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Drugs from Bugs: Bioprospecting Insects to Fight Superbugs

(Credit: Yusnizam Yusof/Shutterstock)

Somewhat like looking down the barrel of a gun, antibiotic resistance is a looming threat to modern medicine. The rise of MRSA, super drug-resistant gonorrhea and other “nightmare” bacteria risk rendering our microscopic defenses useless. What to do when your last-last-last resort fails to kill these pathogens?

Someday, perhaps sooner than later, we’re going to need new antibiotics, not to mention medicines for cancer, depression, and other conditions that aren’t readily treatable by current prescriptions. So, how do we find new pharmaceuticals?

Some argue that we’ve reached “peak pharma,” but Ross Piper, an entomologist and research fellow at the University of Leeds, contends that we haven’t even begun looking. Our best bet may be beneath our feet, in the diminutive world of insects, and he says this research might also ignite conservation efforts.

“It could be a treasure trove of useful chemistry. Look at what compounds have been isolated from reptiles and snakes,” Piper said in a video call with Discover. His favorite example is exenatide, a synthetic hormone that treats diabetes mellitus type 2, originally derived from the saliva of Gila monsters. Between 2014 and 2016, sales of this drug reached $2.49 billion. “Who would have thought just by looking at the compounds in the saliva of a bloody lizard that you can produce a blockbuster drug for type 2 diabetes?”

For the past year, Piper has been engaged in what he calls “ecology-led drug discovery,” and he believes insects are the most promising lead. Bugs and other arthropods, awash in a tiny world of filth, need to protect themselves from disease, and have evolved many novel defenses.

While insect bioprospecting, as it’s called, is not entirely new, there’s much to be done. There’s an estimated 5.5. million different insect species on earth, but only around 20 percent have been described. Yet, entomologists are becoming scarce—so why isn’t bioprospecting bugs more popular?

Millions Of Insects, Millions Of Chemical Defenses

Humans have known about the medicinal benefits of compounds derived from insects—anti-bacterials, analgesics, anticoagulants, diuretics and antirheumatics—for hundreds, if not thousands, of years.

In a 2005 review, Eraldo Costa-Neto identified 64 different arthropod species from around 14 orders, all used medicinally by different cultures across five continents. In traditional Korean medicine alone, there are at least 19 insects and other arthropods commonly prescribed, including centipedes, cicada nymphal skins, and ghost moth larvae infected with the paralyzing fungus Ophiocordyceps sinensis.

More recently, scientists found that wasp venom can pop cancer cells while alloferon, a peptide isolated from the blood (hemolymph) of a species of blow fly, has antiviral and antitumor properties.

But one of the biggest problems is scaling. Once you find a chemical in something as tiny as a fly, how do you make sure you can make enough of it?

“Previously, you would have been restricted by not being able to find sufficient quantity of that particular species,” Piper says. “You maybe needed thousands of them to be able to extract enough of whatever that produces from whatever gland you’re looking at. But you can do that with much smaller quantities now.”

With advances in transcriptomics, not to mention all the buzz about CRISPR-Cas9, Piper believes we can isolate certain genes and insert them into the cell line of something else to mass-produce it. Alternatively, you could insert genetic material into other insects, such as crickets or mealworms, and mass-produce medicine this way.

“You could put vaccine genes or something like that, like they do in tobacco, into insects,” explains Aaron Dossey, an entomologist and pioneer in the insect-based food industry. He’s also the founder of All Things Bugs, a company that manufactures whole cricket powder. “Then use them as a mass production vehicle for your vaccine, your possible drug of choice or enzyme or bioactive peptide or some vitamin.”

Dossey suggests that stick insects or phasmids make “attractive model organisms for biosynthesis studies” due their large size and wide range of chemical defenses.

“Given the number of phasmid species analyzed…the number of novel compounds found in phasmids so far, and the total number of species in this order, phasmids represent a significant potential source of new compounds,” he wrote in a 2010 analysis.

Putting The Ant In Antibiotic

Among the most promising bugs to look for drugs are eusocial insects, especially in the order Hymenoptera — bees, wasps and ants. An anthill, which can contain hundreds of millions of workers with high genetic relatedness in compact, clustered living quarters, is the perfect place for disease outbreak.

“If one individual gets infected, a worker could spread it to thousands of individuals within a few hours,” says Clint Penick, an assistant research professor at Arizona State University who studies ant relationships. “Soil is the most by microbially dense and diverse habitat on the planet.” Therefore, ants need strong antimicrobials, which many species secrete from the metapleural glands on their back.

In research published in Royal Society Open Science in February, Penick and his colleagues tested the antimicrobial strength of 20 different ant species against Staphylococcus epidermidis, a common, generally benign, skin-dwelling bacteria. Using a vacuum-like device called a pooter, he collected ants from the sidewalk, in his backyard and on the way to work at North Carolina State University, where he was researching at the time.

“We hit all three of the major ant sub-families, which is a pretty good breadth of their diversity,” Penick says. Sixty percent of the ants tested inhibited bacterial growth, but efficacy was not dependent on colony population or even the size of the ant. In fact, one of the smallest ants tested—the thief ant, Solenopsis molesta—displayed the strongest antimicrobial properties.

