Fly on the Wall

Making fly science approachable for everyone

Month: August 2014

Breaking research: A study in fruit flies finds a possible drug target to compensate for symptoms of Parkinson’s disease

Parkinson’s disease is caused by the progressive death of neurons important for movement and results in symptoms such as shaking or rigidity in the limbs, slow movements, and difficulty walking. The primary treatment is a drug called L-Dopa, which compensates for the neuron loss but eventually becomes less effective as more and more neurons die off. Uncovering the cause of neuron death is necessary before treatments can be developed to stop it, and research in fruit flies has already begun to advance our understanding of the disease. A new study published in the open-access journal eLife by the Guo lab expands upon this previous work and uncovers a possible treatment option.

Although most cases of Parkinson’s disease have an unknown cause, about 10-15% are genetic. Two of the implicated genes, PINK1 and Parkin, have been well-studied in Drosophila melanogaster. Just as in humans, a mutation in these genes in fruit flies leads to neuron death and the loss of motor skills. But how? Fruit fly research has shown that PINK1 and Parkin maintain mitochondria, the structures inside cells that provide energy (think of them as little power plants). A single cell can have hundreds or even thousands of mitochondria, depending on its energy needs. Over time, mitochondria can become damaged and begin functioning abnormally.  These rogue mitochondria must be broken down and replaced with healthy ones before their dysfunctional behavior can cause damage to the cell. This is where the proteins created by the PINK1/Parkin genes come in.

Cartoon of mitochondrial maintainanceFigure 1. Pink1 latches onto mitochondria to determine whether or not they are healthy. If the mitochondrion is healthy, Pink1 is quickly removed. Otherwise, Pink1 binds to a passing parkin protein, triggering the destruction of the unhealthy mitochondrion. Image modified from Diedrich et al, 2011

PINK1’s job is to latch on to the surface of mitochondria and detect whether or not they are functioning normally. If the mitochondrion is fine, PINK1 gets removed and nothing else happens. On the other hand, if the mitochondrion has been damaged, PINK1 stays put and binds to a passing Parkin protein, which triggers the destruction of the offending mitochondrion. As you’ve probably guessed, a mutation in either the PINK1 or Parkin gene results in an accumulation of dysfunctional mitochondria and leads to cell death. This provides some explanation for why neurons are dying in patients in Parkinson’s disease.

PINK1/Parkin also maintain mitochondria in another way. Mitochondria regularly join with each other and then divide again to replenish their numbers. PINK1/Parkin helps to prevent damaged mitochondria from joining with healthy ones by breaking down a protein called mitofusin, which is responsible for joining mitochondria together. Cells with mutations in PINK1/Parkin have too much mitofusin, which means that damaged mitochondria can hurt the healthy ones by joining with them. To make matters worse, the ratio of joins to divisions is tightly controlled, so when the balance is tipped in favor of joining, big clumps of joined mitochondria begin to form.

The researchers in the Guo lab investigated other proteins involved in mitochondrial maintenance, searching for one that could compensate for mutations in PINK1/Parkin by preventing damaged mitochondria from joining with others and restoring the balance between joins and divisions. They turned their attention on MUL1, a protein that had previously been shown to interact with mitofusin. The authors discovered that adding extra MUL1 proteins into cells with a PINK1/Parkin mutation fixed the mitochondrial problems caused by the mutations!  Drosophila neurons with a mutation in PINK1/Parkin have clumps of mitochondria, while normal cells show mitochondria evenly spread out. Incredibly, mutant cells with extra MUL1 protein showed a normal spread of mitochondria. Adding extra MUL1 into mutant cells somehow compensated for the PINK1/Parkin mutations and returned the balance between joins and divisions to normal.

How was the extra MUL1 able to reverse the over-joining of mitochondria? The authors answered this question by manipulating and measuring MUL1 and mitofusin levels in a variety of situations. They found that cells with a non-functional mutation in the MUL1 gene had clumps of mitochondria and too much mitofusin, just like in PINK1/Parkin mutants. On the other hand, normal cells with extra MUL1 protein actually had too little mitofusin and mitochondria that were small and fragmented, suggesting that the balance in these cells had shifted toward too much division. With further investigation, the authors realized that MUL1 protein was actually breaking down mitofusin just like Parkin.

