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Personalized medicine “on the fly”

Updated: Jan 31

Cancer, Parkinson’s, and viruses. How tiny insects are helping scientists make great strides in human disease research and precision medicine.

 

Whenever I proudly tell people that I use fruit flies to conduct research on Alzheimer’s disease, I am often met with stares of utter bewilderment and confusion: “The ones that hang around my rotting bananas? I didn’t know they had brains.”

It is difficult to comprehend how the same pesky creatures that we swat around with a rolled-up newspaper in our kitchens can be useful for science, yet we actually have quite a lot in common. Fruit flies, or Drosophila melanogaster, are genetically similar to humans. Out of the 20,000 genes that have been associated with human diseases, 75% of them have analogous counterparts in flies. This makes the fly a tremendously powerful tool to mimic human diseases and follow their pathogenic progressions. Our resemblance does not end here. We also share common ancestry for our intellect—a recent study from King’s College London showed that the basic mechanisms behind the formation of brain areas responsible for attention and memory are the same between humans and flies 1. Sometimes, flies can even exhibit incredibly anthropological behavior. For example, when male flies are rejected by female flies during sexual courtship, they purposefully seek out alcohol 2 (to drown their sorrow perhaps?). So, the next time someone compares your attention span to that of a fruit fly, do not take it seriously—it may not be an insult after all.

An animal model that can surprisingly, do it all


The fly is a perfect vehicle for large-scale genetic studies, partly due to its time- and cost-efficiency as an animal model of physiological and psychological conditions. A single female fly can lay up to 300 healthy embryos in her lifetime. An embryo develops into a sexually mature fly in merely 10 days. To maintain a culture of 100 adult flies costs around $20 per month, a miniscule amount compared to zebrafish ($180) or mice ($2,100) 3. Since fruit flies are invertebrates, there is no complicated ethical approval process, stringent vetting, or meticulous post-procedure care usually involved in animal testing.


Over the past century, as our technology advances, research scientists have created more and more genetic tools in flies to accompany cutting-edge techniques. Some flies are excised of certain proteins that are the key promoters of dementia. Some are recipients of the exact human genes responsible for hereditary breast cancer through gene transfer. Some have curly wings. Some have white eyes…Scientists can freely edit these flies’ genome in their desired manner to serve a specific research purpose. Once a group of genetically identical flies, termed a “line”, is established, it can be propagated for perpetuity.


Today, more than 100,000 unique fly lines are commercially available and can be mixed and matched through breeding, tailoring to almost any experimental need imaginable. With this immeasurable number of combinations, it is no surprise that Drosophila research has garnered 6 Nobel Prizes in physiology and medicine so far 4. The next breakthrough cure is plausibly sitting right in front of us, waiting to be discovered.


One of the most common fly flines, w[1118], was established in the 1980s and has since been the ancestor to more than 40,000 unique genetic constructs.


From lab benches to hospital beds


Traditional drug treatments employ an “one size fits all” strategy but often run into pitfalls when patients from various clinical backgrounds respond to drugs differently. This means that the same drug may be beneficial for some but ineffective for others. For complex diseases such as cancer, a more precise approach is required to customize care for each unique patient. In this avenue of “personalized medicine”, each patient’s genome is thoroughly analyzed and incorporated into a one-of-the-kind profile that considers risk factors, family history, and environmental contributors. Using this profile, clinicians can then devise a custom-made healthcare plan for their patients.

The fly is emerging as a big player in this modern vision of medical care. A 2019 study published in Science Advances details how a team from the Icahn School of Medicine, New York, replicated a cancer patient’s condition in flies to design a personalized cocktail of chemotherapy 5. The patient, a 53-year-old man diagnosed with colon cancer, had previously received multiple rounds of single-agent chemotherapy. Sadly, the treatment was ineffective, and the cancer metastasized to his lungs and liver. Suspecting that his tumors were extensively mutated and resistant to the drugs used, his physicians took a sample and sequenced its DNA. They found more than 100 mutations in his tumors. The team, led by Dr. Ross Cagan, then isolated 9 key mutations that were most relevant to tumor regulation and introduced those same mutations into a single fly line. Since the active mutations were largely lethal in the larval stage, they combined the mutations with a promoter system so that the mutations would not take effect until the scientists were ready to switch them on for the drug screen. To date, this “personalized fly avatar” is one of the most complex transgenic animals ever created.