The exact chemical properties behind these insects’ homegrown pharmacopeia is unknown. More research is needed to isolate these substances, but it’s getting easier all the time.

“What we developed was a method where you can measure a lot of ant species at once. We were able to run 96 samples in a day whereas other groups might be able to just run a couple dozen,” Penick says. “We’ve shown that we can scale this and look at more species. We’ve also narrowed down a little bit about which species might be interesting.”

No Rock Left Unturned

It’s easy to overlook some compounds because lab-grown insects often rely on native plants in their diet in order produce the same chemicals. For example, blister beetles, especially the so-called Spanish Fly, are noted for the extremely toxic cantharidin they produce. A terpene commonly used in wart cream, cantharidin has some anti-tumor properties, and can even potentially treat cardiac failure.

Male meloid beetles gift cantharidin to females, who in turn squirt it on their eggs to deter predators. They can make it themselves, but other so-called canthariphilous flies have to accumulate this blistering chemical by chomping on bastard teak, Butea frondosa, flowers or eating bugs that produce it.

Rove beetles also produce a vesicating toxin with potential antitumor properties called pederin, which they make using endosymbiotic bacteria that live in their hemolymph. Likewise, brown planthoppers make antibiotics using symbiotic bacteria.

So try to study these insects without the right diet or habitat and you may not find the same interesting chemicals, according to a 2010 analysis by Konrad Dettner, a now retired entomologist from the University of Bayreuth who specializes in the chemical ecology of insects.

“[W]hen bacteria or fungi were isolated from the insect hosts…in most cases these compounds have not even been shown to be present within the insect hosts,” he wrote. “Therefore, the biological significance of these natural compounds in symbiotic or parasitic systems where insects represent hosts is usually not known.”

This is partially why Piper argues that this type of research can benefit conservation efforts. Not only is preserving original habitats important for understanding chemical relationships, for every forest or swamp that is bulldozed into a Starbucks, there’s potentially billions of dollars worth of medications being destroyed. However, in his exenatide example, not a single cent of the billions generated from this hormone has gone back to preserve the home of the lizard where it was discovered.

“If you did find something and it was really successful, you could completely revolutionize the amount of cash available for conservation work,” Piper says. “We’re losing species that could have all sorts of potential applications. But then…you have to tread a fine line, because you can easily go down the road of putting a monetary value on things.”

Insects, it turns out, may be priceless.

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Health

The Aftermath of Michael Jackson’s Antigravity Lean

The infamous lean.

In Michael Jackson’s 1987 music video “Smooth Criminal,” the legendary performer leans forward 45 degrees from a straight-up position — and comes back. It’s a feat that seemingly defies both physics and physiology, and the move has become another element of MJ’s aura of mystery.

Some type of cinematic or mechanical trick must be responsible, since most people can manage only a 20-degree forward tilt before toppling headlong. Yet Jackson performed the move live on tours around the world for years.

Lean In

In a study published this week in the Journal of Neurosurgery, three scientists examine the so-called Antigravity Lean, not from a physics but from a physiological perspective. The three neurosurgeons, all at the Postgraduate Institute of Medical Education and Research in Chandigarh, India, combine in the article their knowledge of Jackson with data on spine biomechanics.

It’s been known for years how Jackson defied gravity. His shoes had a slot that slid onto a bolt in the floor, allowing him to perform the dramatic lean.

Bending forward is limited by the erector spinae muscles, which act like cables to support forward bends up to 20 degrees, though some dancers can achieve 30 degrees, the paper says. When near the max of a bend, you can feel the strain on the Achilles’ heel as the ankles become the fulcrum for balance. People soon return to vertical or catch themselves from falling headlong.

Though Jackson’s 45-degree bend is not physically possible without trickery, the King of Pop still needed incredible core strength and leg muscles to pull it off, the authors write. Not just anyone can lock their shoes into the floor and become Michael Jackson, it seems.

“Several MJ fans, including the authors, have tried to copy this move and failed, often injuring themselves in their endeavors,” the researchers write.

Figure A shows the Antigravity Tilt (a 45-degree forward bend) and the normal limit that most people can bend forward. Jackson used shoes with a slot that slid onto a bolt in the floor. Figure B shows the shift when the body’s fulcrum is the hip and when it’s the Achilles’ tendon. (Illustration courtesy of Manjul Tripathi)

Figure A shows the Antigravity Tilt (a 45-degree forward bend) and the normal limit that most people can bend forward. Jackson used shoes with a slot that slid onto a bolt in the floor. Figure B shows the shift when the body’s fulcrum is the hip and when it’s the Achilles’ tendon. (Illustration courtesy of Manjul Tripathi)

Tough Act to Follow

Jackson’s sleight of foot inspired generations of dancers who push the limits physically. This has resulted in spinal stresses not previously seen by neurosurgeons.

This is not to point the finger at Jackson. But it does suggest the reality that injuries can occur that might require implant spinal surgery, the article says, something potentially devastating to a dancer.