So the addition of extra MUL1 protein can compensate for PINK1/Parkin mutations by breaking down the extra mitofusin, thus returning mitofusin levels back to normal and rebalancing the ratio of mitochondrial joins to divisions. But this research was in fruit flies, so how do we know this will be useful for humans? The authors took their research a step further by demonstrating that MUL1 has the same function in mouse neurons and HeLa cells (human cells), and that extra MUL1 in these models still compensates for PINK1/Parkin mutations.

This is a fantastic finding, but unfortunately it doesn’t mean we’re ready to give MUL1 pills to Parkinson’s patients and cure the disease. The authors introduced extra MUL1 proteins genetically using a method called gene overexpression (check out this Wikipedia article on gene expression for more information). Basically, the authors made the cells produce their own extra MUL1, but a possible treatment would require developing and testing a drug that either forces cells to start making more MUL1 or adds MUL1 directly. Second, MUL1 doesn’t play a role in targeting and destroying damaged mitochondria. This means that while extra MUL1 could help to prevent clumps of mitochondria (which would have spread the damage from unhealthy ones faster), it can’t actually remove damaged mitochondria. So this treatment would not be able to completely stop the accumulation of dysfunctional mitochondria. But there is still hope! This option will be better than our current treatments because it could slow the progression of cell death instead of simply compensating for the loss. And in the future, research in this area will build upon these findings to develop an even better drug.

Cartoon of balance between PINK1/Parkin and MUL1Figure 2.  An increase in MUL1 levels can compensate for loss of PINK1/Parkin and maintain normal mitofusin (mfn) levels (A). A loss of either MUL1 (B) or PINK1/Parkin (C) alone causes an increase in mfn levels. Cells with a loss in both PINK1/Parkin and MUL1 show an even greater increase in mfn levels (D). Image modified from Yun et al, 2014







For more information on Parkinson’s disease research in fruit flies, check out the Parkinson’s Translational Findings post.


  • Yun J., Huan Yang, Michael A Lizzio, Chunlai Wu, Zu-Hang Sheng & Ming Guo (2014). MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin, eLife, 3 DOI:
  • Diedrich M., Grit Nebrich, Andrea Koppelstaetter, Jie Shen, Claus Zabel, Joachim Klose & Lei Mao (2011). Brain region specific mitophagy capacity could contribute to selective neuronal vulnerability in Parkinson’s disease, Proteome Science, 9 (1) 59. DOI:

Translational Findings: How fruit flies are helping us understand Parkinson’s disease

Parkinson’s disease is the second most common neurodegenerative disorder, and patients experience primarily movement-related symptoms including shaking and rigidity in their limbs, slow movements, and difficulty walking, all of which progressively worsen over time. It was formally recognized as a disease in 18171, but didn’t receive much attention until it was given its name in 1861. Parkinson’s disease was not very well understood, and there were no real treatments for about 100 years. Then, in the 1960s researchers discovered that Parkinson’s patients had low levels of dopamine, a chemical in the brain that some neurons use for communication. This finding led to the use of L-Dopa (also known as levodopa) as a treatment. L-Dopa is taken orally and can reach the brain, where it is converted to dopamine2. Now approximately 40 years later, L-Dopa is still the primary treatment for Parkinson’s disease.

Cartoon of dopamine loss in Parkinson's diseaseFigure 1. Parkinson’s patients show a decrease in dopamine levels in the brain. source

The problem is that L-Dopa doesn’t work forever. Since the 1960s, we have learned that Parkinson’s disease is caused by progressive damage and eventual loss of dopaminergic (DA) neurons (these are the ones that release the dopamine), most severely in an area of the brain important for movement known as the basal ganglia3. As more and more DA neurons become damaged and die off, L-Dopa loses its ability to compensate and the symptoms start to come back.  To make matters worse, L-Dopa has a number of side effects that need to be treated with yet more drugs. Of course, L-Dopa is currently very necessary for treating Parkinson’s disease and can give patients an extra 5-15 years of quality symptom-free life. Even as L-Dopa’s effectiveness begins to decrease, it’s still better than no treatment at all. But newer and better treatments need to be developed.

Unfortunately, we can’t fix the disease until we understand what’s causing it. Why are the DA neurons dying? How can we stop it and then reverse the damage? We’ve learned just about everything we can from (ethical) research in humans. It’s time to bring in the model animals! The humble fruit fly Drosophila melanogaster has emerged as a particularly important model because while most cases of Parkinson’s disease occur randomly, about 10-15% of cases are due to inherited genetic mutations. And for genetic research, flies are our best bet.

