16 - Worms as Model Organisms (w/ Mahtab Peyambari!)
16. Worms as Model Organisms (w/ Mahtab Peyambari!)
Squirm! I’m a worm. With a name as long as Caenorhabditis elegans, you might expect this model organism to be larger. What is a model organism? Why would a researcher use a worm to represent research as a model? What is the historical basis of C. elegans research? Let’s learn to be scientifically conversational.
General Learning Concepts
1) What is a worm?
a. What a worm is: Scientific name CAENORHABDITIS ELEGANS. Commonly called “a worm” or a nematode. 1 mm long at adulthood. Though it’s been used as a model organism since 1965, originally proposed by Sydney Brenner, C. elegans were only described as their own species in 1900 by Emile Maupas. Found in compost heaps or humus, researchers have been capable of finding C. elegans worldwide. C. elegans is capable of self-fertilization (as a hermaphrodite, generates females) or by hermaphrodites breeding with males, Worms follow two alternative life cycles, one of which prevents full development if there is limited food, dense population, or an incorrect temperature. Because C. elegans is capable of self-fertilizing, it can purge deleterious recessive alleles by natural selection.
C. elegans mainly eats bacteria and single celled eukaryotes, but often ends up as prey as well. Parasites are capable of infecting the nematoad, and the worm is even capable of harboring exterior fiofilms.
b. What is a lab worm? The average lifespan in the lab is 20 – 30 days. These worms tend to be mated or altered genetically in order to query specific investigations. Otherwise, morphologically and genetically, lab worms do not have outwardly large differences from worms in the wild. That being said, the standard lab worm had about 12 years of differences from the natural worm found in a compost heap. 
c. What is a model? It’s hard to learn every single thing about every single organism. Using systems that seem to be generalizable allows for comparisons and development of more complex, in-depth experimental developments.
i. Very similar to a model in real life; you can’t necessarily picture what you’ll look like with that jacket until you see it on the model. That being said, it’s not the picture of what you look like, but it is representative. Some models are better than others.
ii. Is the organism good to rear? Is the size convenient? Is it inexpensive? How long is the lifecycle? Can you manipulate the genetics? Will the results be useful? Will others use the model?
iii. Example: The natural course of a disease in humans may take dozens of years. In contrast, a model organism can quickly develop a disease or some of its symptoms. That allows researchers to learn about the disease in a much shorter time
2) What are the pros and cons of using worms as models?
a. Pros: C. elegans has a short generation time and can be fed E. coli. Because of their multiple forms of development (lifecycles), the lifecycle can be extended or shortened. C. elegans can be frozen and stored at -80 C, allowing for future experiments. Self-reproduction allows for generation of homozygous stocks, a true treat for geneticists. C. elegans egg shells are resistant to many environmental stressors like bleach, allowing for the lab to synchronize the lifecycle to embryos and remove microbial contamination. C. elegans can have natural parasites, allowing for understanding of its microbiome and virome. C. elegans has an olfactory response and is capable of responding to its environment through chemical signaling (eg. salt concentrations). Neurons and their connections are all well known. Fully sequenced genome. Estimation of 65% human disease genes that have homologs in C. elegans. 
b. Cons: C. elegans lacks a central nervous system and a simple anatomy (eg. organs). Extra handling due to small size. Small size also gives less sample to use for down path analysis. Specific ways of defining characteristics; like death being defined as a lack of movement. Genetically, C. elegans is removed and many genes have no homologs. The lab strains have less allelic variation, which can reduce the biological relevance of a population. 
3) What is the historical basis of using mice as model systems?
a. First occurrence: Many C. elegans researchers use a strain named N2, collected from mushroom compost in 1951 from Bristol, England. Originally isolated from the sample by Warwick Nicholas. These nematodes were brough to Ellsworth Dougherty’s lab in Richmond, California in 1957. Sydney Brenner was looking for a model organism for neurobiology research and spoke with Dougherty and requested an N2 strain which was sent in 1963. After passaging, a single hermaphrodite was selected and used for all subsequent work: N2. The strain was frozen in 1969 by John Sulston.
b. Humanized worms: Like mice, it is capable to replace genes of interest within worms to the exact DNA that humans possess to “humanize” worms.
c. RNAi: In 2006, Andrew Fire and Craig Mello shared a Nobel Prize in Physiology or Medicine for their work on RNA interference using E. elegans as a model organism. RNAi molecules are capable of doing gene regulation. Double stranded RNA is destroyed by a protein named dicer, leaving small snippets of RNA floating around. Those RNA snippets are picked up by the RNA-induced Silencing Complex (RISC) and are split to become single stranded. Those strands are used to locate matching messages (mRNA) and are destroyed by slicer. In nature, this process helps protects from viruses (and jumping genes). They also seem to be relevant for development and gene expression.  
4) Fun Tidbits
a. What is the WormBook? WormBook is a comprehensive, open-access collection of original, peer-reviewed chapters covering topics related to the biology of Caenorhabditis elegans and other nematodes.
b. What is a worm pick? A glass pipette with a piece of platinum wire sticking out of the top that some researchers use to moving worms.
c. 2002 Nobel Prize in Physiology or Medicine: Sydney Brenner, John Sulston, and Robert Horvitz won the prize for learning about programmed cell death using C. elegans. Essentially, the 1,000 or so cells within C. elegans that makes up the multicellular organism are capable of being killed by a couple of important genes. 
5) Solicited Naïve Questions
a. Are nematodes the same worms I see in my garden? Not really (or at least not closely related)! They’re both invertebrates. That being said, not all nematodes are small; they can range from millimeters to over 8 meters in size.
b. Can worms feel pain? Worms have touch sensation and neurons, though no central nervous system. What humans understand as discomfort probably is a different ballgame for worms but is an active area of research for pain.