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
Outline of the talk
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Some histories
Some data
Some interpretation
Some stories
A few more data
Some interpretation
Technology
1973
1975-7
1981
1983
1986
1989
1995
1996
2001
Recombinant DNA
DNA sequencing
Desktop PC (1984 Macintosh)
PCR (1986 Cold Spring Harbor talk)
Automated DNA sequencing
World Wide Web
Micro-arrays
SNPs (1999 SNP Consortium)
Haplotype map (2003 officially launched)
Science
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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?)
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
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
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
1940
1941
1942
1943
1944
1945
1946
1947
1948
1949
1950
1951
1952
1953
1954
1955
1956
1957
1958
1959
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
1974
1975
1976
1977
1978
1979
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
NIH Appropriations 1940-2003
30
25
20
15
$ billion (2000
dollars)
10
5
0
Year
S1
National Health Expenditures
1,200
1,000
800
National Health Expenditures (billions)
adjusted by Y2000 deflator
600
400
200
00
20
98
19
96
19
94
19
92
19
90
19
88
19
86
19
84
19
82
19
80
19
78
19
76
19
74
19
72
19
70
19
68
19
66
19
64
19
62
19
60
0
19
$ Billion (Y2000 constant dollars)
1,400
20
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
00
98
96
94
92
90
88
86
84
82
80
78
76
74
72
70
68
66
64
62
60
Percent
Health R&D as Percent National
Health Expenditures
4.00
3.50
3.00
2.50
2.00
1.50
1.00
0.50
0.00
Health Research Funding
1940
7%
1965
24%
38%
55%
Philanthropy
1998
8%
Industry
68%
46%
49%
5%
Government
Federal Health (budget function 550) v PhRMA R&D 1970-2000
Thousand $ (1996 dollars)
25,000.00
20,000.00
15,000.00
10,000.00
5,000.00
PhRMA
NSF pharma
Fed Health R&D (550)
00
99
20
98
19
97
19
96
19
95
19
94
19
93
19
19
92
91
19
90
19
89
19
88
19
87
19
86
19
85
19
84
19
83
19
82
19
81
19
80
19
79
19
78
19
77
19
76
19
75
19
74
19
73
19
72
19
71
19
19
19
70
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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
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
Which policies mattered?
• Health research (and genomics) funding?
• Availability of capital for high-tech, whizbang science
• Stronger patent protection
• Tech transfer policy
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).
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
[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
Number of Patents Retrieved by Search Algorithm by Year of Issue
5000
Number of Patents Retrieved by Search Algorithm
4500
4000
3500
3000
2500
2000
1500
1000
500
03
02
20
01
20
00
20
99
20
98
19
97
19
96
19
95
19
94
19
93
19
92
19
91
19
89
90
19
Year of Issue
19
88
19
87
19
86
19
85
19
84
19
83
19
82
19
81
19
80
19
79
19
78
19
77
19
76
19
75
19
74
19
73
19
72
19
19
19
71
0
This research was supported by Grant No. R03 HG02683-02, “DNA Patent Policies at Academic Institutions,” from the National Human Genome Research Institute, NIH, and Grant No. DE FG 02 01ER63171,
“Enhancing the DNA Patent Database,” from the U.S. Department of Energy; Io Nami Wolk 02-25-04.
Preliminary Data about the 30 Entities Holding the Largest Numbers of DNA-Based Patents
(as of 02-05-04)
Entity Name
0
University of California
United States Government
GlaxoSmithKline
Incyte Genomics
Aventis
Chiron
Genentech
Bayer
Wyeth
Novartis
Merck
University of Texas
Human Genome Sciences
Amgen
Johns Hopkins University
Applera
Massachusetts General Hospital
Novo Nordisk
Harvard University
Pfizer
Stanford University
Lilly
Salk Institute
Cornell University
MIT
Affymetrix
Columbia University
University of Wisconsin
Washington University
University of Pennsylvania
100
200
300
Number of DNA-Based Patents
400
500
600
700
Academic Institution
800
Government
900
1000
For Profit Firm
This research was supported by Grant No. R03 HG02683-02, “DNA Patent Policies at Academic Institutions,” from the National Human Genome Research Institute, NIH, and Grant No.
DE FG 02 01ER63171, “Enhancing the DNA Patent Database,” from the U.S. Department of Energy. Io Nami Wolk 03-03-04
Sir John Sulston and the Open Genomics of the Worm
The Worm Project
Coming: Rachel Ankeny: The Conqueror Worm
Another Story
The Third Way
Celera: Data by subscription
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 $
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
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 draftfirst 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
Is the genome project a success?
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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
Genomics Funding: private>public
(Year 2000)
Genomics research funding
($ million US)
2,500
2,000
2,061
1,653
1,500
900
1,000
500
0
Gov&nonprofit
Genomics firms
Pharma&biotech
Source: World Survey of Funding for Genomics Research
Stanford in Washington Program
http://www.stanford.edu/class/siw198q/websites/genomics/
Genomics firms with publicly traded stock
Data through Year 2000
80
60
Market Cap figures for end of year
40
Number of firms at end of each year
20
0
# firms
1994
1995
1996
1997
1998
1999
2000
8
10
14
19
25
28
73
Year
Growth of Commercial
Genomics
100
90
80
70
60
50
40
30
20
10
0
$B market value
1994
1996
1998
2000
R&D v Market Cap
Sum of R&D Expenditures for 15 Genomics Firms
1,800
60,000
Total R&D Expenditures
1,600
Total Market Cap
50,000
Market Cap (Million US$)
R&D (Million US$)
1,400
1,200
40,000
1,000
30,000
800
600
20,000
400
10,000
200
-
2000
2001
Year
2002
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
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