A team headed by Nobel laureate Arthur Kornberg has developed a laboratory system that could prove crucial in understanding the reproduction of living cells and ultimately the relationship of the process to diseases such as cancer in which the cells undergo rapid and uncontrolled growth.
The new test-tube system devised by scientists at the Stanford University School of Medicine offers a tool for studying the complex mechanism that signals a cell to make exact copies of its genetic material. Kornberg, a biochemist, considers it a "milestone" in basic genetic research.
Despite the major advances in basic genetics and the recent applications of this research in the burgeoning new field of "recombinant DNA" technology, the question of what triggers a burst of new chromosome synthesis, as part of the overall cycle of cell division and growth, had remained unanswered.
The new test-tube technique succeeds for the first time in combining all the component parts needed, in effect, to turn on the switch that begins the duplication of the chromosome of a common bacterium. This chromosome, which is composed of genes of DNA or deoxyribonucleic acid, controls all of the organism's cellular activities.
While the Stanford researchers have succeeded in getting duplication of chromosomes started in the laboratory, they still have to identify the specific biochemical parts--such as proteins and similar molecules--responsible for turning it on.
Although the system is relatively simple, it may serve as a model for the more complicated genetic processes in higher animals and man.
The work is significant because the mechanism that starts duplication of DNA, the essential genetic matter common to all living things, affects the overall rate of cell division and growth.
"We can't understand the operation of a machine unless we know its working parts. We can't repair a car if we don't know what goes on under the hood. This is the basic approach to understanding the working parts of the cellular machinery that is responsible for duplicating the chromosome and making division and growth possible," he explained.
"If there are aberrations in the control of this--when the car is running instead of being idle, as is the case with cancer, or not running when it should be active, as in other diseases--basic questions need to be answered before we can understand what's gone wrong," he added.
When applied to animal cells, the technique also could help explain why the cells in developing organisms continuously create new copies of their genetic material, or chromosomes, while adult cells slow down and remain relatively quiet, Kornberg says.
The scientist emphasized that he was "not promising anything in terms of payoffs" in the near future but simply proceeding on the long-term genetic research that began when the structure of DNA was discovered.
Kornberg has been a pioneer in that effort. The latest research, funded by federal and private grants, is the culmination of four years of work by scientists in his laboratory, including Robert S. Fuller and Jon M. Kaguni.
It builds upon his own 25 years of genetic research.
In 1959 Kornberg received the Nobel Prize for creating synthetic DNA in the laboratory for the first time. In 1967 he announced the first successful test-tube creation of DNA that was shown to be biologically active, or functioning as it does in nature.
The new research, published in the latest issue of the Proceedings of the National Academy of Sciences and released today, is another achievement long sought by reseachers in a number of laboratories worldwide.
They used genetically engineered rings of DNA, or plasmids, found in the common Escherischia coli bacteria, organisms that have long been the workhorses in this field.
The plasmids contained a genetic segment inserted from the main bacterial chromosome called the "origin," which is known to be associated with the initiation of DNA replication, or duplication.
Genetic engineering allowed the researchers to grow large quantities of this special region and isolate it more readily for further study. The plasmid is easier to work with because it is only one-thousandth the size of the bacterial chromosome.
The bacteria, in turn, have a "crucial advantage," says Kornberg, over working with the far larger chromosomes found in humans, which each may be 1,000 times larger.
After breaking open the manipulated bacterial cells and collecting the contents, he and his colleagues found that DNA duplication could be initiated in the test tube by adding an amount of a salt that separated out certain chemicals necessary for getting it started.
Evidence confirmed that this was taking place, said Kornberg, including electron microscope photographs showing that the test-tube duplication of DNA proceeded in two directions at once from the point of origin, just as it does in bacteria found in nature.