160804_AWP_WISE16GeneDrive

Austin Wright-Pettibone
Department of Chemical Engineering
University of Washington
Washington Internships for Students of Engineering
American Institute of Chemical Engineers
August, 2016
Driving the Future
GOVERNANCE CHALLENGES FOR BIOTECHNOLOGY IN THE AGE
OF GENE DRIVE

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Executive Summary
The emergence of Zika virus in the United States has drawn renewed attention to the threat posed
by vector-borne disease. Combined with malaria, dengue, and Chikungunya, mosquito-borne
diseases affect more than half the world’s population. The recent emergence of gene drive
technology offers unprecedented ability to interrupt transmission of these diseases, preventing
mosquitoes from infecting human populations.
Gene drives bias inheritance by ensuring the propagation of desired genes in sexually reproducing
species. Using a gene drive, a target gene can be spread over successive generations to rapidly affect
fast-breeding pest populations; however, they are ineffective at altering humans and other slow-
breeding species. This makes them ideal for controlling or mitigating mosquitoes, without fear the
technology will be used to directly harm human populations.
Four principles have guided this project and its various recommendations.
 Principle I: Avoid the use of global drives.
 Principle II: Localize drives to specific consenting communities.
 Principle III: Consider gene drive a process for spreading genes, rather than any specific
gene-edited product.
 Principle IV: Expand the Coordinated Framework for Regulation of Biotechnology to
include agencies with stakeholder interest in public health and the environment.
Together, these principles advance an inclusive approach to considering gene drive technology. In
avoiding the use of global drives to instead favor locally confined mechanisms, gene drives can be
targeted to specific communities. This may not be advantageous in all approaches, but it eases any
approval process considered by local and federal authorities. Open dialogue with the public and
conversations between federal agencies are critical for moving forward with any proposed
application. By considering gene drives as a process, rather than a product, these principles
additionally attempt to recognize the purpose gene drives have to alter fast-breeding populations.
After brief introductions to the technical details of gene drive in Sections 1 and 2, subsequent
sections address various areas of concern.
Most acutely, the U.S. regulatory system appears ill-equipped to handle the emergence of these
advanced applications of biotechnology. After overviewing the regulatory landscape, Section 3
argues for a process-based classification of gene drive technology and a product-based approach to
regulation. It is likely gene drives will be regulated as a drug under the statutory authority granted
U.S. Food and Drug Administration by the Food, Drug, and Cosmetics Act. In this case, FDA
should exercise its discretionary authority to ensure the safety of gene drives generally and then
prioritize review for products of greatest concern: action should be taken only to regulate gene edits
that result in non-natural alleles.
Section 4 address confinement issues. Given their intent to spread, steps must be taken to ensure
gene drives can be localized to consenting communities. By developing mechanisms that split up the
various gene drive components, and then monitoring their spread using autonomous monitoring

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systems, proposed applications can be confined and tracked to protect against unintended
consequences.
Advanced applications of biotechnology have generated significant biosecurity concerns. Many of
these are echoed with gene drive and are detailed in Section 5. Despite the concern, gene drives are
unlikely to function as effective bioweapons. More distressing is the potential for misuse. To defend
against this, The White House should convene intergovernmental policy coordinating groups to
bring threat analysts into conversation with federal regulatory, trade, and funding agencies around
gene drive research and application.
Gene drives offer unparalleled potential to address entrenched problems in public health. As
discussed in Section 6, however, the combination of gene drive and patent law may complicate
conversations around deployment by granting effective ownership over entire species. Furthermore,
concerns about the safety of the technology may slow proposed release. To incentivize
precautionary approaches, Congress should allow developers to claim ownership over gene drive-
modified organisms, but simultaneously extend liability to said organisms. This would allow
developers to protect their intellectual property, while giving the public confidence that premature
applications will not be released.
Section 7 returns to the issue of governance by federal agencies to argue for statutory changes for
regulating biotechnology. Given their intent to alter populations, gene drives should be regulated for
their intended environmental effects, rather than the health impacts of a gene edit on any individual
organism. Under this classification, Congressional action is warranted to give the U.S.
Environmental Protection Agency authority to regulate gene drives as a pesticide, under an
expanded definition of “pesticide.”
While streamlining regulations is important, as Section 7 additionally argues, it may advantage federal
regulators to expand the Coordinated Framework for Regulation of Biotechnology. This would
recognize new stakeholders for modern applications of biotechnology. By incorporating the Centers
for Disease Control and Prevention, as well as the Fish and Wildlife Service, capacity can be built to
ensure a comprehensive, meaningful, and logical review process for the future of biotechnology.
Gene drives are an exciting development that nevertheless highlight several stresses in the U.S.
regulatory system for biotechnology. Addressing these challenges alongside refinements to the
technology will not only be critical for considering potential applications of gene drive, but will also
be necessary for ensuring continued innovation in the field. Public health is a common problem that
requires collective engagement. By taking action now to encourage the ethical and sustainable
development of gene drives, developers and regulators can design a system for bettering improving
the health of local communities across the world.

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Contents
Executive Summary...........................................................................................................................................ii
Table of Figures ................................................................................................................................................vi
Abbreviations ...................................................................................................................................................vii
Preface................................................................................................................................................................ix
Acknowledgements ......................................................................................................................................ix
About Washington Internships for Students of Engineering................................................................ix
About the Author.........................................................................................................................................ix
Introduction........................................................................................................................................................1
1. A Brief History of Molecular Biology.........................................................................................................2
From Natural Selection to Genetic Engineering: The Evolution of Inheritance ................................2
Engineering Biology: Recombinant DNA and the Rise of Metabolic Engineering ............................3
2. The Science of Gene Drives ........................................................................................................................5
Overview.........................................................................................................................................................5
Mechanistic Principles of Gene Drive........................................................................................................6
CRISPR-based gene drives...........................................................................................................................8
Public health applications of gene drive technology ..............................................................................12
3. Regulating Biotechnology in the United States.......................................................................................14
4. Confinement: Local Drive..........................................................................................................................21
Localized gene drives allow for geographic confinement......................................................................21
Monitoring is essential for providing real-time data on drive spread ..................................................23
5. Biosecurity: Preventing Misuse..................................................................................................................25
Gene drives are impractical bioweapons..................................................................................................25
Minimizing the threat of misuse................................................................................................................27
Incorporating threat and risk assessment.................................................................................................28
6. Property: Can you Own a Species? ...........................................................................................................29
The Patent Landscape.................................................................................................................................29
Gene Drive Ownership ..............................................................................................................................32
Developers only own mosquitoes they physically control ................................................................32
Developers own the gene drive construct and, by consequence, all gene drive-modified
organisms..................................................................................................................................................33
7. Governing Gene Drive Technology: Considerations for Deployment...............................................36
Phased testing promotes precaution and opportunity for public engagement...................................36

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Governance options in the US context....................................................................................................37
International Cooperation..........................................................................................................................40
Conclusion and Recommendations...............................................................................................................42
Recommendations for Federal Agencies..................................................................................................42
Recommendations for Funders.................................................................................................................43
Recommendations for Developers ...........................................................................................................43
Recommendations for Legislators.............................................................................................................44
Bibliography......................................................................................................................................................45

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Table of Figures
Figure 1: Principles of Mendelian Inheritance .............................................................................................3
Figure 2: Gene drive-modified organisms increase in frequency over time within the population.....5
Table 1: Gene drive candidate species are fast breeding, sexually reproducing organisms ...................6
Figure 3: Homing endonucleases...................................................................................................................7
Figure 4: CRISPR-mediated gene editing.....................................................................................................9
Figure 5: The “mutagenic chain reaction” describes the behavior of gene drives ...............................10
Table 2: Select Statutes Regulating Animal Biotechnologies in the United States and Questions for
Federal Agencies Raised by Gene Drives.....................................................................................................15
Figure 6: Contrasting product- and process-based regulatory approaches for gene drives. ...............17
Figure 7: Daisy Drive.....................................................................................................................................22
Table 3: Types of patents ..............................................................................................................................29
Table 4: Proposed FIFRA update will allow all forms of gene drive to fall under EPA jurisdiction38
Figure 7: Regulating Biotechnology in the United States.........................................................................39

