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Commercial implications of the human genome project
113
Commercial implications of the Human Genome Project
yet available for human genome sequencing. Thus, unlike model organisms, which were initially proposed as pilot projects, human genome sequencing will require the
additional production oflligl~-resol-
The Human Genmnr Project (HGP) promises to have a major impact on the development of genetics and molecular medicine. Like the recombinant-DNA revolution two decades before it, the genomic revolution has spawned a biotechnology industry based upon positional, rather than functional, cloning that is consuming millions of dollars. The progress of the HGP in 1996 was reviewed at a recent meeting* that placed emphasis on the industrial and commercial applications of genomic knowledge, and that focused on the value of this information.
Progress
and prospects
The HGP has made remarkable progress since its oficial initiation in 1990. In his keynote speech, Francis Collins [National Center for Human Genome Kesearch (NCHGK). Bethesda, MD, USA] reviewed the unprecedented progress in physical mapping and technological development that has put the project ahead of schedule. He also introduced the new era of large-scale DNA sequencing that is being initiated in 1996. Most significantly, his address emphasized the continued con6dence of scientists and funding agencies alike that the human genome will be completely sequenced (i.e. 99% ofthe sequence will have been determined at an accuracy approaching 99.99%) ahead ofschedule and on budget. With major efforts being initiated this year in the USA and ehewhere, and with the anticipated ‘scale-up’ of sequencing efforts in the next 2-3 yean, it is hoped that the human genome will be completely sequenced by 2003, if not earlier. Francis Collins outlined the anticipated goals and accomplishments of the ‘post-genome’ era, including functional analysis, large-scale gene knockouts, and the sequencing of the complete genome of the mouse and other model organisms.
Industrial Lee ington,
Copyright0
genomics
Rowan Seattle,
1996,
(University of WashWA, USA) gave an
Elsewr
Science
Ltd. All rights reserved.
overview of large-scale sequencing and the proposal for large-scale ‘endsequence’ databases. Glen Evans (University of Texas, Southwestern Medical Center, Dallas, TX, USA) described the construction of an endsequencing database as well as COINventional and alternative strategies for high throughput sequencing, including COW (cosmid-oriented walking); this has the potential to be a completely automatable strategy that uses high-throughput oligonucleotide-primer synthesis that is programmed by automated DNA synthesizers. A new 192-channel oligonucleotide synthesizer, the MEKMADE, was described, which can be programmed by the Al31 377 automated gene sequencer, and may be useful for high-throughput DNA sequence finishing. The significance and utility of effective automation and instrumentation was a theme throughout the meeting. Significantly, Matthew Murray (Union Bank ofswitzerland) gave an overview of the methods used by investment bankers for valuing the genomic and biotechnology industry. He emphasized the value of current and future genetic information, as well as the significance of propretary and public domain genomic databases for furthering the value of genomics-based companies. The information content of the genome and the methods of data handling were summarized by Mark Boguski (National Center for Biotechnology Information, Washington, DC, USA). The value and public service provided by initiatives such as GenBank and Entrez have been of immeasurable value to both the commercial and academic sectors.
Sequence
mapping
Although 1996 essentially marks the completion of physical mapping and the start of large-scale sequencing, the meeting emphasized the importance of the development of techniques for the construction of sequence-ready maps. Unlike genome projects on model organisms, such as Cuuwrhabditis elegam and Sncchawnyces cerevisiae, sets of overlapping clone ‘contigs’ of sufficient quality and accuracy are not 0167
- 7799/96/$15.00
PII: SO167.7799(96)30007-3
ikleeting report
ill\l:*-r::~il,iad:iil:
ution maps. However, it is clear that sequence-ready map production must develop hand-ill-hand with sequencing efforts. A session on physical mapping covered the COIIstruction of expressed sequence tag (EST) transcript maps fJames Sikela; University of Colorado, Boulder. CO, USA): EST databases [Mark Adams; The Institute for Genomic Research (TIGK), Gaithersburg, MD, USA] and hybridization-based ‘binning’. Mark Perlin clone University. (Carnegie Mellon Pittsburgh, PA, USA) described the construction of sequenceable maps using a hybridization-based technique called ‘inner product mapping’. Paul Siebert (Clontech Laboratories, Palo Alto, CA, USA) and John Brunbaugh (LI-COR, Lincoln, NC, USA) described commercial solutions to problem5 of gap-filling and nrap-closure that involve new sequencing technolo&T and longrange PCK.
