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Crawling Toward Breakthrough Treatments

Modern medicine continues to make enormous progress, but big challenges still lie ahead.

Somewhat like looking down the barrel of a gun, antibiotic resistance is a looming threat. The rise of MRSA, super drug-resistant gonorrhea and other “nightmare” bacteria may render our microscopic defenses useless. So, what are we going to do when your last resort fails to kill these pathogens?

We’re going to need new antibiotics, in addition to better medicines for cancer, depression, and other conditions that aren’t readily treatable by current prescriptions.

FOR DECADES, no industry has been a more reliable moneymaker than pharmaceuticals. Immune to recession, drug companies regularly score 15 percent profit margins year-after-year. There is no danger of market saturation and, in the U.S., little prospect of government restraint of prices. Nearly all regulatory submissions win approval, and turnaround times are steadily decreasing. If you are an investor, what’s not to like?

But all dominant and expanding industries are fueled by resources of one type or another. Some of these are tangible and obvious, like gold deposits. Their exploitation follows a familiar arc. There is an initial rush to simply pick nuggets up off the ground. When the nuggets have been picked, miners must search for pebbles, then sand, then dust. There are still fortunes to be made, but more and more capital investment is needed to separate the gold from the dross.

As we have previously discussed in Trends, there are several emerging tools involving genomics, big data and artificial intelligence, that will help us discover drugs. The question is where do we look for these molecules.

Some argue that we’ve reached “peak pharma,” that is, we’ve run out of good places to look. But, according to Dr. Ross Piper, an entomologist and research fellow at Britain’s University of Leeds, “we haven’t even begun looking.” And, our best bet may be beneath our feet, in the diminutive world of insects.

“It could be a treasure trove of useful chemistry. Look at what compounds have been isolated from reptiles,” Piper said in a recent Discover magazine article. His favorite example is exenatide, a synthetic hormone that treats type 2 diabetes, which was originally derived from the saliva of Gila monsters. Between 2014 and 2016, sales of this drug reached $2.5 billion. “Who would have thought just by looking at the compounds in the saliva of a lizard that you can produce a blockbuster drug for type 2 diabetes?”

Today, insects offer perhaps the most promising untapped opportunity for drug discovery. Because insects and other arthropods are awash in a very dirty world, thay need to protect themselves from disease, and have many novel defenses.

While so-called “insect bioprospecting,” is not entirely new, there’s much to be done. For instance, there are an estimated 5.5. million different insect species on earth, but only around 20 percent have been described. However, entomologists investigating them are becoming scarce.

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

In a 2005 review, Eraldo Costa-Neto identified 64 different arthropod species from around 14 orders, being 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 explode cancer cells while alloferon, a peptide isolated from the blood of a species of blow fly, has antiviral and antitumor properties.

In order to use insect-based compounds in pharmaceuticals 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.” But with breakthroughs in transcriptomics and advances in CRISPR-Cas9 technology, we can isolate certain genes and insert them into the cell line of a microorganism that will mass-produce it.

Alternatively, you could insert rare genetic material into large common insects, such as crickets or mealworms, and mass-produce medicine this way. Aaron Dossey, an entomologist and the founder of All Things Bugs says, “You could put vaccine genes into insects. 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 in a 2010 analysis that “stick insects.” or phasmids. will particularly make “attractive model organisms for biosynthesis studies” due their large size and wide range of chemical defenses.” He also observes that, “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.”

Among the other most promising insects to analyze for drugs are social insects, especially 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 a disease outbreak. If one individual gets infected, a worker could spread it to thousands of individuals within a few hours. Soil is by far the most microbially dense and diverse habitat on the planet. Therefore, ants need strong antimicrobials, which many species secrete from the metapleural glands on their back.

Research by Arizona State University Professor Clark Pinick, published in the journal Royal Society Open Science in February 2018, tested the antimicrobial strength of 20 different ant species against Staphylococcus epidermidis, a common, generally benign, skin-dwelling bacteria. He collected ants is all three of the major ant sub-families. Sixty percent of the ants tested inhibited bacterial growth and one of the smallest ants tested displayed the strongest antimicrobial properties.

One of the challenges is to chemically study insects in their native environments rather than in the lab. Why? Many bugs rely on eating specific plants grown in specific conditions to enable them to synthesize certain compounds. Entomologist Ross Piper insists that if we’re going to get maximum benefit from insect-based chemical compounds, we’ll need preserve their natural habitats.

Given this promising trend, we offer the following forecasts for your consideration.

First, progress in this field will be limited by a shortage of entomologists.

As in so many specialties, the skills-gap has real-world consequences. Fortunately, combining information technology with cross-training should enable the pharmaceutical industry to fill this gap over the coming decade. And, once career options expand, many biology-oriented undergraduates will redirect their focus toward entomology.

Second, the extremely large volume of compounds potentially derived from 5.5 million insect species will be addressed by state-of-the-art digital drug discovery tools.

Automated “robot laboratories” will permit a handful of technicians to run and monitor tens of thousands of controlled, error-free experiments, simultaneously. Modern genomics and proteomics technology permits the rapid, low-cost sequencing of genomes and proteins. Body-on-a-chip technology will dramatically accelerate pre-clinical tests for toxicity and other side-effects. And AI-based systems will help identify the most promising “needles in the chemical haystack.” And,

Third, by 2030 a whole new generation of insect-derived treatments will be entering the market or finishing clinical trials.

Many of these compounds will be safer and more effective replacements for existing pharmaceuticals. This will include antibiotics that work against today’s superbugs. The rest will address conditions and ailments that have, until now, been untreatable.

References

1. Troy Farah. DiscoverMagazine.com, April 13, 2018. Drugs from Bugs: Bioprospecting Insects to Fight Superbugs.

http://blogs.discovermagazine.com/crux/2018/04/13/drugs-insects-antibiotics-superbugs/

2. Drew Smith. Undark.org, January 2, 2018. We Have Reached Peak Pharma. There’s Nowhere to Go But Down.

https://undark.org/article/peak-pharma-drug-discovery/

3. Eraldo Medeiros Costa-Neto. Journal of Ethnobiology, 2005. Entomotherapy, or the Medicinal Use of Insects.

http://www.bioone.org/doi/abs/10.2993/0278-0771(2005)25%5B93:EOTMUO%5D2.0.CO%3B2