Sequencing the worm

From the beginning

Young South-African-born scientist, Sydney Brenner, had worked with Francis Crick looking at the function of DNA. For him the task was clear: the future of molecular biology was to be in investigating development and the nervous system. However, he needed to find an appropriate animal model on which to base his work.

The nematode worm is an organism with simple and rapid genetics, it grows quickly and can be kept in the lab conveniently.

In the 1960s, Caenorhabditis elegans (C. elegans), a soil-dwelling, bacteria-eating nematode worm about 1 mm in length, was an unknown in the world of biological research. However, its characteristics fitted Sydney’s experimental criteria very neatly. The nematode worm is an organism with simple and rapid genetics, it grows quickly and can be kept in the lab conveniently, and is small, so its anatomy and development can be examined easily.

The worm is much simpler than humans, for example, it doesn’t have bones, a heart or a circulatory system. Despite this simplicity, many of the signals involved in C. elegans development are also found in more complex organisms.

The new model organism brought much excitement to the field.

With the goal of making the link between genes and behaviour, Sydney Brenner started making mutants in his lab in Cambridge, UK. These were then used to find the specific genes responsible for behaviour, the nervous system and muscle movement. The new model organism brought much excitement to the field, and consequently, during the late 1960s and 1970s, worm research expanded considerably.

Programmed cell death

Owing to the worm being transparent, the fine detail of the cells inside the worm can be seen under a microscope.

John Sulston joined Sydney’s group in 1969 and spent the next decade working out how the worm develops from a single cell to an adult. Owing to the worm being transparent, the fine detail of the cells inside the worm can be seen under a microscope. It is therefore possible to follow the division of cells as the worm develops into an adult.

It took about a decade for scientists to completely map the development of the worm from a single cell to a mature adult, which contains about 1,000 cells. This mapping project revealed an entirely new biological phenomenon. Some of the initial cells never make it into the adult worm, but are programmed to die during development. The process was given the name ‘programmed cell death’ or ‘apoptosis’.

This mapping project revealed an entirely new biological phenomenon.

Cell death has a fundamental role in human development (for example, removing cells in our hands to create fingers) and human disease. In AIDS, neurodegenerative diseases, stroke and heart attacks, cells are lost through excessive cell death. In other diseases, such as autoimmune conditions and cancer, cells survive that are normally destined to die.

An American biologist Robert Horvitz spent a large portion of his working life exploring apoptosis, using C. elegans as an experimental model. He was particularly interested in the role of apoptosis in human neurodegenerative disease. He showed that cell death is often an active process and that many of the genes that control the death of neurons in the worm, have counterparts in the human brain. Robert’s discoveries paved the way for new treatments for diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease.

Sydney Brenner, John Sulston and Robert Horvitz were jointly awarded the Nobel Prize in Physiology or Medicine.

In October 2002, Sydney Brenner , John Sulston andRobert Horvitz were jointly awarded the Nobel Prize in Physiology or Medicine for their work studying organ development and programmed cell death. However, none of it would have been possible without the help of the humble nematode worm, C. elegans.

Mapping the genome of C. elegans

The next logical step was to map the genome of the worm to highlight where each gene is located in the genome.

By the early 1980s, a large number of C. elegans mutants had been created (this means that genes or sections of DNA were added or removed to change certain characteristics of the worm). It started becoming clear that researchers needed to find the genes responsible for the mutants in order to understand what was going on at the genetic level. So, the next logical step was to map the genome of the worm to highlight where each gene is located in the genome.

Gene or genome mapping is when scientists identify the locations of different genes on specific chromosomes, a bit like pointing out key landmarks on a geographical map. The advantage of this technique is that you know where genes are in relation to each other. Mapping of the C. elegans genome was carried out by John Sulston along with his colleagues Alan Coulson and Bob Waterston. The map consisted of multiple overlapping fragments of DNA, arranged in the correct order. Mapping of the C. elegans genome marked the beginning of the study of animal genomes. The next step would be to work out the exact order of the letters in the C. elegans genome.