Developing
technology
The initiative to sequence the hu~xa~~ genome has been spurred-on by technological developments. However, most large-scale efforts have adapted sequencing strategies that are based on shotgun cloning of large insert clones [e.g. cosmids. PACs (bacteriophage PI -derived artificial chromosomes) and BACs (bacterial artificial chromo~ome~)] and Sangertype analysis using fluorescent-dye primers or terminators, followed by gel analysis. An enormous impact could be made by the development of new sequencing strategies. Technology under development that w-as discussed at the meeting included fast-separation capillary electrophoresis (Edward Yeung: Iowa State University, Ames, IA, USA), high-throughput capillav-array electrophoresis using enerm-transfer dyes Uingyue Ju: University of California, Berkeley, CA, USA), alternative and more-accurate DNA polymerases (Stanley Tabor; Harvard Medical School, Boston, MA, USA), and laser-based DNA mass-spectrometry (Chris Becker; GeneTrace Systems, Menlo Park, CA, USA). While these approaches promise rapid and major improvements in throughput and cost compared with TIBTECH MAY1996b'OL141
f OYUrn ‘conventional’ automated DNAsequencing technology, they are still in the development phase. With the promised rapid advancement and scale-up of sequencing eff^orts by the NCHGR and other agencies this year, a race to move these technologies to the ‘production’ phase is likely to ensue. Additional talks on related technologies, automated genetic analysis and genotyping (J. William Efcavitch; Perkin-Elmer, Applied Biosystems Dlvlslon, Foster City, CA, USA) and non-electrophoretic mapping (David Schwartz; New York University, NY, USA) gave a vivid insight into the future. Miniaturizing analytical techniques One of the most exciting aspects of genome technology that has been proposed over the past few years is the miniaturization ofDNA analysis, manipulation and sequencing. Andrei Mirzabekov (Englehart Institute, Moscow, Russia, and Argonne National Laboratory. Argonne, IL, USA) unveiled a robotic system for manuiacturing DNA ‘chips’ on glass surfaces with gel-coated. L)NAlaced, analysis sites. A variety of devices with applications for diagnostics, DNA re-sequencing and mutational analysis were described, including an integrated microfabricated device for L1NA-fragment analysis (Gregory Went; CuraGen, Branford, CT, USA), DNA probe arrays on glass ‘chips’ (Robert Lipshutz; Afimetrix, Santa Clara, CA, USA) and microfabricated electrode-array devices (Michael Heller; Nanogen. San Diego, CA, USA). Lloyd Smith (University of Wisconsin, Madison, WI, USA) and Radoje 11rmanac (Hyseq, Sunnyvale. CA, USA) described array sutfacehybridization techniques for analysing genetic variation, clone ordering and DNA sequencing by hybridization. These approaches are potentially poweriul, and impressive advances have been made, but many hurdles must still be overcome in the development of reliable diagnostic products involving new array-type methods. However, L1NA ‘chips’ promise to be one of the most exciting and potentially profitable areas of biotechnology development. Genomic information The value of genomic information, both as a scientific resource and as a commercial product, was the TlBTECHMAY1996(VOL141
focus of a session on informatics and sequence databases, with representatives from commercial, proprietary and the governmental and public donrain databases presenting differing viewpoints. Randal Scott (Incyte Pharmaceuticals, Palo Alto, CA. USA) described the proprietary LIFESEQT” genomic database, and compared its relevance and utility with the publicly accessible GenBank. It is clear that the sequences of only a fraction (perhaps between 30% and 70%) of all human genes now exist in some form in various databases, indicating that there are still genes yet to be found and investigated. Alan Williamson (Merck, Kahway, NJ, USA) described the Merck Gene Index project, which was initiated as a collaborative etrort between Merck and the Washington University Genome Sequencing Center. He emphasized the benefits ofthe release of genetic information into the public domain. However, it is clear that the immediate release of information from sequencing initiatives will be a major topic of public debate. Marc Paris, France) Vasseur (Genset, described the company’s innovative approach to selecting and sequencing regulatory regions of genes, as opposed to the coding region expressed in cDNAs and as ESTs, and