Why study the genetic mutations if only 10-15% of cases are caused by them? The easiest answer is because we can introduce mutations into the same genes in fruit flies to find out what those genes do. If researchers can figure out what’s causing damage to the DA neurons in the genetic cases, those findings can be directly applied to the random cases. So even if we don’t yet know what caused them,  treatments that protect DA neurons and compensate for their damage should still work to improve symptoms in both genetic and random cases of Parkinson’s disease.

Since the late 1990s, mutations in five genes have been found to lead to inherited forms of Parkinson’s disease in some families. Each was given a cryptic name: SNCA4, Parkin5, PINK16, DJ-17, and LRRK28-9. Once those genes were identified in human patients, researchers were able to mutate the same genes in animal models to figure out what they do and how their failure leads to Parkinson’s disease. Luckily for us, fruit flies already have four of those genes, so it was relatively easy to make a fly line with a mutation in them.  The remaining gene, SNCA, can still be studied by introducing the human mutation into flies using a binary expression system (UAS/GAL4).

Magnified image of Lewy body in brain of Parkinson's patientFigure 2. alpha-synuclein proteins clump to form masses called Lewy bodies. Figure depicts magnified image of a Lewy body surrounded by neurons in the substantia nigra (a part of the basal ganglia) in a patient with Parkinson’s disease. Photo by Suraj Rajan / CC BY-SA 3.0

So what have we learned so far from our winged friends?  An overview of fruit fly research for each gene is listed below, but if you just want the punchline, here it is: Parkin, PINK1, DJ-1, and LRRK2 are all involved in maintaining and/or protecting mitochondria, which are structures inside cells that create the fuel the cell uses as energy (think of them as little power plants). When any of these four genes is mutated, mitochondria begin to function abnormally and are more sensitive to damage from environmental stressors such as toxins. As more and more damage accumulates, DA neurons begin to die off, which may explain why Parkinson’s disease is progressive and usually begins later in life. On the other hand, although the role of normal SNCA is still unknown, a mutated SNCA gene creates masses in the brain called Lewy bodies that may cause damage to DA neurons. Although it’s not fully understood why mutations in these genes affect DA neurons more severely than other neurons in the brain, it is thought that DA neurons may simply be more sensitive to environmental toxins.

Okay, but what about the random cases?  While the cause of most of the random cases of Parkinson’s disease remains a mystery, results from research in the genetic cases can give us a clue. It is currently thought that this form of Parkinson’s disease is caused by a combination of factors such as accumulated damage and genetic mutations with age, exposure to environmental toxins such as pesticides, and genetic predisposition (meaning that there may be genes that don’t directly cause Parkinson’s disease, but may increase your risk if exposed to certain environmental triggers).

Research in fruit flies has definitely improved our understanding of the underlying causes of Parkinson’s disease, which will ultimately lead to the development of better treatments. Instead of simply compensating for reduced dopamine levels, future treatments may target the Lewy bodies or bolster the cell’s protective mechanisms for mitochondria. Treatments such as these will have longer lasting effects because they could potentially prevent further loss of DA neurons. And fruit flies aren’t our only hope. Many of the findings described above have already been used for designing studies in mammalian models, and research in mammals has also led to important discoveries not mentioned here.


Findings in fruit flies specific to each Parkinson-related gene:

  • Parkin/PINK1: I grouped these two mutations together because fruit fly researchers have recently discovered that these genes play similar roles in neurons10-12. PINK1’s protein actually interacts with Parkin’s protein to maintain and protect mitochondria. As a result, a mutation in either PINK1 or Parkin causes mitochondrial defects and increases sensitivity to environmental stress from toxins. The accumulation of damage leads to death in DA neurons and, of course, the resulting impairments in movement as seen in Parkinson’s patients. Further understanding of how PINK1 and Parkin work will allow researchers to develop drugs to compensate for lost function in these genes.
  • SNCA: Many Parkinson’s patients develop dense masses in their brains called Lewy bodies, which are formed when large molecules called proteins accumulate abnormally and bind to each other. Lewy bodies are primarily made up of the protein alpha-synuclein bound to various other proteins (alpha-synuclein is made from the instructions in the SNCA gene). But why is alpha-synuclein clumping together? Researchers introduced the mutated version of the human SNCA gene in fruit flies and found that mutant flies showed progressive DA neuron death and loss of motor skills, just like the symptoms in human Parkinson’s patients13. And of course, they found clumps of protein. Studies in this fly model are now focused on understanding why the mutated version of alpha-synuclein clump together and cause DA neuron death. Once these questions have been answered, researchers can develop treatments that either prevent formation of Lewy bodies, break them down, or prevent them from damaging neurons. Interestingly, researchers have found that when they add extra normal PINK1 or Parkin protein in this SNCA mutant, the extra PINK1 or Parkin actually helps to protect against DA neuron death14-15. So, another treatment option for Parkinson’s patients with Lewy bodies may be to stimulate extra PINK1 or Parkin protein production as a protective measure.
  • DJ-1:  Researchers have found that fruit flies with a mutation in DJ-1β (flies actually have two versions of this gene, and DJ-1β is similar to the human version) are more sensitive to environmental toxins, demonstrating that this gene plays a protective role16. Flies with this mutant gene also showed reduced lifespan and locomotor defects, as seen in Parkinson’s patients17. Finally, mutant DJ-1 protein resulted in abnormal mitochondrial function, suggesting that this gene, like PINK1 and Parkin, is necessary for normal functioning in mitochondria18.
  • LRRK2: Mutations in LRRK2 are likely the most common genetic cause of Parkinson’s disease in humans, but it has so far been the most inconsistent in fruit flies, making it a difficult gene to study. Researchers have performed several kinds of genetic manipulations, including completely knocking-out LRRK2 function, introducing the mutated version of the human gene, or mutating it in a way that changed its function instead of making it completely non-functional. Some researchers found that the mutations led to DA neuron death and severely impaired movement, some researchers found no effect, and others found a result somewhere in the middle19. A few important reliable discoveries have come out of research in this gene, however. First, all of the mutants were more sensitive to various environmental toxins. Second, researchers found that LRRK2 proteins interact with mitochondria, suggesting that it, like PINK1 and Parkin, plays a role in maintaining and/or protecting these structures. These findings support an increasingly convincing conclusion that Parkinson’s disease may be caused by mitochondrial defects or damage that leads to death in DA neurons.


Interested in recent Parkinson’s disease research in fruit flies? Check out the Breaking Research post on MUL1.