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Abbreviations
APHIS Animal and Plant Health
Cas CRISPR associated protein
CBB Centre for Biosecurity and Biopreparedness
CBD Convention on Biological Diversity
CDC Centers for Disease Control and Protection
CRISPR Clustered regularly interspersed short palindromic repeat
CVM Center for Veterinary Medicine
EIS Environmental Impact Statement
EPA Environmental Protection Agency
ERA Environmental Risk Assessment
FDA Food and Drug Administration
FFDCA Federal Food, Drug, and Cosmetics Act
FIFRA Federal Insecticide, Fungicide, and Rodenticide Act
FMIA Federal Meat Inspection Act
FNWA Federal Noxious Weed Act
FPPA Federal Plant Pest Act
FSA Federal Seed Act
FWS Fish and Wildlife Service
HEG Homing endonuclease
HHS Department of Health and Human Services
MSR Microsoft Research
NAS National Academies of Science, Engineering, and Medicine
NEPA National Environmental Policy Act
OSTP White House Office of Science and Technology Policy
PPIA Poultry Products Inspection Act
PQA Plant Quarantine Act
PVPA Plant Variety Protection Act
R&D research and development

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rDNA recombinant DNA
TALEN transcription activator-like effector nuclease
TSCA Toxic Substances Control Act
USDA United States Department of Agriculture
VSTA Virus-Serum-Toxin Act
WHO World Health Organization
ZFN Zinc finger nuclease

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Preface
Acknowledgements
The author would like to thank the many people who shared their thoughts, views, and expertise.
Kirk Dammen and Alex Bolton for their legal perspectives on intellectual property, property, and
liability. Dr. Tomoko Steen, Dr. Heather Meeks, and Dr. Kathleen Vogel for their thoughts on
biosecurity. Dr. Kevin Esvelt and Dr. Ray Monnat, Jr., for their technical expertise. Dr. Malia
Fullerton for her perspective on ethics. Dr. Sarah Carter, Dr. Stas Burgeil, and Dr. Genya Dana for
sharing their understanding of the U.S. regulatory system. Dr. Jason Delborne, Dr. David Smoller,
Dr. Peter Ryan, Gavan Petracco, and Scott Spencer for their holistic comments on the manuscript.
Keegan Sawyer and Audrey Thévenon for their thoughts and support on the project’s early outline.
Dr. Michael Marcus and Lisa Guay for their mentorship. Erica Wissolik and IEEE for providing
office space and support. And Steve Smith and AIChE for their sponsorship.
About Washington Internships for Students of Engineering
Founded in 1980 through the collaborative efforts of several professional engineering societies, the
Washington Internships for Students of Engineering (WISE) has become one of the premier
Washington internship programs. The WISE program provides future leaders of the engineering
profession in the United States opportunities to learn about and contribute to modern debates at the
intersection of science, technology, and public policy.
About the Author
Austin Wright-Pettibone is a rising senior in chemical engineering at the University of Washington.
An undergraduate researcher in metabolic engineering, his lab work focuses on designing RNA-
based post-transcriptional controls for modulating the production of plastics in E. coli. Currently, he
also serves as sole the student member of the University of Washington Board of Regents. He
worked as a lobbyist for the Associated Students of the University of Washington, where he helped
successfully pass the first tuition reduction in modern Washington State history. Previously, he
served as a representative for the UW Graduate and Professional Student Senate, as well as an intern
for The White House Office of Digital Strategy. Austin is interested in the intersections of science
and policy, particularly in the way the public interacts with and reacts to emerging biotechnology.
Post-graduation, Austin hopes to continue his work at the intersections of science and policy to look
at ways we can use technology to improve the lives of communities and individuals.

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Introduction
The emergence of Zika virus in the Americas has drawn renewed attention to the threat of
mosquito-borne disease. More than 3 billion people live in regions ravaged by Zika, malaria, and
related disease (WHO 2014). Despite tremendous efforts, the World Health Organization (WHO)
estimates between 655,000 and 1.2 million people die from malaria each year, many of them children
(WHO 2014). Traditional mosquito suppression and control techniques have proven ineffective at
eradicating disease in developing countries and are being challenged by the spread of Zika (WHO
2016). Recent developments in biotechnology offer a potential alternative to existing methods. The
science of gene drive is newly established, but already gene drives have shown significant potential
to address major problems in public health by preventing the ability of mosquitoes to serve as
vectors for disease (Chen 2016). However, this technology is still in its infancy: much must be done
to address basic technical questions and create appropriate governance regimes prior to
consideration of any proposed release.
It is important the United States maintain its leadership in research and development so U.S.
scientists, technologists, and regulators can take part in shaping the ethical and sustainable
development of emerging technologies. However, advanced applications of biotechnology broadly
challenge the existing U.S. regulatory structure. This threatens to undermine the ability of federal
authorities to effectively regulate emerging technologies. As decisions are being made about
governance, key stakeholders must also engage the public. Without robust engagement strategies,
there will be little incentive for the public to accept emerging biotechnologies. To improve public
perception, regulators should incentivize precautionary approaches that look to ensure the safety of
gene drive technology prior to proposed deployment. After reviewing the science of gene drives and
current regulations governing biotechnology, this paper outlines recommendations for drive
monitoring, governance, and ownership.
This paper is intended for federal agencies, funders, developers, and legislators. Those unfamiliar
with genetics will find Section 1 valuable in understanding the intent and function of gene drives.
Those familiar with Mendelian and super-Mendelian inheritance should begin at Section 2 for a
technical review or Section 3 for a discussion on the current state of U.S. biotechnology regulations.
Recommendations specific to regulators, funders, developers, and legislators are addressed in the
conclusion and expanded upon in each of the relevant sections.

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1. A Brief History of Molecular Biology
From Natural Selection to Genetic Engineering: The Evolution of Inheritance
Charles Darwin details the Theory of Natural Selection explaining the evolution of species
The science of gene drive fits within a long history of human progress on the study of inheritance
that finds its roots in the work of Darwin and Mendel. In Darwin’s account, traits that improve an
organism’s ability to compete and reproduce in its environment tend to get passed on, while those
that decrease an organism’s fitness tend to be eliminated (Darwin 1859). Fitness reflects the
reproductive success of an organism. Traits that improve an organism’s fitness tend to make it better
at reproducing in its environment, while fitness costs reflect traits that make an organism less
successful. Populations evolve by means of natural selection, slowly changing as advantageous traits
outcompete ones with high fitness costs in a never-ending interplay between a species and its
environment.
Gregor Mendel outlines the rules of Mendelian Inheritance, the basis of modern genetics
Gregor Mendel buttressed Darwin’s work through his studies on inheritance. By breeding plants that
always produced offspring with certain characteristics (so-called true-breeding plants), Mendel was
able to deduce the fundamental rules of inheritance. True-breeding green pea plants always produce
offspring with green peas, while true-breeding yellow pea plants always produce offspring with
yellow peas. By crossing these two plant types, Mendel noticed that all the yellow pea plants
disappeared (Mendel 1866). Surprisingly, these observations held across seven different
characteristics. Consequently, Mendel concluded that, in each case, two types of traits existed: a
dominant trait, like green peas, that showed itself whenever it was present in the organism, and a
recessive trait, like yellow peas, that only expressed itself when no dominant trait was present. To
streamline his nomenclature, Mendel distinguished between traits and so-called alleles. A trait was
characteristic of the organism (e.g., pea color). On the other hand, alleles are the subset of traits that
describe specific distinctions (e.g., green pea color vs. yellow pea color).
Mendel then went one step further and crossed the first generation offspring with each other to
create a second generation. In doing so, he observed a remarkable return of the recessive alleles in ¼
of the population. Mendel concluded that in the first generation one allele for yellow pea plant and
one allele for green pea plant must have been passed on (see Figure 1). Both the mother and father
contributed to the genetic make-up of the offspring, and these alleles were passed down through the
generations. Going one step further, he drew a fundamental distinction between genotype, or the
specific alleles passed on by a mother and father, and phenotype, or the particular allele an organism
displays. True-breeding plants, like those Mendel started out with, were termed homozygous: both
alleles were the same, therefore they always passed on the phenotype-determining allele. By contrast,
the first generation offspring were termed heterozygous, they contained one dominant allele that
determined the phenotype and one recessive allele that remained “hidden.” The return of the
recessive phenotype in the second generation offspring was the result of both heterozygotes passing
on the recessive allele, generating a homozygous recessive offspring.
In what became known as the Principle of Segregation, Mendel devised a statistical system for
predicting the passage of genes from parent to offspring. Given two parents, one of whom is
homozygous dominant and one who is homozygous recessive, the genotypes can be represented
generally as BB and bb, respectively.

