On rainy summer evenings, molecular biology graduate student Sarah Brozio would leave the northern Trinidad field center she shared with lizards, tarantulas and human colleagues to search the forests for a peculiar substance called frog foam. Rolling slowly along the roads in a weathered sedan, her small group would drive in silence, listening to the buzzes and squawks of the nightlife until they heard a pinging sound akin to arcade laser guns. The lone ping would soon be followed by an entire chorus—the distinct ruckus of male Túngara frogs vying for a mate.
When one of these males impressed a female with his melodious bravado, the two got frisky in a soggy ditch along the roadside. He hugged her from behind and fertilized her eggs, which she released along with a soup of proteins. Together, both partners whipped the mixture into a thick froth using their back legs. This dome of foam prevented the eggs from drying out while also offering protection from predators, extreme temperatures and damage from ultraviolet rays and harmful bacteria.
Given the foam’s utility and durability, Brozio and her colleagues wondered if this enigmatic material might have clinical applications for humans. They flew the foam they’d collected back to their lab in Scotland to test its properties and determine if it could be used like existing pharmaceutical foams to deliver drugs to the skin. In a study published today in Royal Society Open Science, they demonstrate that the amphibian lather could indeed be an effective alternative to the foams that doctors currently prescribe for conditions such as cuts or burns.
The project took root in 2014, a year before Brozio’s first foam-collecting trip to the Caribbean island of Trinidad. Like many intrepid research proposals, it began as an idea over drinks. Microbial biochemist Paul Hoskisson and pharmaceutical engineer Dimitrios Lamprou formed an unlikely partnership at a pub at the University of Strathclyde, in Glasgow.
Hoskisson’s lab specializes in developing antimicrobials, so he was intrigued by the fact that frog foam could naturally resist bacterial colonization. Based on Hoskisson’s descriptions, Lamprou wondered if the material’s stability and structure might also make it conducive to carrying and releasing drug compounds. Shortly thereafter, the two recruited Brozio, who joined Hoskisson’s lab as a PhD student. She accompanied Hoskisson on several trips to Trinidad, and then got to work testing the foam in the lab.
“This is the first time an amphibian foam has been used for drug delivery,” says Hoskisson, the study’s co-senior author. These foams, he adds, “should give us a really nice, safe delivery vehicle that can be administered to patients without any fear of making them sick, unlike many of the other synthetic delivery vehicles.”
For years, industrial foams have been used to apply cosmetics and deliver medications like antibiotics dermally, rectally and vaginally. These synthetic concoctions dispense drugs across large swathes of skin, but many collapse within minutes or hours and dump their cargo prematurely. When treating wounds and burns with foams, doctors often have to frequently remove medical dressings so the foam can be re-applied. In addition to disrupting the healing process, this increases the risk of infection and antibiotic resistance. What’s more, synthetic foams can sometimes act as allergens and irritate a patient’s skin.
Túngara frogs are not the only animals that produce foam nests; for example, other frog species, spittlebugs and Siamese fighting fish make them as well. While these natural products are more likely to be compatible with human skin than artificial substances, it’s tricky to find functional foams in the wild that last longer than an hour or two. Túngara frog foam, by contrast, is gentle enough to incubate tadpoles, and can persist in harsh tropical environments for over a week.
To test their theory that frog foam could serve as a drug delivery system, the researchers employed a series of standard pharmaceutical techniques to probe its structure, composition, viscosity and stability. Close-up, the foam is comprised of densely packed bubbles called vesicles. These sturdy vesicles capture and hold drug molecules while allowing the foam to be spread across large surface areas without collapsing. The warm temperature and decreased pH of human skin causes the vesicles to dissolve, freeing the drug over time.
The researchers determined that the foam could be used to encapsulate dyes that dissolve easily in solution as well as those that do not—hinting that the froth could carry a variety of drugs with a range of properties. The team also loaded the foam with the common antibiotic rifamycin, which was released over the course of a week—a promising timeframe because patients are often treated with antibiotics for five to 14 days. Roughly half the antibiotic was delivered in the first 24 hours, but the slow release that followed over the next six days was longer and steadier than existing pharmaceutical foams. However, the study authors won’t know precisely how their foam measures up to specific synthetic options without side-by-side comparisons.
What co-senior author Lamprou, now a professor at Queen’s University Belfast, can say with certainty is that frog foam could change the way pharmaceuticals are manufactured and delivered if it performs well in follow-up studies. He and his colleagues determined that the foam was safe to apply to human skin cells in a dish. But next they will need to test the foam on entire swaths of mammalian skin—probably pig skin from a local farm—and eventually on live animals, such as mice or rats, and later rabbits and pigs. He envisions eventually using it to deliver a variety of drugs in addition to antibiotics, perhaps even biological molecules like proteins or mRNA.
Yang Shi, a biomedical engineer at RWTH Aachen University in Germany who was not involved with the study, had never heard of frog foam before this paper—let alone considered it for medicinal purposes. “It's a highly novel and even crazy idea to use the material from frogs in pharmaceutical drug delivery,” he says.
Using foams to deliver drugs to specific areas of skin is an attractive and more comfortable alternative to pills and needles, Shi explains. He specializes in cancer chemotherapy and immunotherapy, and could see a potential role for the amphibian froth in delivering treatments to kill skin cancer cells. But, he cautions, the technology is still very much in its nascent stages, and many additional studies are warranted before it could become commercially available. For example, frogs won’t be able to produce enough foam to meet manufacturing demands, so the key proteins in the lather would need to be purified and replicated in large quantities at a reasonable cost.
Brozio has since graduated from the University of Strathclyde, but much of her PhD thesis was devoted to brewing the individual foam ingredients from scratch without the need for froggy fornication. She provided the bacteria with frog DNA and coaxed them into generating several of the six key proteins in the foam. Even when she used just one of these proteins to make her own foam, the concoction would last at least a week or two, she says. Next, the Hoskisson lab will need to determine the ideal amount of each protein for their foam recipe—and whether all six proteins are even necessary, which could streamline the manufacturing process.
Beyond their remarkable foam, frogs may offer other medicinal inspiration. Biochemist Milena Mechkarska, who was not involved with the study, also investigates the therapeutic potential of amphibian-derived materials in her lab at the University of the West Indies’ St. Augustine Campus in Trinidad. She often spots Túngara foam nests during her field expeditions, but focuses instead on other frog species, which ooze short proteins called peptides from their skin to ward off predators and disease-causing microbes. Mechkarska is exploring whether these peptides could be used as alternatives to antibiotics in human patients, or perhaps incorporated into medicines to help mount a more balanced immune response, ensuring the immune system eliminates an infection without overreacting and attacking the body. She wonders if Túngara foam could regulate the immune system in similar ways, in addition to being used as an antibiotic-laden, bubbly wound dressing.
The study, she says, “is an excellent example of research inspired by Mother Nature.” Many researchers aim to extend their ideas from the lab to the clinic—“bench to bedside,” as the saying goes. But Mechkarska believes frog foam could span an even greater distance: “from nature to bedside,” as she puts it.