  1. Parkinson J. (1817). An Essay on the Shaking Palsy, Journal of Neuropsychiatry, 2002, 14 (2) 223-236. DOI:
  2. <Cotzias G.C. (1967). Dopa and Parkinsonism, BMJ, 3 (5563) 497-497. DOI:
  3. Blandini F., Cristina Tassorelli & Emilia Martignoni (2000). Functional changes of the basal ganglia circuitry in Parkinson’s disease, Progress in Neurobiology, 62 (1) 63-88. DOI:
  4. <Polymeropoulos M.H. (1997). Mutation in the -Synuclein Gene Identified in Families with Parkinson’s Disease, Science, 276 (5321) 2045-2047. DOI:
  5. Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y., Minoshima S., Yokochi M., Mizuno Y. & Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism., Nature, PMID:
  6. Valente E.M. (2004). Hereditary Early-Onset Parkinson’s Disease Caused by Mutations in PINK1, Science, 304 (5674) 1158-1160. DOI:
  7. Bonifati V. (2003). Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism, Science, 299 (5604) 256-259. DOI:
  8. Paisán-Ruı́z C., E.Whitney Evans, William P. Gilks, Javier Simón, Marcel van der Brug, Adolfo López de Munain, Silvia Aparicio, Angel Martı́nez Gil, Naheed Khan & Janel Johnson & (2004). Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson’s Disease, Neuron, 44 (4) 595-600. DOI:
  9. Zimprich A., Petra Leitner, Peter Lichtner, Matthew Farrer, Sarah Lincoln, Jennifer Kachergus, Mary Hulihan, Ryan J. Uitti, Donald B. Calne & A.Jon Stoessl & (2004). Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology, Neuron, 44 (4) 601-607. DOI:
  10. Clark I.E., Changan Jiang, Joseph H. Cao, Jun R. Huh, Jae Hong Seol, Soon Ji Yoo, Bruce A. Hay & Ming Guo (2006). Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin, Nature, 441 (7097) 1162-1166. DOI:
  11. Park J., Sungkyu Lee, Yongsung Kim, Saera Song, Sunhong Kim, Eunkyung Bae, Jaeseob Kim, Minho Shong, Jin-Man Kim & Jongkyeong Chung & (2006). Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin, Nature, 441 (7097) 1157-1161. DOI:
  12. Yang Y., Y. Imai, Z. Huang, Y. Ouyang, J.-W. Wang, L. Yang, M. F. Beal, H. Vogel & B. Lu (2006). Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin, Proceedings of the National Academy of Sciences, 103 (28) 10793-10798. DOI:
  13. Feany M.B. & Bender W.W. A Drosophila model of Parkinson’s disease., Nature, PMID:
  14. Bell J. & Brian E. Staveley (2008). Pink1 suppresses α-synuclein -induced phenotypes in a Drosophila model of Parkinson’s disease , Genome, 51 (12) 1040-1046. DOI:
  15. Haywood A.F.M. & Staveley B.E. (2004). Parkin counteracts symptoms in a Drosophila model of Parkinson’s disease., BMC neuroscience, PMID:
  16. Yang Y., Md. E. Haque, Y. Imai, J. Kosek, L. Yang, M. F. Beal, I. Nishimura, K. Wakamatsu, S. Ito & R. Takahashi & (2005). Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling, Proceedings of the National Academy of Sciences, 102 (38) 13670-13675. DOI:
  17. Meulener M., Cecilia E. Armstrong-Gold, Patrizia Rizzu, Peter Heutink, Paul D. Wes, Leo J. Pallanck & Nancy M. Bonini (2005). Drosophila DJ-1 Mutants Are Selectively Sensitive to Environmental Toxins Associated with Parkinson’s Disease, Current Biology, 15 (17) 1572-1577. DOI:
  18. Hao L.Y. & N. M. Bonini (2010). DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function, Proceedings of the National Academy of Sciences, 107 (21) 9747-9752. DOI:
  19. Muñoz-Soriano V. (2011). Drosophila Models of Parkinson’s Disease: Discovering Relevant Pathways and Novel Therapeutic Strategies, Parkinson’s Disease, 2011 1-14. DOI:


General references and reviews:

Breaking research: A new technique for uncovering cell-specific differences in the Drosophila “interactome”

You’ve probably heard the term “genome” before, which refers to the set of genes in an organism.  Biology has a lot of buzzwords for describing what’s going on inside cells, and one of the recent ones is “interactome”. The word “interactome” refers to all of the interactions that are occurring between proteins, the large molecules that do most of the work inside your cells. Proteins are built from their corresponding gene’s instructions, and they drive cellular processes by interacting with each other. For example, when a receptor protein on the cell membrane is triggered—such as by recognizing an invading virus—it temporarily binds to another type of protein, which interacts with yet another protein and so on, until the cell’s immune response is fully activated and self-defense proteins are released to deal with the invaders.  This series of protein interactions is called a “signaling cascade”.

As you might have guessed, if one of the proteins in a signaling cascade isn’t interacting properly, it leads to problems which can be the basis of diseases, such as Alzheimer’s disease, ALS, or cancer. As a result, it is very important to understand how proteins interact, especially when mutations can lead to human diseases. Unfortunately, a single protein can have dozens or even hundreds of binding partners. To make matters worse, it is thought that proteins have cell-specific interactions, which means that a given protein may interact with one set of proteins in one type of cell, and a different set of proteins in another cell type. However, current techniques for studying a protein’s binding partners use whole brains or brain structures consisting of many different types of cells and cannot distinguish among them.

A recent paper1 published in the Griffith lab addresses this problem by taking advantage of the genetics tools developed in Drosophila melanogaster. They created a fly line with a mutation in the gene for the protein of interest, and then used a binary expression system (UAS/GAL4) to reintroduce normal versions of the protein into specific subsets of cells. The authors then followed up with current techniques for studying the protein’s interactions, but they knew that the binding partners were specific to the cells they were interested in.

