I once knew a baby zebrafish called Geoffery. He was only 24 hours old, but this little guy already had eyes, a brain, the building blocks of a fully functional spinal cord and a wiggly little tail. By all accounts, he was a pretty spunky chap; the kind of fish-egg you couldn’t help but like. But he was so much more than just a likeable, young fish; Geoffery, and his aquatic siblings, hold the potential to help cure disorders of the nervous system, such as autism and schizophrenia.
Zebrafish (Danio rerio), like Geoffery, are a tropical fresh-water species originating from Eastern Asia and yes, the adults are stripy. They were first recognised as a prime model for disease back in the 1980s by geneticist, Dr. George Streisinger. Much of Streisinger’s early career was spent investigating genes and development in the T4 bacteriophage (a bacteria-infecting virus), but he was frustrated by the limitations of attempting to draw parallels between viruses and humans. In 1984, Streisinger published a seminal paper, in which he successfully demonstrated that zebrafish could be cloned and analysed genetically. Since then, there has been an explosion in the number of neurobiological research labs using zebrafish as a model for human diseases.
So, what is it that makes zebrafish such good subjects for scientific research? For a start, they are easy to maintain thanks to their hardy, placid nature. The females are high-yielding, providing a steady supply of offspring all year round. Because fish are vertebrates, they share more commonalities with humans than invertebrate models (such as worms, flies and Dr.Streisinger’s bacteriophages). On top of this, the genome of the zebrafish is well-sequenced, meaning that scientists have almost translated the entire DNA code; this enables them to use genetic manipulation techniques. Now, what makes the zebrafish super-cool is that, unlike their stripy adult counterparts, their eggs and embryos are optically clear. This transparency allows scientists to see through their skin and directly observe their nervous system, making zebrafish prime subjects for optogenetics.
Optogenetics refers to a range of procedures that combine optical imaging with genetic manipulation. One such technique is known as in vivo labelling. This works by inserting sections of DNA that code for fluorescent proteins into the zebrafish genetic code in such a way that only specific cell types will express the fluorescence. Scientists can then use microscopes to visualise how the fluorescing cell type develops in real time. In other words, they can watch how specific cell types divide and grow as zebrafish embryos develop. The most famous fluorescent protein of all is the jellyfish-derived Green Fluorescent Protein (GFP), but there are others that fluoresce blue, yellow and red, allowing multiple different cell types to be tracked simultaneously. In the world of neuroscience, these labelling strategies allow scientists to tag and track neurons as the zebrafish grow, meaning scientists can actually watch the nervous system develop.
Researchers at King’s College London and University College London are now putting together an atlas of images derived by using techniques similar to those described above. The project, simply entitled ‘The Zebrafish Brain Atlas’, collates a series of neuroanatomical images, depicting the structure and development of the zebrafish nervous system. The idea is that the resource will not only be invaluable for researchers, but will also act as an interactive educational site for anyone interested in brains, fish, or pretty colours. I urge you to take a look at some of the images produced – not only are they good for science, but they are seriously beautiful too! Whoever said science and art couldn’t coincide?
It’s all well and good that cell types can be tracked, but how does that help us to cure diseases? Many disorders of the nervous system, such as autism, schizophrenia and ADHD are thought to be triggered by aberrations of neural development. So, if scientists can track such alterations of brain development in zebrafish, this may be able to shed some light on the disease in humans. It might seem difficult to imagine a fish providing a suitable model for conditions within humans. However, according to a paper by William Norton, “by 6 days, larval fish swim continuously, search for food, and are able to escape from predators, thus demonstrating a range of behaviours”. No other model exhibits such complex behaviour at such an early stage whilst still being handily transparent. Just one example of scientists exploiting the precocious behaviours of zebrafish to investigate neurodevelopmental conditions comes from a team of French scientists led by Professor Lange. By comparing development in normal and mutant zebrafish, they found that a gene linked to ADHD appears to play a crucial role in the development of a certain kind of nerve cells called dopaminergic neurons. Or course, it remains to be seen whether this finding will translate into clinical successes for humans. Nevertheless, it gives a real insight into the genetic basis of neurodevelopmental conditions, and points future research in a promising direction.
It is incredible and inspiring to think that little Geoffery, my zebrafish friend, might have gone on to help scientists work towards solutions for conditions we usually associate only with humans. It is up for debate whether fish really can provide truly insightful models for human disorders – and if we decide they cannot, we have to question whether it is ethical to manipulate animals in this way for such purposes. This is an interesting and open debate and deserves a whole separate blog post. But for now, suffice to say, we owe a lot to our little zebrafish friends – the unsung heroes of neuroscience.