By JUSTIN POPE, AP Business Writer - (Published September 7, 2003)

   WOBURN, Mass. (AP) - It's been three years since scientists completed a rough draft of the human genetic code,
   but nobody's rushing out yet for a personal DNA analysis. That's because the first draft took 12 years and cost
   billions of dollars.

   Today, the cost has fallen, but only to around $50 million. The target price is orders of magnitude away: $1,000 for
   an individual's DNA sequence.

   That's the price considered essential for giving scientists the thousands of sequenced samples they need to
   understand how genes work, and giving patients access to a personalized DNA snapshot at the doctor's office
   that could show the diseases they are at risk of developing.

   Some scientists believe the old methods of sequencing DNA, though improving, will never produce a $1,000
   genome, and they are exploring radically different ways to map the blueprint of human life.

   Their methods remain far from proven. But there have lately been signs of headway on several fronts.

   "It's not clear which of these things will be the ultimate success, but I think these are all pieces of the puzzle
   moving us in the direction we need to go," said Jeff Schloss, program director for technology development at the
   National Institutes of Health's National Human Genome Research Institute.

   The human genome project yielded the first complete sequence of the 3.2 billion base pairs that comprise the DNA
   molecule of a person (actually, it sequenced a composite of a few people). Each base is one of four chemicals,
   their order governing a human being's development.

   But that was only a starting point.

   While the DNA of one person is 99.9 percent identical to another's, it is the 0.1 percent of variation that interests
   many scientists because the differences may answer questions like why some people develop certain diseases
   and others do not.

   To answer those questions, scientists must compare the DNA sequences of thousands of people. To get them,
   they must find a way to sequence DNA that, unlike the first sequencing, doesn't require thousands of lab
   technicians and dozens of supercomputers.

   "To actually deliver everybody's genome, you can't apply that kind of brute force strategy," said George Church, a
   researcher at Harvard Medical School.

   For years, scientists sequencing DNA have relied on a lumbering technique called electrophoresis. But it requires
   expensive chemicals, and without expensive hardware an average lab would be hard-pressed to sequence more
   than 1,000 base pairs a day. At that speed, it would take almost 10,000 years to get through the 3.2 billion base
   pairs in human DNA.

   The new techniques start from scratch.

   In April, a group led by Caltech researcher Stephen Quake published the first successful results from "single
   molecule sequencing," or reading DNA one base pair at a time. Quake's group uses a fluorescent label to mark the
   free molecules that surround DNA, then tracks which molecules are used when the DNA makes a copy of itself. The
   technique works on only five base pairs at a time, but Quake says many sequences can be read at once.

   Meanwhile, in an article published in the August edition of Science, Church's lab reported progress on bathing DNA
   in different frequencies of light to produce a color-coded snapshot revealing the order of a DNA sequence.

   Daniel Branton, a Harvard colleague of Church, is working on a method Schloss considers among the most
   promising: shooting DNA through a tiny hole called a nanopore and measuring the electric signals each base pair
   emits.

   And in another recent development, a Branford, Conn., company called 454 Life Sciences announced it had
   sequenced the genome of a virus - about 30,000 base pairs long - by dropping DNA into tiny wells, and is now
   working on bacteria, with 2 million to 8 million base pairs. The company hopes to work its way up to humans.

   Other technologies can compare one strand to a reference, like that provided by the human genome project, and
   highlight differences. That could help scientists identify the 99.9 percent of identical base pairs, and allow them to
   focus on the remaining 0.1 percent.

   Woburn-based U.S. Genomics, for example, tags certain sequences then shoots them past a laser, which detects
   the tags as they go by.

   Many of these techniques solve some shortcomings of electrophoresis, but none solves them all. Knotty obstacles
   remain, like "blurring" of the base pairs' fluorescence, or finding computers that can crunch all the numbers these
   methods produce.

   One skeptic, Elaine Mardis, a genetics expert at Washington University in St. Louis, worries that too many labs are
   releasing "data by press release" rather than subjecting the information to scientific review. She isn't convinced
   that scientists are solving problems such as how to read longer DNA snippets or in developing precise instruments
   to perceive fluorescent light.

   "Honestly, it's going to take us 10 or 15 years to get there," she said of the $1,000 genome. "The non-scientific
   public is hearing this and saying that sounds really great, and people must be at that goal because they're talking
   about it. That's totally not the case. This is the plan for the future, and the future is not now."