March 6, 2003

1

Biotechnology and Ethics
March 6, 2003 Edward E. Penhoet, Ph.D.
2
Benefits of Biotechnology

• A virtually safe blood supply
• Cure for anemia
• Reduced spread of hepatitis
• Saving lives after heart attacks
• Slowing the progression of multiple sclerosis
• Better quality of life for diabetics
• Longer life for cancer patients
• Reducing the Debilitating Effects of Rheumatoid
  Arthritis
• Slowing the Progression of HIV Infection
• Improved outcomes for Chronic Hepatitis C

3
(No Transcript)
4
(No Transcript)
5
(No Transcript)
6
(No Transcript)
7
Biotech Industry Vital Statistics

• Market capitalization of the biotechnology
  industry at the end of 1999 was 312 billion
• 1999 estimated sales of all biotech products
  18 billion
• 1999 sales by biotech industry 13.4 billion
• 9.9 billion spent on research in 1998
• Top five biotech companies spent 121,400 per
  employee on RD compared with 30,600 at the top
  five pharma companies

Source Biotechnology Industry Organization.
8
Biotech Industry Vital Statistics

• U.S. continues to dominate
• 1,283 biotechnology companies
• 373 publicly-traded biotechnology companies
• Total employees Greater than 150,000

Source Biotechnology Industry Organization.
9
Four Generations of Biotechnology Products

• Recombinant DNA
• Insulin, hGH, EPO, ?, ? and ?-interferon, IL-2,
  t-PA, PDGF, vaccines etc.
• Monoclonal antibodies
• ReoPro, Rituxan, Herceptin etc.
• Small molecule compounds
• Viracept, Agenerase etc.
• Gene therapy

10
Biotech Products Two Decades of Progress
Insulin Growth Hormone I
. . . . . . . . . . . . . . . . . . .
Pre-1986
1986
1998
1999
?-Interferon OKT3 Antibody Hepatitis B V vaccine
I
Integrilin Refludan Provigil Thyrogen Vitravene E
nbrel Herceptin LYMErix Remicade RotaShield Simule
ct Synagis Thymoglobulin
Depocyt Luxiq NeoTect Tamiflu Targretin Unadex He
xtend Nabi-HB NovoSeven Ontak Wellferon
TPA EPO HCV Test GCSF IL-2 DNAse ?-Interferon
11
Biotech Industry Trends Submissions to FDA
Increase
Biotech INDs/IDEs Compared to Total
Total INDs/IDEs Received Biotech INDs/IDEs
Source CBER Burrill Company.
12
Blurring of the Borders Between Biotech and Pharma
Pharma companies become life sciences companies
AVENTIS PHARMA. AVENTISA new world leader
American Home Products Corporation is a global
leader in vaccines, biotechnology, and animal
health care.
We are committed to providing answers that matter
in medicine, life sciences and healthcare.
13
Blurring of the Borders Between Biotech and Pharma
Biotech companies become fully integrated
Genzyme
Genentech
Gilead
Amgen
MedImmune
Chiron
Cephalon
Immunex
Biogen
14
Blurring of the Borders Between Biotech and Pharma

• Combinatorial chemistry now deployed broadly
• Affymax, Alanex etc.
• Small molecule capabilities in biotech companies
• Chiron, Vertex, Biogen, Pharmacopeia, Axys etc.
• Pharma companies relying more heavily on biotech
  partnerships
• Pharma companies investing in internal protein
  therapeutics development
• Pharma companies become life science companies

15
Benefits of Biotechnology

• A safe blood supply
• Protection against hepatitis B infection
• Improved outcomes for chronic hepatitis B and C
• Slowing the progression of HIV Infection
• Cure for anemia
• Saving lives after heart attacks
• Slowing the progression of multiple sclerosis
• Better quality of life for diabetics
• Longer life for cancer patients
• Reducing the debilitating effects of rheumatoid
  arthritis

16
Biotech Industry Vital Statistics

• U.S. continues to dominate
• 1,457 biotechnology companies
• 342 publicly-traded biotechnology companies
• Total employees Greater than 190,000

Source Biotechnology Industry Organization.
17
Biotech Industry Vital Statistics

• Market capitalization of the biotechnology
  industry in mid-2002 was 224 billion
• 2001 estimated sales of all biotech products
  20.7 billion
• 15.6 billion spent on research and development
  in 2001
• Top five biotech companies spent 89,400 per
  employee on RD