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During the process of reproduction, each parent passes on one of its two alleles, with an equal
chance of passing down either allele. All first generation offspring of homozygous parents will have
genotypes Bb and display the dominant phenotype. If the heterozygous offspring then breed with
each other, they will have genotypes BB, Bb, Bb, and bb and exhibit a 3:1 dominant: recessive
phenotypic ratio: ¾ of all offspring will display the dominant allele, while ¼ will display the
recessive allele.
Figure 1: Principles of Mendelian Inheritance. (A) An organism’s genotype consists of two alleles. The organism can be either
heterozygous or homozygous for an allele. Phenotype reflects the allele that presents in an organism. (B) In a true-breeding (homozygous)
population, parents produce only one type of gamete. Parents can only pass down one type of allele. When the gametes from two different true-
breeding parents fuse, the offspring will be homozygous. When those offspring breed with each other, the recessive allele will reemerge ¼ of the
time. When the genotype contains a dominant allele, the phenotype will always reflect the dominant allele.
Not all genetic elements exhibit Mendelian inheritance characteristics
In the 1980s, researchers discovered a protein with super-Mendelian inheritance characteristics. That
is, the protein appeared to be inherited at frequencies much greater than the 50% predicted by
Mendel’s Principle of Segregation. These proteins, known as homing endonucleases (HEGs),
aggressively insert themselves into both copies of the DNA, converting organisms that have a HEG
allele and a non-HEG allele into organisms with only the HEG allele (Dujon 1989). In doing so,
they assure their perpetuation into the next generation, driving themselves throughout a population.
While Darwin’s Theory of Evolution by Natural Selection held that unfavorable traits would tend to
be selected against, remarkably, these HEGs appeared to propagate largely irrespective of the fitness
cost to the organism (Burt and Koufopanou 2004).
Engineering Biology: Recombinant DNA and the Rise of Metabolic Engineering
Genetics in the 20th
century remained mostly an observational science until the refinement of
recombinant DNA (rDNA) technology in the 1970s and 80s. In rDNA, a circular piece of DNA
known as a plasmid is inserted into a cell, where it then integrates with the cell’s DNA (Pray 2008).

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This process allows researchers to engineer cells that produce chemicals they would not otherwise
make. The novelty of this process is that it recognizes organisms as essentially “living machines”:
cells follow a set of instructions written in the DNA, passed on to the RNA, and carried out by
proteins (Reichard 1968). By inserting DNA, researchers can modify the instructions a cell follows
to produce new functions.
Early applications of recombinant DNA technology were cumbersome. If an organism is like a
finely-tuned factory, beginning rDNA techniques were akin to adding multiple new production lines.
The factory couldn’t handle all the changes, so production fell. With refinement, however, the
factory could be slowly changed to efficiently produce a new line of products. To optimize the flow
of chemicals researchers refined a careful balance of allowing and disallowing certain proteins to be
expressed (Cameron 2014). Metabolic engineering seeks to engineer this balance in cells. That means
adding DNA using rDNA techniques or removing it with molecular “scissors,” like the
endonucleases previously discussed. Unfortunately, many early techniques for adding or excising
DNA left scars1
, which reduced the effectiveness of the edit, and took much effort to engineer. The
advent of modern techniques, discussed in Section 2, radically changed the landscape by enabling
easy, scarless edits. As a result, super-Mendelian inheritance could conceivably be rationally
engineered. With modern genetic engineering techniques, a gene could be engineered to “drive”
itself through a population largely irrespective of fitness cost.
1 Scarred assembly processes leave specific nucleotide sequences after the gene edit, which may or may not be desired.
These nucleotides must either be accounted for in the editing process or risk altering the functionality of the target gene.

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2. The Science of Gene Drives
Overview
Gene drives function in sexually reproducing species with short life cycles
Gene drive is a broad term that describes genetic elements with super-Mendelian inheritance. In a
gene drive system, a limited number of initial drive elements can be seeded in a population. As the
gene drive-modified organisms mate with wild-types, the drive elements aggressively pass themselves
into the next generation. Offspring are biased to contain the gene drive. Over time, the drive
elements spread throughout the population and the number of gene drive-modified organisms
increases relative to the wild-type (see Figure 2). This increase in frequency continues until the gene
drive breaks down or reaches fixation, spreading to all organisms within the population.
Figure 2: Gene drive-modified organisms increase in frequency over time within the population. Gene drive-modified organisms that mate with
non-gene drive-modified organisms (wild-types) pass the gene drive element onto all offspring. When those offspring mate with wild-types, their
offspring receive the drive. Gene drive, therefore, offers an effective way to autonomously spread genes throughout a population.
Because gene drives aggressively pass themselves into the next generation, this increase in drive
element frequency tends to occur independent of the fitness cost to the organism. That is, unlike
normal traits, which decrease in frequency if they evolutionarily disadvantage the organism, gene
drives tend to increase in frequency irrespective of fitness cost2
(Burt 2003). This makes gene drives
highly applicable to population engineering.
However, not all organisms are suitable for population engineering using gene drives. Two main
factors determine gene drive function and effectiveness:
1. The candidate species must sexually reproduce.
2. The faster the candidate species breeds, the less time it takes to spread the drive.
Gene drive works in sexually reproducing organisms, where alleles from both the mother and father
contribute to the progeny’s genome, allowing the drive elements to spread via the fusion of gametes.
It does not work in asexually reproducing species, which transfer genetic information vertically from
mother to daughter without spreading laterally3
(see Table 1). Heterogamous species, which alternate
between sexual and asexual reproduction, are similarly ill-suited for efficiently spreading gene drives
throughout a population (NAS 2016a). In selecting species on which to use a gene drive, it is better
2 Strictly speaking, if the fitness cost associated with the drive is too great it will not spread effectively. For a more
complete discussion, see (Noble et al, 2016b).
3 Excluding horizontal gene transfer.

