The Secrets of the Cell

No man-made piece of machinery is nearly so complex. Capable of countless chemical reactions, it can fend off attackers, reproduce itself and perform all the other activities that characterize life. In laboratories around the world, thousands of researchers are busily trying to understand--and in some cases, duplicate--the cell's vital chemistry. Last week two teams of scientists made significant advances toward those goals.

Endless Variety. At the University of Wisconsin, a group headed by a distinguished Indian-born molecular biologist, Har Gobind Khorana. 47, reported that it had achieved the first artificial synthesis of a gene--the basic unit of heredity in the nuclei of all cells. Although genetic material has been made in the laboratory before, scientists have always had to use at least some natural cellular material in the process. The Wisconsin achievement marks the first time that a single gene has been created entirely out of off-the-shelf chemicals.

The task was formidable. Hidden in the chromosomes, genes are basically sections of an extremely complex molecule called deoxyribonucleic acid (DNA). Twisted together like a spiral staircase, or double helix, the twin strands of the DNA molecule are linked by "steps" composed of pairs of mutually attracting chemicals, or bases, called nucleotides. DNA contains only four different kinds of nucleotides, but they can be arranged in an endless variety of complex sequences. Each complete sequence--some including thousands of steps on the molecular staircase--is a single gene containing a coded message of heredity. With that message, the gene can order the cell to produce one of the untold number of proteins out of which all living organisms are made.

As his model, Khorana picked a relatively simple gene from the common yeast cell; its nucleotide sequence is only 77 steps long. But those 77 steps made the building process immensely complex. Adding one lab-made nucleotide at a time in complex chemical processes, Khorana's team patiently assembled small, single-stranded segments of the 77-step chain. After each step forward, the scientists had to backtrack: every new combination had to be unraveled in order to check that the nucleotides were still in the right sequence and had not been damaged by chemical side effects. When enough strands had been produced to make complementary pairs, Khorana lined them alongside each other to form segments of the full, double-stranded molecule. Finally, with the help of a newly discovered enzyme, or chemical catalyst, called DNA ligase, he succeeded in putting together the last large pieces of the puzzle. The full 77-nucleotide synthetic yeast gene had been five years in the making.

An ingratiatingly shy and modest man. Khorana emphasizes that his man-made gene is relatively crude. It lacks, for example, the coded signals that start and stop the production of protein. But his work has brought closer the day when artificially created genes may be used to replace defective ones in order to cure such genetic diseases as hemophilia and muscular dystrophy. Another possibility, Khorana concedes, is "the genetic planning of individuals--tailoring people to fit patterns, turning out athletes or intellectuals." But, he adds, "it is a very very long time off."

Tiny Bubbles. The week's second major announcement came from two cell biologists at New York University. After five years of experimenting, Gerald Weissmann and Grazia Sessa disclosed that they had succeeded in trapping the cellular enzyme lysozyme in tiny microscopic bubbles of fatty substances called lipids. That might seem like a minor bit of work. But for the first time, scientists had synthesized a simple replica of a complete cellular component (the gene, on the other hand, is only one small part of the nucleus). Their creation: a rudimentary lysosome, one of the vital structures in the cytoplasm surrounding the nucleus of a cell.

The lysosome's job is to defend the cell from hostile viruses, bacteria and other materials by engulfing the invaders and dissolving them with its enzymes. Sometimes it does its work too enthusiastically; it attacks part of the cell's own material and destroys it. Such an outburst, if it occurs in enough cells, can cause the inflammation that occurs in a disease like rheumatoid arthritis. Laboratory experiments with Weissmann and Sessa's creation may now help explain why the lysosome turns against its own cell and surrounding tissues, and could eventually lead to the prevention of crippling inflammatory diseases.

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