First Bristolians in Space?

Back in November, the Guardian published a brief article about how thousands of worms were carried into space on board the space shuttle Atlantis on mission STS-129 to the International Space Station.

What got my interest was the fact that the worms concerned were from Bristol – having been collected from a local rubbish tip shortly after the end of World War II.

This seemed like a good basis for a somewhat tongue-in-cheek New Year blogpiece that if some relatively simple creatures from Bristol can make it all the way into space, that perhaps over the course of this coming year it might not be too much to ask that some more advanced Bristolian creatures might be able to work together to solve some more down-to-earth problems – like traffic congestion, job creation, homelessness, health care provision, etc, etc.

However, it seems that I may have underestimated the Bristol worms. Space travel is just one of their achievements and perhaps not even their greatest accomplishment.

The worms concerned are nematodes known as Caenorhabdtis elegans, or C. elegans for short, and usually about 1mm in length. The Bristol strain of C. elegans was isolated from mushroom compost by the National Agricultural Advisory Service, mainly to study the effect of C. elegans on mushroom yields. By 1949, the Bristol version of C. elegans had made their way to the Universite de Lyon’s Victor Nigon. Nigon had collected another strain of C. elegans from Bergerac in France but the Bergerac strain could not be cultured at temperatures above 18 degrees as they became infertile, thus restricting their usefulness – the Bristolians on the other hand were happy to mate at temperatures well beyond this.

Nigon and an American scientist called Ellsworth Dougherty did some classic mating studies using the Bristol worms, and began to realise that they were prime candidates for genetic studies; C. elegans is a multicellular eurkaryotic organism that is relatively simple to study, cheap to breed, and able to be frozen yet still remain viable when thawed allowing for easy storage and transfer. It is also transparent allowing the study of cellular differentiation and, finally, it is one of the simplest organisms to also have a nervous system.

News of the work by Nigon and Dougherty made its way to Britain’s Medical Research Council (MRC) and, in particular, the South African molecular biologist Sydney Brenner.

In April 1953, with the support of the MRC, Crick and Watson had modelled the structure of DNA at Cambridge University. Within a few days of this discovery, Brenner travelled to Cambridge and soon realised that many fundamental genetic questions were hard to tackle by studying higher animals. Therefore, a genetically amenable and multicellular model organism simpler than mammals was required. After meeting with Dougherty, Brenner (now also working at the MRC labs) collected some nematodes from his own back garden in Cambridge which he called the N1 strain but it was only when he received some of the Bristol worms, which he rechristened N2, that his work really progressed. Virtually all C. elegans genetics has since been done with the Bristol (N2) strain.

In 1998, N2 became the first multicellular animal to have its entire genome mapped, (paving the way for the decoding of the Human Genome completed in 2003).

In 2002, Brenner and two other scientists (H. Robert Horvitz and John Sulston) received a Nobel Prize for their work on C. elegans. Their work identified key genes regulating organ development and programmed cell death and has shown that corresponding genes exist in higher species, including ourselves. The discoveries are important for medical research and have shed new light on the pathogenesis of many diseases. In his acceptance speech, Brenner said “Without doubt the fourth winner of the Noble prize this year is Caenorhabdtis elegans; it deserves all the honour”.

One of the aspects of the research was the identification of the genes involved in programmed cell death. By identifying the C. elegans genes involved in initiating cell death, and with the knowledge that a third of C. elegans genes are shared with humans, it was possible to begin research into the possibility of programming genes to initiate cell death in cancer cells – in other words a potential cure for cancer that didn’t involve being subjected to debilitating treatments.

In 2006, the Bristol worms provided the basis for research that produced another Nobel Prize, this time for Andrew Fire and Craig Mellow for their discovery of RNA interference in C. elegans. In simplistic terms, Fire and Mellow discovered that they could affect how DNA is copied and prevent some proteins from being reproduced – this has important consequences for diseases which are caused by an overproduction of a particular protein. One proposed use which is being tested is as a means to treat age-related degeneration of part of the retina. This condition is common among elderly people and can severely reduce eyesight, and is caused by the growth of blood vessels, largely due to a substance called VEGF. An injection can reduce the growth rate of VEGF. It is also being tested as a method to combat Respiratory Syncytial Virus (RSV), which can cause severe respiratory infections in small children. The principle behind the treatment is that, via inhalation, viruses in the lung will be deactivated and the infection will be terminated.

A third Nobel Prize came the way of C. elegans in 2008. Martin Chalfie received a one third share for his work on green fluourescent protein (GFP) in C. elegans. Chalfie realised that, given the fact that C. elegans is transparent, it would be a perfect way of mapping the activities in its cells and in particular the activation of genes to produce proteins.

For instance, when you have eaten a big bag of sweets and your blood-sugar level is too high, the insulin gene in the pancreatic beta cells is switched on and the insulin gene begins to be copied. The copy of the insulin gene is used to bring the amino acids together, forming the protein insulin. The insulin is released into the bloodstream where it sticks to muscle and fat cells, which absorb and store sugar from the blood. Chalfie’s idea was that by connecting the gene for GFP with various gene switches he would be able to watch cells gene switches activate and he would be able to see where different proteins were produced. The possibilities are obvious when you realise that the C. elegans gene daf-2 bears a remarkable resemblance to the human gene that encodes the insulin receptor and thus understanding how this gene operates may help to provide a cure for diabetes.

“I consider this year’s Prize to be the third worm prize” Chalfie’s Nobel Lecture.

As well as research into potential cures for Cancer and Diabetes, the Bristol worms have also formed the basis for research into;

Aging – and in particular how the Bristol worms are able to switch from a more active genetic model to a “sleep mode” enabling longer cell life. This has implications for age-related diseases such as Alzheimer’s, Type 2 Diabetes, and cardiovascular diseases that tend to result from cellular decay.

Muscle Atrophy – the reason for the Bristol worms flight into space mentioned earlier was to study the affect of weightlessness on muscle development – but this research is not just for astronauts, it also has useful results for the long-term bedridden and also in geriatrics.

Nicotine – a 2006 discovery is that the Bristol worms have a similar physical reaction to nicotine as humans, opening a route to the possibility of providing a quick and permanent cure for tobacco addiction.

So, to conclude, C. elegans “Bristol (N2)" has managed to travel into space, has paved the way for the mapping of the Human Genome, produced three Nobel Prizes, and may yet offer up cures for or treatments for the prevention of; Cancer, Diabetes, Alzheimers, Heart Attacks, RSV and blindness. It may even provide a quick and painless route to give up smoking.

Not bad for some worms from a Bristol compost heap.