To demonstrate their new technique, the authors studied a protein called CASK. In mammals, CASK is important for signaling between neurons and is implicated in two human developmental disorders. In flies, CASK is present in almost all neurons, and CASK mutants have problems with locomotion and learning. Researchers already knew that different types of neurons were responsible for each of these behaviors, and thought that CASK may have different interactions based on the type of cell. To test this hypothesis, the authors used a fly line with a non-functioning mutation in the CASK gene, and then reintroduced normal versions of the protein in three different types of neurons.  They were then able to use current identification techniques (check out this link on mass spectrometry, if you’re interested) to determine which proteins had bound to CASK in each of the three lines and compare them to each other (as well as to a fly line where they had reintroduced CASK in all neurons). They found that while there were many proteins that interacted with CASK in all of the neuron subtypes, each group also had a set of unique interactions.

So what’s the bottom line?  How can the findings in this paper help us? Because abnormal protein interactions are the basis of many human diseases, the only way to treat them is to determine which proteins are involved and understand their function. Only then we would know how to fix the problem. Unfortunately, while many of those interactions are specific to certain types of cells, current techniques require researchers to investigate the protein’s binding partners from many cell types.  This creates unnecessary complexity because only specific populations of neurons are affected in some diseases. For example, in Parkinson’s disease, a type of cell known as dopaminergic neurons are most seriously affected. Researchers are studying proteins known to be involved in the disease, but may benefit from being able to limit the interactions to those that occur within dopaminergic neurons. Using fruit flies, the Griffith lab developed a technique for uncovering cell-specific differences in a protein’s interactions. In the future, researchers will be able to use Drosophila as a model organism for studying cell-specific protein interactions involved in human disease, and this technique may even be modified for use in mammalian systems.

  1. Mukherjee K., Bethany L. Christmann & Leslie C. Griffith (2014). Neuron-specific protein interactions of Drosophila CASK-β are revealed by mass spectrometry, Frontiers in Molecular Neuroscience, 7 DOI:

Translational Findings: How fruit fly research has already contributed to human health

In my previous post, I described how Drosophila melanogaster serves as an important and relevant model organism for biological research.  But how is fruit fly research actually helping us to better understand ourselves?  In my future “Translational Findings” posts, I will talk about how fruit flies are furthering our understanding of a specific human-related issue. These will include diseases such as Parkinson’s or Alzheimer’s disease, developmental and genetic disorders such as autism or Down syndrome, and other human concerns like addiction, sleep, or aging.

In this first Translational Findings post, however, I would like to give an overview of the history of fruit fly research and how it has already contributed to human health. Fruit flies have been used as a model organism for over a century, so the list is long. To narrow it down, I will focus on describing the important findings that led to Nobel Prizes: four of them since Thomas Hunt Morgan published the first scientific paper using Drosophila melanogaster in 19101!

Comparison of eye color in fruit fliesFigure 1. The fly on the top has a mutation that causes white eyes. The fly on the bottom has normal red eyes. source

The first Nobel Prize was awarded to Thomas Hunt Morgan himself in 1933. He studied heredity and was interested in understanding how physical traits were passed down through generations. Morgan began by searching for visible variations among fruit flies so he could determine how those traits were inherited. Finally, he found white-eyed flies among a stock of normal red-eyed flies (Figure 1). He and his students began studying the pattern of inheritance for the white-eyed trait, and they later found other mutations to study as well. Their findings led to a radical new theory of heredity which suggested that genes (the pieces of DNA that contain the information for the traits) are carried in a linear arrangement on chromosomes, and these chromosomes are passed down through generations. Their findings showed the physical mechanism for genetic inheritance and are now considered the foundation of modern genetics.

The second Nobel Prize was awarded to Hermann Müller, one of Morgan’s students. After leaving Morgan’s lab, Müller began researching methods for inducing mutations in fruit flies instead of waiting for them to occur spontaneously. In the 1920s, he made a breakthrough when he noticed a connection between radiation and lethal mutations and, in 1927, published a paper demonstrating that X-rays damaged chromosomes and caused genetic mutations2. Although the public was beginning to realize that radiation was dangerous (Marie Curie died in 1934 as a result of her own research), this was the first evidence of specific harmful effects. Müller began publicizing the dangers of radiation soon after, and earned a Nobel Prize in 1946 for his work.

In 1995, the third Nobel Prize for fruit fly research was shared by Christiane Nüsslein-Volhard, Eric Wieschaus, and Ed Lewis. Using recently developed techniques that allowed DNA to be more easily manipulated (such as X-ray induced mutations), these scientists screened thousands of mutant flies and identified several genes responsible for development in Drosophila melanogaster3. Their research paved the way for understanding how multicellular organisms develop from single cells, and showed that development is genetically controlled. Shortly after their discoveries, studies in other species found closely related developmental genes in vertebrates, confirming an evolutionary link between fruit fly and human biology.

