Saving bugs in the name of drugs

  • Written by  Ross Piper
  • Published in Opinions
Tessaratomidae nymphs produce powerful defensive chemicals that could have potential applications Tessaratomidae nymphs produce powerful defensive chemicals that could have potential applications Ross Piper
10 Feb
2017
More drugs than you might think are derived from, or inspired by, compounds found in living things - and with every bit of wilderness that disappears under plough or concrete, we deprive ourselves of potential medicines 

Looking to nature for the soothing and curing of our ailments is nothing new – we have been doing it for tens of thousands of years. You only have to look at other primates - such as the capuchin monkeys who rub themselves with toxin-oozing millipedes to deter mosquitoes, or the chimpanzees who use noxious forest plants to rid themselves of intestinal parasites - to realise that our ancient ancestors probably had a rudimentary grasp of medicine. Pharmaceutical science and chemistry built on these ancient foundations and honed the extraction, characterisation, modification and testing of these natural products, as well as the development of techniques, to produce medicinal compounds from scratch.

Medicines have come a long way since the nibbling of toxic leaves to rid the body of parasites, but nature is and will always be an important source of useful compounds and inspiration. For a while, modern pharmaceutical science shifted its focus away from nature to the laboratory bench to designing compounds from scratch. The main reason for this shift is that although promising chemistry abounds in nature, finding it is not all that easy. Securing sufficient numbers of the organism in question, isolating and characterising the compounds of interest, and producing large quantities of said compounds are all significant hurdles.

littlebugThis fungus beetle uses fungal toxins to keep itself safe (image: Ross Piper)

Laboratory bench drug discovery has achieved varying levels of success, which has prompted the development of new approaches with a shift back towards natural products. With the ability to mine genomes for useful compounds it is now evident that we have barely scratched the surface of nature’s molecular diversity, which has been honed by more than three billion years of trial and error. This realisation and several looming health crises, such as antibiotic resistance, has put bioprospecting – the search for useful compounds in nature - firmly back on the map.

The staggering diversity of the animals and their potential as sources of novel pharmaceuticals has barely been explored

Many of the medicines derived from nature are of plant, bacterial or fungal origin, however, our fellow animals have yielded medicines that save and improve millions of lives every year. Unfortunately, the exploration of animals as a source of novel medicines has been largely restricted to vertebrate venoms, leech saliva and the venoms and secretions of a few, mostly marine lineages (e.g. sponges, tunicates, molluscs and ectoprocts). The staggering diversity of the animals and their potential as sources of novel pharmaceuticals has barely been explored. Regardless, the tiny sliver of animal diversity investigated thus far has provided us with successful treatments for several types of cancer, cardiovascular disease, type 2 diabetes, autoimmune diseases and chronic severe pain.

VYING FOR VENOMS

We normally associate venom with an urgent need for medical attention, but venoms have lots of properties that make them desirable to modern medicine. For example, many compounds in snake venoms (particularly vipers) destroy cells, killing the prey and kick-starting digestion before the hapless victim is swallowed. These properties might not sound very promising, but if used in the right quantities and at the right time these compounds can be harnessed to dilate the blood vessels and dissolve blood clots to treat life-threatening conditions, such as hypertension and heart failure.

Worldwide, at least 300 million people have type-2 diabetes, some of whom benefit from a medicine derived from the spit of the gila monster, a type of lizard. The gila monster eats very infrequently, but when it does it tends to gorge – normally on bird’s eggs, which results in a sudden rush of glucose into the lizard’s blood. A hormone in the lizard’s saliva stimulates the production of insulin, bringing the blood glucose levels back under control. The ability of the hormone to regulate blood glucose levels led to the development of a synthetic version, which is now used to treat type 2 diabetes. In 2014, the synthetic hormone generated sales of $767 million, of which none found its way back to the conservation of the near-threatened gila monster.

shutterstock 477500044 The near-threatened Gila monster inspired a novel treatment for type 2 diabetes (image: shutterstock)

Marine animals have always been a favoured target for those interested in new medicines, but two-thirds of animal-derived drugs currently on the market come from terrestrial or freshwater species. Insects are the undisputed masters of the terrestrial domain, where they occupy every conceivable niche. Consequently, they have a bewildering array of interactions with other organisms, which has driven the evolution of an enormous variety of very interesting compounds for defensive and offensive purposes. Their diversity is also nothing short of dazzling and dwarves every other group of animals on the planet combined. To date, more than one million insect species have been described and there are many millions more out there still to be described. Even though insects are far and away the most diverse animals, their potential as sources of therapeutic compounds is yet to realised. Of the tiny proportion of insects that have been investigated, several interesting compounds have been identified. For example, alloferon, an antimicrobial compound produced by blow fly larvae is used as an antiviral and antitumour agent in South Korea and Russia. The larvae of a few other insect species are being investigated for the potent antimicrobial compounds they produce. Beyond flies, a compoun from the venom of the wasp Polybia paulista, has potential in cancer treatment.

