Saving bugs to find new drugs

Zoologist Ross Piper looks at the potential of insects in pharmaceutical research

A

More drugs than you might think are derived from, or inspired by, compounds found in living things. 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 too probably had a basic grasp of medicine.

B

Pharmaceutical science and chemistry built on these ancient foundations and perfected the extraction, characterization, modification and testing of these natural products. Then, for a while, modern pharmaceutical science moved its focus away from nature and into the laboratory, designing chemical compounds from scratch. The main cause of this shift is that although there are plenty of promising chemical compounds in nature, finding them is far from easy. Securing sufficient numbers of the organism in question, isolating and characterizing the compounds of interest, and producing large quantities of these compounds are all significant hurdles.

C

Laboratory-based drug discovery has achieved varying levels of success, something which has now prompted the development of new approaches focusing once again on 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. This realization, together with several looming health crises, such as antibiotic resistance, has put bioprospecting – the search for useful compounds in nature – firmly back on the map.

D

Insects are the undisputed masters of the terrestrial domain, where the occupy every possible niche. Consequently, they have a bewildering array of interactions with other organisms, something which has driven the evolution of an enormous range of very interesting compounds for defensive and offensive purposes. Their remarkable diversity exceeds that of every other group of animals on the planet combined. Yet even though insects are far and away the most diverse animals in existence, their potential as sources of therapeutic compounds is yet to be realised.

E

From the tiny proportion of insects that have been investigated, several promising compounds have been identified. For example, alloferon, an antimicrobial compound produced by blow fly larvae, is used as an antiviral and antitumor agent in South Korea and Russia. The larvae of a few other insect species are being investigated for the potent antimicrobial compounds they produce. Meanwhile, a compound from the venom of the wasp Polybia paulista has potential in cancer treatment.

F

Why is it that insects have received relatively little attention in bioprospecting? Firstly, there are so many insects that, without some manner of targeted approach, investigating this huge variety of species is a daunting task. Secondly, insects are generally very small, and the glands inside them that secrete 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.

G

My colleagues and I at Aberystwyth University in the UK have developed an approach in which we use our knowledge of ecology as a guide to target our efforts. The creatures that particularly interest us are the many insects that secrete powerful poison for subduing prey and keeping it fresh for future consumption. There are even more insects that are masters of exploiting filthy habitats, such as faeces and carcasses, where they are regularly challenged by thousands of micro-organisms. These insects have many antimicrobial compounds for dealing with pathogenic bacteria and fungi, suggesting that there is certainly potential to find many compounds that can serve as or inspire new antibiotics.

H

Although natural history knowledge points us in the right direction, it doesn’t solve the problems associated with obtaining useful compounds from insects. 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. And although the road from isolating and characterizing compounds with desirable qualities to developing a commercial product is very long and full of pitfalls, the variety of successful animal-derived pharmaceuticals on the market demonstrates there is a precedent here that is worth exploring.

I

With every bit of wilderness that disappears, we deprive ourselves of potential medicines. As much as I’d love to help develop a groundbreaking 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. 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 power of play

Virtually every child, the world over, plays. The drive to play is so intense that children will do so in any circumstances, for instance when they have no real toys, or when parents do not actively encourage the behavior. In the eyes of a young child, running, pretending, and building are fun. Researchers and educators know that these playful activities benefit the development of the whole child across social, cognitive, physical, and emotional domains. Indeed, play is such an instrumental component to healthy child development that the United Nation High Commission on Human Rights (1989) recognized play as a fundamental right of every child.

Yet, while experts continue to expound a powerful argument for the importance of play in children’s lives, the actual time children spend playing continues to decrease. Today, children play eight hours less each week than their counterparts did two decades ago (Elkind 2008). Under pressure of rising academic standards, play is being replaced by test preparation in kindergartens and grade schools, and parents who aim to give their preschoolers a leg up are led to believe that flashcards and educational ‘toys’ are the path to success. Our society has created a false dichotomy between play and learning

Through play, children learn to regulate their behavior, lay the foundations for later learning in science and mathematics, figure out the complex negotiations of social relationships, build a repertoire of creative problem-solving skills, and so much more. There is also an important role for adults in guiding children through playful learning opportunities.

Full consensus on a formal definition of play continues to elude the researchers and theorists who study it. Definitions range from discrete descriptions of various types of play such as physical, construction, language, or symbolic play (Miler & Almon 2009), to lists of broad criteria, based on observations and attitudes, that are meant to capture the essence of all play behaviors (e.g. Rubin et al. 1983).

A majority of the contemporary definitions of play focus on several key criteria. The founder of the National Institute for Play, Stuart Brown, has described play as ‘anything that spontaneously is done for its own sake’. More specifically, he says it ‘appears purposeless, produces pleasure and joy, [and] leads one to the next stage of mastery’ (as quoted in Tippett 2008). Similarly, Miller and Almon (2009) say that play includes ‘activities that are freely chosen and directed by children and arise from intrinsic motivation’. Often, play is defined along a continuum as more or less playful using the following set of behavioral and dispositional criteria (e.g. Rubin et al. 1983).

Play is pleasurable: Children must enjoy the activity or it is not play. It is intrinsically motivated: Children engage in play simply for the satisfaction the behavior itself brings. It has no extrinsically motivated function or goal. Play is process oriented: When children play, the means are more important than the ends. It is freely chosen, spontaneous and voluntary. If a child is pressured, they will likely not think of the activity as play. Play is actively engaged: Players must be physically and/or mentally involved in the activity. Play is non-literal. It involves make-believe.

According to this view, children’s playful behaviors can range in degree from 0% to 100% playful. Rubin and colleagues did not assign greater weight to any one dimension in determining playfulness; however, other researchers have suggested that process orientation and a lack of obvious functional purpose may be the most important aspects of play (e.g. Pellegrini 2009).

From the perspective of a continuum, play can thus blend with other motives and attitudes that are less playful, such as work. Unlike play, work is typically not viewed as enjoyable and it is extrinsically motivated (i.e. it is goal oriented). Researcher Joan Goodman (1994) suggested that hybrid forms of work and play are not a detriment to learning; rather, they can provide optimal contexts for learning. For example, a child may be engaged in a difficult, goal-directed activity set up by their teacher, but they may still be actively engaged and intrinsically motivated. At this mid-point between play and work, the child’s motivation, coupled with guidance from an adult, can create robust opportunities for playful learning.

Critically, recent research supports the idea that adults can facilitate children’s learning while maintaining a playful approach in interactions known as ‘guided play’ (Fisher et al. 2011). The adult’s role in play varies as a function of their educational goals and the child’s developmental level (Hirsch-Pasek et al. 2009).

Guided play takes two forms. At a very basic level, adults can enrich the child’s environment by providing objects or experiences that promote aspects of a curriculum. In the more direct form of guided play, parents or other adults can support children’s play by joining in the fun as a co-player, raising thoughtful questions, commenting on children’s discoveries, or encouraging further exploration or new facets to the child’s activity. Although playful learning can be somewhat structured, it must also be child-centered (Nicolopolou et al. 2006). Play should stem from the child’s own desire.

Both free and guided play are essential elements in a child-centered approach to playful learning. Intrinsically motivated free play provides the child with true autonomy, while guided play is an avenue through which parents and educators can provide more targeted learning experiences. In either case, play should be actively engaged, it should be predominantly child-directed, and it must be fun.