What is a Model?

When a scientist wants to understand how something works, they have two main ways of approaching the problem. The first way is to try to study the thing itself, observing it closely, and taking careful measurements. However, in some cases, direct observation may not be possible because the phenomenon that the scientist is interested in may be too rare or difficult to measure. In these cases, scientists turn to models to simplify the problem into a version that they can more easily study. For example, if you wanted to understand how an airplane wing works, but you did not live anywhere near an airport, you could build a simple model from paper and throw it out the window. You may not think this is a very good representation of an actual airplane, with its complicated engines and electrical components, however, if you were only interested in how its wings moved through the air, then the model version may be good enough to help you come up with some ideas.

We can use similar models to understand the brain. The human brain is one of the most complicated structures in existence, consisting of over 100 billion cells that are connected in intricate patterns, and in constant communication with the rest of the body. Furthermore, most humans do not want their brains to be removed from their heads and studied—even in the name of science! Far from being put off by the difficulties presented by the brain’s complexity and inaccessibility, the field of neuroscience is one of the most active fields in modern science. Neuroscientists study the brain because brain function is a fundamental scientific mystery, and also because if scientists and doctors want to treat diseases of the brain, they need to understand how it works. Some scientists do study the brain directly using sophisticated technologies like magnetic resonance imaging scanners. However, many researchers prefer to use simpler models, on which experiments can be more easily conducted.

Flies As a Model For Brain Studies

Models for neuroscience studies can take many forms. Some can exist entirely within a computer, in which approximations of brain function are built purely from mathematical principles. Many scientists choose to study mice because mice and humans are both mammals, so we share many similarities. However, it is unethical to do unlimited experiments on mice, and the mouse brain is still very complicated! Therefore, scientists can turn to simpler animals such as fruit flies. The fly brain contains around 200,000 brain cells compared to humans’ 80 billion [1]—therefore, fly brains are much simpler. Despite its small size, the fly brain can coordinate complicated behaviors, and many of the basic principles of its function are the same as those of the human brain.

Many diseases are caused by mutations—changes in the DNA sequence. Around 75% of the genes that are responsible for diseases in humans are also found in flies [2]. One of the reasons that scientists love to use flies is that they can make mutations in fly genes very easily. Therefore, by making equivalent mutations in the fly DNA, scientists can create models of human diseases. When they study these mutations, scientists can often see that the flies experience the same (or similar) symptoms as humans (Figure 1). Scientists have been studying flies for over 100 years, and they understand the fly brain better than almost any other animal.

The lifecycle of a fly—the time it takes to develop from an egg to a mature adult—is only 10 days. This means that scientists can breed lots of experimental subjects in a very short time. The longest an adult fly can live is around 100 days. This makes them especially useful to model diseases that get worse as people get older, as experiments looking at “middle aged” flies will take only a few weeks, while they would take months or years using other model animals like mice or rats.

Testing Behavior in Model Flies

Once scientists have made a model by changing the fly’s DNA to include a disease-causing mutation, the next step is to see what effect the mutation has on the fly. Diseases affecting the brain can cause a wide range of symptoms. Some, such as Alzheimer’s Disease, affect a person’s ability to make new memories and recall old ones, while other diseases, such as Parkinson’s Disease, affect the ability to move [3]. Diseases may shorten people’s lifespans, affect their moods, or disrupt their sleep. Because scientists have been studying flies for so long, they understand fly behavior very well, and they can design experiments to test whether a mutation affects a fly’s normal behavior.

When scientists choose what sort of model to use to study a disease, it is important to think about what sort of experiments they will need to do. For example, if a disease primarily affects people’s ability to speak, scientists might not be able to learn much from a fly model. On the other hand, flies exhibit many behaviors that are similar to ours, though usually simpler. They sleep, can form memories and recall them days later, and of course they can move around. If a brain disease affects any of these behaviors, scientists can test whether the behavior is altered in the fly model.

There are many types of experiments to test a fly’s ability to move. These experiments can be simple and “high throughput”, which means scientists can test a lot of flies very rapidly. For example, experiments might involve testing how long it takes a fly to climb a certain distance [4]. Other experiments could be more complicated, which means they are slower to perform and fewer flies can be tested quickly, but they give scientists much more information. For example, scientists can take high-speed videos of flies walking to view them in slow motion, and use a computer program to analyse changes in fly movements too small for the scientists to see with their eyes (Figure 2). Experiments will always be performed on a test subject and a control, which is used to establish a baseline to compare the test subject to. In this case, the control would be a healthy fly with normal movement, so scientists can see whether the mutation changes movement when compared to a healthy fly.

