By Karen Pihl-Carey

In what has been called a major scientific achievement in the history of mankind, scientists from Celera Genomics and the publicly funded Human Genome Project announced significant advances in understanding the human genetic blueprint.

Celera, of Rockville, Md., completed the first assembly of the human genome, having sequenced 99 percent of it, while the Human Genome Project assembled a working draft of the genome's sequence. The accomplishments mean the two research groups know the location and order of the letters of genetic code along the chromosomes, but they don't yet know the function of specific genes.

"There is much still to be done. In the basic science arena, we need to finish this job," said Francis Collins, director of the National Human Genome Research Institute of the National Institutes of Health. "We should not be satisfied with a book of life that has gaps and errors in it."

While the announcement by itself is a major scientific accomplishment, it is only the first step. One analyst compared it to the announcement in 1903 when the Wright brothers got their plane off the ground for 12 seconds. It still took several years before the public benefited from the flight. Others compared the announcement to the moon landing, or the discovery of the smallpox vaccine and penicillin.

Carl Feldbaum, president of the Biotechnology Industry Organization, compared the accomplishment to handing Columbus a 21st century map of the New World before he set sail, or the start of a marathon with researchers lacing up their shoes.

"The availability of the genome sequence makes it more possible to pursue biological discoveries in different ways," said David Stone, a partner at the Cambridge, Mass.-based Applied Genomic Technology Capital Fund LP (AGTC Funds), a new venture capital fund for early-stage genomics companies. "Up to this point, biologists have had to work on trying to expand their knowledge around the little islands of what was known amid the large sea of what was unknown.

"The availability of the genome sequence shines a light at least dimly on all of the actors and all of the space of what we've been calling the source code for nature's operating system."

The Human Genome Project has confirmed by experimental evidence 38,000 predicted genes. Estimates of how many genes there are range widely, from around that amount to several times as many. Researchers now will concentrate on discovering which genes cause disease and developing therapeutics to treat genetic diseases, such as heart disease and cancer. They may even be able to diagnose a person's susceptibility to disease, providing a more preventative treatment approach. And they may be able to correct genetic flaws before birth.

"It's an exciting day for all of us," said J. Craig Venter, president and chief scientific officer of Celera.

Celera began to sequence the human genome in September 1999, and its assembly has revealed a total of 3.12 billion base pairs, a figure similar to the one uncovered by the Human Genome Project. Despite Celera's news Monday, which had been expected for some time, its stock (NYSE:CRA) fell 10 percent, to close at $114, down $13.

Celera, Others Now Search For Function

The company now is moving into the analysis and annotation phase to better understand the function of the genes. It used a different sequencing method than the Human Genome Project in that it used the whole genome shotgun technique of randomly shearing human chromosomes into millions of pieces of 2,000 and 10,000 base pairs in length. The fragments were copied millions of times and scientists sequenced both ends of each fragment. The sequences were then assembled in order using genome assembly algorithms and Celera's supercomputing facility. Celera chose five individuals, both men and women from different ethnic backgrounds, to act as donors for the project.

In its hierarchical shotgun method, the Human Genome Project placed large fragments of DNA in the proper order to cover all of the human chromosomes, and determined the DNA sequence of the fragments. Its assembly consisted of overlapping fragments covering 97 percent of the human genome, of which sequence already has been assembled for about 85 percent of the genome. The working draft cost about $300 million worldwide to put together. About half was funded by the National Institutes of Health.

The two sequencing methods are complementary, Venter and Collins agreed. By comparing the data generated, they will be able to fill in each others gaps.

The Human Genome Project has a goal of producing a completely finished sequence with no gaps and a 99.99 percent accuracy by 2003. It also expects to have discovered 1 million single nucleotide polymorphisms (SNPs) - human genetic variations - by the end of the year.

The completed sequence and identification of SNPs will enable scientists to understand why certain people respond to certain drugs. CuraGen Corp., of New Haven, Conn., is one genomics company working on how SNPs make people different, and how protein products of genes may be able to treat disease.

"This is an exciting time," said Jonathan Rothberg, founder, chairman and CEO of CuraGen. "It's the first time you can go into a bar and tell someone you work on the genome."

Rothberg said his company is well positioned to leverage the genome across the world markets. "We feel we now have the raw material. We'll be adding function to it," he said.

Stone said the map is beneficial for its wealth of potential new targets and characterized genes, but it does create a bottleneck in the discovery and development process. "You do have a lot more targets to look at," he said, "but all of your competitors are looking at the same set and are at the same starting point."

Gary McKnight, director of research information systems at Seattle-based ZymoGenetics Inc., said the completed sequence will help his company in making protein therapeutics, but a lot of work lies ahead.

Celera's Entry Speeded The Process

"Instead of doing hundreds of proteins, we now have hundreds of thousands to millions of proteins to evaluate biologically," he said.

ZymoGenetics uses bioinformatics technologies to develop protein therapeutics. "In terms of protein discovery, we're at least going to have now a potential list of all the possible axons and eventually all the possible protein isoforms which the human cell can generate," McKnight said. "In the short term, what this will do is instead of saying, 'Well maybe we haven't yet found the gene,' instead it will be a process of elimination."

Work on the Human Genome Project began 10 years ago, while Celera began working last fall in what some have called a race to produce a human genome map. Both Venter and Collins denied that the two research groups were racing.

"If it was truly a race, truly a competition, our own company which makes these instruments would not have provided them in massive amounts to the public program," Venter said.

In March, President Clinton and British Prime Minister Tony Blair said human genome research should be made publicly available. Clinton later revised the statement to say that discoveries with "specific commercial application" should be covered by patents. (See BioWorld Today, March 16, 2000, p. 1; and April 7, 2000, p. 1.)

The Human Genome Project has supplied its information free to scientists via a public Internet database, called GenBank. While Celera has not publicly offered its information, it is exploring the possibility of a simultaneous publication with the Human Genome Project later this year.

A commercial application for Celera could be its work on the mouse genome. Celera has made no secret that it hopes to commercialize some of its findings, and while it may make its work on the human genome publicly available, its findings on the mouse genome could be something offered only to subscribers. Once scientists find the genes, they still will need to discover the purpose of each gene, and because the mouse and human genome are so similar, they can discover the purpose by conducting tests on mice. The company has completed half the sequencing of the mouse genome.

"By layering the mouse genome on top of the human genome, over the next few months we expect to find accurately the structure of the human genes," Venter said.