GOVERNING BENEFITS AND RISKS OF EMERGING BIOTECHNOLOGIESRETROSPECTIVE AND CURRENT CASES
10:05-10:25 AM 17 FEBRUARY 2022
Professor Kenneth A. Oye
MIT Political Science and Data Systems and Society
OUTLINE
Risk Governance Under Uncertainty: Permissive, Precautionary, Adaptive
Retrospective and Current Biotechnology Cases• Agriculture: Genetically Engineered Plants and Animals• Industry: Synthesis of Biofuels, Fragrances, and Drugs• Medicine: SCGT, Regenerative Medicine, HGGT
• Environment: Gene Drives
A Closing Conundrum: Governing Risks with Information Hazards
The research, conferences and workshops on which this presentaiton is based have been supported by
the Netherlands Rijksinstituut voor Volksgezondheid en Milieu; the US Defense Advanced Research
Projects Agency, US National Science Foundation Molecular and Cellular Biology, the MIT Center for
Biomedical Innovation, the International Risk Governance Council and Richard Johnson.

Slide 01

GOVERNING BENEFITS AND RISKS OF EMERGING BIOTECHNOLOGIESRETROSPECTIVE AND CURRENT CASES
10:05-10:25 AM 17 FEBRUARY 2022
Professor Kenneth A. Oye
MIT Political Science and Data Systems and Society
OUTLINE
Risk Governance Under Uncertainty: Permissive, Precautionary, Adaptive
Retrospective and Current Biotechnology Cases• Agriculture: Genetically Engineered Plants and Animals• Industry: Synthesis of Biofuels, Fragrances, and Drugs• Medicine: SCGT, Regenerative Medicine, HGGT
• Environment: Gene Drives
A Closing Conundrum: Governing Risks with Information Hazards
The research, conferences and workshops on which this presentaiton is based have been supported by
the Netherlands Rijksinstituut voor Volksgezondheid en Milieu; the US Defense Advanced Research
Projects Agency, US National Science Foundation Molecular and Cellular Biology, the MIT Center for
Biomedical Innovation, the International Risk Governance Council and Richard Johnson.

Slide 02APPROACHES TO RISK GOVERNANCE UNDER UNCERTAINTY
Permissive
Allow innovation unless environment, health, security are clearly compromised
After-the-fact reaction if crisis materializes; backlash may limit innovation
Examples: DDT, post-Fukushima nuclear shutdown, US stasis on gene therapy

PrecautionaryLimit innovation unless environment, health and security are clearly protected
Diversion of innovation to less regulated areas may heighten risks
Examples: EU on GMOs, US on stem cell research, Y2K

Planned Adaptive* Prepare: Fund research to inform priors on benefits and risks* Discriminate: Foster initial applications with most favorable priors* Observe: Harvest and process information from initial experience* Adapt: Learn from experience and update/correct practices

Slide 03

GOVERNING BENEFITS AND RISKS OF EMERGING BIOTECHNOLOGIESRETROSPECTIVE AND CURRENT CASES
10:05-10:25 AM 17 FEBRUARY 2022
Professor Kenneth A. Oye
MIT Political Science and Data Systems and Society
OUTLINE
Risk Governance Under Uncertainty: Permissive, Precautionary, Adaptive
Retrospective and Current Biotechnology Cases• Agriculture: Genetically Engineered Plants and Animals• Industry: Synthesis of Biofuels, Fragrances, and Drugs• Medicine: SCGT, Regenerative Medicine, HGGT
• Environment: Gene Drives
A Closing Conundrum: Governing Risks with Information Hazards
The research, conferences and workshops on which this presentaiton is based have been supported by
the Netherlands Rijksinstituut voor Volksgezondheid en Milieu; the US Defense Advanced Research
Projects Agency, US National Science Foundation Molecular and Cellular Biology, the MIT Center for
Biomedical Innovation, the International Risk Governance Council and Richard Johnson.

