How three scientists can thank nematode worms for Nobel prize

Heard the one about the Englishman, the South African and the American who spent a lifetime studying a tiny worm no bigger than a pinhead?

It may sound like a joke, but the last laugh is with John Sulston, Sydney Brenner and Bob Horvitz, who yesterday shared the biggest prize in science.

This year's Nobel Prize in Physiology or Medicine – worth about £700,000 – has been awarded to the three scientists for their pioneering insights into how a relatively complex organism develops from a single fertilised egg.

Brenner, Sulston and Horvitz, who began their collaboration at the world-renowned Medical Research Council Laboratory of Molecular Biology (LMB) in Cambridge, have painstakingly studied the nematode worm for more than 30 years.

"I first met the worm in 1969," said Sulston, who was until last year the leader of Britain's research effort into deciphering the human genome where he fought a bitter battle against attempts to patent the genetic code of man.

"This is the first worm prize. Hopefully there will be many others," he added.

The Nobel Assembly of the Karolinska Institute in Stockholm said it was awarding the prize for the team's discoveries concerning the "genetic regulation of organ development and programmed cell death" – or how a many-celled body is sculpted into shape by a trade-off between cell division and cell suicide.

Studies of the nematode worm, Caenorhabditis elegans, led to a fundamental reappraisal of the importance of genes in the deliberate killing of certain cells during normal development. Such programmed cell death has been critical for a deeper insight into human disease, the Karolinska said.

"Knowledge of programmed cell death has helped us to understand the mechanisms by which some viruses and bacteria invade our cells," the Karolinska's citation said.

"We also know that in Aids, neurodegenerative diseases, stroke and myocardial infarction [heart attacks] cells are lost as a result of excessive cell death.

"Other diseases, like autoimmune conditions and cancer, are characterised by a reduction in cell death, leading to the survival of cells normally destined to die," it added.

The story of how the three men won the most coveted prize in science dates back to the 1960s when Sydney Brenner, who came to Britain from his native South Africa in 1952, had the brilliant idea of studying the transparent nematode worm in order to understand how genes control development from a fertilised egg.

Brenner, 75, thought that C. elegans was the perfect subject for a study of how a complete organism can be made from the genetic code of DNA. Each mature worm has exactly 959 cells and its rapid development from egg to adult can be easily viewed down a microscope.

Many of Brenner's colleagues were sceptical. Jim Watson, the codiscoverer of the DNA double helix, said the project was too ambitious and that he wouldn't give Brenner a penny to do it. "He said I was 20 years ahead of my time," Brenner said.

In 1969, Brenner recruited a young post-doctoral researcher to his nematode team. Sulston, the son of an ordained minister in the Church of England and an English schoolteacher, was to become the first scientist to map what happens to each and every nematode cell during development.

Sulston, 60, remembers that on his arrival at the LMB – the same laboratory where Jim Watson and Francis Crick discovered the DNA double helix – he was given a just metre-wide stretch of working space.

"Sydney and Francis [who were joint heads of the LMB at that time] believed that keeping the lab tightly packed encouraged people to interact and that desks encouraged time-wasting activities," Sulston said.

"I found myself among a group of young researchers, astonished that we were being paid to do what we wanted to do anyway, and knowing that we had no one to blame but ourselves if we did not succeed," he said.

Five years later, in 1974, Brenner brought another young researcher to Cambridge. Bob Horvitz, originally from Chicago, was a mathematically trained economist with a thirst for hard data.

Writing in his book The Common Thread, Sulston remembers Horvitz as "bespectacled, intense and extremely thorough in his approach" and steeped in the hi-tech ambience of the American East Coast laboratories.

"When Bob looked at what I had been doing, just looking down a microscope and drawing, he was unimpressed, 'Where's the data?' he asked me," Sulston said.

"He couldn't understand how you could do any kind of analysis if you didn't have something like a tape or readings from a scintillation counter .... I convinced Bob that they were both data, and that my observations were at least as rich in data as his measurements, if not more so," he said.

In a series of scientific publications beginning in 1976 Sulston not only mapped the lineage of every nematode cell, he also described the visible steps in programmed cell death and demonstrated the first genetic mutations involved in the process.

Horvitzbuilt on Brenner's and Sulston's insights with a series of elegant experiments in which he identified the first two bone fide "death genes", ced-3 and ced-4, which played a critical role in programmed cell suicide.

"Horvitz showed that the human genome contains a ced-3-like gene. We now know that most genes that are involved in controlling cell death in C. elegans have counterparts in humans," the Karolinska Institute said yesterday. Horvitz, 55, is now at the Massachusetts Institute of Technology. Brenner is now at the Molecular Sciences Institute in Berkeley, California where he is working on the genetics of the puffer fish and the chimpanzee.

Sulston, who last year retired as head of the Wellcome Trust Sanger Institute in Cambridge where he led Britain's efforts on the human genome project, said that the prize came as a surprise.

"I just had a phone call from Sweden in the morning. I was here in the lab. I phoned Daphne, my wife and we both said 'oh my God'," he said.

Sulston, who was knighted in 2001, said he may use his share of the prize money to further his study of alternatives to market-orientated globalisation.

He said he was interested in how research and intellectual property are handled. "We are going for ownership through patents far too readily," Sulston said.

"I think people are recognising the need for other sorts of globalisation than simply free-market competition. There is a need to bring people onto more of a level playing field and time is getting short," he said.

The winners and their microscopic subject

A tiny, wriggling stretch of cells lies at the heart of the discoveries that have been awarded this year's Nobel prize in medicine.

Few organisms can have been subjected to such intense scrutiny as the microscopic wormCaenorhabditis elegans. This nematode, measuring just one millimetre from head to tail, lives in the soil and feeds on bacteria and other micro-organisms. It can grow from egg to adult in just three days.

Scientists like the nematode because it can be easily kept in the laboratory – it happily chomps it way through a "lawn" of E. coli bacteria growing in a petri dish – and it has a remarkably simple body plan.

When fully grown, each nematode has just 959 cells, and because the worm is almost transparent the development of each cell can be viewed down the microscope. Each worm generates 1,090 cells, but precisely 131 of these are eliminated in a process known as programmed cell death.

Most adult nematodes are hermaphrodites, with both eggs and sperm, andproduce several hundred offspring through self-fertilisation. Occasionally the odd male is produced, resulting in sexual reproduction and a shuffling of genes.

Despite having less than a thousand cells, the nematode still has recognisable tissues. "It consists basically of two tubes, one inside the other," said John Sulston, one of the three Nobel prizewinners.

"The outer tube includes the skin, muscles, excretory systems and most of the nervous system; the inner tube is the gut," he said.

Sydney Brenner realised that the nematode's simplicity could be exploited to understand how a multi-celled organism is created from genetic information encoded in a DNA molecule.

"My contribution to this was learning to watch the cells dividing, and sometimes dying, under the microscope," said Sulston.

In the human body, which is composed of 100 trillion cells, there has to be a fine balance between cell division and cell death. The work has shown that the process governing the growth of this tiny worm is fundamentally similar to the forces at work in humans.

The Nobel Assembly of the Karolinska Institute, Stockholm, said: "It is of considerable biological and medical importance to understand how these complicated processes are controlled."