On the Shoulders of Giants: Private Sector Leverages HGP Successes

Data, Technologies Catalyze a New, High-Profile Life Sciences Industry

The deluge of data and related technologies generated by the Human Genome Project (HGP) and other genomic research presents a broad array of commercial opportunities. Seemingly limitless applications cross boundaries from medicine and food to energy and environmental resources, and predictions are that life sciences may become the largest sector in the U.S. economy.

Established companies are scrambling to retool, and many new ventures are seeking a role in the information revolution with DNA at its core. IBM, Compaq, DuPont, and major pharmaceutical companies are among those interested in the potential for targeting and applying genome data.

In the genomics corner alone, dozens of small companies have sprung up to sell information, technologies, and services to facilitate basic research into genes and their functions. These new entrepreneurs also offer an abundance of genomic services and applications, including additional databases with DNA sequences from humans, animals, plants, and microbes.

Other applications include gene fragments to use for drug development and target identification and evaluation, identification of candidate genes, and RNA expression information revealing gene activity. Products include protein profiles; particular genotypes associated with such specific medically important phenotypes as disease susceptibility and drug responsiveness; hardware, software, and reagents for DNA sequencing and other DNA-based tests; microarrays (DNA chips) containing tens of thousands of known DNA and RNA fragments for research or clinical use; and DNA analysis software.

Broader applications reaching into many areas of the economy include the following:

• Clinical medicine. Many more individualized diagnostics and prognostics, drugs, and other therapies.
• Agriculture and livestock. Hardier, more nutritious, and healthier crops and animals.
• Industrial processes. Cleaner and more efficient manufacturing in such sectors as chemicals, pulp and paper, textiles, food, fuels, metals, and minerals.
• Environmental biotechnology. Biodegradable products, new energy resources, environmental diagnostics, and less hazardous cleanup of mixed toxic-waste sites.
• DNA fingerprinting. Identification of humans and other animals, plants, and microbes; evolutionary and human anthropological studies; and detection of and resistance to harmful agents that might be used in biological warfare.

A Public Legacy
Substantial public-sector R&D investment often is needed in feasibility demonstrations before such start-up ventures as those by Celera Genomics, Incyte, and Human Genome Sciences can begin. In turn, these companies furnish valuable commercial services that the government cannot provide, and the taxes returned by their successes easily repay fundamental public investments. Following are a few key public R&D contributions that made some current genomics ventures commercially feasible. These examples describe DOE investments, but substantial commitments by NIH and the Wellcome Trust in the United Kingdom were equally important.

Scientific Infrastructure. The scientific foundation for a human genome initiative existed at the national laboratories before DOE established the first genome project in 1986. Besides expertise in a number of areas critical to genomic research, the laboratories had a long history of conducting large multidisciplinary projects.

Genomic Science and Pioneering Technology. GenBank, the world's DNA sequence repository, was developed at Los Alamos National Laboratory (LANL) and later transferred to the National Library of Medicine. Chromosome-sorting capabilities developed at LANL and Lawrence Livermore National Laboratory enabled the development of DNA clone libraries representing the individual chromosomes. These libraries were a crucial resource in genome sequencing.

Sequencing Strategies. When the HGP was initiated, vital automation tools and high-throughput sequencing technologies had to be developed or improved. The cost of sequencing a single DNA base was about $10 then; today, sequencing costs have fallen about 100-fold to $.10 to $.20 a base and still are dropping rapidly.

DOE-funded enhancements to sequencing protocols, chemical reagents, and enzymes contributed substantially to increasing efficiencies. The commercial marketing of these reagents has greatly benefitted basic R&D, genome-scale sequencing, and lower-cost commercial diagnostic services.

Sequencing Technologies and Biological Resources. Other major factors in cost and time reduction are greatly improved sequencing instruments and efficient biological resources such as the following:

• DOE-funded research on capillary- based DNA sequencing contributed to the development of the two major sequencing -machines now in use. The core optical system concept of the Perkin-Elmer 3700 sequencing machine (used by Celera and others) was pioneered with DOE support. The instrumentation concepts that matured as the MegaBACE sequencer were pioneered by Richard Mathies (University of California, Berkeley). The DOE JGI chose this sequencing hardware platform after competitive trials.
• DNA sequencing originally was done with radiolabeled DNA fragments. Today, DOE improvements to fluorescent dyes -decrease the amount of DNA needed and increase the accuracy of sequencing data.
• Bacterial artificial chromosome (BAC) clones, developed in the DOE program, became the preferred starting resource in sequencing procedures because of their superior stability and large size. A critical component of public- and private-sector sequencing, BACs were used to assemble both the draft and final human DNA reference -sequences.
• Further extending the usefulness of BACs, the DOE HGP funded the production of sequence tag connectors (STCs) from BAC ends. This early information enabled the selection of optimal BACs for complete sequencing, thus saving time and money. STC use for the HGP was advocated by Craig Venter and Nobelist Hamilton Smith (both at Celera), and Leroy Hood (now at the Institute for Systems Biology).

  A Successful Transformation
  These successes transferred much of the repetitive labor from humans to automated machines. In addition, new software for data processing both alleviated and sped human decision making. Over the last decade, advances in instrumentation, automation, and computation have transformed the entire process. Further innovations, however, still are needed for completing many large sequences and increasing the effectiveness of sequencing. [Denise Casey (HGMIS) and Marvin Stodolsky (DOE)]

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  The electronic form of the newsletter may be cited in the following style:
  Human Genome Program, U.S. Department of Energy, Human Genome News (v11n1-2).

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