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if they reproduce only by sexual reproduction, since the drive will only spread during cycles in which
the species sexually reproduces.
Table 1: Gene drive candidate species are fast breeding, sexually reproducing organisms
To maximize drive efficiency, the sexually reproducing species should also have short generation
times. Gene drives spread trans-generationally, meaning the time for a drive to increase in frequency
is determined by the time it takes for a gene drive-modified organism to breed and mature offspring.
Species that are slow breeding (e.g., have long generation times), would slowly spread the drive
elements, making it impractical as an engineering tool on any human-relevant timescale. For
example, theoretical models estimate that a gene drive initially introduced into 1% of the population
could spread to 90% of its equilibrium point within 12 generations (Burt 2003). Humans tend to
have generation times on the order of 20 years. On the basis of these characteristics, a gene drive
originally introduced into 1% of the human population would take approximately 240 years to reach
90% of its equilibrium point. Gene drive would not be particularly useful for affecting changes to
human populations. In contrast, mosquitoes, such as Anopheles stephensi, have an average lifespan of 8
days (Riesen and Mahmood 1980). At approximately one week per generation, it would take just 84
days (3 months) for a drive to spread to 90% of its equilibrium point after a 1% introduction.
Introducing the drive to more organisms will speed up the rate of spread, but depending on the
species it may be less practical to engineer (Noble et al 2016a). Additional factors, such as the
mobility of the species, the density of original release, and the genetic load introduced by the gene
drive all factor into the drive’s effectiveness at spreading (NAS 2016).
Mechanistic Principles of Gene Drive
Several methods exist for achieving gene drive. The first super-Mendelian inheritance pattern found
was Barbara McClintock’s “jumping genes” in Maize (McClintock 1956). These transposable
elements (transposons) tended to increase in frequency over time within the genome by copying
themselves into various new regions of the DNA. In so doing, they increased their chance to
propagate into the next generation. A decade after McClintock’s discovery, C.F. Curtis postulated
these transposable elements could be used to “fix” a desirable gene in the environment (Curtis
1968). Later discoveries showed that transposons could indeed be engineered to aggressively push
themselves throughout a population, increasing in frequency over time (Carareto et al 1997).
Unfortunately, transposons tend to copy themselves imprecisely, making them difficult to reliably
engineer (Sinkins and Gould 2006).
Recognizing these shortcomings, Austin Burt proposed using a homing endonuclease to act as a
gene drive element. HEGs are part of a wide class of proteins known as endonucleases, which are
Example Species:
- C. neomexicanus (New Mexico
Whiptail)
Example Species:
- Anopheles gambaie (Mosquito)
- Mus musculus (Mouse)
Example Species:
- Homo Sapiens (Human)
- Elephas maximus (Elephant)
Good gene
drive
candidate
Fast Breeding Slow breeding
Bad gene
drive
candidate
Generation Period
Sexually
Reproducing
Asexually
Reproducing
Reproduction
Method
Example Species:
- Escherichia coli (E. coli)

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broadly used in engineering applications for their ability to induce double-stranded breaks in the
DNA. Normally, when a break to the DNA occurs it affects only one of the two strands, and the
cell is quickly able to repair itself using the other strand as a template (Cortez 2015). In double-
stranded breaks, however, there is no complimentary strand available to use as a template, so the cell
cannot repair using normal mechanisms. Diploid organisms, such as humans or mosquitoes, have
two copies of each chromosome, one from each parent. In a double-stranded break, the cell
searches for the homologous (matching) chromosome to use as a template for repairing the broken
DNA in a process known as homology directed repair.
HEGs exploit this mechanism to ensure their genetic information is copied into subsequent
generations. The gene, which encodes the endonuclease, is flanked by two sequences. In
chromosomes that do not have the HEG, these sequences abut (see Figure 3). The HEG identifies
these sequences and creates a double-stranded break between them. Using homology directed repair,
the cell tries to salvage what it understands to be lost genetic information. It identifies the flanking
sequences on the homologous chromosome, and replicates everything in between, repairing the
DNA and copying the HEG gene as a byproduct of this repair (Burt 2003). The HEG, now copied
into both chromosomes, assures its passage into subsequent generations.
Figure 3: Homing endonucleases. Reprinted from Burt 2003.
Burt theorized HEGs could be adapted for human use to affect site-specific changes to entire
populations. By engineering a HEG to recognize a sequence in the middle of an essential gene one
could simultaneously disrupt an essential gene and protect against evolutionary changes4
(Burt and
Koufopanou 2004). After insertion into an embryo, the HEG would target specific recognition sites
in the genome to insert itself. When that organism bred, the HEG would be passed along on a
4 Essential genes are less likely to be targeted as crossing over sites than non-essential ones. They are more stable
(Champer 2016).

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chromosome from the HEG-modified parent. If the offspring contained only one copy of the HEG
(that is, if it were heterozygous for the HEG), the HEG would recognize the target site on the
homologous chromosome to insert itself into both chromosomes, thus promoting homozygosity in
a previously heterozygous organism. Over time, the HEG would thereby drive itself through the
population, silencing genes that it disrupted along the way.
Elegant in theory, HEGs suffer from being difficult to engineer. Most recent genetic engineering has
been accomplished using zinc-finger nucleases (ZFNs) (Urnov et al 2005) or transcription activator-
like effector nucleases (TALENs) (Christian et al 2010). While both techniques allow for targeted
engineering of the genome, they require time-intensive specialist labor to design and implement
(Esvelt and Wang 2013).
Zinc-finger nucleases fuse a zinc-finger DNA binding domain to a nuclease cleavage domain (Urnov
et al 2010). Each zinc-finger is a small protein that specifically targets a site along the genome. By
reengineering the zinc-finger protein, different sites along the genome can be targeted by the ZFN.
Unfortunately, protein engineering is a nontrivial task. Proteins must first be identified and tested in
vitro for affinity and specificity towards the intended target. They must then must be tested in vivo to
assure specificity is conserved when used in the context of the larger genome. Chromatin structure
may interfere with target recognition, providing an additional hurdle. Altogether, each individual
protein must be custom-made, limiting the ease and desirability of designing homing-based drive
systems.
TALENs are functionally similar to ZFNs. They utilize the same nuclease as ZFNs to cut DNA at
specific regions (Li et al 2011). Rather than employing a zinc-finger protein, however, TALENs rely
on a TAL effector domain for targeting, which must be individually specified for the intended
application. Recent studies have documented a tendency for TALENs to recombine with each
other, resulting in loss of function (Koo et al 2015). Fortunately, the development and adaptation of
CRISPR/Cas9 gene editing techniques offers an easy way to engineer site-specific edits to the DNA.
CRISPR-based gene drives
CRISPR/Cas9 is a gene editing tool that contains an endonuclease protein (Cas9), which cuts DNA,
and a guide RNA sequence, which brings the endonuclease to specific sites along the DNA. In
contrast to ZFNs and TALENs, which rely on uniquely engineered proteins for individual
applications, interchanging the guide RNA sequence is sufficient to change the gene editing target
(Deltcheva et al 2011). Each guide RNA is specified by a unique sequence in the DNA that contains
a targeting sequence complimenting the desired site of gene editing. By changing the DNA
sequence, the guide RNA can be made to target different sites along the genome. Since the
endonuclease is conserved, a single protein can target multiple regions of the DNA by subsequently
binding different guide RNAs. Furthermore, early work developing CRISPR/Cas9 for application
found that guide RNA sequences less than 100 base pairs long can target unique sites along the
genomes of most species (Jinek et al 2012). This gives researchers a cost- and time-effective means
of editing DNA. For example, DNA can be synthesized for $0.23/bp (“Gene” n.d.). Therefore,
unique sites in the genome can be targeted for $23/site. This contrasts ZFN synthesis, which in
2015 was on the order of $5,000/site (Perkel 2013), and TALEN synthesis, which costs
approximately $65/site (Yamamoto n.d.). After ordering the sequences, the guide RNA can be

