Sunday, 10 February 2013

Lord of the Fly

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From little things, big knowledge grows. Upulie looks at how much the human race owes the humble, tiny, short-lived Fruit Fly.

During a policy announcement in the 2008 Presidential election, McCain’s Vice Presidential pick, Sarah Palin, was unimpressed by some of the research projects funded by government money:

“You guys have heard some of the examples of where those dollars go,” the fun Alaska Governor said to the guys in the audience, acknowledging their media savvy about Congress members, who sometimes acquire public money for frivolous projects. “You’ve heard about the bridges. And some of these pet projects. They really don’t make a whole lot of sense.”

A troubled look crossed her face. “And sometimes these dollars go to projects that have little or nothing to do with the public good, things like …” she grinned, shaking her head side to side, her voice rising to a facetious pitch “… fruit fly research in Paris, France.” Feeling in tune with the guys in her audience, she added, “I kid you not.”

[Salon.com, 2008]

Palin isn’t known for her enthusiasm for methodical, evidence-based analysis, but does she have a point? Why are tax dollars spent studying, of all creatures, fruit flies? And in France? I want that junket.

Why fruit flies? They’re those annoying buggers that turn up in Summer, too small to be more than a speck in your vision, too big to ignore, especially when they are all over your bananas, lurking under fruit trees, infesting rotten fruit.

The 3mm long Drosophila melanogaster is a scientific hero. The species is responsible for teaching us most of what we now know about genetics. They’ve taught us about the development of organisms from an embryo into a complex, multicellular organism and studying them led to three Nobel Prizes. We have even begun to understand what genes may be involved with certain cancers, thanks to these tiny insects.

Hundreds of fruit flies species are found all over the world. Intriguingly, the location and spread seems clearly linked to humans: humans may have accidentally carried fly larvae and flies around with them. Their ancestral home seems to have been West Africa and over 6000 years they have migrated across the planet with us, wherever we went. They reached the Americas about 500 years ago, probably via the first slave ships. The Ancient Greeks knew of them and, around 1900, William Castle and Charles Woodworth were the first to breed Drosophila melanogaster in a lab, at Harvard University. They used the flies as a model organism to try to understand fertility.

Enter Thomas Hunt Morgan. He took the idea of using Drosophila as a model organism from Castle and Woodworth, and decided to breed them in the lab to study inheritance. He was a developmental biologist – used to looking at embryos and trying to figure out how such complex organisms as mammals and birds arose from a single, seemingly featureless egg. He also wasn’t a fan of Darwin’s idea that evolution arose solely from natural selection – that is, that there will be variations between organisms of a species, and the conditions of their environment mean that individuals, variants that are best adapted, will survive and these traits will be passed down through generations. Darwin proposed that a gradual process like this resulted in the evolution of life on earth. Morgan thought that a more radical, faster process of mutation would better explain how species changed and evolved. How such mutations came about was yet to be determined.

One of the ways biologists can study things like inheritance and evolution is through the use of model organisms. They are a handy surrogate for studying universal themes like development, evolution and genetics.

Model organisms are selected for specific reasons; they usually have a shorter life span than humans so that many generations can be analysed in a relatively short space of time, are easy and cheap to care for and have distinct traits that we can study. For example, Gregor Mendel famously used pea plants to study genetics. His plants were purebred and had distinct traits that he could study and follow through generations of breeding. They came in several forms: ones with wrinkled seedpods, ones with smooth seedpods, varied flower colours and stalk formations and so on. The pea plant used by Mendel was one of the first model organisms ever used.

The other reason for the use of model organisms is based on Darwin’s theory of common descent. He came to the conclusion that all living things must have descended from a common ancestor. This means that all organisms are distantly related, so that some of the processes that occur in the body, or plant, are common to all living things and must have a similar biochemical basis. So by studying a particular organism, we should be able to understand how some aspects of human biology work.

Morgan thoughtfully chose Drosophila for his work. Drosophila are very easy to breed. Their entire life cycle can take place over a period of 14-28 days. Eggs are laid in a kind of thick jelly made of agar, molasses and wheat – fruit flies like sweetness. The tiny maggots – it seems unfair to call such tiny larvae a word as nasty as maggots – take up to five days to eat, form a cocoon or pupa and emerge as perfect, fully formed flies. The males are smaller than the females and have tiny black structures on their legs called sex combs and a black bottom. The females don’t have either and are larger than the male flies. So you can glance at a vial of fruit flies and easily pick out the girls from the boys by eye. For about 16 hours, the females will be sexually immature. This means that they are virgins. Yes, this is important to know. If you watch your flies carefully, you can pick out the girl flies that have just emerged, haven’t yet mated and separate them. They can then be mated with the males of your choice. You can also slow down the development of Drosophila by keeping them at 18oC – they seem to slow down their rates of growth at this temperature, compared to 25oC – which is handy if you are a scientist who likes to take holidays. Thus, is genetics studied.

Drosophila also have distinctive traits. The wings have the same little veins on them, the same pattern in all flies. The eyes are bright red. They can be examined more closely using microscopes. You take your flies, in a vial with food at the bottom and stoppered with cotton wool, and you insert a small tube into the vial, with gas coming out of it. The gas knocks the flies out. They are then taped on to a pad that also has gas fuming out, so the flies remain unconscious. (In the past, ether was used to knock the flies out. It’s highly flammable and also makes human examiners high, so eventually a switch was made over to carbon dioxide.) Very thin paintbrushes are used to turn the flies over, very gently, without damaging them. This is how fruit flies are wrangled.

So Morgan was breeding thousands of flies in small vials. One day, Thomas Morgan was looking through his flies – hundreds and hundreds of them can be kept in a single room. Amongst the sea of red-eyed flies was one that stood out: a fly with a white eye. A male fly, just one, with a white eye.