But it’s not all bad news — neurosurgeons have gained a lot of new information on how to treat spinal cord injuries in recent years, something that could be in part thanks to MJ’s envelope-pushing dance moves.

“The King of Pop has not only been an inspiration but a challenge to the medical fraternity,” Tripathi says.

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Health

Your Emergency Contact Does More Than You Think

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You know when you’re filling out your medical paperwork and it asks for your emergency contact? Sure, the process might be annoying, but that emergency contact could actually be put to good use by researchers.

Since many of us use a family member, those contacts can help scientists create family trees. And they can also be used for genetics and disease research, according to a study released Thursday in Cell. Discovering what diseases are inheritable can be a laborious and expensive process — patients must be recruited and researchers must clearly determine patients’ phenotypes (physical traits that include eye color, height, and overall health and are often influenced by your genes).

To make that process easier researchers from three major New York medical centers generated family trees from millions of electronic medical records to create a database.This is the first time electronic health records have been used to trace ancestry and it’s the largest study of heritability using such records.

The More You Know

The researchers identified 7.4 million relatives with an algorithm that matched names, addresses and phone numbers from three medical centers. They found 500 inheritable phenotypes in the data just by looking at test results and observations in health records. The traits included diseases affecting skin, blood and mental health.

The data can help determine the heritability level of many common diseases. For example, researchers found that having an increase of HDL (good) cholesterol is 50 percent heritable, while LDL (bad) cholesterol is only 25 percent heritable. The study’s findings were consistent across the participating medical centers and published studies.

Previous heritability research primarily documented Caucasians of northern European descent, according to the study’s first author Fernanda Polubriaginof, but this research is much broader.

“This dataset will allow us for the first time to compute whether there are differences in other races and ethnicities,” said Polubriaginof in a news release.

Future studies could look at medical records for the hereditary contribution of any trait. Due to privacy issues, patient identifiers were removed for the data, which can only be used for research at the moment. Though, with patient consent, emergency contacts could be put to important use in the future.

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Mosquito Bites Leave A Lasting Impression On Our Immune System

(Credit: Kokhanchikov/Shutterstock)

Mosquito bites are like a gross form of French kissing — the insects swap your blood with their saliva, and leave a trail of salivary secretions behind like mosquito cooties. Some of those compounds prevent clotting as the insects slurp up your blood. Now researchers find mosquito spit aggravates your immune system for days afterward. The findings could help scientists develop vaccines for mosquito-born diseases like Zika.

Rebecca Rico-Hesse, a virologist at Baylor College of Medicine in Houston, Texas, wanted to know how mosquitoes exploit our immune systems with their drool. So, she and her team exposed mice with human-like immune systems to live mosquitoes. Then, they sized up the mice’s immune response as it reacted to the mosquito spittle.

The bug’s saliva toyed with their immune systems in both bone marrow and skin cells with effects that lasted up to seven days after biting, the team reports today in PLoS: Neglected Tropical Diseases. The researchers say their discovery could explain how these tissues might act as virus incubators and help spread disease.

Master Manipulators

In 2012, Rico-Hesse was looking to untangle how Dengue virus causes Dengue hemorrhagic fever — an illness that affects 400 million people each year and can lead to death — when she came across a strange occurrence. Mice infected with the virus from mosquito bites fared far worse than mice that had received an injection of the virus but hadn’t been served as a mosquito meal. The result made Rico-Hesse take a step back.

It seems that mosquito bites caused the immune system to behave differently, and in ways that could potentially give infectious diseases a leg up.

To find out, Rico-Hesse and her team set starving Aedes aegypti mosquitoes on mice that had received a dose of human stem cells to make their immune systems look more like a human’s. Each mouse endured eight mosquito bites total. Then the team checked out different parts of the immune system — blood, bone marrow, spleen, and skin cells — six and 24 hours after biting, as well as seven days later. By then, the immune system should have returned to normal.

Sneaky Viruses

Instead, the team discovered immune cells that had disappeared from the skin at least six hours post-bite came back seven days later after maturing in bone marrow, something that shouldn’t have happened. If those cells harbored a virus, they could then pass it on to new mosquitoes, who could infect others.

The research is pointing out new ways in which mosquito bites affect our immune systems, and it goes beyond simple itching and scratching.

“Mosquito saliva has evolved to modify our immune system,” Rico-Hesse said. And as their new research shows, viruses and parasites could be hijacking that activity to get to the cells they reproduce in, like bone marrow cells, faster, according to her.

Essentially, viruses might be taking advantage of the immune system’s response to travel from their point of entry — the skin — to a place they can multiply in that’s away from attacks by the immune system.

“It’s mind-blowing,” Rico-Hesse said. “No one has ever seen this before.”

Ultimately, the work could lead to infection-blocking vaccines, said Duane Gubler, an international health expert who was not involved in the research.

That’s what Rico-Hesse hopes, too. “If we can make a vaccine that would protect us against the effects of the [mosquito] saliva, or blocking our immune reaction … then we could stop global vector-born diseases,” she said.

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