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Quick Links to questions and answers on this page: Private Sector Leverages HGP Successes Rivals or Partners? Government Regulation of Partnerships Successful Collaborations Areas of Biotech Industry

Craig Venter (head of Celera Genomics), Ari Patrinos (director of DOE Human Genome Program and Biological and Environmental Research Program), and Francis Collins (director, NIH National Human Genome Research Institute).

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).

HGP and the Private Sector: Rivals or Partners?

With the June 26, 2000, announcement by the publicly funded Human Genome Project (HGP) and Celera Genomics that the draft sequence of the human genome was essentially complete, the complementary aspects of the public and private sectors sequencing projects were realized.

Since spring 1998, when Celera Genomics announced its sequencing goal, other private companies also have declared their intention to sequence or map genomic regions to varying degrees. Some people questioned whether the HGP and the private sector were duplicating work, and they wondered who would win the race to sequence the human genome. Although the HGP and private companies do have overlapping sequencing goals, their finish lines are different because their ultimate goals are not the same.

In a sense, through its policy of open data release, the HGP has all along facilitated the research of others. Additionally, the HGP funds projects at small companies to devise needed technologies. DOE, NIH, the National Institute for Standards and Technology, and other governmental funding sources also are supporting further application and commercialization of HGP-generated resources.

HGP products have spurred a boom in such spin-off programs as the NIH Cancer Genome Anatomy Project and the DOE Microbial Genome Program. Genomes of numerous animals, plants, and microbes are being sequenced, and the number of private endeavors is increasing. Technology transfer from developers to users and participation in collaborative, multidisciplinary projects closely unite researchers at academic, industrial, and governmental laboratories.

Scientific vs Commercial Goals
The HGPs commitment from the outset has been to create a scientific standard (an entire reference genome). Most private-sector human genome sequencing projects, however, focus on gathering just enough DNA to meet their customers needsprobably in the 95% to 99% range for gene-rich, potentially lucrative regions. Such private data continue to be enriched greatly by accurate free public mapping (location) and sequence information. Celeras shotgun sequencing strategy, for example, creates millions of tiny fragments that must be ordered and oriented computationally using HGP research results. Most data at Celera, Incyte, and other genomics informationbased companies are proprietary or available only for a fee. In addition, companies are filing numerous patent applications to stake early claims to genes and other potentially important DNA fragments. See patenting page.

More than the Reference Sequence
DNA sequencing will continue to be a major emphasis for the foreseeable future as gene sequences are surveyed across various populations. Both the DOE and NIH genome programs are continuing to support the development of fully integrated and innovative approaches to rapid, low-cost sequencing.

Other near-term HGP goals from the latest 5-year plan are to enhance bioinformatics (computational) resources to support future research and commercial applications. The HGP also aims to explore gene function through comparative mouse-human studies, train future scientists, study human variation, and address critical societal issues arising from the increased availability of human genome data and related analytical technologies.

Robert Waterston, directory of the HGP sequencing center at Washington University, St. Louis, pointed to fruitful data sharing by the HGP and the private sector. Examples include (1) collaborations led by the pharmaceutical company Merck to develop partial sequences identifying genes and (2) the fruit fly sequencing project by Celera and the HGP.

Examples of private-sector enrichment of public data include the SNP consortium, which is generating a publicly available map containing human DNA variations. (See article.) In September, Celera Genomics announced a reference database with more than 2.8 million unique SNPs, including those screened from public-sector databases. In October a public-private consortium announced the joint sequencing of the laboratory mouse. (See article.) Also, a Monsanto-University of Washington project recently generated a draft sequence of the rice plant genome to be released to the public. These efforts show the value of sharing data to increase knowledge and ensure future discoveries for mutual benefit.

Neal Lane (Assistant to the President for Science and Technology and Directory of the Office of Science and Technology Policy) echoed the importance of partnerships between public and private sectors in his testimony to the House committee. His observations follow.

"Sequencing the genome...is only the beginning of genomics," he said. "It is the first step into a future of discoveries and innovations that genomics will enable, that the public and private sectors must pursue together...An expanding, evolving partnership has made human genomic discoveries possible and is now poised to make those discoveries beneficial for everyone...I believe that the policies we have pursued will help to strengthen this partnership, allowing genomic discoveries and innovations to move steadily forward for the benefit of our nation and for all humankind."

Public and Private Sector Research Areas
As genomics grows, several important research concentrations emerge among both the public and private sectors. Among these areas are

(1) Bioinformatics and Information. Bioinformatics combines biology with computer science to create useful databases to interpret the more than 3 billion base pairs of genomic code; relate these databases to proteomics databases and databases of model organisms to determine gene function.

Some of the private companies involved in this research include Celera (CRA), Incyte (INCY), DoubleTwist, and Tripos (TRPS).

