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Four men who shook the world

They are the Oscars of science. This week's three Nobel Prizes, worth £600,000 each, represent a lifetime's achievement in chemistry, physics and medicine. Four scientists from around the world now join an exalted list of names that includes Albert Einstein, Jim Watson and Francis Crick. Steve Connor looks at how this year's winners changed the world of science

Each one of the 100,000 billion cells that make up the human body is a vastly complex, if microscopic, chemical factory. A human cell contains about one billion protein molecules, which would be a recipe for total anarchy if it were a car factory making a similar number of models.

Each one of the 100,000 billion cells that make up the human body is a vastly complex, if microscopic, chemical factory. A human cell contains about one billion protein molecules, which would be a recipe for total anarchy if it were a car factory making a similar number of models.

It was Günter Blobel, the winner of the Nobel Prize in Physiology or Medicine, who worked out how the cell controls the movements of protein products from their production conveyor belts to their final position in the body. He likened it to the postal codes used to send letters to their correct destinations.

The cytoplasm of a cell - the stuff outside the central nucleus - is far from being the inactive, jelly-like substance once portrayed in biology textbooks. It is riddled with lipid membranes, folded into intricate, three-dimensional patterns that are now known to be the crucial highways along which the protein products of a cell are transported.

Proteins are themselves highly complex molecules. Each is manufactured by using the genetic code of a gene as its template. Some are used as building-blocks for the cells themselves, and are used to make hair, eyes, skin, blood, bone and other tissues. But most proteins are enzymes, the biological catalysts that speed up biochemical reactions within our bodies to ensure that we can digest and release the energy locked up in food, make more living cells to replace those that are worn out, and excrete waste products.

Each protein is composed of a certain sequence of the 20 different amino acids. The total number of amino acids in a protein chain can number anything from about 50 to several thousand.

A key finding of Professor Blobel, a cell and molecular biologist at the Rockefeller University in New York, was that an extra sequence - which may be between 10 and 30 amino acids long - is added to the protein during the manufacturing process. This, he proposed, acted as a "luggage tag" to tell the cell where the protein belonged.

Blobel, who was born in Waltersdorf in Germany but emigrated to the US more than 30 years ago, in the Sixties began to examine the problem of how large proteins are transported around the cell. At that time this was an immense puzzle, because it was known that the internal lipid membranes of the cell were tightly sealed. How could a protein get across the membrane surrounding an internal cell structure, known as an "organelle", scientists wondered?

In 1971, Blobel formulated the first version of his "signal hypothesis" whereby he proposed an internal signalling mechanism being somehow incorporated into each protein. In 1975 he showed in a series of elegant biochemical experiments that the signal was a sequence of amino acids which, he suggested, acted as a key that opened the molecular gates of the lipid membranes. Five years later he formulated the general principles of how these membrane channels work, allowing some proteins through and blocking the path of others.

"Günter Blobel's discovery has had an immense impact on modern cell biological research," says the Nobel Assembly of the Karolinska Institute in Stockholm, which awarded the prize.

"When a cell divides, large amounts of proteins are being made and new organelles are formed. If the cell is to function correctly, the proteins have to be targeted to their proper locations."

The discovery has opened up new approaches to the treatment of those genetic diseases that result from the incorrect "postal code" being added to a protein. One such disease, hereditary hyperoxaluria, results in children developing kidney stones. Blobel's work will eventually play an important role in bringing the fruits of the Human Genome Project to medicine. It will also be crucial to the successful genetic reprogramming of cells - the key aim of gene therapy.

Chemistry - Ahmed Zewail

The fastest camera in the world has recorded the chemical reactions that underpin everything from the way the eye sees to how a plant captures the energy of a sunbeam. It has also resulted in this year's Nobel Prize in Chemistry being won by Ahmed Zewail, a professor of chemistry at the California Institute of Technology, Pasadena, who pioneered the camera to study the almost unbelievably fast events that unfold during a chemical reaction.

Zewail, who was born in Egypt but moved to the United States, where he has dual nationality, virtually invented the branch of science known as femtochemistry, named after the processes that can take place within a matter of femtoseconds - one femtosecond being one thousandth of a millionth of a millionth of a second. To give an idea of the scale on which he works, one femtosecond is to a second what one second is to 32 million years.