9
transfected into the organism along with the endonuclease, avoiding the added time validating
functionality that is requisite for optimizing ZFNs and TALENs.
Esvelt et al outlined the potential applicability of CRISPR/Cas9 to gene drive research in a 2014
eLife manuscript. The CRISPR/Cas9 system functions equivalently to a HEG (Esvelt et al 2014). By
inserting the CRISPR/Cas9 system into a cell along with two flanking sequences, researchers can
functionalize a HEG-like system using interchangeable guide RNAs. Essentially, researchers design a
plasmid to contain the genes which code for (i) the Cas9 protein, (ii) the guide RNA(s), (iii) any
additional genes to be expressed in the system, and (iv) the flanking sequences corresponding to the
sequences abutting the Cas9 cleavage site (see Figures 4 and 5). After doing so, the cell copies the
plasmid DNA into its genome during homology directed repair. Not only that, but if this DNA is
introduced into a system that does not contain the gene drive plasmid, then (like the homing
endonuclease) the system will induce a double-stranded break to introduce itself into all homologous
chromosomes that contain the sequence targeted by the RNA.
Figure 4: CRISPR-mediated gene editing. A guide RNA pairs to the Cas9 to form a complex capable of recognizing and binding to specific
sites along the DNA. Once bound, the Cas9 induces a double-stranded break in the DNA. Using homology directed repair, the cell attempts
to fix the break. By inserting template DNA along with the CRISPR/Cas9, researchers can induce the cell to integrate non-native DNA
into its genome. Reprinted from Esvelt et al 2014.
Gantz and Bier demonstrate CRISPR-based gene drives in Drosophila
As of July 2016, unique proof of concepts using CRISPR-based gene drives have been published in
four species. Valentino Gantz and Ethan Bier published the first study of CRISPR-based gene drives
in Drosophila (Gantz and Bier 2015, see Figure 5). Terming the process a “mutagenic chain reaction,”
Gantz and Bier inserted a plasmid containing two flanking sequences, the Cas9, and the guide RNA

10
(which recognized the flanking sequences only when they abutted). The guide RNAs targeted an X-
linked gene responsible for coloration. Upon cleavage of the DNA by the Cas9, the cell identified
the flanking sequences on the plasmids as matching the two ends of the cleaved DNA and repaired
the DNA using homology directed repair. This copied the Cas9 and guide RNA into the Drosophila
genome and silenced the X-linked gene, generating a homozygous recessive mutation in the affected
fly.
Figure 5: The “mutagenic chain reaction” describes the behavior of gene drives. After injecting an organism with a plasmid containing the gene
drive construct, CRISPR/Cas9 induce a double-stranded break in one strand of DNA. Using homology directed repair, the plasmid is used
as a template to copy the gene drive into the genome. The gene drive then acts again to target the other strand of DNA. This multi-step process
makes an organism homozygous for the gene drive, ensuring its passage into subsequent generations. Reprinted from Gantz and Bier 2015.
Upon breeding, Gantz and Bier noted 97% of female progeny were homozygous recessive for the
X-linked trait. This indicated the drive had passed on at super-Mendelian rates of inheritance.
Further, organisms heterozygous for the drive were being converted into ones homozygous for the
drive, ensuring that it would continue to be passed on to subsequent generations.
A key limitation of the design, however, was its uncontrolled spread. Because the guide RNA and
endonuclease are contained on the same plasmid, the drive will continuously cut at the sites of guide
recognition to perpetuate itself into both chromosomes of gene drive-modified organisms. This
creates a so-called autonomous drive (Akbari et al 2015). Absent the probabilistic tendency for the
drive to break down, the acting assumption is that the drive will spread to fixation (Burt 2003). As
discussed in Section 4, the spreading capability of gene drives makes confinement an area of concern
for developers and regulators. How does one limit the capacity of a gene drive to spread to
undesirable areas while allowing drives to spread in desired regions? Due to the global spreading
capability of autonomous drives, it is possible a single developer could release a small number of
gene drive-modified organisms to affect an entire species (DeFrancesco 2015). This creates
biosecurity concerns addressed in Section 5.

11
Dicarlo et al propose the use of molecular safeguards in gene drive experiments
James DiCarlo and colleagues preliminarily addressed the issue of drive spread in a subsequent proof
of concept. Using Saccharomyces cerevisiae (yeast), DiCarlo et al engineered a split drive system that
separated the Cas9 and guide RNA onto different plasmids (DiCarlo et al 2015). The guide RNA
was flanked by two sequences that combined on the homologous chromosome to form a
continuous sequence. The guide RNA targeted in the center of the sequence to drive itself into both
chromosomes when the Cas9 was present using homology directed repair. The Cas9, on the other
hand, resided on a plasmid without drive capability. Over time, the Cas9 would be probabilistically
lost, ending the ability of the guide RNA to exhibit drive. The guide RNA would then be passed on
at rates predicted by the Principle of Segregation. Separating out the Cas9 and guide RNA
represented the first example of a molecularly confined drive (Akbari et al 2015).
CRISPR-based gene drives can efficiently propagate active cargo genes to prevent the spread of disease
Early theory focused on using gene drive to silence target alleles, but gene drive is most useful in
spreading a target gene throughout a population. For example, mosquitoes are susceptible to
infection by malaria, which makes the insect act as a vector for the disease. Some mosquitoes
contain genes that make them more resistant to infection. These mosquitoes do not transmit
malaria. By spreading these genes throughout the mosquito population, one could efficiently and
effectively starve the disease of an effective host. Mosquitoes could still bite, but they would no
longer transmit the disease that makes them so deadly. Several months after publishing the
mutagenic chain reaction, Gantz et al demonstrated the use of a CRISPR-based gene drive to
propagate an anti-malaria gene through a population of An. stephensi (Gantz et al 2015). In their
experiment, Gantz et al created a plasmid containing (i) two flanking sequences corresponding to an
uninterrupted chromosomal sequence, (ii) guide RNA targeting the uninterrupted sequence, (iii)
Cas9 endonuclease, (iv) a red eye marker to visually indicate gene drive-modified mosquitoes, and (v)
the anti-malaria genes, m2A10 and m1C3. After integration of the plasmids into the founder
population, the modified mosquitoes were bred with wild-type adults. In one of the two crosses
bred, all offspring showed red eyes, indicating successful gene drive conversion in these populations.
Crossing the first generation offspring with more wild-type flies, the second generation offspring
also exhibited red eyes at super-Mendelian levels. More than 99% of second generation offspring
were red-eyed. Through transcriptional modeling of the first and second generation offspring, Gantz
et al confirmed the transcriptional activity of the anti-malaria genes, demonstrating the use of gene
drive to promote desirable alleles in a population.
Despite their success, several limitations indicate a need for continued technical refinement. For
transgenic males mating with wild-type females, the drive system worked as expected, resulting in
high levels of conversion. The offspring of transgenic females, however, were more prone to exhibit
mosaicism (speckled red and white eyes) or white eyes, indicating premature activation of the drive
system. As noted in their article, this appears to reflect a tendency for premature drive activation to
disfavor homology directed repair in the cell: the CRISPR/Cas9 in the egg cleave the unmodified
DNA from the sperm before it is in proximity to the modified DNA in the egg, increasing the
chances the cell will resort to other repair mechanisms, rather than using the egg’s DNA as a
template for repairing the sperm’s DNA. Research is ongoing in finding ways to promote later drive
activation and to increase the propensity of the cell to undergo homology directed repair.

