Life factory opens up

The ribosome, nature's ultimate nanotechnologist, is now starting to surrender its secrets. Giselle Weiss reports.

Researchers have announced the latest in a series of spectacular developments illuminating the simplest and most elementary step in life. The centre of all the attention is the ribosome, a blobby-looking cellular component that is responsible for making the proteins that sustain living things.

The ribosome's molecular structure eluded researchers for 40 years. But last autumn, three separate groups of researchers managed to pin it down, an event that Bruce Stillman, director of the Cold Spring Harbor Laboratory in New York, calls the biggest advance in understanding how proteins are made since the genetic code was broken in 1969.

The ribosome is a crucial bit of apparatus: the machine that makes the machines. On the scale of molecules, it is gargantuan. Two subunits - one large, one small, each with its own job - form a complex, jostling architecture of bridges, platforms, basins and tunnels.

Tens of thousands of ribosomes are at work in the cells of every living organism from yeast to humans, decoding the instructions from the DNA in our chromosomes and translating those instructions into proteins with factory speed and precision.

"The ribosome does stuff that should make the average nanotechnologist weep with envy," says Peter Moore who, together with his Yale colleague Thomas Steitz, cracked the structure of the large ribosomal subunit extracted from Haloarcula marismortui , a Dead Sea bacterium.

Solving the structure of the ribosome is the first step in figuring out how it works. Researchers are able to pinpoint the location of atoms in a crystalline form of the ribosome using X-ray crystallography, and that information can then be fed into a computer to generate a kind of contour map.

For years, efforts were hampered by difficulties in obtaining crystals. In the early 1980s, Ada Yonath, now at the Weizmann Institute in Israel, and the late Heinz Gunther Wittmann produced the first crystals of ribosomes at the Max Planck Institute in Berlin. Yonath also pioneered a widely used technique for stabilising them. But work progressed slowly over the next 15 years.

A core cluster of research groups emerged from a meeting of the ribosome community in 1995 in Victoria, British Columbia. Moore and Steitz at Yale took on the large ribosomal subunit, Venkataraman Ramakrishnan at the Medical Research Council's Laboratory of Molecular Biology in Cambridge and Yonath tackled the small subunit independently, and Harry Noller at the University of California, Santa Cruz set about mapping the structure of the whole ribosome.

The groups began producing increasingly well-resolved maps that culminated with the publication in August 2000 of the first atomic-level structure by Moore and Steitz, followed shortly by those of Yonath and Ramakrishnan. Although Noller's complete structure is less detailed than the images of individual subunits, results from his team, reported online a few weeks ago in the journal Science , show important parts of the ribosome not previously visible.

Taken together, the findings confirm that the ribosome is a sophisticated, dynamic machine, not "a pot with a lid to make proteins in" as many once thought. What is more, the engine at the core of all the activity is not protein, but RNA, ribonucleic acid. That the ribosome has both protein and RNA parts is not news, but RNA was long believed to be inert. Then, in 1982 and 1983, Thomas Cech and Sidney Altman astonished the scientific community and won a Nobel prize by showing that RNA could catalyse reactions, just like enzymes.

Moore and Steitz's work adds weight to that finding, suggesting that the RNA part of the ribosome is where the action is in terms of the key protein-making machinery, and that the ribosome's RNA is also the catalyst for this reaction. Exactly how the RNA catalyses the reaction is a matter of some discussion, and Moore acknowledges "there is a serious need for further experimentation".

Nonetheless, the fact that the heart of the ribosome is RNA goes a long way towards supporting the "RNA world" hypothesis for the origin of life, resolving the chicken-and-egg question of whether ribosomes or proteins came first. Indeed, says Noller, the ribosome looks like an RNA machine with 50-odd proteins stuck on as a kind of afterthought.

From a practical standpoint, the information provided by the structural studies should aid in designing and making antibiotics, and in improving existing ones. Time has forged a clear division between human and bacterial ribosomes, allowing antibiotics to disrupt the latter while leaving the former intact.

In assembling the components that will produce a protein, the ribosome must select and reject with exquisite accuracy.

Ramakrishnan is investigating how antibiotics could disable the ribosomes of bacteria by binding them and then inducing them to make mistakes.

The next stage is to catch ribosomes in the act of doing things. "The ribosome changes conformation as it performs its function," says Moore. "We now know something about one of its configurations. The challenge is to work out what its other configurations are, and thus understand how it promotes protein synthesis."