Fruit flies can be a bother in the kitchen when they appear in your fruit bowl. But did you know that these tiny insects digest food in a very similar way to us, share 70 per cent of our disease-causing genes, and might be the key to finding new treatments for rare inherited genetic disease?
In this special instalment of LIMS Explains for Rare Disease Day, Dr Travis Johnson and Dr Sarah Mele discuss how one fruit fly species, Drosophila melanogaster, is helping them in the search for new treatments for ECHS1 deficiency – an extremely rare, inherited genetic disorder which causes neurodegeneration in babies and young children.
--
Why do scientists use fruit flies to better understand human genetics?
When thinking about scientific research, mice often come to mind. But there are many other, simpler organisms out there which have genetic similarities to humans which are also used when investigating disease. One of these is Drosophila melanogaster, which is a particular species of fruit fly. You might have seen them before – they’re the tiny flies which can appear when you leave bananas out in the kitchen.
Surprisingly, the genetics of a fly is not all that different from our own; 70 per cent of human disease-causing genes have an equivalent gene in flies. Because of this similarity, these flies have been used in genetics research for over a century, leading to breakthroughs in how we understand chromosomes, genetic inheritance and the fundamental workings of the nervous system.
Fruit flies play a key role in your research, which focuses on a rare genetic disease called ECHS1 deficiency. First of all, tell us about the disease.
ECHS1 deficiency is a childhood neurodegenerative disease that causes severe physical and mental developmental disability. It occurs when a child has two non-functioning copies of the Short-chain enoyl-CoA hydratase 1 (“ECHS1”) gene, and is extremely rare; in fact, there have only been about 90 confirmed cases of the disease worldwide.
The ECHS1 gene is responsible for the production of a digestive enzyme which helps us break down protein in our food – specifically, an amino acid called “Valine”. ECHS1 deficiency is usually triggered in infancy or early childhood, and when it happens, the child is no longer able to break down Valine and convert it into the energy they need to grow.
The interesting thing about this disease is that because it is caused by the loss of a digestive enzyme, treatment might be possible by changing what affected children and babies eat. That’s something we’re seeking to discover in our research.
Why did you decide to use fruit flies to investigate ECHS1 deficiency?
In our lab, Drosophila has always been the study specimen. However, it was only recently that we branched into investigating metabolic diseases because we thought flies could have a major impact.
The enzymes and chemical reactions in digestion have remained almost identical over millions of years – an indication how important they are to life, as evidenced by the loss of a single enzyme in ECHS1 deficiency. Because the process has been the same for so long, flies and humans still break down food in a similar way. When we put that together with the genetic similarities, we realised that it was feasible to emulate metabolic diseases like ECHS1 deficiency in flies.
The Drosophila have a short life cycle – growing from embryo to adult in two weeks – which means we see many generations over just a few months. Since they have been used in laboratories for so long, there are now lots of strategies for editing their genomes to create fly versions of human diseases, such as ECHS1 deficiency and because they’re so small and grow rapidly, we can have thousands of “fly patients” at once and test many potential treatment combinations in a relatively short space of time.
What have you discovered about ECHS1 deficiency through using fruit flies as a model?
The first step was to find out what ECHS1 deficiency looks like when you induce it in a fly. What we discovered was, flies with ECHS1 deficiency only lived for about 10 days, had extremely delayed development, and could not grow to the size of the healthy control flies which didn’t have ECHS1 deficiency. This was a promising start as it was reflective of the disease’s progression in humans, and meant we could use it as a baseline to improve upon during treatment testing.
We then wanted to see what was going on in the metabolism of these sick flies – how they digested nutrients and converted them into energy to promote growth. It turned out, a lot more was going wrong than we thought. As well as being unable to break down Valine, we saw big changes to how the flies digested sugars. This was unexpected, but it made sense as the ECHS1 enzyme is integral to energy metabolism and with the loss of Valine as an energy source, the flies were finding other ways to compensate.
Finally, we trialled some preliminary dietary treatments, which saw us feed the flies different diets using a specially made, synthetic nutrient formula. We found that although the flies responded best to the diet which lacked Valine, the formula was still not a complete cure, and the flies were still unable to progress though all their developmental milestones. This suggested to us that metabolism plays a central role in the disease, and while reducing Valine from the diet was helpful, the condition is still a long way from being rectified.
With this knowledge, we’re now working to find other, potentially complementary, ways to treat the disease that does not involve severe restriction of essential nutrients.
What do you hope the impact of your research will be?
There are more than 1,400 individual genetic disorders, all of which are extremely rare. Our goal is to shed new light on disorders like ECHS1 deficiency, which are largely overlooked and under-researched. This has led to a severe lack of treatment options which meaningfully improve quality of live for those affected by rare genetic disorders.
Using Drosophila melanogaster fruit flies as a model gives us the ability to quickly investigate many possible treatments for many different disorders. If we find a way to restore health in our fruit flies, the research can then go on to the next step – validating the treatment in more complex organisms, or possibly even direct translation to patients in the clinic.
Who knows – maybe one day soon, our humble little fruit flies might show us a treatment that can change the lives for those who need it.
--
Dr Johnson and Dr Mele’s ECHS1 deficiency research is supported by a National Health and Medical Research Council (NHMRC) Ideas Grant, and a generous gift from Archie’s Embrace, an ECHS1d deficiency charity which was established to help find new treatments for, and raise awareness of, rare genetic disease.
Their research is conducted in conjunction with Dr Mathew Piper and his team at Monash University, and colleagues at La Trobe University, the University of Melbourne, and the Murdoch Children’s Research Institute.
Read their most recent paper in the Journal of Inherited Metabolic Disease here.