described potential applications of this information to drug discovery. The genomics industry The genomics industry, including the handful of companies formed for gene isolation and drug discovery, are roughly divided into two categories: the cequencing companies [e.g. Human Genome Sciences (HGS; Rockville. MD, USA) and Incyte], and the mapping or positional cloning companies [e.g. Myriad Genetics (Salt Lake City. UT, USA), Sequana Therapeutics (La Jolla, CA, USA) and Millennium Pharmaceuticals (Cambridge, MA. USA)]. Alexander Kamb (Myriad Genetics) described this hositional-cloning-based company’s strategy for moving from the positional map to the final gene sequence. The competitiveness of this
technology in the face of increasing amounts of raw and completed DNA sequence for most areas of the genome was discussed in relationship to the changing market for genomic information. Chris Fields (National (Ienter for Genome Resources, Santa Fe, NM, USA) and Douglas Smith (Genome Therapeutics, Waltham, MA, USA) discussed the usefulness of genomic information from the perqpectives of a public database and ptivate company, respectively. Speaking ‘tongue in cheek’, Matthew Murray likened biotech companies to pharmaceutical conpanies without products, and genomic companies to biotech conpanies without even the potential for products. This view may be extreme, but a number of experts discussed the difficulties in product development and the long time-course from map position to drug. Rolf Ehrnstriim (Pharnracia Biotech, Piscataway, NJ, USA) described the diagnostic applications of automated DNA sequencand Steven Clark (Genetics mg. Institute, Cambridge, MA. USA) described a computational and informatic?-based approach. David Baily (Pfizer, Southport, NC, USA) described the development pathway from genes to drugs, and pregented a large pharmaceutical company’s view on the integation of genomic information into a traditional pharmaceutical-development strategy. Throughout the meeting, the concept of the value of genomic information for commercial, as well as academic, exploitation was apparent. Francis Collins best summarized the situation by; indicating that the conpletion of the human genome sequence will not be the end of the story - scientists now have, and will have f$- into the future, a hunger for the sequence ofDNA that is unlikely to go away.
Glen A. Evans
Students Didyou knowthat you are entitledto a 50%discounton a subscriptionto TBTECH? Seethe subscriptionorder card in this issuefor details.
Commercial implications of the Human Genome Project
yet available for human genome sequencing. Thus, unlike model organisms, which were initially proposed as pilot projects, human genome sequencing will require the
additional production oflligl~-resol-
The Human Genmnr Project (HGP) promises to have a major impact on the development of genetics and molecular medicine. Like the recombinant-DNA revolution two decades before it, the genomic revolution has spawned a biotechnology industry based upon positional, rather than functional, cloning that is consuming millions of dollars. The progress of the HGP in 1996 was reviewed at a recent meeting* that placed emphasis on the industrial and commercial applications of genomic knowledge, and that focused on the value of this information.
Progress
and prospects
The HGP has made remarkable progress since its oficial initiation in 1990. In his keynote speech, Francis Collins [National Center for Human Genome Kesearch (NCHGK). Bethesda, MD, USA] reviewed the unprecedented progress in physical mapping and technological development that has put the project ahead of schedule. He also introduced the new era of large-scale DNA sequencing that is being initiated in 1996. Most significantly, his address emphasized the continued con6dence of scientists and funding agencies alike that the human genome will be completely sequenced (i.e. 99% ofthe sequence will have been determined at an accuracy approaching 99.99%) ahead ofschedule and on budget. With major efforts being initiated this year in the USA and ehewhere, and with the anticipated ‘scale-up’ of sequencing efforts in the next 2-3 yean, it is hoped that the human genome will be completely sequenced by 2003, if not earlier. Francis Collins outlined the anticipated goals and accomplishments of the ‘post-genome’ era, including functional analysis, large-scale gene knockouts, and the sequencing of the complete genome of the mouse and other model organisms.