Sequencing the genome of C. elegans

The worm sequencing project began in 1990 and, working with the new automated DNA sequencing machines, met its target of sequencing the first three million bases of worm DNA in three years. This was only three per cent of the whole worm genome (100 million bases) but was an important proof-of-principle for the Human Genome Project. It showed that the DNA sequencing technology was scalable and that with more money, more people and more machines, the three billion bases of DNA in the human genome could be tackled.

In 1998, the sequence of the entire C. elegans genome was published – it was the first animal to have its genome completely sequenced.

In 1998, the sequence of the entire C. elegans genome was published. It was the first animal to have its genome completely sequenced. Knowledge of the worm’s 20,500 genes has already had a big impact on worm research. The full genome has allowed whole gene families to be identified and the patterns of gene expression to be examined.

The worm has allowed huge leaps in scientific discovery to be made.

The worm has become a classic model organism to work with over a relatively short period of time and has allowed huge leaps in scientific discovery to be made. Being able to understand the genetics of the worm has allowed scientists to understand more about human genetics and disease.

Ongoing research

As a model organism, C. elegans is useful for studying a whole range of human diseases and conditions:

Aging

C. elegans is a good model for studying the ageing process in an entire organism.

Over the last 20 years, it has been shown that C. elegans is a good model for studying the aging process in an entire organism. In the nematode worm it is possible to highlight specific mechanisms and genes that limit the lifespan of C. elegans and therefore explore the equivalent processes in humans. C. elegans exhibit many physical and behavioural traits that, like humans, decline with age. In addition to this, the signalling pathway that regulates ageing in worms, the insulin/insulin-like growth factor-1 (IGF-1) signalling pathway, is also present in higher organisms, including humans.

Telomeres, which form protective caps on the ends of our chromosomes, have long been implicated in the aging process of humans. It has been suggested that the length of these telomeres is indicative of lifespan. However, studies in C. elegans have shown that telomere length of C. elegans chromosomes is independent of their ageing process. Worms with short telomeres were found to live for just as long as worms with long telomeres. This was an important finding to human studies of ageing.

Overall, the worm is a very useful model for providing important clues about how we age and why age-related diseases, such as cardiovascular disease and Alzheimer’s, occur.

Cancer

Understanding how human cancer genes function is crucial for developing treatments.

Studying C. elegans has provided important clues about the role of oncogenes and tumour suppressor genes in cancer development. Understanding how human cancer genes function is crucial for developing treatments. The C. elegans is proving invaluable in this area of research and is allowing scientists to ‘worm’ their way even deeper into cancer research. It has been shown that genes involved in human cancers are significantly more likely to have an equivalent gene in C. elegans than in other model organisms. Although C. elegans do not form tumours, certain processes caused by mutations are clearly relevant in their biology. For example, apoptosis is an important mechanism in worm development and cancer. In humans it is important for preventing cancer. If cell division becomes unregulated cells will normally undergo apoptosis to prevent cancer from developing.

Alzheimer’s

C. elegans are being used to screen for potential new treatments for Alzheimer’s disease. This approach is focusing specifically on tau, a protein involved in maintaining brain cell structure that becomes abnormally clumped together in cases of Alzheimer’s and other related disorders. In one lab, scientists worked out a way to express an abnormal form of the human tau protein in the nerve cells of C. elegans. The result was behavioural abnormalities and loss of nerve cells, all characteristics of Alzheimer’s. It is hoped that drugs for Alzheimer’s can also be tested using C. elegans.

WormBase

WormBase is a collaborative project aiming to find and distribute information about the biology of C. elegans.

Originally started in 2000, WormBase is a collaborative project aiming to find and distribute information about the biology of C. elegans.One of the key strategic goals of the project is to provide a central resource for scientists working on C. elegansand related nematodes.

WormBase is constantly being updated and is used as a mechanism to publish and distribute experimental data from different scientists. The data recorded is highly detailed and includes genetic maps of various nematode worms, information on different mutants and their characteristics, and details about the worms’ nervous system. It provides a central resource for scientists around the world who are researching the biology of nematode worms.