Insects are the undisputed masters of the terrestrial domain, where they occupy every conceivable niche

Why is it that insects have received relatively little attention in bioprospecting? There are several reasons for this, some of which were touched on at the start of this article. Firstly, there are so many insects that without some manner of targeted approach this huge variety of species can appear to be rather daunting and bioprospecting becomes the proverbial needle in a haystack. Secondly, insects are generally very small and the glands inside them that secrete interesting, potentially useful compounds are smaller still. This can make it difficult to obtain sufficient quantities of the compound for subsequent testing. Thirdly, although we consider insects to be everywhere, the reality of this ubiquity is vast numbers of a few extremely common species. Many insect species are infrequently encountered and very difficult to rear in captivity, which, again, can leave us with insufficient material to work with.

wolfWasps, in this case the beewolf (Philanthus triangulum) often secrete cocktails of chemical compounds to paralyse and preserve prey (image: Ross Piper)

The good news is that there are ways to overcome these difficulties by combining good old fashioned natural history with the latest molecular biology techniques. Myself and colleagues at Aberystwyth University have developed an approach we term ‘ecology-led drug discovery’ because we use natural history knowledge as a guide to target our efforts. Numerous insect species advertise the production of potentially useful compounds in the way in which they live and where they live. There are many insects that produce potent, complex venom for subduing prey and keeping it fresh for their offspring. There are even more insects that are past masters of exploiting filthy micro-habitats, such as faeces and carcasses where they are regularly challenged by thousands of micro-organisms. The insects in both examples have a battery of antimicrobial compounds to deal with pathogenic bacteria and fungi, the backbone of which are small antimicrobial peptides (SAPs). The spectrum of activity of SAPs has not been intensively studied, but, at the very least, there is certainly potential to find many compounds that can serve as or inspire new antibiotics.

Although natural history knowledge points us in the right direction it doesn’t solve the problems associated with the small size of insects and the tiny quantities of interesting compounds they produce. Fortunately, it is now possible to snip out the stretches of the insect’s DNA that carry the codes for the interesting compounds and insert them into cell lines that allow larger quantities to be produced. From isolating and characterising compounds with desirable qualities to developing a commercial product is a very long road beset with pitfalls, but as the variety of successful, animal-derived pharmaceuticals on the market demonstrates there is a precedent here that is worth exploring.

waspThe venom of solitary wasps, like this kebab wasp (Oxybelus uniglumis) contain compounds to quickly disable the prey's nervous system and to prevent colonisation of the prey by microbes (image: Ross Piper)

As much as I’d dearly love to help develop a block-buster, insect-derived medicine, my main motivation for looking at insects in this way is conservation. I sincerely believe that all species, however small and seemingly insignificant have a right to exist for their own sake, but this sentiment lacks the clout that decision makers need to fight for the urgent preservation of nature in all its glorious forms. We need something more tangible, something that is directly relevant to people and you would be hard pressed to find anything that is held so dear as health.

We need something more tangible, something that is directly relevant to people and you would be hard pressed to find anything that is held so dear as health

If we can shine a light on the darker recesses of nature’s medicine cabinet, exploring the useful chemistry of the most diverse animals on the planet I believe we can make people think differently about the value of nature. The Nagoya Protocol of the Convention on Biological Diversity seeks “the fair and equitable sharing of benefits arising out of the utilization of genetic resources”, but since this is only signed and not ratified by the USA it is a bit toothless. What we need is an agreement where the successful commercialisation of natural products should give something back by funding basic exploration, species discovery and natural history studies to better understand and appreciate the species we share the planet with. 

Ross Piper (rosspiper.net) is an entomologist, zoologist, author and a visiting research fellow at the University of Leeds and the University of Essex

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