Industrial Lee ington,
Copyright0
genomics
Rowan Seattle,
1996,
(University of WashWA, USA) gave an
Elsewr
Science
Ltd. All rights reserved.
overview of large-scale sequencing and the proposal for large-scale ‘endsequence’ databases. Glen Evans (University of Texas, Southwestern Medical Center, Dallas, TX, USA) described the construction of an endsequencing database as well as COINventional and alternative strategies for high throughput sequencing, including COW (cosmid-oriented walking); this has the potential to be a completely automatable strategy that uses high-throughput oligonucleotide-primer synthesis that is programmed by automated DNA synthesizers. A new 192-channel oligonucleotide synthesizer, the MEKMADE, was described, which can be programmed by the Al31 377 automated gene sequencer, and may be useful for high-throughput DNA sequence finishing. The significance and utility of effective automation and instrumentation was a theme throughout the meeting. Significantly, Matthew Murray (Union Bank ofswitzerland) gave an overview of the methods used by investment bankers for valuing the genomic and biotechnology industry. He emphasized the value of current and future genetic information, as well as the significance of propretary and public domain genomic databases for furthering the value of genomics-based companies. The information content of the genome and the methods of data handling were summarized by Mark Boguski (National Center for Biotechnology Information, Washington, DC, USA). The value and public service provided by initiatives such as GenBank and Entrez have been of immeasurable value to both the commercial and academic sectors.
Sequence
mapping
Although 1996 essentially marks the completion of physical mapping and the start of large-scale sequencing, the meeting emphasized the importance of the development of techniques for the construction of sequence-ready maps. Unlike genome projects on model organisms, such as Cuuwrhabditis elegam and Sncchawnyces cerevisiae, sets of overlapping clone ‘contigs’ of sufficient quality and accuracy are not 0167
- 7799/96/$15.00
PII: SO167.7799(96)30007-3
ikleeting report
ill\l:*-r::~il,iad:iil:
ution maps. However, it is clear that sequence-ready map production must develop hand-ill-hand with sequencing efforts. A session on physical mapping covered the COIIstruction of expressed sequence tag (EST) transcript maps fJames Sikela; University of Colorado, Boulder. CO, USA): EST databases [Mark Adams; The Institute for Genomic Research (TIGK), Gaithersburg, MD, USA] and hybridization-based ‘binning’. Mark Perlin clone University. (Carnegie Mellon Pittsburgh, PA, USA) described the construction of sequenceable maps using a hybridization-based technique called ‘inner product mapping’. Paul Siebert (Clontech Laboratories, Palo Alto, CA, USA) and John Brunbaugh (LI-COR, Lincoln, NC, USA) described commercial solutions to problem5 of gap-filling and nrap-closure that involve new sequencing technolo&T and longrange PCK.
Developing
technology
The initiative to sequence the hu~xa~~ genome has been spurred-on by technological developments. However, most large-scale efforts have adapted sequencing strategies that are based on shotgun cloning of large insert clones [e.g. cosmids. PACs (bacteriophage PI -derived artificial chromosomes) and BACs (bacterial artificial chromo~ome~)] and Sangertype analysis using fluorescent-dye primers or terminators, followed by gel analysis. An enormous impact could be made by the development of new sequencing strategies. Technology under development that w-as discussed at the meeting included fast-separation capillary electrophoresis (Edward Yeung: Iowa State University, Ames, IA, USA), high-throughput capillav-array electrophoresis using enerm-transfer dyes Uingyue Ju: University of California, Berkeley, CA, USA), alternative and more-accurate DNA polymerases (Stanley Tabor; Harvard Medical School, Boston, MA, USA), and laser-based DNA mass-spectrometry (Chris Becker; GeneTrace Systems, Menlo Park, CA, USA). While these approaches promise rapid and major improvements in throughput and cost compared with TIBTECH MAY1996b'OL141
f OYUrn ‘conventional’ automated DNAsequencing technology, they are still in the development phase. With the promised rapid advancement and scale-up of sequencing eff^orts by the NCHGR and other agencies this year, a race to move these technologies to the ‘production’ phase is likely to ensue. Additional talks on related technologies, automated genetic analysis and genotyping (J. William Efcavitch; Perkin-Elmer, Applied Biosystems Dlvlslon, Foster City, CA, USA) and non-electrophoretic mapping (David Schwartz; New York University, NY, USA) gave a vivid insight into the future. Miniaturizing analytical techniques One of the most exciting aspects of genome technology that has been proposed over the past few years is the miniaturization ofDNA analysis, manipulation and sequencing. Andrei Mirzabekov (Englehart Institute, Moscow, Russia, and Argonne