Technology, Science, Money, and Health

1. Technology, Science, Money, and Health A Policy History of Genomics Robert Cook-Deegan, MD Center for Genome Ethics, Law, and Policy Institute for Genome Sciences and Policy

2. Outline of the talk • Some histories • Some data • Some interpretation • Some stories • A few more data • Some interpretation

3. Technology • Recombinant DNA 1975-7 DNA sequencing • Desktop PC (1984 Macintosh) 1983 PCR (1986 Cold Spring Harbor talk) • Automated DNA sequencing 1989 World Wide Web • Micro-arrays • SNPs (1999 SNP Consortium) 2001 Haplotype map (2003 officially launched)

4. Science • 1950s Phage group • 1960s Emergence of molecular biology • 1970s Dominance of molecular biology • 1980s Scale-up of molecular biology • 1990s Capital-intensive biology • 2000 Draft sequence • 2003 Reference sequence • 2004 Genetic variation • Next? Integration with organismal biology and clinical research (beyond lip service?)

5. Policy issues • 1985-88 To fund or not to fund • Big Science v cottage industry • Human genetics or worm-yeast sociology • 1989-1993 Launch phase • Getting maps done • NIH-DOE leadership competition; international collab. • 1993-2003 Public-private competition • Sequencing • 2004 Making information useful

6. ELSI priorities • Early • Genetic discrimination, genetic privacy • Transition from gene discovery to genetic test • Eugenics history • Middle • Health professional education • Regulation of tests, “screening” use • Newer • Race, diversity, health disparities • Intellectual property • Next • Reimbursement, coverage, cost, cost-effectiveness

7. Money • 1940 Industry > philanthropy > gov’t • 1950-60 Fed > industry > philanthropy • 1990 Industry > fed > philanthropy • 19976-80 first wave of biotech startups • 1981 Applied Biosystems founded • 1992-3 first wave of genomics startups • Incyte, Human Genome Sciences, Millennium, Mercator, Myriad, etc. • 1998 Celera • 2000 peak of genomics bubble • 2004 continued R&D increases, but market cap decline

8. NIH Appropriations 1940-2003

9. National Health Expenditures

10. Health R&D as Percent National Health Expenditures

11. Health Research Funding Philanthropy Industry Government

13. Intellectual property 1980 Diamond v Chakrabarty 1980 Cohen-Boyer 1980 Bayh-Dole; Stevenson-Wydler 1982 Court of Appeals for the Federal Circuit 1991 EST controversy 1994 Eisenberg-Merges; Varmus abandons EST patents 1995 OTA dies before publishing DNA patenting report 1995 ten-sequence rule 1995 TRIPS 1999 Examination guidelines (utility; written description) 1999 NIH guidelines on research tools 2000 US adopts 18-month publication rule 2004 NIH draft guidelines on patent licensing

14. Which of these histories matters? Scientific, practical, and commercial value of DNA information • Analysis, networking and distributed work through computers and telecomm • Stronger patents • Tighter links between academe and pharma/biotech

15. Which policies mattered? • Health research (and genomics) funding? • Availability of capital for high-tech, whiz-bang science • Stronger patent protection • Tech transfer policy

16. Translation of Delphion Search Algorithm 1. Search US Patent classes 047 (plant husbandry), 119 (animal husbandry), 260 (organic chemistry), 426 (food), 435 (molecular biology and microbiology), 514 (drug, bio-affecting and body treating compositions), 536/subclasses 22 through 23.1 (nucleic acids, genes, etc., but not peptides or proteins), subclasses 24 and 25 (various nucleic acids, variants, and related methods), and class 800 (multicellular organisms).

17. 2. Select patents from that group that include one or more of the following terms in their claims: antisense cDNA centromere deoxyoligonucleotide deoxyribonucleic deoxyribonucleotide DNA (with or without following letters, such as DNAs) exon gene or genes (exact match only) genetic genome genomic genotype haplotype intron mtDNA (with or without following letters such as mtDNAs)—exact case match only nucleic nucleotide

18. [List of terms continued] oligonucleotide oligodeoxynucleotide oligoribonucleotide plasmid polymorphism polynucleotide polyribonucleotide ribonucleotide ribonucleic recombinant DNA (exact match for case and words only) RNA (all upper case only, with or without following letters such as RNAs) mRNA (exact case match only, with or without following letters such as mRNAs) rRNA (exact case match only, with or without following letters such as rRNAs) siRNA (exact case match only, with or without following letters such as siRNAs) snRNA (exact case match only, with or without following letters such as snRNAs) tRNA (exact case match only, with or without following letters such as tRNAs) ribonucleoprotein hnRNP (exact case match only, with or without following letters such as hnRNPs) snRNP (exact case match only, with or without following letters such as snRNPs) SNP (exact case match only, with or without following letters such as SNPs) Terms were tested for specificity and sensitivity

21. Sir John Sulston and the Open Genomics of the Worm

22. The Worm Project Coming: Rachel Ankeny: The Conqueror Worm

23. Another Story

24. The Third Way Celera: Data by subscription

25. Spectrum of data access • Bermuda rules: 24-hour data release • Merck EST database, cancer Genome Anatomy Program, Mammalian Gene Collection, mouse mutant collections • Apply for patent and abandon: SNP Consortium • Celera: data by subscription • Universities: genes for a license fee • Incyte: high-priced multilateralism • Pharma: publish occasionally • HGS: trade secrecy plus patent Yellow = private R&D $; White = public $

26. Policy story: cDNA sequencing • Incorporated into OTA budget plan (1987 “costs” workshop) • Omitted from NIH initial 5-year plan 1990 • EST patent controversy 1991 • Incyte, HGS based on cDNA sequencing 1992-3 • Merck EST index 1994-5 • Cancer genome anatomy program, Mammalian gene collection 1996 • Lesson: gov’t mistake, private sector adaptation

27. Policy story: whole-genome shotgun sequencing • Sulston&Waterston propose rapid draft sequencing • Afeyan&Hunkapiller: 96-capillary sequencer for genomic sequencing • Venter and Celera 1998 • Public project concentrates resources, focuses on draft-first strategy • Celera moves up end-date, incorporates GenBank data • Temporary Truce June 2000; dueling drafts Feb 2001 • Celera moves to pharma model; Venter out; refined sequence out • April 2003 “reference sequence” to coincide with DNA 50th • Lesson: public sector spurred to action by private sector threat

28. Is the genome project a success? • Ask a scientist • Ask a doctor or patient • Ask a lawyer • Ask an anthropologist • Ask someone worried about health disparities • Ask a legislator or governor • Ask an economist

29. Genomics Funding: private>public(Year 2000) Source: World Survey of Funding for Genomics Research Stanford in Washington Program http://www.stanford.edu/class/siw198q/websites/genomics/

30. Data through Year 2000 Market Cap figures for end of year Number of firms at end of each year Growth of Commercial Genomics

31. R&D v Market Cap

32. When did the market have the economic value of genomics right? • Early 1990s (near-zero investment) • 1993-1995 first wave of genomics firms • 1998-2001 euphoria and hype: the bubble • Very high valuation of IP • 2002-2004 • conversion to pharma model • very low valuation of IP

33. Making assumptions explicit • Genome data and technologies are a Big Deal in science, and will work their way into applications • Time scale is over a decade hence • Not a revolution but a foundation • Chokepoint is clinical utility, not fundamental knowledge • A robust scientific commons is immensely important to capturing social benefit