Source Biotechnology Industry Organization.
18
Biotech Industry Trends FDA Approvals Increase
New Biotech Drug and Vaccine Approvals/New
Indications by Year
Source BIO
19
Biotechnology Reliant on Local Resources,
especially Research Universities
Picture source http//www.pigparadise.com/
20
Geographical Clustering
21
California Has Most Developed Cluster of Biotech
Companies

• California leads the nation with greater than 33
  of all biotechnology companies
• California biotech companies account for 45,000
  highly-skilled jobs at an average salary of
  65,800
• California universities, federal laboratories,
  and private institutions account employ an
  additional 41,000 people
• 80 of California biotech companies plan to
  expand in the next two years
• 88 of biotech companies anticipating growth
  intend to grow in California

22
Pharmaceutical Companies Seek to Capitalize on
California Biotechnology

• Novartis founds Novartis Research Institute in
  San Diego
• Novartis takes major equity stake in Chiron
• Roche heavily invested in Roche Biosciences as
  well as Genentech
• Pfizer heavily invested in Agouron and Gene
  Networks through Parke-Davis/Warner Lambert
  acquisitions
• Merck acquires Sibia
• Bayer locates Worldwide Biotech Headquarters in
  Berkeley

23
Intellectual Assets, Capital, and Infrastructure
Drive Biotech Clusters

• Universities essential for biotechnology growth
• Nearly one-third of Bay Area biotech companies
  are spin-offs from academic research institutions
• Two-thirds of Bay Area biotech companies have
  research agreements with California academia
• Universities continue to train skilled scientific
  personnel

24
Universities Essential to Biotechnology
Bay Area Biotechs Founded by University Faculty
Alumni
Source California Healthcare Institute San Jose
Mercury News, February 10, 2000.
25
Explosive Development of New Information

• Human Genome project
• Genetic analysis of disease
• Pathological mechanisms
• Gene expression in normal and pathological states
• New metrics
• Diagnostic and therapeutic monitoring
• Gene therapy

26
Individualized Information and Metrics Will Drive
Clinical Practice
Genetic Profile
Genetic Expression
Optimized and Customized Prevention Treatment
Infectious Agent Genodynamics
Immune Competence
Social/Family Data
Epidemiological Data
27
Data Mining, Informatics, and Information Portals
Fuel Better Targeting of Medical Advances
Data Mining and Information

• Celera, Gene Logic, Incyte, etc.

Bioinformatics Software

• NetGenics, DoubleTwist, etc.

Tool Companies

• Affymetrix, Caliper, ACLARA, Orchid, etc.

Pharmacogenomics

• Millennium, HGS, Axys PPGx etc.

The Internet
28
Positive Trends for Biotechnology

• High visibility in Washington
• Expanded funding for NIH
• New FDA guidelines for biologicals
• Continued pressure for accelerated drug approvals
• Consolidation of healthcare purchasing and
  testing
• Less infrastructure required for effective
  marketing
• Increasing awareness and activism about personal
  health issues
• Concern over infectious diseases
• Employer recognition for value in prevention
• Premium for reduction of risk
• Third largest use of the Internet
• Baby boomers have both money and political clout
  to sustain quality of life

29
Biotechnologies for the 21st Century

• Genetic analysis
• Expression Analysis

Diagnostics

• Integrated therapies

• Therapeutic vaccines for cancer and infectious
  diseases

Immuno Therapy
Genomics

• Explosion of new targets for drug discovery

Pharmaco-genomics

• Customization of medicine
• Rational patient selection for clinical trials

Proteomics

• High-throughput validation of gene products

• DNA
• Direct transfer
• Vector mediated
• Live virus

Nucleic Acid Therapy Gene Therapy

• RNA
• Anti-sense
• Ribozymes
• RNA ligands

• Nervous system repair
• Immune reconstitution

Cell-Based Therapies

• Tissue regeneration

30
Number of Genes Reported to Increase
Susceptibility to Selected Conditions
Mental retardation Congenital Abnormalities Cancer
Heart Disease Anemia Infection Diabetes Thyroid D
ementia Arthritis Asthma
872 594 554 408 331 318 292 242 137 111 55
31
Monogenic Diseases