Slide 04

WHY BIOENGINEERING IS CHANGING SO FASTENABLING TECHNOLOGIES DEVELOPING AT EXTRAORDINARY RATESMaking DNA: Cost and speed of DNA synthesis
Reading DNA: Cost and speed of DNA sequencing
Characterizing and Designing DNA: AI and data storage
Editing DNA: From zinc fingers and talens to CRISPR and base editing

Fundamentals: Legal, Categorical andConsequentialist Standards
Fundamentals: Implied Duties and Concrete
Obligations N

Cost of DNA Synthesis & Sequencing

Info Deposited in Data Bases

Design/Editing Tools

Slide 05

AGRICULTURE

EMERGING APPLICATIONS
GM Crops and Livestock N Fixation, Glowing Plants, Aquabounty

INDUSTRY

Synthesis of Organic Materials

MEDICINERegenerative Medicine, Somatic and Germline Cell Therapy

ENVIRONMENTRemediation; Control Vector Borne Disease and Invasive Species

Fuel, Flavors, Drugs

Slide 06

FISH STORY: DEVELOPERS AND REGULATORS LIMIT RISKSAQABOUNTY ATLANTIC SALMON WITH POUT AND CHINOOK GENES
FOOD SAFETY: FDA compared non-GE farmed and GE salmon, withfocus on estradiol, testosterone, 11-ketotestosterone, T3, T4 andinsulin-like growth factor 1 (IGF1)) + complete compositional analysis.
ENVIRONMENT: FDA issued “Finding of No Significant Impact” (FONSI)
Physical containment: All fish in land based tanks with safeguards
Geophysical containment: High water temp or bad water quality g
Biological containment – organism design• Adults sterile triploid(diploid broodstock)• Adults all female• Fitness disadvantage relative to wild type due to limited food supply
Slide 07

AGRICULTURE

EMERGING APPLICATIONS
GM Crops and Livestock N Fixation, Glowing Plants, Aquabounty

INDUSTRY

Synthesis of Organic Materials

MEDICINE

Regenerative Medicine, Somatic and Germline Cell Therapy

ENVIRONMENT

Remediation; Control Vector Borne Disease and Invasive Species

Fuel, Flavors, Drugs

Slide 08

INDUSTRIAL APPLICATIONS: MAKING LOW VALUE MATERIALS
SGI, Sapphire, Algenol
synthesis of biofuels
Universal Biomining
extraction and effluent treatment
Economics > low cost containment > environment release probable
Environmental effects• Fitness / reproduction / propagation• Horizontal gene flow
• Mutation > effects on fitness, gene flow?
Raceways and Sluices

Plastic Bags

Surface Ponds

Slide 09

ALGAE BIOFUELS CONTAINMENT WORKSHOP

Slide 1010TECHNOLOGISTS DESIGN TO LIMIT RISKS OF RELEASE
Daisuke Kiga: Synthetic Amino Acids
Biocontainment Design: Church and Isaacs Labs
Unfilled gap - independent systematic demonstration and testing

Slide 11

INDUSTRIAL APPLICATIONS: MAKING HIGH VALUE MATERIALS
Keasling/Amyris/Sanofi
Prather
EvolvaSmolke, Dueber, Martin, Facchiniamorphadien, artemisinen
glucaric acidvanillinreticuline, hydrocodone, morphine

Slide 12

OPIATE PRODUCTION IN YEAST DUEBER, MARTIN, SMOLKE
Benefits: Ability to vary scaffolds, control intermediates, create novel analgesics
Hazard: Production beyond control of cartels and law enforcement
Technical Measures: markers, finicky strains, unappealing final product
Policy Measures: lab security, licensing, synthesis screening

ScienceSlide 13

OPIATE PRODUCTION IN YEAST: TWO RESEARCH GROUPS
Smolke, Thodey, Hawkins (Stanford)
Dueber (UCB), Facchini (Calgary), Martin (Concordia)
KM Hawkins, CD Smolke, “Production of benzylisoquinoline alkaloids in Saccharomyces cerevisiae,” Nature Chem. Biol. 4, 564–573 (2008).
K Thodey, S Galanie, CD Smolke, “A microbial biomanufacturing platform for natural and semisynthetic opioids,” Nature Chem. Biol. 10, 837–844 (2014).
WC DeLoache, ZN Russ, L Narcross, AM Gonzales, VJJ Martin, JE Dueber, “An enzyme-coupled biosensor enables (S)-reticuline production in yeast fromglucose,” Nature Chem Biol, accepted 2015.
E Fossati, L Narcross, A Ekins, JP Falgueyret, VJJ Martin, “Synthesis of morphinan alkaloids in Saccharomyces cerevisiae,” PLoS ONE, at press 2015.
KA Oye, T Bubela, JC Lawson, “Regulating Home Brew Opiates,” Nature, at press, 2015.