The final Nobel Prize was award to Jules Hoffmann, Bruce Beutler, and Ralph Steinman in 2011 for their research in immunity. Humans have two methods for defending against infections: innate immunity, which is inherited, and adaptive immunity, which responds to invaders and “learns”. Hoffman’s research in fruit flies showed that a gene called Toll was important for the fly’s innate immune system. He found that the Toll gene contained instructions for a receptor responsible for recognizing certain bacterial and fungal infections and triggering an immune response4. Beutler later found related “Toll-like” receptors with the same function in mammals, demonstrating that this innate immunity control mechanism is shared across species through evolution. A few years later, Steinman showed that Toll-like receptors activate the adaptive immune system in mammals as well.

Fruit fly research has already made huge contributions to understanding human biology, and it shows no signs of stopping. In today’s research environment, research in flies has gone beyond the genetic research it founded and has moved into more complex issues such as disease and behavior. Which new major contribution will earn this little insect its fifth Nobel Prize?

  1. Morgan TH (1910). SEX LIMITED INHERITANCE IN DROSOPHILA. Science (New York, N.Y.), 32 (812), 120-2 PMID: 17759620
  2. Muller HJ (1927). ARTIFICIAL TRANSMUTATION OF THE GENE. Science (New York, N.Y.), 66 (1699), 84-7 PMID: 17802387
  3. Nüsslein-Volhard C, & Wieschaus E (1980). Mutations affecting segment number and polarity in Drosophila. Nature, 287 (5785), 795-801 PMID: 6776413
  4. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, & Hoffmann JA (1996). The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell, 86 (6), 973-83 PMID: 8808632

Fly Life: Why fruit flies are a good model organism for research

Since this is my first post, I’d like to start by talking about the basics: Why are we doing research with fruit flies, or even animal models in general? How can these simple organisms possibly provide us with relevant data for future human research? Generally speaking, animal models are important for biological research because they allow scientists to reproduce human diseases or abnormal behavior without the ethical concerns inherent in human studies. Although there are obvious differences between humans and other animals, there are many molecular and cellular processes that are shared among all species through evolution. Many complex human behaviors are also seen in animals, such as aggression, circadian rhythms, sleep, learning and memory, and mating. By studying these processes and behaviors in animal models, researchers gain an understanding of the basic biology underlying them and can use this knowledge to figure out how diseases occur when things go awry (and then, how to fix it).

One important feature of an animal model is the ability to manipulate its genome and investigate the function of specific genes. For example, scientists know that a mutation in the Pink1 gene is responsible for early-onset Parkinson’s disease in humans1, but they don’t know what the gene does. Researchers need to know the gene’s function before they can investigate how the mutation leads to Parkinson’s disease and how to treat it. In animal models, researchers can study the gene’s function by manipulating the relevant gene in the animal’s genome. One important type of genetic modification is a gene “knock-out”, which means they induce mutations in a specific gene so that it becomes inactive or non-functional. By observing the resulting change in physiological processes or behavior, researchers can determine what role the gene played in normal functioning. In our example, scientists can knock-out the Pink1 gene in fruit flies or mice and observe on a cellular level which processes fail. As an added benefit, researchers can also observe the animals themselves to see if they display the same behavioral phenotypes as patients with Parkinson’s disease, such as tremors and slow movement.

Another type of genetic manipulation is called a “knock-in”, where researchers instead insert a gene from another animal into the genome (or, in many cases, replace the endogenous gene with another version). For example, researchers often insert a mutated version of a human gene implicated in a disease, which allows them to determine what effect that particular mutation has on the gene’s function. To return to our previous example, scientists can insert the specific human Pink1 mutation that leads to early-onset Parkinson’s disease in an animal’s genome instead of knocking it out completely. It also allows them to test the effectiveness (and side effects) of various promising therapeutic drugs before going to human trials.