12
Suppression drives can control mosquito populations, but require additional refinement to reduce fitness costs
Historical efforts in mosquito control have focused on reducing mosquito populations below levels
necessary to spread disease. The latest proof-of-concept echoed this by developing a suppression
tool that promoted female sterility in gene drive-modified mosquitoes. Hammond et al’s
“suppression drive” was intended to work in the germline only (Hammond et al 2016). Organisms
homozygous for the drive would be infertile, while ones heterozygous for the drive would be fertile,
but produce infertile offspring. A more complicated construction than Gantz’s population editing
technique, Hammond et al saw mixed results. While the suppression drive transmitted with greater
than 90% efficiency, it also appeared to reduce the overall fertility of the transgenic populations.
Organisms homozygous for the drive were sterile as expected. Unexpectedly, mosquitoes
heterozygous for the drive also showed reduced fitness levels. Significantly reduced fitness increases
the chance the drive will break down by reducing the number of viable offspring. Consequently,
finding ways to reduce the fitness cost in heterozygous gene drive-modified organisms will be
important in the longer term sustainability of the drive construct.
Public health applications of gene drive technology
The theoretical development of gene drive and recent proof of concept experiments have excited
the scientific community and popular press. Given their power to affect entire populations, gene
drives can be used in public health settings to prevent the spread of vector-born disease (Chen 2016,
Wade 2015, Gantz et al 2015). As Gantz et al demonstrated in their landmark paper, a gene drive is
not only capable of propagating itself, but can also push cargo genes (i.e. the allele intended to be
propagated) through a population. By seeding a gene drive to propagate anti-malaria alleles
throughout a mosquito population, scientists can prevent the mosquito from acting as a vector for
disease, effectively starving the disease-generating parasites of a suitable host. Nearly half the world’s
population lives in malaria-affected regions (WHO 2014) and more live in regions affected by
various other mosquito-borne diseases. Deploying a gene drive in these regions could alleviate much
suffering by providing a self-propagating, cost-effective means of eradicating vector-borne disease.
Not all organisms are suitable candidates for gene drive modification. Mosquitoes and other fast-
breeding pest species represent ideal candidates. Their short generation times means an allele can
rapidly spread throughout a population on a human-relevant time scale. Slower breeding species,
such as humans, elephants, or whales, would be less suitable candidates for gene drive modification.
Changes would require several hundred years to effectively propagate throughout these populations,
making them irrelevant on any human timescale.
Confinement issues present a significant technical and logistical challenge. While one community
may want to deploy a gene drive to solve a local problem, gene drive may not be the best solution
for all areas. Containment by way of physical safeguards (Gantz and Bier 2015, Gantz et al 2015,
Akbari et al 2015, Hammond et al 2016), such as the barrier facilities used in laboratory testing offer
a means for preventing the accidental release of gene drives. In situations where the drive is intended
for release, however, containment is insufficient. Split drive systems limit the geographic spread of
gene drives by reducing the drive capability. Modeling work suggests split drives may have
insufficient spreading capabilities for widespread use (Noble et al 2016). Fortunately, recent
proposals to localize gene drives indicate a potential refinement of the molecular confinement
system that offer several advantages. Through all this scientific development, however, a complex

13
series of regulations were built to govern the industry of biotechnology. Over time, the regulatory
agencies would act in concert with each other to support, understand, and direct the ethical
development of gene editing technologies and their various applications.

14
3. Regulating Biotechnology in the United States
The biotechnology sector in the United States is subject to regulation by multiple regulators with
overlapping – and often ambiguous – jurisdictional authority. Depending on the application, new
biotechnologies are jointly regulated by the U.S. Food and Drug Administration (FDA), the U.S.
Environmental Protection Agency (EPA), and the U.S. Department of Agriculture (USDA). This
paper focuses specifically on the public health applications of gene drives deployed in animals.
Therefore, biotechnology regulations will be discussed with a focus on animal-related regulations.
Agricultural regulations will be only briefly mentioned. FDA regulates a wide class of products under
the Federal Food, Drug, and Cosmetics Act (FFDCA). EPA draws authority from two statutes: The
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Toxic Substances Control Act
(TSCA). USDA has broad authority for regulating agricultural biotechnology under several different
statutes5
and more limited authority for regulating veterinary biologics under the Virus-Serum-Toxin
Act (VSTA). They secondarily protect animal and plant health and welfare through the Animal and
Plant Health Inspection Service (APHIS). The 1986 Coordinated Framework for Regulation of
Biotechnology (Framework) streamlines the regulatory process by designating lead agencies for
specific applications. To the extent possible, these agencies coordinate with other relevant federal
partners specified under the Framework to minimize the regulatory burden placed on technology
developers.
In 1992, the Framework was updated to include a scoping document, which outlined a risk-based
approach to regulation. Recognizing the resource constraints of federal agencies, the White House
Office of Science and Technology Policy (OSTP) stipulated in the scoping document that regulators
should (a) exercise their authority where it will provide the “most net beneficial protection of public
health and the environment,” and (b) focus on product-based, rather than process-based regulation6
.
At the time, the stipulations reflected an evolving scientific consensus that the products of
biotechnology were not ipso facto dangerous, but that specific applications may be of concern.
While the Framework has streamlined many biotechnical regulatory processes, emerging
technologies such as gene drive challenge this structure. Table 2 (see Page 14) broadly outlines the
regulatory framework for regulating biotechnology. It additionally details pressing questions raised
by gene drives that highlight the ambiguous nature of current regulations.
5 USDA designates the most relevant statutes for regulating plant products to be the Federal Plant Pest Act (FPPA), the
Plant Quarantine Act (PQA), the Federal Noxious Weed Act (FNWA), the Federal Seed Act (FSA), the Plant Variety
Protection Act (PVPA), the Federal Meat Inspection Act (FMIA), and the Poultry Products Inspection Act (PPIA).
Together, these give USDA the authority to inspect and regulate the safety of agricultural products and safeguard crops.
6 Exercise of Federal Oversight Within Scope of Statutory Authority: Planned Introductions of Biotechnology Products
into the Environment, 57 CFR 6753 1992.

15
Table 2: Select Statutes Regulating Animal Biotechnologies in the United States and
Questions for Federal Agencies Raised by Gene Drives
FDA regulates under the Federal Food, Drug, and Cosmetics Act
FDA regulates under FFDCA. FFDCA stipulates that drugs are “articles (other than food) intended
to affect the structure or function of the body of man or other animals”7
. Under these provisions,
FDA requires pre-market review of all animals modified by rDNA techniques, arguing that for the
purposes of regulation, genome alteration categorically affects the structure or function of an animal.
For biotechnical products that are “identical or virtually identical to an approved substance,”8
only a
supplemental application is needed during the pre-market review. For animal drugs, regulation is
administered by the Center for Veterinary Medicine (CVM). Animal biologics, on the other hand,
are licensed by USDA under the Virus-Serum-Toxin Act. The distinction between a new animal
drug and a new animal biologic is non-trivial and whether a recombinant DNA technology is
considered a drug or biologic for the purposes of regulation is decided by a joint committee of
representatives from USDA and FDA9
.
7 Federal Food, Drug, and Cosmetics Act, 21 USC §321(g)(1)(c).
8 Ibid.
9 Coordinated Framework for Regulation of Biotechnology, 51 FR 23302 1986.
Agency
Not applicable. Gene
drives unlikely to be
considered a biologic.
Not applicable. Gene
drives ineffective in
bacteria.
Which agency should lead
gene drive regulation?
Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA), last
amended 1972
Federal Food, Drug, Cosmetics Act
(FFDCA), last amended 2007
- Regulates new drugs in man and animals.
- Defines drugs to be "articles (other than food) intended
to affect the structure or fuction of the body of man or
other animals." 21 USC §321(g)(1)(c)
- FDA defines genetic edits in animals to be new animal
drugs. Uses statute to regulate all proposed genetic edits to
animals.
- Regulates pesticides, which are statutorily defined to be:
"any substance or mixture of substances intended for
preventing, destroying, repelling, or mitigating any pest" 7
USC §136(u)
Coordinated Framework for
Regulation of Biotechnology, 51 FR
23302 1986
- Streamlines the regulatory process by designating lead
agencies to oversee specific applications of biotechnology.
FDA
- Authorizes pre-market review of intergenic modifications
to microorganisms.
Questions for gene drive
Should FDA regulate gene
drives as a drug given their
intent to cause population-
level changes?
Should gene drives be
considered a pesticide if
intended to suppress pest
populations?
Statute Description
Virus-Serum-Toxin Act (VSTA),
last amended 1985
- Regulates animal biologicsUSDA
EPA
Toxic Substances Control Act
(TSCA), last amended 2016
Should gene drives be
regarded as a process for
editing populations or a
product of gene editing?
How does classification
affect the scope of
regulatory review?
- Stipulates that regulators should:
(a) exercise their authority where it will provide the “most
net beneficial protection of public health and the
environment;” and
(b) focus on product-based, rather than process-based
regulation.
1992 Scoping Document, 57 FR
6753 1992
OSTP