National Laboratory. Argonne, IL, USA) unveiled a robotic system for manuiacturing DNA ‘chips’ on glass surfaces with gel-coated. L)NAlaced, analysis sites. A variety of devices with applications for diagnostics, DNA re-sequencing and mutational analysis were described, including an integrated microfabricated device for L1NA-fragment analysis (Gregory Went; CuraGen, Branford, CT, USA), DNA probe arrays on glass ‘chips’ (Robert Lipshutz; Afimetrix, Santa Clara, CA, USA) and microfabricated electrode-array devices (Michael Heller; Nanogen. San Diego, CA, USA). Lloyd Smith (University of Wisconsin, Madison, WI, USA) and Radoje 11rmanac (Hyseq, Sunnyvale. CA, USA) described array sutfacehybridization techniques for analysing genetic variation, clone ordering and DNA sequencing by hybridization. These approaches are potentially poweriul, and impressive advances have been made, but many hurdles must still be overcome in the development of reliable diagnostic products involving new array-type methods. However, L1NA ‘chips’ promise to be one of the most exciting and potentially profitable areas of biotechnology development. Genomic information The value of genomic information, both as a scientific resource and as a commercial product, was the TlBTECHMAY1996(VOL141
focus of a session on informatics and sequence databases, with representatives from commercial, proprietary and the governmental and public donrain databases presenting differing viewpoints. Randal Scott (Incyte Pharmaceuticals, Palo Alto, CA. USA) described the proprietary LIFESEQT” genomic database, and compared its relevance and utility with the publicly accessible GenBank. It is clear that the sequences of only a fraction (perhaps between 30% and 70%) of all human genes now exist in some form in various databases, indicating that there are still genes yet to be found and investigated. Alan Williamson (Merck, Kahway, NJ, USA) described the Merck Gene Index project, which was initiated as a collaborative etrort between Merck and the Washington University Genome Sequencing Center. He emphasized the benefits ofthe release of genetic information into the public domain. However, it is clear that the immediate release of information from sequencing initiatives will be a major topic of public debate. Marc Paris, France) Vasseur (Genset, described the company’s innovative approach to selecting and sequencing regulatory regions of genes, as opposed to the coding region expressed in cDNAs and as ESTs, and described potential applications of this information to drug discovery. The genomics industry The genomics industry, including the handful of companies formed for gene isolation and drug discovery, are roughly divided into two categories: the cequencing companies [e.g. Human Genome Sciences (HGS; Rockville. MD, USA) and Incyte], and the mapping or positional cloning companies [e.g. Myriad Genetics (Salt Lake City. UT, USA), Sequana Therapeutics (La Jolla, CA, USA) and Millennium Pharmaceuticals (Cambridge, MA. USA)]. Alexander Kamb (Myriad Genetics) described this hositional-cloning-based company’s strategy for moving from the positional map to the final gene sequence. The competitiveness of this
technology in the face of increasing amounts of raw and completed DNA sequence for most areas of the genome was discussed in relationship to the changing market for genomic information. Chris Fields (National (Ienter for Genome Resources, Santa Fe, NM, USA) and Douglas Smith (Genome Therapeutics, Waltham, MA, USA) discussed the usefulness of genomic information from the perqpectives of a public database and ptivate company, respectively. Speaking ‘tongue in cheek’, Matthew Murray likened biotech companies to pharmaceutical conpanies without products, and genomic companies to biotech conpanies without even the potential for products. This view may be extreme, but a number of experts discussed the difficulties in product development and the long time-course from map position to drug. Rolf Ehrnstriim (Pharnracia Biotech, Piscataway, NJ, USA) described the diagnostic applications of automated DNA sequencand Steven Clark (Genetics mg. Institute, Cambridge, MA. USA) described a computational and informatic?-based approach. David Baily (Pfizer, Southport, NC, USA) described the development pathway from genes to drugs, and pregented a large pharmaceutical company’s view on the integation of genomic information into a traditional pharmaceutical-development strategy. Throughout the meeting, the concept of the value of genomic information for commercial, as well as academic, exploitation was apparent. Francis Collins best summarized the situation by; indicating that the conpletion of the human genome sequence will not be the end of the story - scientists now have, and will have f$- into the future, a hunger for the sequence ofDNA that is unlikely to go away.
Glen A. Evans
Students Didyou knowthat you are entitledto a 50%discounton a subscriptionto TBTECH? Seethe subscriptionorder card in this issuefor details.