Slide 14

(NOT) BREWING BADPERSONNEL SECURITY
Psychological disorders•Psychopathy•Borderline personality disorder•Narcissistic personality disorder
Other Risk Factors•Financial stress•Status insecurity•Sleep deprivation•Perceived unfairness

LAB SECURITY•Entry and exit control•Materials access•Inventory management•Information controls
REDUCE APPEAL OF STRAINS•Insert markers for traceability•Make hard to cultivate•Stop short of opiates•Make distasteful to consume

Slide 15

AGRICULTURE

EMERGING APPLICATIONS
GM Crops and Livestock N Fixation, Glowing Plants, Aquabounty

INDUSTRY

Synthesis of Organic Materials

MEDICINE

Regenerative Medicine, Somatic and Germline Cell Therapy

ENVIRONMENTRemediation; Control Vector Borne Disease and Invasive Species

Fuel, Flavors, Drugs

Slide 16

VERSION 1.0
ADVERSE EFFECTS, OFF TARGET EFFECTS AND MUTATIONSSlide 17

VERSION 1.5
CURRENT SOMATIC CELL GENE THERAPY (SCGT)
Single gene alterations to cure thalassemia, cystic fibrosis, hemophilia.
800+ SCGT now under development
Bluebird LentiGlobin BB305 for β-thalassaemia approved by EMA FDA

18Slide 18

VERSION 2.0
REGENERATIVE MEDICINEREPLACEEngineer differentiated tissue/organ
Insert/transplant in subject• Tracheal implants - Macchiarrini• Retinal Tissue Implant – Kurimoto
REGENERATE
Trigger internal healing in subject
Insert extracellular matrix, modified stem cells• Own cord blood stem cells• Donor stem cells, marrow• Procymal for graft-versus-host disease
PMDA “Conditional Time Limited Authorization”

19

Slide 19

VERSION 2.0
REGENERATIVE MEDICINEREPLACEEngineer differentiated tissue/organ
Insert/transplant in subject• Tracheal implants - Macchiarrini• Retinal Tissue Implant – Kurimoto
REGENERATETrigger internal healing in subject
Insert extracellular matrix, modified stem cells• Own cord blood stem cells• Donor stem cells, marrow• Procymal for graft-versus-host disease
PMDA “Conditional Time Limited Authorization”

20Slide 20

VERSION 3.0 GERMLINE GENE THERAPY (GGT)
SCGT works in individual, GGT changes in germline will be heritable• Huang@Sun Yat-sen edited β-thalassaemia gene 28 embryos.
Experiment failed with many off-target effects (4/2015 Protein&Cell)• Zhang@Broad Improved Cas9 Specificity (12/2015 Science)• Joung@MGH Hi-fi CRISPR no off-target effects (1/2016 Nature)• Mitalipov@Oregon GGT pathogen in human embryo (8/2017 Nature)• HGP Write – ultra-safe cells with codon knockout to limit gene flow

21Slide 21

BEYOND THERAPEUTICSOLYMPIC ENHANCEMENTS• SIZE• SPEED• AGILITY• PAIN THRESHOLD• JOINT STRENGTH• EYE-HAND COORDINATION• DEPTH PERCEPTIONMILSPEC ENHANCEMENT• PAIN THRESHOLD• TOLERANCE OF SLEEP LOSS
• VISUAL ACUITY• PARALLEL PROCESSING• COURAGE• POSITIVE OWN GROUP AFFECT• NEGATIVE OUT-GROUP AFFECT
WHICH ENHANCEMENTS ARE IN FACTFEASIBLE? ETHICAL?

Slide 22

AGRICULTURE

EMERGING APPLICATIONS
GM Crops and Livestock N Fixation, Glowing Plants, Aquabounty

INDUSTRY

Synthesis of Organic Materials

MEDICINE

Regenerative Medicine, Somatic and Germline Cell Therapy

ENVIRONMENT

Remediation; Control Vector Borne Disease and Invasive Species

Fuel, Flavors, Drugs

Slide 23

Slide 24
24

WHAT IS A GENE DRIVE ?
Mendelian:
50% odds genetic alteration will pass to next generation
IFF fitness or reproductive edge, THEN propagate
Gene drive:
99.5% odds alteration will pass to next generation (caveat)
Edit whole population without fitness or reproductive edge
FOR WHAT APPLICATIONS?
Environment: Control invasive species
Agriculture: Cut herbicide/pesticide resistance, eradicate pests
Health: Control vector borne diseases by eradicating or modifying vector

Slide 25

ENVIRONMENTAL ISSUES
Mutation of gene drives inevitable, will alter effects
Lateral gene transfer may reduce discrimination
Immunization and reversal may not be effective
Diseases borne by vectors will evolve
Environmental effects will vary by species and alterationSECURITY ISSUES
Gain-of-function enabling ability to host diseases
Suppression of crops and livestock in traditional agriculture
Suppression of pollinators and other keystone species
Immunization drives may protect self and allies from effects
Reversal drives may be withheld for economic or political gain
Security implications uncertain - note ingenuity and creativity
Slide 26