16
Interestingly, for some gene edits, the product-based regulatory approach outlined in the 1992
Scoping Document appears at odds with the FFDCA requirement for pre-market approval. As
Carroll et al have noted, it is unclear whether a gene therapy intended to generate a naturally
occurring allele would fall inside the current regulatory framework (Carroll et al 2016). If, for
example, the developer wants to devise a gene therapy that prevents an individual mosquito from
transmitting malaria by interrupting its ability to act as a vector for plasmodium falciparum10
, the
process would fall under FDA’s rule regarding rDNA, triggering pre-market review. However, the
alleles (m2A10 and m1C3) that prevent mosquitoes from serving as a vector for malaria occur
naturally. The gene editing product therefore occurs naturally. If the mosquitoes were selectively
bred to increase the frequency of desired alleles within a population, they would not trigger FDA
review. It is only because the process of gene editing was used that FDA reviews the product.
On one level this approach is understandable. FDA’s process is agnostic to the function of the edit:
Whether a novel allele was created as opposed to one that otherwise existed in nature is irrelevant
from FDA’s perspective. In a strict sense, gene editing alters the structure of the DNA within an
organism, which has the effect of altering the function of that organism relative to the state it had
prior to the gene edit. Thus, the very process of gene editing yields new products, which triggers
review.
However, the 1992 Scoping Document also calls for agencies to prioritize their oversight to
situations that provide the “most net beneficial protection of public health and the environment.” In
this case, FDA has cause to consider whether the product of gene editing occurs naturally. They
neither need, nor should be agnostic towards the function of the edit. Rather, they should consider
situations that would trigger pre-market review; within that category, they should then take action on
the select products that rank highest on the list of concern. To regulate all products of gene editing
is akin to arbitrarily deciding to regulate the process of gene editing, rather than the specific products
of gene editing that generate most concern.
 Recommendation 3-1: FDA should consider regulating only those gene edits that do not
produce naturally occurring alleles. In this sense, FDA would then regulate the products of
greatest concern, rather than the overall process of gene editing.
Regulating only the products, rather than the process of gene editing ensures new alleles are being
given full regulatory consideration, without forcing developers to come for approval each time they
want to use gene editing to promote natural alleles. Some may consider this foolish: what happens if
a developer wants to engineer an organism to have a deleterious naturally occurring allele? On the
face of it, this is strong justification for maintaining the current process of FDA reviewing all
products of genetic engineering. However, one would have to also ask what reason there is for
engineering a deleterious allele. If it is for controlling the population, then is FDA the best agency to
lead the regulatory process?
10 Plasmodium is a genus of pathogenic protozoa, many of which cause malaria in their hosts (CDC 2015).

17
Figure 6: Contrasting product- and process-based regulatory approaches for gene drives.
Under existing paradigms, it is reasonable to expect FDA will claim authority over gene drives as a
new animal drug. Gene drives alter animal function by either promoting infertility (in a suppression
drive) or editing a specific trait (e.g., giving mosquitoes resistance to malaria), thereby meeting the
threshold classification to define the technology as a new animal drug. However, gene drives arenot
designed to alter any one animal alone, but rather entire populations. This complicates the decision
on whether to designate FDA as the lead regulatory agency. While FDA may be strictly able to claim
authority over the technology as creating a new product designed to promote trait homozygosity in
affected organisms, the intent of drive technology to alter populations does not appear to
correspond with the spirit of FDA’s mission to protect human and animal health.
There is additional argument to be made that gene drives should not require any additional
regulation under a product-based regime. Gene drive as a technique is more about a process of
pushing genes throughout a population than it is about creating a specific product (see Figure 6). If
gene drive is considered a process, rather than a product, then what aspects of gene drive would
FDA pre-market review look at? Further, if the process of gene drive is approved, should
subsequent proposals to use gene drives in new settings be additionally regulated by FDA? If the
alleles spread using a gene drive are naturally occurring or have been found to be safe under earlier
rulings, and the process of gene drive was found to be safe, then on what grounds would FDA
regulate these additional proposals?
In summary, as gene drive technology develops, FDA (in partnership with EPA and USDA) will
need to clarify what aspects of gene drive they are regulating and the frequency with which that
regulation is intended to occur. Which agency should take charge in regulating gene drives? Given

18
their intent to alter populations, should gene drives be considered a drug for purposes of regulation?
Will gene drive be considered a process or a product? If a product, will all applications trigger pre-
market review?
EPA regulates under the Federal Insecticide, Fungicide, and Rodenticide Act, and the Toxic Substances Control Act
Under FIFRA, EPA has broad authority to regulate pesticides. For purposes of regulation, EPA
defines a pesticide as “any substance or mixture of substances intended for preventing, destroying,
repelling, or mitigating any pest”11
. Thus, genome alterations designed to destroy a pest organism’s
offspring or bolster an organism’s resistance to disease would fall under the scope of FIFRA
regulation, but edits designed to increase fitness12
would not (EPA 2016c). Similarly, gene drives
intended to suppress a population may meet the definition of a pesticide, but ones intended to
spread an allele, such as malarial resistance, throughout a population would not.
Prior to environmental release, developers of biotechnology with pesticide applications must prove
to EPA that their product will not cause “unreasonable adverse effects to humans or the
environment”13
. Depending on the level of concern, there is a two-tier system for EPA review. In
both, the developer must demonstrate the safety of their product through small scale field testing.
Following small-scale trials, EPA may decide to require large-scale tests prior to registration of the
product. After registration, the developer may market their technology.
TSCA supplements EPA’s FIFRA authorities by granting it ability to regulate microorganisms prior
to environmental release. In their TSCA-related rule-making, EPA has claimed the authority to
regulate microorganisms that are the product of intergenic modifications14
. In intergenic
modifications, genes naturally occurring in one species are transferred to another species where the
target gene is neither naturally found in that organism nor any organism within the genus of the
species to which the insertion is made. These contrast with intragenic modifications, where the
transferred DNA comes from a species within the genus. EPA’s reasoning, as laid out in the 1986
Framework, is that intragenic modifications are more likely to naturally occur as a result of
horizontal gene transfer than intergenic modifications, due to the closer affiliation between the
donor and recipient species. Therefore, there is a greater likelihood the intergenic modification may
result in a detrimental change to the organism or its environment.
Under TSCA, both the microorganism and the chemicals produced by said organism may be subject
to review provided they meet the criteria described above. Plants and animals, however, were
explicitly excluded from the 1986 rulemaking15
, except when transgenic microorganisms are
intentionally incorporated into the plant or animal, or when specific chemicals are extracted from
the plant or animal that are themselves subject to TSCA. Neither TSCA nor FIFRA grants EPA the
broad regulatory authority to govern transgenic plants or animals released into the environment.
That said, EPA is able to provide advice and input to other agencies on the environmental effects of
proposed biotechnologies. When Oxitec proposed using a genetically engineered mosquito to
11 Federal Insecticide, Fungicide, and Rodenticide Act, 7 USC §136(u).
12 Except when that fitness increase is associated with an increase in resistance to a pesticide.
13 The Coordinated Framework for Regulation of Biotechnology, 51 FR 23302(EPA)(II)(A) 1986.
14 Ibid.
15 The Coordinated Framework for Regulation of Biotechnology, 51 FR 23302(EPA)(III)(B)(3) 1986.