• Hemophilia
• Huntingtons Disease
• Cystic Fibrosis
• Phenylketonuria
• Alpha-1-antitrypsin Deficiency
• Sickle Cell Anemia
• Thalassemia

• Hemochromatosis
• Glucocorticoid Remediable Aldosteronism (GRA)
• Liddles Syndrome
• Congenital Adrenal Hyperplasia
• Duchenne Muscular Dystrophy
• Fragile X Syndrome

32
A search for Lawful Regularities in the joint,
interactive effects of social and biological
factors

• Not pathways
• E.g., testosterone sexual behavior, aggression
• E.g., social conflict allostatic load
• Not multilevel analysis
• E.g., subordinate social position decreased
  ovulatory cycles and estradiol atherogenesis
• Not just statistical interaction
• E.g., gene x environment interaction liability
  to illness

33
Gene x Environment Interactions Kendler
Eaves, 1986

• Genes and environment have additive, independent
  effects

Genes control degree of sensitivity to
environmental influence
Genes control susceptibility to environmental
pathogenesis
AA
AA
AA
Aa
Aa
Aa
aa
Liability to Illness
Liability to Illness
Liability to Illness
aa
aa
Protective
Predisposing
Protective
Predisposing
Protective
Predisposing
Environment
Environment
Environment
34
Examples of possible Lawful Regularities in
social x biological interactive effects

• Biology controls sensitivity to environment
  effects
• E.g., family stress x cardiovascular reactivity
  childhood injuries and respiratory illness
• Biology exaggerates social-context effects
• E.g., amphetamines augment dominance behavior in
  dominant macaques and subordinate behavior in
  subordinates
• Social context generates undifferentiated risk
  biology constrains pathologic specificity
  (Steinberg Avenevoli, 2000)
• E.g., loss depression in one child, but
  disordered conduct in another
• Biological susceptibilities are amplified during
  rapid or intense contextual change
• E.g., biological or gender-based vulnerabilities
  to depression during middle school transition
• Biology controls liability to experiencing
  predisposing environments
• E.g., genes for skin color

35
Pathways linking psychiatric and physical
disorders (Cohen Rodriguez, 1995)
Biological

• SAM, NPA
• Target tissues, e.g., immune system
• Treatment side effects
• Sleep disturbance

Behavioral

• Poor health practices
• Health care utilization/adherence
• Disruption of routines
• Sick role behaviors

AffectiveDisorder
PhysicalDisorder
Cognitive

• Biased interpretation of sx
• Biased health care decision making
• Cognitive distortions
• Perceived stress, loss of control

Serial

• Interference with role functioning
• Deterioration of social networks
• Avoidance by network members
• Interference with role functioning

36
The 4 As of the Human Genome Project

• The sequence must be accurate (99.9 or better)
• The human sequence must be assembled into long
  pieces that reflect the original genomic DNA
• Technology development must make the acquisition
  of human DNA sequence affordable
• Human DNA sequence should be accessible within 24
  hours through public databases

37
Early Genomics
HIV Genome
HIV Proteins
HIV Diagnostics
Protease Inhibitors
38
Ethical, Legal, Social Implications (ELSI) of
Genome Research

• 5 of the Human Genome Projects annual research
  budget is earmarked to study
• The use and interpretation of genetic information
• Clinical integration of genetic technologies
• Issues surrounding genetics research
• Public and professional education and training
  about genetics research issues
• Identifying and addressing issues that link
  genetics to personal identify and racial, or
  ethnic background
• The implications of personal identify and
  genetics for philosophical and religious
  traditions

39
Genetics Becomes Genomics

• Transition from understanding single genes and
  their functions to understanding the action of
  multiple genes and their control of biological
  systems.
• DNA chips/micro arrays
• Genome scale studies of genetic variation
• Detection of heterogeneous gene mutation
• Gene expression

40
Actionable Genetic Diseases
HD
Alzheimers
Familial Hypercholesterolemia
Hemochromatosis
BRCA 1 2
HNPCC
PKU
1999
Treatment available, highly successful
Risk reducible
No options to reduce risk to self
Familial Hypercholesterolemia
Hemochromatosis
BRCA 1 2
Alzheimer's
HNPCC
PKU
HD
2010 ?
Treatment available, highly successful
Risk reducible
No options to reduce risk to self
Source Genetics public health in the 21st
Century (Leslie Fink Francis S. Collins).