(2) Functional Genomics. Sequencing the human genome is just the first step in understanding humans at the molecular level. When the sequencing phase of the Human Genome Project is complete, many questions will remain unanswered. One of the primary things that will still be unknown is the function of most of the estimated 100,000 genes found in the human. Of the genes that have been found to date, we know the function of less than XX%. Researchers also don't know the role of single nucleotide polymorphisms (SNPs) --single amino acid base changes within the genome-- or the role of non-coding regions and repeats in the genome. Understanding the function of genes and these other parts of the genome is known as Functional Genomics. Functional genomics research is done largely through model organisms such as mice. Model organisms offer a cost-effective way to follow the inheritance of genes (that are very similar to human genes) through many generations in a relatively short time. Studies of gene function will lead to a deeper understanding of normal biological processes and how they go awry in disease states. These insights will allow the development of better and earlier predictive tests and eventually usher in a field of prevention-based medicine and diagnostics.

For more information, see Fact Sheet on Functional Genomics.

(3) Proteomics. Proteomics is the global search for and identification and prediction of protein function. The availability of entire genomic sequences offers investigators the opportunity to perform comparative analysis from an evolutionary perspective, identify conserved genes and metabolic capabilities based on protein sequence homology, and predict protein structures. What are practical applications of this?

(4) SNPs. Single nucleotide polymorphisms (SNPs) are DNA sequence variations that occur when a single nucleotide (A,T,C,or G) in the genome sequence is altered. For example a SNP might change the DNA sequence AAGGCTAA to ATGGCTAA. Two of every three SNPs involve the replacement of cytosine (C) with thymine (T). SNPs occur every 100 to 1000 bases along the 3-billion-base human genome. SNPs can occur in both coding (gene) and noncoding regions of the genome.

Many SNPs have no effect on cell function, but scientists believe others could predispose people to disease or influence their response to a drug. They assert that SNP maps will help them identify the multiple genes associated with such complex diseases as cancer, diabetes, vascular disease, and some forms of mental illness. These associations are difficult to establish with conventional gene-hunting methods because a single altered gene may make only a small contribution to the disease.

For more on SNPS, see Fact Sheet on SNPs

In addition to the Human Genome Project's SNP research goals, several companies are involved in SNP research. In April 1999, ten large pharmaceutical companies and the U.K. Wellcome Trust philanthropy announced the establishment of a consortium headed by Arthur L. Holden to find and map 300,000 common SNPs. The goal is to generate a widely accepted, high-quality, extensive, publicly available map using SNPs as markers evenly distributed throughout the human genome.

For more, see the SNP Consortium's Web site.

(5) Pharmaceuticals and Pharmacogenomics -use genome-based research to develop better targets for drug development

Within the next decade, researchers will find and gain insight into the functioning of most human genes. Explorations into the function of each one --a major challenge extending far into the 21st century --will shed light on how faulty genes play a role in disease causation. With this knowledge, commercial efforts will shift away from diagnostics and toward developing a new generation of therapeutics based on genes. Drug design will be revolutionized as researchers create new classes of medicines based on a reasoned approach using gene sequence and protein structure function information rather than the traditional trial-and-error method. The drugs, targeted to specific sites in the body, promise to have fewer side effects than many of today's medicines.

The potential for using genes themselves to treat disease--known as gene therapy--is the most exciting application of DNA science. It has captured the imaginations of the public and the biomedical community for good reason. Although still in its infancy, this rapidly developing field holds great potential for treating or even curing genetic and acquired diseases, using normal genes to replace or supplement a defective gene or to bolster immunity to disease (e.g., by adding a gene that suppresses tumor growth). Many technological and biological issues must be resolved, however, before it becomes a practical treatment.

Some major companies involved in pharmacogneomics: Human Genome Sciences, Millenium Pharmaceuticals, AmGen, Biogen, Genentech, Immunex, Genzyme, and Chiron.

(6) Instrumentation

A long-standing goal of the Human Genome Project has been to develop instrumentation for genomics. It is the development of this instrumentation over the past decade that has brought biotechnology to the point it is today. Current advances in instrumentation have made it so researchers can sequence DNA quickly and affordably. DNA sequencers and fluorescent dyes are examples of the technology that has brought us to the biology century. After 2005 the ongoing need will be for fast and cost-effective determination of DNA sequence to compare sequences among individual humans and also to determine the genomes of numerous organisms of biomedical and commercial interest. Additionally, with the continuing acquisition of this remarkable base of biological data, high-throughput experimental tools will be required to assist in a practical and useful understanding of gene function.

Some companies involved in instrumentation development are Perkin Elmer Biosystems (PEB), Amersham Pharmacia Biotech, Waters Corporation (WAT), Biacore International (BCORY), and Molecular Dynamics (MDYN).