Once scientists have established that a mutation has an effect on the animal—whether this is impaired movement, inability to sleep normally, or inability to form new memories—the next step is to understand how this is happening. Understanding how mutations cause problems gives insight into how the brain works and how scientists and doctors might go about treating the disease. One way to understand the effects of a mutation is to investigate the structure and function of the brain. The most important cells in the brain that talk to each other via electrical signals are called neurons. Neurons form complicated networks, in which one neuron may connect to and communicate with thousands of others. Each neuron has a unique shape and form, allowing it to perform its specific job. Using high-powered microscopes, scientists can investigate whether neurons in the brain of a disease model fly have an abnormal shape compared to healthy controls. Abnormal neurons might affect the function of the brain network, and because everything we do depends on these brain networks working correctly, these abnormal neurons might be the cause of altered behaviors. If there is a difference in the shape of a neuron, it may be because the neuron failed to form correctly in the young developing brain (which is why some diseases are present from birth), or it may be because the neuron initially formed correctly, but then began to degrade and die later on (which is why some diseases do not occur until people are older, and get worse with age).

Together, experiments like these can tell scientists a lot about how a mutation causes a disease, and how they might treat it. For example, in Parkinson’s disease, certain neurons die off more quickly than usual as people get older, which affects the brain’s ability to control movement. Some people with Parkinson’s have mutations in a gene called PRKN. Scientists made fly models with the same mutations in the fly version of the PRKN gene, and tested their behavior. The flies could move normally when they were younger, but as they aged, their ability to climb and fly got worse much more quickly than usual. This helped prove that the mutation in PRKN was causing Parkinson’s disease, and scientists are continuing to research how it does so and why it kills certain neurons [3].

Using Flies To Find New Medicines

When people get sick, sometimes their illnesses can be treated with medicines. Medicines often change something in the person’s body to make them feel better. Medicines can work by helping an illness to improve, or by minimizing the symptoms that make a person feel bad—for example, you may take a painkiller when you have a common cold or a headache. For many diseases, there are already medicines available that a doctor can prescribe. However, for some diseases there are few or no medicines available. In these cases, scientists and doctors are trying to discover new medicines that can help these patients. Unfortunately, it can be very difficult and take a long time to discover new drugs that can become safe medicines.

This is where flies come in! Research on flies is relatively fast and cheap compared to some other scientific techniques, because scientists can generate lots of flies in a small amount of time, and their food and upkeep are very affordable. Fly models of disease can be fantastic tools to find new medicines for people with brain diseases that may not have many drug treatments currently available [5]. Testing new drugs on flies can be the first step to find out if a drug may be helpful for a patient. For example, if a drug improves the way a fly can walk, then it is possible the drug may have a similar effect in patients with the disease that scientists are modeling (Figure 3). Again, these experiments can be “high throughput”—since flies are cheap and quick to grow, scientists can test lots of drugs on flies in a short space of time. Any drugs that look like they rescue some features of a brain disease in the fly can be taken forward for more testing, to ensure they are effective and safe before being given to humans. The ultimate aim of this kind of research is to find new drugs that might help patients with diseases to feel much better.

The Future For Flies in Research

The effort to understand and develop treatments for brain diseases is an ongoing process. Many years more research will be required to fully understand the nervous system and its disorders, but with a large variety of tools at their disposal, scientists are making great progress. We hope that we have convinced you that, although they are tiny, flies are an important resource for tackling these problems.

Glossary

Models: ↑ A simpler version of a complicated system that scientists can easily perform experiments on. This leads to better understanding of the complex system.

Neuroscience: ↑ The scientific field that addresses questions relating to the nervous system.

Unethical: ↑ If an experiment is unethical it does not adhere to the moral standards of society. This may be because it causes undue suffering to an animal.

Mutations: ↑ Changes in the DNA sequence of a gene that may cause disease.

Gene: ↑ A section of the DNA that affects a physical characteristic, like hair or eye color.

Control: ↑ An experimental group in which no changes are made. Controls are used to compare to a test condition to see if it produces any effect.

Neurons: ↑ One of the main cell types of the brain. Neurons communicate with other cells using electrical signals.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This work was funded by a MRC Senior Non-Clinical Fellowship (MR/V03118X/1) and BBSRC Project Grant (BB/X00094X/1) to JJ.