This was curious. Morgan bred this fly to some red-eyed females and examined the offspring. All but three male offspring were red eyed males and female. He kept all of them, and then bred them against each other. Suddenly, more white eyed flies began appearing in the second generation of flies – again mostly in males. Morgan had found a mutation he could study: a marker that would allow him to work out how traits were inherited through generations. It was clear – a white eye really stands out – and it was discrete, because there was no mixed colouring, no half-way colour. Morgan suggested that the gene was on a sex chromosome, since it only began appearing in the second generation and chiefly in males. It was the first time anyone had ever suggested, or found evidence that a gene could be part of a sex chromosome.

Morgan expanded his work, and eventually went on to establish, with other notable scientists, that genes were located on chromosomes – heavily coiled, extremely long molecules of DNA. They went on to show that genes are located at distinct points on chromosomes and to understand the nature of chromosomes in inheritance. Morgan was awarded the Nobel Prize and eventually left Drosophila genetics to go back to his first love, embryology. If he had stuck around in fly genetics, he would have discovered how useful the fruit fly would become in the study of development and our understanding of how animals end up with the right number of limbs in the right place, and so on.

Morgan successfully established fruit flies as a model organism for studying genetics. Little did he know how important that little bug, chosen because it was easy to breed and study, would become in our understanding of how organisms developed – and how closely we are related.

Over the next fifty years, DNA would be established as the chemical basis for inheritance, the coding basis of genes which are the units of inheritance. But while DNA coded for genes, on its own it couldn’t tell us much about how the genes interacted. That is where the fruit fly comes in. Definitive work by Eric Lewis, Christiane Nüsslein-Volhard and Eric Wieschaus showed us how genes interacted and what genes were the basis for the development of organisms from an embryo.

In the same way that finding a single mutation like a white fly eye gave Morgan a trait to watch through generations, Lewis, Nusslein-Volhard and Wieschaus found or created a range of mutations that they could track through generations. They found that some mutations affected the colour of the eye, and others the thickness of the bristles on the fly itself. Still other mutations affected the veins on the wing and the tiny hairs on the wings. By crossing these mutations to other mutations and watching how they affected each other, they came to realize that the body pattern of the fly was based on discrete units and a single kind of patterning gene called a homeobox. If you mutated the flies – say by inducing a second homeobox gene, you could end up with multiple wings and a double thorax [body segment] on the fly. Other mutations resulted in the shifting of the legs to other parts of the body, sometimes even growing the legs out of the head.

The genes responsible for these traits were located on the chromosomes and eventually their DNA sequence was determined. As more and more organisms had their DNA sequenced, we began to understand how many genes had similar sequences across species. For instance, one gene may say, “pattern eye” but it doesn’t say, “put eye here.” So shifting the location where the gene is turned on, by moving the gene for patterning a fly eye to where genes for patterning a fly leg were located could result in the formation of a perfect fly eye on a fly leg. Still more interesting was the realization that patterning genes – the genes that say “make thorax,” “make legs,” and that direct where these traits are located on the organism, were similar across species. More curious still was the finding that Drosophila had a single copy of many important genes that could be found across species. So a simple animal, an insect like this fly, had genes that related it to more complex organisms like mammals.

Taking this information, scientists looked for these genes in more complex animals like mice and rats. Some of the genes found in Drosophila were found in these organisms, but in multiple copies. So more complex organisms would have arisen from mutation, repetition of genes, mixing and moving of genes along the genome.

One amazing example of the power of Drosophila genetics is the Pax6 gene. Found in mice, this gene is responsible for creating a mouse eye in, well, mice. Scientists put this gene into flies, and made sure it would appear in the leg of the fly so that we could tell it was this alien gene and not the fly gene. Not only did the mouse gene tell the fruit fly to make an eye successfully, but it made a fruit fly eye, not just a mouse eye! Perhaps that common ancestor is closer than we think. As Bill Bryson put it in his wonderful book, A Short History of Nearly Everything, “all life is one, and that’s the truest most profound statement there is.”

The humble fruit fly has given us a vast amount of information about genetics and how organisms develop. In more recent times, we’ve been able to use Drosophila’s peculiar development processes to understand cancer. For example, a Drosophila egg is so large that we can easily observe the movements of cells and the formation of layers of cells which eventually become organs. Some of these processes can be used to study the basics of cancer – the genes that control the proliferation of cells, the way a cancer cell starts out as an ordinary, differentiated cell and becomes an undifferentiated tumour cell. We can also use these processes to hunt for genes that might be involved in cancer development, giving us targets for drug development.

While Sarah Palin’s comments were based on ignorance, it’s easy to see how the idea of studying fruit flies might seem exotic and flippant. Yet, Drosophila isn’t the strangest model organism we study, though it has been one of the most useful. The tiny worm Caenhorabditis elegans has taught us that cells monitor themselves and actually self-terminate if there is something wrong with them, and in doing so, prevent cancer. For a cancer to form, these detection mechanisms must be broken. Other organisms like the zebra fish and the Xenopus frog have all given us valuable information in a short amount of time. We cannot highly-enough praise, or sufficiently thank these species for the knowledge they have given us. And in studying them, we have learnt about the elegance and beauty of seemingly ordinary organisms and how closely related all life is.

So the next time you hear someone dissing the tiny fruit fly, put them in their place. The 3mm long Drosophila melanogaster is a scientific hero. An idol. A goddess. Worship ye mighty fruit fly.

Upulie Divisekera

Upulie Divisekera is a cake-loving molecular biologist and science communicator with an evangelical interest in dinosaurs.

Follow her on Twitter @scienceupulie