The behavior of proteins has turned out to be another example of incredible complexity within the cell. When fi rst discovered, sin-
gle molecules seemed incredibly powerful and important, like the stars of fi lms. But just as a director, cameraman, and dozens of other specialists are needed to get an actor onto the screen, pro- teins also require a huge amount of technical support to do their jobs. They usually work in “machines” of various sizes, the larg- est probably containing more than a hundred molecules. These are continually being disassembled and rebuilt to do new things.
In 2005, Anne-Claude Gavin, Giulio Superti-Furga, and their colleagues at the company Cellzome in Heidelberg, Germany, worked with scientists from the nearby European Molecular Bi- ology Laboratory to capture the fi rst complete snapshot of all the machines at work in a eukaryotic cell. They discovered 491 machines in yeast; human cells probably build at least six or seven times that number.
Most of the protein machines in yeast are found in a simi- lar form, using related proteins in human cells. This is strong evidence of evolution and gives important insights into how it works. The most important machines arose in an ancient cell. The components were passed down to humans, other animals, and plants, where they assembled into similar machines. Along the way, there has been a lot of fi ne-tuning: Machines have acquired new functions through the addition of new parts or slight changes in their shapes. Many have a “snap-on” structure: The cell prefabricates and assembles most of the parts ahead of time, often leaving a few pieces to be made when the machine is needed.
Building machines requires precise timing in the production of thousands of molecules, and the completion of genomes has brought along new methods to watch how this happens. One of the most important techniques is the microarray, or the DNA chip, developed in 1994 by Patrick Brown of Stanford University and the California-based company Affymetrix. The technology acts as a surveillance system that can detect whether cells have produced RNAs from particular DNA sequences.
DNA chips compare the gene activity of cells—for example, a healthy cell and one that has become cancerous or cells that have specialized into different types—to try to discover differences in the behavior of genes. A scientist extracts RNAs from both kinds
of cells and tags them with different fl uorescent markers. Then he or she exposes them to the DNA chip, which traps them. The effect is like going to a football stadium and trying to decide where the fans of each team are sitting. That will be easy if a lot of people have come to the game in team colors and are sit- ting together. A DNA chip compares the “cancer team” (suppose they are dressed in red) to the “healthy team” (in green). Some parts of the stadium will look mostly red—in cellular terms, this means that the cancer cell produces more of a molecule than the healthy one. A part that looks mostly green means that the healthy cell produces more of a particular molecule. Some parts of the stadium may have an equal mix of colors (the molecule is active in both cells), and others may be entirely empty (meaning the gene is not used by either type of cell).
Experiments with DNA chips reveal when and where the cells in an organism’s body activate particular genes (including the components of specifi c machines) and watch how that be- havior changes during disease. Switching on a single gene may trigger an avalanche of responses from other genes, with effects such as telling it to divide, altering the cell’s form and behavior, or prompting its development into a new type. Disrupting any of these processes can lead to diseases such as cancer, in which cells forget their identities and functions, reproduce at the wrong time, and go on strange migrations through the body.
The discovery of so many protein machines has changed how scientists look at genetic diseases and other types of illnesses, such as cancer. Therapies may need to focus on fi xing machines rather than trying to replace single, defective molecules—the way a clever engineer may be able to repair a motor by improvising something new if the original part is no longer available.
DNA chips and other technologies that can monitor the entire genome have given scientists their fi rst look at the true complexity of biological processes. But they are only a begin- ning. The next step is to understand how organisms coordinate the activity of hundreds of millions of cells in organs such as the heart and the brain, and then to understand how those organs work together. Only then will the infl uence of genes on peo- ple’s behavior and lives be truly understood. Today’s scientists
are developing a new genetic toolbox that has already shed a bit of light on the issues. The following sections discuss the state of the art and outline some of the questions that tomorrow’s biologists will face.