(MOST) WIZARDS ARE ACTING RESPONSIBLY
Code of Conduct, Use IP to Enforce, Open Access to Data

Slide 27

Slide 28

ACADEMICS, GOVERNMENTS AND NGOS DELIBERATEUN Biological Weapons Convention Meeting of Experts Geneva August 2014International Experts Group on Biosecurity Regulation, Berlin 2015
National Academy of Sciences, Consensus Committee, Washington DC 2016
European Union Synergene Amsterdam, June 2016
OECD Gene Editing Workshop, Ottawa October 2016
IUCN World Conservation Congress Hawaii September 2016
UN Convention on Biodiversity COP13 Cancun December 2016
UN Convention on Biodiversity SBSTTA-22 and SBI-2 Montreal July 2018
NIH Novel and Exceptional Technologies Advisory Committee Gene Drive Group 2021
Outreach Network for Gene Drive Research August 2021

Slide 29

GOVERNING BENEFITS AND RISKS OF EMERGING BIOTECHNOLOGIESRETROSPECTIVE AND CURRENT CASES
10:05-10:25 AM 17 FEBRUARY 2022
Professor Kenneth A. Oye
MIT Political Science and Data Systems and Society
OUTLINE
Risk Governance Under Uncertainty: Permissive, Precautionary, Adaptive
Retrospective and Current Biotechnology Cases• Agriculture: Genetically Engineered Plants and Animals• Industry: Synthesis of Biofuels, Fragrances, and Drugs• Medicine: SCGT, Regenerative Medicine, HGGT
• Environment: Gene Drives
A Closing Conundrum: Governing Risks with Information Hazards
The research, conferences and workshops on which this presentaiton is based have been supported bythe Netherlands Rijksinstituut voor Volksgezondheid en Milieu; the US Defense Advanced Research
Projects Agency, US National Science Foundation Molecular and Cellular Biology, the MIT Center for
Biomedical Innovation, the International Risk Governance Council and Richard Johnson.

Slide 30

INFORMATION HAZARDS: A CONUNDRUM
Information should be shared among biotechnology geeks to validate work and toprovide building blocks for scientific advance.
Information should be shared with biosecurity policy wonks and biosafety officers toenable effective risk management.
Information should not be shared with malevolent or negligent actors to reduce the riskof harmful applications.
Compartmentalization of information is difficult / impossible.

Slide 31

PAST EXAMPLES?
How to make mammal-to-mammal transmissible strains of avian flu (2012)

Slide 32CURRENT EXAMPLES?
How to synthesize horsepox (2018), How to make COVID variants (2021)

Slide 33

Technologists have a duty to engage with risks of their own work**Note: with info hazards responsible conduct is even more critical
Duty: Those proposing/conducting/funding research have a duty to evaluate actions
with reference to both legal standards and ethical norms
Concrete Obligations that Follow from Duty:
101 Align own work with law/norms based on existing knowledge
201 Encourage others to align their work with laws/norms
301 Identify important gaps in knowledge and fill gaps through research
401 Identify gaps in legal coverage and join in debate on gaps
Engage early in order to allow time to:
101 Modify own work to fit law/norms
201 Organize to improve conduct of others
301 Initiate research on benefits/risks
401 Evaluate and influence policy

before tech designs lock in
before bad conduct locks inin time to inform choices
before policy designs lock inSlide 34

GOVERNING BENEFITS AND RISKS OF EMERGING BIOTECHNOLOGIESRETROSPECTIVE AND CURRENT CASES
10:05-10:25 AM 17 FEBRUARY 2022
Professor Kenneth A. Oye
MIT Political Science and Data Systems and Society
OUTLINE
Risk Governance Under Uncertainty: Permissive, Precautionary, Adaptive
Retrospective and Current Biotechnology Cases• Agriculture: Genetically Engineered Plants and Animals• Industry: Synthesis of Biofuels, Fragrances, and Drugs• Medicine: SCGT, Regenerative Medicine, HGGT
• Environment: Gene Drives
A Closing Conundrum: Governing Risks with Information Hazards
The research, conferences and workshops on which this presentaiton is based have been supported by
the Netherlands Rijksinstituut voor Volksgezondheid en Milieu; the US Defense Advanced Research
Projects Agency, US National Science Foundation Molecular and Cellular Biology, the MIT Center for
Biomedical Innovation, the International Risk Governance Council and Richard Johnson.

Slide 35