"Femtochemistry enables us to understand why certain chemical reactions take place, but not others," says the Royal Swedish Academy of Sciences in Stockholm in its explanation of why it has given the prize to Zewail. Scientists are using his femtosecond camera technique to study reactions in gases, liquids and solids.

"Applications range from how catalysts function and how molecular electronic components must be designed, to the most delicate mechanisms in life processes and how the medicines of the future should be produced," the academy says.

The high-speed laser camera uses laser flashes that are no longer than a few femtoseconds in duration, which is about the time it takes for the molecules involved in a chemical reaction to come and go.

One of the immediate benefits of being able to "observe" this is that scientists are able to discover the nature of the extremely short-lived intermediate molecules involved. Heating is known to kick the energy of most chemicals over the barrier that has to be overcome before a reaction takes place, enabling chemical bonds to break and new ones to form. The camera used by Zewail enables chemists to look at the path of a molecule as it goes over this barrier and to see the changes that occur as it goes through the transition state.

"The contribution for which Zewail is to receive the Nobel Prize means that we have reached the end of the road; no chemical reactions take place faster than this," says the Swedish Academy of Sciences.

"Femtochemistry has fundamentally changed our view of chemical reactions. From a phenomenon described in relatively vague metaphors such as 'activation' and 'transition state', we can now see the movements of individual atoms as we imagine them."

Physics - Gerardus 't Hooft and Martinus JG Veltman

There is arguably no other branch of science quite as esoteric as particle physics ÿ the study of the particles within atoms and the forces that may or may not hold them together.

Particle physics tells us not only something about the fundamental basis of matter, but also how it may have been created at the beginning of the Universe, some 12 billion years ago. At its heart lies the theory of quantum electrodynamics, which, among other things, describes to a high degree of accuracy the interactions of subatomic particles such as electrons and positrons, and light at low energies.

This year's Nobel Prize in Physics was won jointly by two pioneers in this difficult field, Gerardus 't Hooft, of the University of Utrecht in the Netherlands, and Martinus JG Veltman, a retired professor from the same university.

When Veltman was asked on Dutch television to explain his work, he gave an honest reply: "It is a difficult and abstract subject, something that I have never been able to explain to my wife and children," he said.

According to the Royal Swedish Academy of Sciences in Stockholm, who awarded the prize, the two scientists have helped to place particle physics "on a firmer mathematical foundation". Their predictions have been so accurate that recent experiments with the particle accelerator at the European Particle Physics Laboratory ÿ Cern ÿ in Geneva, Switzerland, have confirmed their calculated expectations.

At the heart of particle physics is the "standard model", which groups all the elementary particles into three families of quarks and leptons. These interact, with the help of "exchange particles", and are involved in the strong and electro-weak forces of matter.

"The theoretical foundation of the standard model was at first incomplete mathematically; in particular it was unclear whether the theory could be used at all for detailed calculations of physical quantities," the academy says. The work of 't Hooft and Veltman put it on to a firmer footing by providing a "well-functioning 'mathematical machinery' that can be used for, among other things, predicting the properties of new particles".

Their work was vital in calculating the mass of a subatomic particle known as the top quark, which was observed for the first time in 1995 at the Fermilab accelerator in Batavia, Illinois. Their theory has also predicted the existence of the Higgs particle, which has not yet been observed. Fermilab plans to use its new accelerator, the Main Injector, to hunt for the elusive Higgs particle. This theoretical particle will also be pursued in the Large Hadron Collider, to be built at Cern, which is expected to be ready in 2005.

Gerardus 't Hooft learnt about his award when he was giving a talk in Bologna, Italy, last Tuesday morning, to physicists who were working on the new Cern accelerator. He was surprised when some in the audience started to applaud.

"Someone had picked it up from the Internet," he explained. "They let me finish my short talk and then everyone started to applaud.

"It is an award for research that we did in the Seventies, but only more recently has the importance of this research become clear. And I am extremely happy that it has now been recognised by Stockholm."

Although few people outside the rarefied atmosphere of particle physics understand the precise details of why these physicists have won the most prestigious award in science, their colleagues are emphatic about the importance of what 't Hooft and Veltman have done.

"This is the entire framework we [particle physicists] use when calculating. We'll get finite answers. Earlier calculations only resulted in nonsense," commented Lars Brink, a professor at Chalmers Technical Institute and a member of the Swedish academy.