Fly aficionado

Using drosophila genetics to find drug targets

By Mark Kankel,
Principal Scientist, Neurology

March 22, 2017

Fruit fly. Drosophila. Yup, I saw your nose wrinkle. These pesky tiny flying machines suddenly appear in your kitchen during the summer, and no matter how hard you try, how often you clean, it’s almost impossible to get rid of them. I once read an article in the New York Times where eminent British dipterologist (one who studies flies), Harold Oldroyd was quoted as saying, “…there is no known remedy for these visitations except to move.” A bit too drastic for me, but then, I may be biased.

I am the proud caretaker of hundreds of fruit flies. In fact, Anindya Sen and I helped introduced these creatures to Biogen, albeit in a much more controlled way than on an overripe banana. Although a nuisance in everyday life, these flies wield great power for modern medicine.

Its simplicity is in its genes.
How, you ask, can a mere fly contribute to drug discovery? The simplicity of a fly is one of the its advantages. Nearly all fundamental biological processes are conserved and occur in the fly and other multi-cellular organisms, so although a fly has only 4 chromosomes (all completely sequenced), about 60-65% of all human genes have an equivalent fly gene. It gets even better.

Flies are cheap. Flies don’t take up much space: you can fit the entire population of Cambridge on your bookshelf. Flies are easy to breed – just look at your fruit bowl at the end of the summer – within 3 weeks, a fly can become a grandparent. Whereas in mice, it takes several generations (months) to introduce a genetic mutation, we can make a whole mutant fly population within weeks - perfect for doing sophisticated genetics in a very timely fashion.

So, the next time you set out your fly tape or bowl with vinegar and dish soap, take a moment to think about how this little fly could, one day, help solve the molecular mystery of a neurodegenerative disease like ALS (amyotrophic lateral sclerosis).

What can a fly do for medicine?
While studying fly embryonic development and signaling pathways in neurodegenerative diseases, I realized that I wanted my research to have more meaning for patients. Joining Biogen offered me both a chance to make a difference at the translational level and to advocate for the unique approach of using fly genetics to accelerate the drug discovery process.

I set up the fly genetics program at Biogen, and we focus on genetic modifier screens. This means that we start with a fly population that has a particular genetic, disease-relevant phenotype and systematically introduce new mutations into this background. We look to see which mutations result in an altered phenotype: if we see improvement, we believe the mutation is a suppressor; if the phenotype worsens, we believe the mutation is an enhancer.

The proof is in the pudding
Let me illustrate this with an example. The team began an ALS investigational project, and within 10 months identified and validated a target; this would generally take 1-2 years or more, using mouse models. We generated transgenic flies carrying either a mutated TPD-43 or Fus gene, both of which are directly linked to ALS. We performed a genetic screen to identify genes that altered the ALS phenotype in flies and found hundreds of candidate genes. The big challenge with these types of screens is to figure out which ones are relevant – and, unfortunately, no one has come up with a consistently good solution.

We took our long list of potential candidates, did our due diligence and narrowed down the list by identifying genes involved in mediating pathological phenotypes (protein aggregation) in the fly that were also seen in patient tissues. We then developed another fly model with a different ALS gene, called C90RF72, and assessed the strongest suppressors of both the TPD-43 and Fus screens on their ability to suppress C9ORF72. From there, bioinformatics was used to look for any connections between the genes we found and other ALS genes in human and mouse models.

Finding a needle in a haystack, and more
By employing this strategy, which included valuable insights from Dr. Chris Henderson (VP Research – Neurology), we found one potential novel candidate. Chris’ group identified that one gene in particular is upregulated in early onset ALS human patients; late onset patients displayed lower levels of this gene. Given this observation, the thinking was if we can reduce the expression of this gene early, we may be able to delay disease onset or ameliorate an ALS phenotype. We conducted an experiment, where we reduced its levels in 3 different models of neurodegeneration in the fly eye and 2 models specific for neuromuscular junctions – all were protected.

To our delight, when we looked at inactivation of several other members of this specific pathway, we found that all of them demonstrated protection against ALS phenotypes. This is great news because it gives us flexibility in treatment design, since we don’t need to solely focus on one gene. This is the beauty of a perfect target and illustrates certain advantages of using the fly. Implicating the entire pathway in this way takes significantly more time and resources to accomplish using mouse models.

A Biogen team, led by Anindya Sen and Emily Peterson, is researching unique chemistry to inhibit its activity, and are working with Columbia University to conduct mouse genetics in ALS models to confirm our findings. Simultaneously, we’re currently developing mammalian cell-based assays with ALS-related pathologies to potentially test additional candidates in a semi high-throughput manner. The team and I are humbled that our work is a very small part of drug discovery at Biogen, and hope that we can help other teams accelerate their science by testing their targets or hypotheses in our fly models and our cell-based assays.

Playing with the big kids now
Most recently, I was invited to take part in choosing targets for the Biogen/Ionis collaboration on ALS. To my delight, some of our fly-derived targets are now on the list, confirming my suspicions that the mere fly does indeed have the potential to be much more than a nuisance.

Although I utilize the fly less for my current work, I’m always going to be a strong advocate for its use to identify and validate targets. Cross-species conservation in a living, multi-cellular organism, even one without a backbone, is extremely valuable, and because we observe human-related pathologies and phenotypes in our flies, we’re leveraging this to research new medicines.

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