Overview of the patient fly avatar for drug testing in personalized medicine. From Bangi et al., Sci Adv (2019) http://doi.org/10.1126/sciadv.aav6528



To find the most effective therapeutics, the team incorporated cancer drugs into the fly food. After individually testing 121 FDA-approved drugs and 86 different mixed “cocktails”, the team found a unique combination that best rescued lethality and allowed the mutant larvae to develop into adult flies. That same combination of drugs was then administered to the patient. Two months later, the patient’s tumor volume decreased by 45%. He remained stable for the next 10 months, and no new mutation was found in his tumors (Ibid.). Yet that is not the most amazing part of the story. The entire process, from the initial biopsy to the finalization of the personalized treatment plan, took only a year. In the world of clinical research and whole animal experiment, the study had progressed at lightspeed.

In March 2021, the same team detailed a new case where they used the personalized fly avatar to find novel combinations of cancer therapeutics for another patient, this time with the help of automated robots 6. The patient sadly relapsed due to the particularly aggressive nature of his tumors, but the cocktail prescribed to him provided more than a year of stability before his final decline and was unique in its specificity. Though the platform clearly does not work 100% of the time, we must remember this: In drug discovery and design, even failures are successful in teaching us something new.

Beyond Cancer


From neuroscience to virology, similar screens using flies are rapidly filling our knowledge gap about drug and disease interaction. A team in Spain recently tested 1,120 different chemical compounds to find therapeutics that alleviated Parkinson’s-like symptoms 7. In the United States, a team has generated fly lines carrying various SARS-CoV-2 proteins to precisely study how COVID-19 impacts different tissues, providing a stepping stone to large-scale drug testing against the virus 8.


Not only will drug screens using whole flies be able to tell us what works, they can also help scientists elucidate how they work and what side effects they might have. In our data-driven world, it is both an opportunity and a responsibility to capitalize on fly research to modernize healthcare and deliver customized treatments to individuals from any socioeconomic situation.

Personalized healthcare is the future, and at each step along this path, tiny fruit flies that feed on our bananas are helping us get there.




References


1. Bridi J. et al. (2020) Ancestral regulatory mechanisms specify conserved midbrain circuitry in arthropods and vertebrates. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1918797117


2. Shohat-Ophir, G et al. (2012) Sexual deprivation increases ethanol intake in Drosophila. Science. https://doi.org/10.1126/science.1215932


3. Kasai Y, Cagan R. (2010) Drosophila as a tool for personalized medicine: a primer. Per Med. https://doi.org/10.2217/pme.10.65


4. McKie, R. (2017) Six Nobel Prizes – What's the Fascination with the Fruit Fly? The Guardian, accessed 3 December, 2021.


5. Bangi E. et al. (2019) A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer. Sci Adv. https://doi.org/10.1126/sciadv.aav6528


6. Bangi E. et al. (2021) A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma. iScience. https://doi.org/10.1016/j.isci.2021.102212


7. Sanz FJ. et al. (2021) A High-Throughput Chemical Screen in DJ-1β Mutant Flies Identifies Zaprinast as a Potential Parkinson's Disease Treatment. Neurotherapeutics. https://doi.org/10.1007/s13311-021-01134-2


8. Zhu J.Y. et al. (2021) Functional analysis of SARS-CoV-2 proteins in Drosophila identifies Orf6-induced pathogenic effects with Selinexor as an effective treatment. Cell Biosci. https://doi.org/10.1186/s13578-021-00567-8



This article was specialist edited by Dr. Michael Rera and copy edited by Cassandra Koh.


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