So what’s this got to do with fruit flies? On the About page on this site, I gave a few of the basic reasons why Drosophila melanogaster are a good model organism for research. They have been used for research at all levels of biology, but genetic research is where these organisms really shine. Genetic manipulations are so much easier in fruit flies because they have a smaller genome which was fully sequenced in March 20002. Their short life cycle and large number of offspring are also advantageous for genetic research because new fly lines are quick and easy to make. As a result, although the manipulations I mentioned above can be performed in other animal models such as mice, mutations in flies can be generated much more easily. Making a new line of flies usually only takes about six weeks and costs less than $300, whereas a new mouse line takes months and can costs thousands of dollars.

But how do researchers initially identify the genes they’re interested in studying? In order to study a process or behavior using specific gene mutations such as those described above, the gene of interest must already be identified. Traditionally, researchers perform genetic “screens”, in which they use mutagenic chemicals or radiation to cause random mutations in animal models, and then screen offspring for abnormalities of interest and identify the mutated gene. But this process is difficult and time-consuming, and often based on luck. Enter Drosophila melanogaster! Using this animal model, researchers can conduct large-scale screens relatively quickly. For example, to find genes that contribute to sensing heat, fly researchers can test hundreds of mutant flies for impaired heat avoidance within a few months. Identifying those relevant gene(s) will then provide a starting point for studying sensory abnormalities in mammals.

Fly head with green eyesFigure 1. Example of GAL4/UAS system being used to express a green fluorescent marker in eye cells. Photo by Wellcome Images / CC by-nc-nd 2.0

Over the years, fly researchers have also developed an impressive array of genetic tools that make Drosophila melanogaster an even better animal model for research. The list is too long to cover in this post, but there is one type of tool I want to introduce called binary expression systems. These systems allow fly researchers to insert a specific gene into a specific set of cells, and even activate or deactivate the gene at specific times. One example binary expression system is called the GAL4/UAS system. In this system, a fly line with genetic instructions for where something should be inserted (GAL4) is mated with a fly line with genetic instructions for what should be inserted (UAS). For example, the GAL4 instructions might define the cells of the eyes while the UAS might be a green fluorescent marker. The individual lines have no abnormal phenotypes, but the offspring will have green glowing eyes! (Figure 1) In practice, if a researcher wants to know in which brain structures a particular gene is expressed, such as Pink1, they can combine a GAL4 that targets “cells with an active Pink1 gene” with the green UAS. They can then view a dissected fly brain under a microscope and see where cells expressing the Pink1 gene are located in the brain. Alternatively, the UAS instructions might describe a gene to be deactivated instead of inserted, so that it is “knocked out” in a very specific set of cells. In this way, fly researchers can investigate the gene’s function in a relevant region without affecting the overall health of the fly, which is important for reproducing human diseases that target specific cell-types. And because genetic modification is so comparatively easy in the fruit fly, the fly community has created a collection of thousands of fly lines for these systems, which researchers are more than willing to share with each other. As a result, it is often very likely that a specific combination is already available for use.

Ultimately, every animal model has its advantages and disadvantages.  Researchers wouldn’t want to use monkeys for a genetic screen, and they wouldn’t use fruit flies to study complex emotions. But although fruit flies may seem very different from us, an estimated 75% of known human disease genes have a match in the fruit fly genome3-4. They are already being used as a genetic model for several human diseases, including Parkinson’s disease, Alzheimer’s disease, Fragile X syndrome, and Rett’s syndrome, in addition to the basic research needed to advance our general understanding of biology and how we work.  So the next time you see a fruit fly in your kitchen, make sure to say “thank you” before you swat it away.

  1. Valente EM, Salvi S, Ialongo T, Marongiu R, Elia AE, Caputo V, Romito L, Albanese A, Dallapiccola B, & Bentivoglio AR (2004). PINK1 mutations are associated with sporadic early-onset parkinsonism. Annals of neurology, 56 (3), 336-41 PMID: 15349860
  2. Adams MD, Celniker SE, Holt RA, Evans CA, Gocayne JD, Amanatides PG, Scherer SE, Li PW, Hoskins RA, Galle RF, et al (2000). The genome sequence of Drosophila melanogaster. Science (New York, N.Y.), 287 (5461), 2185-95 PMID: 10731132
  3. Reiter LT, Potocki L, Chien S, Gribskov M, & Bier E (2001). A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome research, 11 (6), 1114-25 PMID: 11381037
  4. Lloyd TE, & Taylor JP (2010). Flightless flies: Drosophila models of neuromuscular disease. Annals of the New York Academy of Sciences, 1184 PMID: 20329357

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