for this data set. At present, the database contains only the 360 recipes indicated with Rx. Now that the proof-of-concept stage is complete, I will expand the database to contain other ingredients which are clearly in recipe format, but may not be marked with Rx.

We are specifically interested in recipes associated with recognizable signs of infection. With Bald’s eyesalve, the combination of ingredients proved to be crucial. By examining the strength of ingredient relationships, we hope to find out whether medieval medical recipes are driven by certain combinations of antimicrobial ingredients.

The database could direct us to new recipes to test in the lab in our search for novel antibiotics, as well as inform new research into the antimicrobial agents contained in these ingredients on the molecular level. It could also deepen our understanding of how medieval practitioners “designed” recipes. Our research is in the beginning stages, but it holds exciting potential for the future.

Erin Connelly, CLIR-Mellon Fellow for Data Curation in Medieval Studies, University of Pennsylvania

This article was originally published on The Conversation. Read the original article.

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Enzymes versus nerve agents: Designing antidotes for chemical weapons

US Official: Russia knew Syrian chemical attack was coming

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Enzymes, the catalysts of biology, can engulf and break down hundreds of nerve agent molecules per second.
Image: Pymol. PDB 4E3T rcsb.org, CC BY-ND

Ian Haydon, University of Washington

A chemical weapons attack that killed more than 80 people, including children, triggered the Trump administration’s recent missile strikes against the Syrian government. The use of illegal nerve agents – apparently by the Assad regime – violated international law; President Trump said he was moved to act by images of the victims’ horrible deaths. The Conversation

But there’s another path to mitigate the danger of chemical weapons. This route lies within the domains of science – the very same science that produced chemical weapons in the first place. Researchers in the U.S. and around the world, including here at the University of Washington’s Institute for Protein Design, are developing the tools needed to quickly and safely destroy nerve agents – both in storage facilities and in the human body.

Nerve agents, a class of synthetic phosphorous-containing compounds, are among the most toxic substances known. Brief exposure to the most potent variants can lead to death within minutes. Once nerve agents enter the body, they irreversibly inhibit a vitally important enzyme called acetylcholinesterase. Its normal job within the nervous system is to help brain and muscle communicate. When a nerve agent shuts down this enzyme, classes of neurons throughout the central and peripheral nervous systems quickly get overstimulated, leading to profuse sweating, convulsions and an excruciating death by asphyxiation.

U.S. Marine Corps specialists performing decontamination procedures.
Sgt. Keonaona Paulo

Chemical weapons are often associated with wars of the previous century – mustard gas in WWI, Zyklon B in WWII. But the worst variety, nerve agents, were never deployed in the world wars, though Nazi scientists developed the first generation of these compounds. Gerhard Schrader, the so-called father of nerve agents, didn’t begin life as a Nazi scientist – he was developing new pesticides to combat world hunger when he accidentally synthesized the first organophosphorus nerve agent. Later, he led the research team that produced sarin, or GB, the most toxic of the all the so-called G-series nerve agents. The U.S. government stated with “very high confidence” that sarin was used in the recent attack near Idlib, Syria.

Beginning in 2013, teams from the Organization for the Prohibition of Chemical Weapons went to Syria and, with help from the Danish, Norwegian, Russian, Chinese and U.S. government, destroyed all declared stockpiles of Syrian chemical weapons. It seems that either not all of Assad’s stockpiles were in fact declared and destroyed, or that new nerve agents arrived in Syria – either via the black market or chemical synthesis – in the intervening years.

Empty sarin containers at Pine Bluff Arsenal.
U.S. Army

Clearing chemical weapons

Twenty-first-century chemists, biochemists and computer scientists are working right now to sap chemical weapons of their horrifying power by designing counter agents that safely and efficiently destroy them.

Sarin sitting in a container – as opposed to in a human body – is relatively easy to destroy. The simplest method is to add a soluble base and heat the mixture to near-boiling temperatures. After several hours, the vast majority – more than 99.9 percent – of the deadly compound can be broken apart by a process called hydrolysis. This is how trained specialists dispose of chemical weapons like sarin.

Nerve agents that make their way inside the body are a different story. For starters, you clearly cannot add a near-boiling base to a person. And because nerve agents kill so quickly, any treatment that takes hours to work is a nonstarter.

There are chemical interventions for warding off death after exposure to certain chemical weapons. Unfortunately, these interventions are costly, difficult to dose properly and are themselves quite toxic. The chemical antidotes pralidoxime and the cheaper atropine were deployed after recent attacks in Syria, but doctors in the area worry their dwindling supplies offer little protection against possible future attacks.

For a medical intervention to work after nerve gas exposure, it has to work fast. If a first responder administers a sarin-destroying molecule, each therapeutic molecule must be capable of breaking down through hydrolysis hundreds of nerve agent molecules per second, one after another.

Enzymes, the genetically encoded catalysts of biology, are up for such a task. Famous enzymes include lactase, which breaks down milk sugars in those who are lactose tolerant. Another known as RuBisCO is vital to the process of carbon fixation in plants. The most efficient enzymes in your body can perform a million reactions per second, and do so under chemically mild conditions.

