A Point Of View: Fly, Fish, Mouse and Worm

Fruit fly

Scientists commonly use just four species to investigate the basic processes shared by all living creatures. Tom Shakespeare explains how the fruit fly, the zebra fish, the roundworm and the mouse found themselves at the forefront of scientific research.

When I was a child, one of my favourite books was called Bear, Mouse and Water Beetle. Today I want to tell you a contemporary story, which you could call Fly, Fish, Mouse and Worm, or for the scientists among you, Drosophila melanogaster, Danio rerio, Mus mus and Caenorhabditis elegans.

You may remember Gregor Mendel and those smooth and wrinkled peas which he grew in the 1850s. Well, at the beginning of the 20th Century, research on mice, fruit flies and guinea pigs helped transform natural history into biological science.

A model animal helps the scientist understand the basic processes common to all living creatures.

But why fly, mouse, fish and worm? What is so great about these animals? Well, if you are a scientist looking for a model animal, there are practical considerations.

You need a species which is small, easy to look after, and a fast breeder. It needs to be simple enough to understand and manipulate. In order to be able to learn lessons for health, you need a species which is diploid, meaning that the offspring gets one set of chromosomes from each parent, as with humans. And for ethical reasons, you would prefer simple organisms.

The fruit fly reproduces quickly, requires no special care, and is so small that many thousands of them can be stored in a small space.

The zebra fish is a tiny goldfish which originated in the river Ganges. It has the key research advantage of being a vertebrate, but it is also transparent, which means that developmental biologists can easily study the developing embryo. In a convenient twist, zebra fish can be fed on left-over fruit flies.

The mouse is even better than fly and fish because it's a mammal, like us. In fact, around 90% of genes are the same in humans as in mice.

Image caption Scientists can observe the development of embryo in the transparent zebra fish

Caenorhabditis elegans is a nematode worm, about 1mm long. It develops step-by-step from egg to an adult with exactly 959 body cells. The British Nobel Prize winner John Sulston and his colleagues traced the development of every one of those cells by peering down a microscope. Subsequently, C elegans became the first multi-cellular organism to have its whole genome sequenced.

What is the point of this history of the fly, fish, mouse and worm? In the past, animal models have vastly contributed to understanding human health and disease, as with the research on guinea pigs which led to the discovery of Vitamin C.

Today, the drive is to find animal equivalents for human genetic problems, and then study what is going wrong. For example, scientists found the zebra fish mutation which corresponds to the mutated gene in those with muscular dystrophy, a rare genetic condition.

Now they had their animal model, they could start testing thousands of different drug combinations on the developing zebra fish embryos, to see which, if any, drug combination prevented the disease.

The fruit fly is often used - strange as it may sound - to study human behaviour. To take one example, there is a genetic variant called arouser in Drosophila which increases the number of synaptic connections, and makes them more tolerant of alcohol - in other words, turns them into alcoholics.

Research published in 2011 shows that manipulating the environment of the adult fruit fly by socially isolating them, reverses the alcohol addiction. Meanwhile, the nematode worm, with its 302 neurons and the zebra fish with its 300,000 neurons are helping scientists understand the functional anatomy of the human brain, with its rather more complex 86 billion neurons.

And why would I want to tell you this story?

First, I think it's a tale which says a lot about science. The model animal approach has relied not just on brilliant detective work, but also on painstaking craft. Keeping animals alive, counting variants, keeping meticulous records, tracing embryological development is both a very fiddly business, and also rather repetitive and tiresome.

Image caption A surprising 70% of genes in the fruit fly have an exact human homologue

Lay people don't tend to hear much about what you might call the housekeeping aspect of biology, and I think that's a shame, because it obscures how science depends on craft. My friend Jackie did her doctoral research on breast cancer, using a mouse model to see if a particular genetic variant played a role. In order to do her work, she had to become skilled at performing mastectomies on mice - that's a pretty fiddly job if you consider the size of a mouse nipple.

Researchers who spend their whole careers on one tiny organism develop not just skills but also an attachment to their creature.

John Sulston tells me about his work on C elegans, for which he was awarded the Nobel. "Although unglamorous to the naked eye", he says. "It shows a wealth of beautiful detail under both light and electron microscopes.

"From the moment I learned how to watch dividing cells in live animals, I was entranced. For me, to sit and watch the cell lineages at 1000x as they unfolded was more a joy than a chore."

Just to remind you, John's talking about a millimetre-long roundworm here. I can understand how biologists fall in love with their tanks full of darting zebra fish, but a worm?

It is also a story about community and cooperation. When many different researchers study the same animal there are tremendous scientific benefits. In the first decade of the 20th Century, it was flies, in the 1970s, it was C elegans. In the 1980s, the fashion was for zebra fish.

Each model species has led to a kinship of researchers, with their operating manuals, newsletters, conferences, all fostering exchanges of knowledge and skills between labs and countries.

For example, while most research communities are rather orthodox in their naming conventions, in the fly community, gene variants are named for what they don't do. Flies with the "tinman" gene have no heart. "Cheapdate" means the fly gets drunk easily.

Second, the model animals story highlights how biologists have gone from knowing a little about a lot of species, to knowing an immense amount about just a few.

My father went up to Cambridge in 1947 to study natural sciences, and ended up specialising in botany. I still have his copy of Turrill's British Plant Life, published in 1948. There is a long chapter on the study of heredity in British plants discussing celandines, poppies, watercress, violets, pansies, campions, clovers, vetch, trefoil, raspberry, blackberry, saxifrage.

Today, a textbook of plant science will almost exclusively tell you about the model plant Arabidopsis thaliana - thale cress - an insignificant weed of absolutely no medical, agricultural or horticultural value. Arabidopsis allows scientists to study, for example, drought resistance in food crops, but if you want someone to accurately identify plants in their natural habitat, you'd be better off turning to an amateur naturalist than a research biologist.

The same goes for animals. We know an enormous amount about a roundworm, a fly, a fish and a mouse. After humans, they are the most studied organisms on the planet. But there are just a handful of model organisms, compared to the nearly nine million species on the earth and in the seas.

It's true that the same genetic processes are conserved across biology - the gene that causes a shortened tail in the zebra fish does the same in the mouse. A staggering 70% of genes in the fruit fly have an exact human homologue. 75% of genes that underlie human disease have a zebra fish counterpart. That's the key principle that makes model animals so important for human health.

A final thought. While model animals epitomise the success of the scientific strategy of reductionism, they may also illustrate the downside. Perhaps we risk losing the bigger picture, amidst all that fascinating detail.

Now, more than ever, biology needs synthesisers, people who can weave together disparate threads of knowledge from different organisms and formulate testable questions. In an era of environmental change and rapid species loss, a wider dialogue is needed between these specialist research communities. After all, the fly, fish, mouse and worm are only chapters in a much bigger and more important story.

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