The neuroscience of worms

May 24, 2022

Written by: Joseph Stucynski

‘Why would you want to study worms?’ is a question almost every person who studies worms has been asked at some point. And it’s a fair question, particularly for neuroscientists who ultimately endeavor to understand how the human brain functions both normally and in disease states. How can a worm possibly relate to a human? Well, in keeping with the theme of my last article focusing on the wide variety of model organisms employed in neuroscience research, here’s an attempt to convince you, dear reader, of the power of the worm.

First let’s clear some things up. When I say ‘worms’, you probably picture the big fat earthworms that wriggle around in the dirt and come to the surface when it rains. While earthworms share some of the same biological organization with the worms most commonly employed in scientific research, they are not the type of worms that are most suited to neuroscience research in the lab. No, I’m talking about an animal called Caenorhabditis elegans (C. elegans for short) that is so tiny you can barely see it with the naked eye. Adult C. elegans worms are about one millimeter long, are completely transparent, and are not infectious or harmful to humans. In nature, C. elegans can be found in temperate regions feeding on the bacteria that grow on things like rotting fruits1 in the soil.

The use of C. elegans as a model organism was brought about by one person, Sydney Brenner, in 1962. Sydney Brenner, born and educated in South Africa, spent 20 years at Cambridge where he made ground-breaking contributions to the field of molecular biology, working there at the same time that the famous discovery of the double stranded nature of DNA was made at nearby Oxford.2 Recognizing that molecular biology could be applied to model organisms to study all different aspects of biology, he then turned his career to establishing C. elegans as a model for neurodevelopment. He was awarded the 2002 Nobel Prize in Medicine and Physiology for his seminal work creating a whole new field of study using C. elegans.

Figure 1 (Adapted from WormBook C. elegans primer3): A) Worms are grown on bacterial lawns in a petri dish and can be easily seen under a x5 microscope. B) Worms are laid as eggs, hatch into very small larvae and grow up over 4 days. C) Close up of a worm illustrating it’s see-through body allowing for close examination of it’s anatomy.

C. elegans has a number of traits that make it a great model organism for neuroscience and other scientific disciplines. It has a short development time of about 3 days after hatching from its egg, which allows for rapid breeding of new worms, and lives only about 2 weeks. The worms are very easy to work with in a petri dish under a microscope and can be grown on bacteria cultured in the lab (Figure 1). They lay thousands of eggs which means that you always have new worms to work with and can conduct very robust experiments with many worms. These traits also mean that the rate of experiments you can do is very rapid, which is great for answering a lot of scientific questions in a relatively short amount of time.

C. elegans are also genetically very powerful because it is very easy to introduce mutations into their DNA using new gene editing tools like Crispr/Cas9. This opens up doors to various cellular and molecular biology experiments that can teach us about how specific genes are controlling different aspects of cell function and even behaviors. In recent years, C. elegans has also become an effective model to test the function of human disease associated genes on cellular functioning, and also how drugs to treat human diseases may work at the cellular level. Since worm neurons and human neurons share many of the same genes and neurotransmitters,4 studying these things in the worm can offer key insights into the cellular mechanisms of diseases that might otherwise remain unknown by studying just humans.

And speaking of cells, there are a grand total of about 1000 cells in the entire worm, and exactly 302 nerve cells (neurons). This number of neurons is so reliable that in fact each of them has been given a name. Try doing that in human brain!

C. elegans was also the first animal to have its entire genome sequenced, and more importantly for neuroscience, the first organism to have its full connectome mapped.5 This means that in addition to knowing where every neuron is in the worm, we know all the physical connections between neurons. In essence, there is a complete wiring diagram of the worm’s nervous system. Now with all this powerful information you would think it’d just be a matter of time before you can understand exactly how the entire nervous system works, but it turns out that neurons and networks are tricky things to understand, even in a worm. While the connection map is a necessary first step, it is not sufficient to explain behavior. One crucial thing that a connectome is missing are the functions of each connection, which affect how the network dynamically behaves. You can loosely think of the anatomical connectome as the hardware and the function of neurons as the software; the hardware may always stay the same, but the software (activation patterns of the neurons) will differ depending on the context and state of the animal.

Harking back to Sydney Brenner’s original ideas, the worm is a great model to study neural development because of its 3-4 day development period. There’s even a fully mapped connectome of the larval nervous system, which is only about 200 or so of the 302 neurons found in adult worms. This allows neuroscientists to ask fundamental questions like how new neurons are birthed, moved into their final positions, and functionally integrated into an existing neural network.

Figure 2: The entire nervous system of C. elegans labeled with fluorescent markers in a live animal. (Adapted from WormBook C. elegans primer.3)

And lastly, C. elegans worms are fully transparent animals which provides tremendous advantages in studying the function of neurons while the worm is displaying behaviors. This is important in the age of neuroscience in which visualization of neurons is often accomplished by labeling them with fluorescent dyes (Figure 2) or stimulating them with light, which can freely pass through the worms’ tissue. For instance, some scientists have put fluorescent markers of neuronal activity in large groups of neurons at once and measured how activity levels of each neuron in the network changes as the worm moves around and attempts to eat or mate.6 These sorts of experiments are extremely powerful in terms of understanding how the known network diagram actually works to enable the worm to function, and it’s that level of detail which neuroscience as a whole is moving towards to get at the most detailed questions about how the brain works.

Despite being a newer model organism compared to the fruit fly Drosophila, which has been used for research since the turn of the 20th century, C. elegans quickly proved their worth as a genetically, developmentally, and neuroscientifically powerful system to study. And while on the surface we humans seem very different from worms, deep down at the cellular and neural level, maybe we aren’t so different after all – a neuron is a neuron, many genes are similar between humans and worms, and fundamental homeostatic behaviors like eating, mating, and sleeping are found in all animals. And that’s what makes studying them worthwhile.

References:

  1. Schulenberg and Felix, The natural biotic environment of C elegans, Genetics, 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419493/
  2. Sydney Brenner Wikipedia page: https://en.wikipedia.org/wiki/Sydney_Brenner
  3. Corsi AK, Wightman B, Chalfie M. A Transparent window into biology: A primer on Caenorabditis elegans. WormBook: The online review of C. elegans biology. http://www.wormbook.org/chapters/www_celegansintro/celegansintro.html
  4. Researchers find new actions of neurochemicals. CM Delude, 2009. https://news.mit.edu/2009/neurochemicals-0702
  5. White JG, Southgate E, Thomson JN, Brenner S. The structure of the nervous system of the nematode Caenorhabditis elegans. Philosophical Transactions of the Royal Society of London, 1986.
  6. Nguyen JP, Shipley FB, Linder AN, Leifer AM. Whole-brain calcium imaging with cellular resolution in freely behaving Caenorhabditis elegans. PNAS, 2015.

Cover image by HeitiPaves via Wikimedia Commons: https://commons.wikimedia.org/wiki/File:Varbuss.jpg

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