Caltech Scientists Develop Super-Fast DNA Analyzer

In a development expected to further accelerate the already rapid pace of research involving genetic engineering, scientists at Caltech announced Wednesday that they have developed an automated instrument that analyzes the chemical components of DNA hundreds of times faster than was previously possible.

The new machine, which “reads” the chemical sequence of DNA within genes, can do in one day almost the same amount of work now performed by a skilled technician in one year.

Scientists said its development could have far-reaching effects on biotechnology and on research into genetic disease and cancer.

Invention of the instrument marks the evolution of biology “from a cottage industry into the big time, with the ability to solve large-scale problems,” said James Brown, director of the molecular biophysics division of the National Science Foundation.

Brown added that every genetic engineering company and every large university’s department of biology “will have to have at least one of the new machines.”

George Rathmann, president of a genetic engineering company, Amgen of Thousand Oaks, said in a telephone interview that the new instrument has the potential to have a “major impact” on genetic engineering research and that it could be a “powerful tool” for identifying new genes.

Biologist Leroy E. Hood, head of the Caltech laboratory that developed the sequencer, told reporters at a press conference Wednesday that the instrument will help scientists “learn as much in the next 15 years as we have learned in the previous 2,000.”

Applied Biosystems Inc. of Foster City will manufacture the automated instruments under a license from Caltech. The company began showing the machine at exhibitions last week, according to marketing vice president Jim Schlater, and expects to begin full production in January. The instrument will sell for $89,500.

Genetic Data Container

All of the genetic information in all living things is contained in deoxyribonucleic acid, better known as DNA. DNA is organized into small units called genes, which are bundled into much larger units called chromosomes. Humans have 26 pairs of chromosomes each.

DNA is composed of four distinct chemicals, called bases, which are commonly known by the abbreviations A, G, C and T. These four bases combine sequentially to form genes and chromosomes in the same fashion that letters of the alphabet combine to form words, sentences and books. The individual bases are assembled into DNA in much the same manner that beads are strung together to make a necklace.

The precise sequence of the bases is important because subtle differences in sequence can have profound biological effects. Sickle cell disease, for example, is produced when one T out of the 1,000 bases in the gene that codes for the hemoglobin in the red blood cell is converted to an A. An estimated 2,500 genetic diseases are caused by such changes, called mutations.

A precise knowledge of the changes in base sequence associated with a genetic disease helps scientists develop ways to detect the defective gene both in adults who might carry the gene and in fetuses who might inherit it. Such knowledge may also aid development of new therapies for genetic diseases.

Gene Transfers

Precise knowledge of the sequence of bases is also useful when genetic engineers wish to transfer a specific gene from one organism to another for the production of drugs or other biological agents. Without such knowledge, gene transfers must necessarily proceed on a hit-or-miss basis.

And finally, biologists have recently found that certain types of cancer may be caused by abnormal genes, called oncogenes, that differ from healthy genes only in the identity of one or a few bases. The ability to determine the sequence of normal genes and the related oncogenes should help scientists obtain a better understanding of how cancer develops. In the past, DNA sequences have been determined via a laborious process in which one base at a time is removed from the end of a gene and identified. Using this technology, which has been partially automated, a skilled technician could identify perhaps as many as 30,000 bases in a sequence in one year.

Hood and his colleagues reported at the press conference and in today’s issue of the British journal Nature that they have devised an entirely new technique to perform the sequencing, and had developed equipment to automate the technique.

Synthetic Copies

First, they produce synthetic copies of fragments of the DNA under study. For example, if a DNA sequence contains 800 bases, they would synthesize 800 copies. The first would be a copy of just one base, the second the first two bases, the third the first three bases, and so on. This step is carried out manually, but the researchers hope to automate it soon.

The new machine sorts the fragments by size and, with the use of color-coded dyes, a laser and a computer, enables scientists to identify the end base on each of the fragments, thus revealing the chemical structure of the entire DNA strand.

The instrument can identify about 1,000 bases per hour.