(7) DNA Chips - -Affymetrix

(8) Gene Testing

DNA-based tests are among the first commercial applications of the new genetic discoveries to medicine. These tests are employed to diagnose a condition or estimate the likelihood for developing one. Test results already are being offered as evidence to support medical and nonmedical cases in courts, including medical malpractice, discrimination, privacy violations, child custody disputes, and criminal cases. Gene tests involve direct examination of the DNA molecule itself. A DNA sample can be obtained from any tissue, including blood. To do a gene test, scientists scan the sample, looking for a specific mutation in a particular DNA region that has been linked to a disorder. Cost can range from hundreds to thousands of dollars, depending on the sizes of the genes examined and the number of mutations tested for, which can vary from a few to hundreds. Although there are several hundred DNA-based tests for different conditions, most are still offered as research tools only. Fewer than 100 gene tests are available commercially, and most are for mutations associated with rare diseases in which just a single gene is involved. Even though some current gene tests have been beneficial and their potential benefit enormous, the science is very new and dynamic. Researchers themselves are unsure how to interpret the results of some commercially available gene tests. Another limitation is the lack of medical options to treat or prevent many of the disorders for which gene tests are used. Researchers acknowledge the long lag time between linking a gene mutation with a disease and developing effective therapeutics. Additionally, patients agreeing to undergo gene testing face significant risks of jeopardizing their employment and insurance status. Patients face an additional burden as well: the psychological impact of testing can be devastating. Because genetic information is shared, all these risks extend to family members as well. Many in the medical establishment feel that uncertainties surrounding test interpretation, the current lack of available medical options for most of these diseases, the potential for provoking anxiety, and the risks of discrimination and social stigmatization could outweigh the early benefits of testing.

Some companies involved in gene testing -Myriad.

(9) Transgenics
"Pharming" animals to produce human drugs. Gene-transfer technologies already are being used to transfer human genes into farm animals such as sheep and goats for the purpose of generating large quantities of expensive human proteins for use as pharmaceuticals. (The process has been called "pharming.") The animals carrying human genes are called "transgenics" and are very difficult and expensive to develop. This situation has encouraged biotechnology companies to explore more efficient ways to reproduce the animals; cloning technologies such as those used to create the famous Scottish sheep Dolly and other cloned mammals like mice, goats, and cows are the results of these efforts. And a reasonable assumption is that many of the new reproductive technologies being perfected in our mammalian cousins will be effective in and applied to humans.

Xenotransplants: from pigs to people. Some 18,000 organ transplants take place each year, not nearly accommodating the 40,000 who wait for appropriate donors. Ten people die each day waiting for suitable human donor organs. Transplanting such organs as hearts and kidneys from genetically altered pigs and other animals into humans, a process called xenotransplantation, may have the potential to save lives. Current research is aimed at using DNA technologies to grow organs having human genes (transgenic animals) that make the organ's surface more "human like" and may help to minimize the chance for rejection upon transplantation into a human host. A concern is the unintended transfer of animal viruses to humans and the effects this might have beyond the patient to the population at large.

(10) Food and Agriculture. Though under a lot of fire, genetically engineered animals and food play

Stronger cotton, healthier livestock. For thousands of years people have modified traits in plants and animals indirectly through selective breeding. Today, our growing ability to directly alter an organism's genetic makeup, called genetic engineering, is having a major impact worldwide on agriculture and animal husbandry. A number of ongoing projects aim to decipher and manipulate the genomes of such economically important organisms as rice, corn, wheat, soy, cotton, sheep, goats, cows, pigs, and fish.

Some of these explorations have led to the development of genetically modified plants that are providing higher yields, are more nutritious, and have increased resistance to herbicides, pests, and extremes of weather and temperature. In the United States this year, about half of all soybeans and a third of all corn planted were from genetically modified seeds, with most modifications aimed at pest and herbicide resistance.

Genetic alterations have produced ornamental crops such as carnations whose "aging genes" have been identified and turned off to allow an extended shelf life. Other plants are being genetically modified to produce biodegradable plastics, industrial oils and chemicals, low-calorie sweeteners, and human pharmaceuticals. Genetically modified animals are more nutritious and leaner, produce more milk, and are sometimes larger and more resistant to disease.

In a few recent examples, researchers reported adding rabbit genes to cotton plants to make the fiber as bright and soft as rabbit hair but stronger and warmer. A new strain of rice announced this spring contains a soybean gene for iron incorporation. This new rice can be used to treat the 30 percent of the world's population who are iron deficient and lack the means for expensive iron supplements.

Growing concerns. Consumer resistance to genetically modified plants and resulting foods, sometimes called "Frankenfoods," is strong in Europe and may be growing in the United States. Concerns center around environmental and consumer safety issues. Particularly in the United Kingdom, the strength of resistance to genetically modified foods stems from a lack of trust in the government to protect its citizens, following the "mad cow" disease scare.

Although genetically modified plants can decrease the use of pesticides and herbicides and thereby benefit the environment, a concern is that plants engineered to be more resistant to herbicides may pass on that trait through cross-pollination to related weed species in the wild. This could result in the creation of extremely resistant weeds requiring treatment with even more herbicides. Also, the impact of new pest-resistance traits on such nontarget organisms as visiting butteráies or birds is not known.

A potential health concern is that genes producing allergy-inducing proteins (such as those from peanuts) could be introduced into other food plants and consumers might unknowingly ingest a substance to which they could be allergic. (In the United States, the federal government is considering voluntary labeling of products derived from genetically modified organisms.) Another controversial issue is that genes introduced from one species into another may cause some consumers to violate religious restrictions against, for example, eating pork or beef.

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