This article was originally published in the Guardian, May 10, 2001; used here with permission.

The Proteome

by Johnjoe McFadden

The announcement of the completion of the first draft of the human genome project was hailed as a scientific revolution, every bit as significant as the first man on the moon. It was a massive achievement. But, compared to putting a man on the moon, it did not develop any new technologies. The earlier discovery of the DNA double helix was the key to understanding heredity, but the human genome has not yet provided any fundamental new insights. And, unlike penicillin, the genome has not yet saved a single life. This should come as no surprise. It's rather like receiving an incomplete blueprint for a spaceship. This genome-like blueprint doesn't list components such as "dynamo" or "engine" with neat pictures showing how they are put together. All it provides is a long string of diagrams of every stripped-down bit of metal, washer and spring.

To understand how the spaceship works, you have to perform the toughest jigsaw puzzle ever to discover how the funny-shaped bolts and nails go together to make engines, dynamos or even those tricky bits that you don't really understand, like the warp-factor drive. The genome, then, is a kind of blueprint but not a very informative one. It is a long way from telling us how a living cell actually works.

So why the optimism? The reaon is that the human genome is the doorway to a far more ambitious project, one that will revolutionise medicine, biology and our understanding of what it means to be alive: the proteome. Our DNA sequence is the genetic code – the long string of As, Ts, Cs and Gs – that make up the genes. But the real players in life's dynamics are the proteins whose codes are written in the genes. Proteins are the next level up from genes. They are the building blocks of the cellular machines that extract energy from food, contract muscles, allow us to see, hear or feel, beat our heart, stimulate our sex drive or make us think. They are nature's nanotechnology, engineering at the scale of atoms and molecules.

To get an idea of what marvels are hidden inside your own cells, consider the F1 ATPase. This is a tiny protein engine that is a component of a cellular machine called the mitochondrion. When cells extract energy from food, they strip off the electrons and pipe them down the mitochondrial membrane. This generates a tiny electric current that is used to drive a pumping station (another protein engine) that pumps protons out of the mitochondrion. Like water from a pumping station, the protons can flow back into the mitochondrion, but only through the F1 ATPase. The resulting proton flow spins the rotor of the F1 ATPase. The revolving rotor powers a molecular hammer that bolts together molecules to make a chemical called ATP, which our cells use to store energy.

Right now, thousands of tiny pumps, turbines, motors, dynamos, hammers and choppers are keeping you alive inside every cell of your body. When they go wrong we suffer from heart disease, lung disease, digestive disorders, kidney disease, dementia or cancer. Up till now, we have developed nearly all of our drugs by crude trial and error: thousands of chemicals are tested to discover which of them might interact with our molecular machines to correct their defects. It's like trying to fix your car by bolting on random bits of metal in the hope that one might do what it takes to get the starter motor turning. We need to design our own molecular engine components to fit precisely on to our cellular machinery and correct any malfunctioning parts. To do this, we need to understand every protein in our cells: the human proteome.

Although the skeleton of the proteome is there in the genome – every gene encodes a protein – we have no idea which bits come together to construct the molecular machines. Scientists have managed to strip down a few of them, like the F1 ATPase. But it's taken decades of painstaking work. The F1 ATPase is not a sin gle protein but has seven parts made from three different proteins, each encoded on different bits of the genome. For most of our molecular machinery, we don't know the genes, the protein parts, or how they are put together. This is the task of proteomics.

Scientists have already started on the proteome project through the Human Proteome Organisation (HUPO). Its task will be to increase support for large-scale protein analysis. The publicly funded human genome project is estimated to have cost about $300m. The proteome will cost far more because it is much harder. When a gene is used to make a protein, its one-dimensional genetic information is translated into a three-dimensional protein wire that is twisted and turned to make unique shapes. But it is the twists and turns that make the molecular hammers, choppers, nuts and bolts. And there is no easy way of predicting these from the genome. That is the challenge of proteomics.

The first job will be to discover which proteins are produced in each of our 200 or so different cell types, work that is already ongoing in a number of labs across the world. The more challenging task will be to map all those folds that turn protein wire into molecular components. Then we need to discover how everything fits together to make molecular machines. The lure of a new genera tion of tailor-made drugs for everything from cancer to depression is tempting many pharmaceutical companies into the contest. Celera, the firm that sequenced the genome in competition with the publicly funded consortium, has announced its own proteome programme. The computer giant IBM has recently launched a $100m research initiative to build the world's fastest supercomputer with the "grand challenge" of modelling protein folding.

And what after the proteome? Scientists have already coined a new buzzword – the metabolome – that will describe how the pumps, motors, engines and turbines within the proteome turn a swirling mass of nutrients into a moving, living cell. And after that? On the distant horizon is a fusion of biology, physics and engineering. Scientists at Cornell University in the US have already bolted a tiny propeller on to the F1 ATPase engine to make a nanoscale motor. Such devices will one day be used to drive miniature machines capable of swimming through our bodies to dispense drugs or perform microengineering on our cells. Eventually, putting together the genes, the proteome and the metabolome into nanoscale engineering vessels, scientists may be able to construct the ultimate nanotechnology device: artificial life.

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