Aside from their astonishing speed, enzymes often display an equally impressive selectivity. That is, they react with only a small number of structurally similar compounds and leave all other compounds alone. Selectivity is useful in the context of the chemical soup that is the cell but problematic when it comes to xenobiotics: those compounds which are foreign to one’s biology. Man-made organophosphates such as sarin are xenobiotics. There are no enzymes that hydrolyze them well – or so we thought.

When farmers spray pesticides, much of it ends up on the ground. Soil bacteria living nearby are challenged by high doses of these potent foreign chemicals. It turns out that efficient detoxifying enzymes have recently evolved inside some of these microbes as a result.

Scientists have identified and isolated a small number of these enzymes and tested them on a range of nasty compounds, including nerve agents, which are structurally similar to some pesticides. A select few did indeed show hydrolytic activity.

Scientists are using computers to design a new generation of proteins to solve 21st-century problems.
UW Institute for Protein Design, CC BY-ND

Improving on the discovery

Researchers have taken these naturally occurring enzymes as raw material. Then, using computer modeling and controlled evolution in the lab, we’ve bolstered the efficiency of the originally found anti-nerve agent enzymes. Enzymes that initially showed only modest activity have been turned into potential therapeutics against VX – a chemical cousin of sarin and the most toxic nerve agent of all.

In a proof-of-concept study conducted jointly by researchers in Germany and Israel in late 2014, guinea pigs under anesthesia were exposed to lethal doses of VX, followed by optimized VX-destroying proteins. Low doses of the protein drug, even after a 15-minute delay, resulted in survival of all animals and only moderate toxicity.

Despite these promising advances, no enzyme yet exists which is efficient enough for lifesaving use in people. Scientists are refining these microscopic machines, and new paradigms in computer-aided protein engineering are unlocking the door to this and other applications of biomolecular design. We may be only a few years away from developing the kind of therapeutics that would make chemical weapons a worry of the past.

As the world grieves over the latest attacks in Syria, it is worth keeping in mind the awesome and often complex power of science. In trying to combat hunger, one might accidentally invent liquid death. In studying soil microbes, one might discover a tool to prevent atrocities.

Ian Haydon, Doctoral Student in Biochemistry, University of Washington

This article was originally published on The Conversation. Read the original article.

Mysterious chambers found hidden in ancient Giza structure

Fascinating:

Two scientists say they’ve uncovered hidden chambers in the Great Pyramid of Giza. Discovered using an advanced X-ray technique the chambers are completely isolated from all other tombs and passages in the 4,500 year-old structure.

The discovery was made by Scan Pyramids, a research project involving universities and advanced scientific instruments. Using a combination of thermography, 3D simulation and radiography imaging, the team discovered anomalies in the structure indicating the presence of holes beneath the rock.

From the expert’s mouth

Chimpanzé (Pan troglodytes)

In this Atlantic piece on how candidates will do in the debates:

“In many ways the performances of Donald Trump remind me of male chimpanzees and their dominance rituals,” Jane Goodall, the anthropologist, told me shortly before Trump won the GOP nomination. “In order to impress rivals, males seeking to rise in the dominance hierarchy perform spectacular displays: stamping, slapping the ground, dragging branches, throwing rocks. The more vigorous and imaginative the display, the faster the individual is likely to rise in the hierarchy, and the longer he is likely to maintain that position.”

In her book My Life With the Chimpanzees, Goodall told the story of “Mike,” a chimp who maintained his dominance by kicking a series of kerosene cans ahead of him as he moved down a road, creating confusion and noise that made his rivals flee and cower. She told me she would be thinking of Mike as she watched the upcoming debates.

“Vigorous and imaginative displays on Trump’s part and steady error avoidance on Clinton’s are the stories of their progress through the primary-cycle debates. Clinton is her party’s nominee independent of anything that happened in the 10 Democratic debates and town halls, and with minimal effect from them on her financial, endorsement, and name-recognition advantages. Trump is his party’s nominee largely because of the Republicans’ 20-some debates, town halls, forums, and other live-television displays.

Don’t let it be forgot

Tintagel

Since I am a complete sucker for anything related to the Arthurian legend, this is so cool:

Archaeologists have discovered the impressive remains of a probable Dark Age royal palace at Tintagel in Cornwall. It is likely that the one-metre thick walls being unearthed are those of the main residence of the 6th century rulers of an ancient south-west British kingdom, known as Dumnonia.

Scholars have long argued about whether King Arthur actually existed or whether he was in reality a legendary character formed through the conflation of a series of separate historical and mythological figures.

But the discovery by English Heritage-funded archaeologists of a probable Dark Age palace at Tintagel will certainly trigger debate in Arthurian studies circles – because, in medieval tradition, Arthur was said to have been conceived at Tintagel as a result of an illicit union between a British King and the beautiful wife of a local ruler.

The account – probably based on an earlier legend – was written by a Welsh (or possibly Breton-originating) cleric called Geoffrey of Monmouth. The story forms part of his greatest work, Historia Regum Britanniae (History of the Kings of Britain), one of the most important books ever produced in the medieval world.

Significantly, it was almost certainly completed by 1138 – at a time when the Tintagel promontory (where the probable Dark Age palace complex has been discovered) was uninhabited. The medieval castle, the ruins of which still stand today, was built almost a century later. Geoffrey of Monmouth’s assertion that King Arthur was conceived in an earlier by then long-abandoned great fortress on the site would potentially therefore have had to have come, in the main, from now long-lost earlier legends, claims or quasi-historical accounts.

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