*Spoiler alert* It looks like panic, questioning whether you've got it all wrong, and thinking 3-years’ worth of experiments was all for nothing!
PhD Hannah Bruce joined me to discuss her studies on zebra fish. Coming to the end of her 4-year PhD, Hannah’s journey has not been a smooth one.
Hannah is looking at a gene called FOXG1. This gene is involved in making sure everything is where it should be when the brain develops. Without enough FOXG1 protein, the two sides of the brain are a lot smaller and aren’t very well connected.
This is what happens in FOXG1 syndrome. FOXG1 syndrome, is a neurological condition where patients experience impaired brain development, cognitive dysfunction, and seizures. This syndrome arises when one of the two copies of this gene is mutated and does not work properly.
To study this condition, the genetic causes of FOXG1 syndrome were replicated in Hannah’s zebra fish. Zebra fish are interesting because their embryos are transparent. In addition, their genes can be edited to glow different colours or flash depending on the cell type. In Hannah’s case, she collects embryos from zebra fish with green and magenta neurones, the colour depends on whether these cells are excitatory or inhibitory.
This allows you to see the relative amounts of each neurone type, if there's too many excitatory neurons compared to inhibitory, then seizures can occur. This is what Hannah observed in the embryos of the zebra fish she studies.
One day, Hannah was looking at some embryos that have two mutated copies of the FOXG1 gene. The mutation means that the protein making machinery stops too soon in the process to make the protein encoded by the FOXG1 gene. Since these embryos don’t have a single functional copy of the FOXG1 gene, Hannah did not expect to find anything being made from these genes…
“Oh my god, this fish is not what we think it is, my entire PhD leading up to this point has been worthless! "
… So you can imagine the surprise when Hannah found that these fish - with no working FOXG1 gene - were able to make a bit of FOXG1 protein. Hannah said "When I saw it I panicked!", she thought there must be something wrong with the fish - maybe they had accidentally ended up with a working FOXG1 gene? - this would mean all her experiments up to this point had been worthless!
It took a moment for the panic to subside and for Hannah to think about this scientifically. When she did some further investigation she found they were somehow making a new, small scrap of protein from a bit of the mutated FOXG1 gene. This small protein was found to cause problems with brain development. Hannah explained ‘If I put this protein into healthy wild type fish, they end up getting more excitatory cells.’
Why is this this finding important?
This means that the faulty FOXG1 gene is not only unable to make a protein that the brain needs to develop, but it is also making a protein that disrupts brain development. This is very interesting because fixing the gene itself is hard, but what can be done is to stop this small but damaging protein with drugs. This might reduce the problems in brain development caused by faulty FOXG1 genes.
So what’s next?
Next Hannah is going to see if this same small protein is made in human cells with FOXG1 syndrome. If this is the case, she already has a drug lined up to test whether it will stop the production of this destructive protein. She hopes the outcome of her research will benefit those affected by this condition.
Stay tuned for our next blog post where I’ll be writing about legless lizards, octopuses, and playing the piano.
Lily