Question: 2. How did you come to discover that zebrafish had a similar genome to humans and why did you choose to study them to investigate the growth and development of human bones?

Lucy McGowan answered on 18 May 2020: last edited 19 May 2020 8:01 am

Thanks – another great question! Sorry for the big answer, it’s a big question and I want to do you justice!
I wasn’t the person who discovered that the zebrafish genome was similar to the human genome. Scientists thought that this would be the case for a long time because we evolved from fish over millions of years and share many features like a spine, a brain, a heart, eyes, ears (yes fish have ears) and more! Therefore, we knew that we should share the same genetic blueprint. It wasn’t until scientists got much better at sequencing genes that we really got a close up look at how similar the zebrafish genome is to humans. This used to be a very slow process but with huge leaps in gene-sequencing technology, the Wellcome Sanger Institute in Cambridge started “The zebrafish Genome Project” back in in 2001. They sequenced the zebrafish genome in unprecedented detail over many years. With this new data, scientists were able to line up the human and zebrafish genomes side-by-side using powerful computers to compare similarities in the genetic sequences from each. If gene sequences match up between the two species with high similarity it is called “gene conservation”. Today, we know that more than 70% of all human genes are conserved in zebrafish. Even better for disease research is that around 85% of the genes which are known to cause disease in humans are conserved in zebrafish.

The fact that zebrafish share many genes with humans is the first reason they are good for this kind of research. Lots of genes have been linked to bone disease in humans but we don’t really know exactly how these genes affect bone development, disease and repair. Without finding out “how”, we can’t design good treatment, drugs or prevent disease. To understand that we need to dig deeper using a model organism. Since many of these disease-associated genes are found in the fish, we can study their function in much greater detail through experiments.

The second reason they are good for this research (linked to the genetic similarity) is that they make bone in the same way as humans, they repair fractured bone in the same way as humans (that’s my research) and they they even get diseases such as osteoarthritis and osteoporosis as they age. Zebrafish have the same cell types as humans which make and repair bone such as osteoblasts, osteoclasts, osteocytes, neutrophils and macrophages. This means that we can use them to study how these bone development and bone diseases work and know that what we find will translate to human health.

But mice are good for that too right? Why not use a different model organism for this research? Well the third reason is what makes them unique. Zebrafish are transparent throughout skeletal development when they are larvae, up to about 4 weeks old when they start to develop scales. Even as adults, their fins remain transparent and contain lots of bones. The transparent fin tissue is like a window for me to view living bone in a living animal. I can plop the fish in some anaesthetic, have a quick look at the bone down the microscope and then plop it back in some fresh water to wake it up. 5 mins asleep and then the fish is back swimming happily again. I can then come back and look at the same fish for days or weeks in the same way. This is great for studying changes to bone over time, which you can’t do with mouse models or humans because they’re unhelpfully not transparent! I have lots of tools available like fish with fluorescent bone/immune cells and microscopes which can video these fluorescent cells over time in the living fish, which without their transparent fins, I wouldn’t be able to see! I also love working with them because the fluorescent images from zebrafish are absolutely stunning! I never get tired of seeing them.

There are lots of other reasons; they have a short life cycle so you can get more done faster, they breed very easily they are relatively easy to work with, keep happy and take care of. If you want to study the effect of a drug on the bone you can just mix it in with the water and hey presto! No complicated injections or stressful procedures for the animal!