19
suppress mosquito populations, FDA claimed authority to conduct the review, classifying the gene
edit as a new animal drug (CVM 2016). Under the National Environmental Policy Act (NEPA),
Oxitec had to submit an environmental impact statement, which CVM reviewed16
. FDA then
consulted experts at CDC and EPA, who provided input on the public health and environmental
effects (CVM 2016). Following their consultation, FDA issued what is known as a “Preliminary
Finding of No Significant Impact,” indicating Oxitec’s product had met the necessary requirements
stipulated by FFDCA and NEPA for a new animal drug that may have environmental impacts.
It is less understood how and to what extent EPA will interact with FDA in regulating gene drives.
Oxitec’s proposal engineered sterility in individual mosquitoes. It was easy to classify the edit as an
animal drug under the FFDCA definition, since one organism was affected by a single edit. It is less
clear with gene drives, where many organisms can be classified by a single edit. In this case, is the
“drug” more akin to a pesticide, as currently defined by FIFRA?
 Recommendation 3-2: Clarify EPA and FDA’s role in regulating gene drives intended to
affect ecological changes. Specifically, clarify FDA’s definition of a drug as it may apply to
gene drives, and the threshold for EPA to regulate gene drives as a pesticide.
USDA regulates agricultural biotechnologies and has authority over animal biologics under the Virus-Serum-Toxin
Act
USDA holistically regulates agricultural products under numerous statutes. The agency has a more
limited role in regulating animal biologics under VSTA. USDA approves the import or interstate
shipment of all animal biologics, preventing their travel if they are worthless, contaminated,
dangerous, or harmful17
. USDA additionally plays a role in licensing veterinary biologics for use,
which gives them the ability to regulate the pre-market approval of genetically-modified
microorganisms. As with FDA and EPA, USDA regulates biologics as a product, rather than
regulating the process of producing the biologic18
. They do not differentiate between biotechnical
and conventional means of production.
Modernizing the Framework to meet advances in biotechnology
In July 2015, OSTP announced they would begin an interagency process of modernizing the
Framework for 21st
century biotechnology (Holdren 2015). Advances in biotechnology have
dramatically altered the product landscape, creating applications far afield from the limited gene-
editing technologies possible when the 1986 Framework was published. Whereas in 1986,
biotechnology was just starting to experiment with recombinant DNA in health, industry, and
agriculture, in 2016 advanced gene editing techniques have allowed regulators to envision a day
where scientists can precisely alter the human genome or change the environment through selective
edits to the DNA of entire populations. Earlier technologies were restricted to editing individual
organisms, but the advent of gene drive has allowed populations of organisms to be affected by a
single edit. And where earlier technologies would take weeks-to-months to engineer precise changes,
current techniques do so in days with minimal off-target effects (Perkel 2013). In this light, the
16 National Environmental Policy Act, 40 FR 1508.18 1978.
17 Virus-Serum-Toxin Act, 21 USC §151 1985.
18 The Coordinated Framework for Regulation of Biotechnology, 51 FR 23302(USDA)(IV)(A) 1986.

20
federal government is taking steps to minimize the regulatory burden on developers, while ensuring
the health and safety of humans and the environment. With the profound applications of current
biotechnologies, effective regulatory oversight and compliance by developers is critical for securing
the public’s trust. Gene drives are among the most promising and powerful new applications for
addressing long-standing challenges in public health. To ensure the ethical and sustainable
development of these technologies, their development should take place alongside conversations
with regulators and the public about their proper use and governance.

21
4. Confinement: Local Drive
The uncontrolled spread of autonomous gene drives raises political, ethical, and legal concerns.
Autonomous gene drives are self-perpetuating elements inside mobile organisms whose spread is
dependent on both the number of generations in which the drive is operational and the mobility of
the gene drive-modified organism (Flor et al 2007). The more generations in which the drive
operates and the greater the mobility of the candidate species, the larger geographic area to which
the drive can be expected to spread. One community may want to deploy a gene drive to solve a
local problem, but an autonomous drive will likely spread beyond that community into others who
may not have consented to deploying a gene drive. It should be self-evident that communities ought
to have input on proposals looking to alter the shared environment. By extension then, the larger
the spread, the more communities that need to be included in the decision-making process.
However, if consent is required prior to deployment, autonomous gene drives, which have potential
to spread across the globe, may be indefinitely stalled as communities debate the merits of the
proposed application. Therefore, the ability to confine a drive to a restricted geographic area may
ease the decision-making process and offer an appealing alternative to autonomous spread.
Localized gene drives allow for geographic confinement
The development of split drive systems offers an initial means to limit spread. By splitting the
autonomous gene drive into two elements, researchers prevent one element from exhibiting drive
and restrict the ability of the overall construct to spread trans-generationally (Esvelt et al 2014,
DiCarlo et al 2015). When both elements are present, the one capable of exhibiting drive will spread
at super-Mendelian rates. The other element, however, will be passed along at normal rates,
subjecting it to selective pressures. The non-drive-exhibiting element will be selected against and
gradually phased out of the population. Subsequently, the other element will cease to exhibit drive
and will itself be subject to selective pressures. Over time, the drive ceases functioning altogether.
Extending this concept, Noble and colleagues developed a “daisy drive” system that limits gene
drive spread by gradually self-destructing over subsequent generations (see Figure 7). In a daisy
drive, multiple genetic elements are placed in series with each other. The cargo is contained in the
last element of the series. No element drives itself, but rather each element drives the next in the
series. As nothing drives the first element, it is passed on at Mendelian rates and subject to selective
pressures. If the initial seeding of the daisy drive is low in relation to the total number of organisms
within the population, the first element will gradually decrease in frequency until it disappears. Then,
the second element loses its ability to drive. As each element loses its ability to drive, the chain is
shortened until no element exhibits super-Mendelian inheritance. At that point, the drive effectively
ceases to function. The number of generations the drive is expected to function can be modeled
(Noble et al 2016a) and correlated to the geographic spread (Flor et al 2007) of any individual
organism to develop a picture of the total expected geographic spread of the daisy drive system. As
expected, the more daisy chain elements in the system the longer the drive maintains itself and the
greater the expected geographic spread. Shortening the number of elements restricts spread,
allowing for more localized confinement of the daisy drive system.

22
Figure 7: Daisy Drive. Reprinted from Noble et al 2016a.
Despite their promise, daisy drives have yet to be fully tested. Experiments have been proposed in
nematodes (Esvelt n.d.) to test the dynamics of the system but, currently, only the split drive system
has been built in a model species (DiCarlo et al 2015). As these systems are refined, they will provide
new ways to locally confine gene drives, offering communities a means to restrict proposed
applications to target regions. Laboratory testing will offer data to refine the assumptions associated
with the population genetics of gene drive spread. Field tests can further add data regarding the
impact on population ecology within a region and refine our understanding of the linkages between
gene and geographic spread.
 Recommendation 4-1: Proposed deployment of gene drives should utilize locally confined
daisy drives. The use of autonomous gene drives should not be considered.
 Recommendation 4-2: Proposals to use a daisy drive should specify the number of
elements in the daisy chain and include analysis of the expected number of generations such
a drive will function. These trans-generational studies should be mapped to the expected
spread of the drive, so the geographic spread can be estimated and understood.
Gene edits intended to affect entire populations offer the potential to sculpt the evolution of pest
populations. However, extensive environmental testing will be required to ensure the drives are
properly confined to an intended species, and that the potential for gene drives to transfer from one
species to another are minimized or, preferably, eliminated (Lunshof 2015). Molecular confinement
strategies such as daisy drive can help in localizing a drive to a target area, but additional
environmental and entomological data is needed before proceeding with field testing of active

23
drives. As discussed in Section 7, the WHO (WHO 2014) and National Academies of Science (NAS
2016a) have recommended phased trial approaches to assist with this by providing data
incrementally to build out a complete picture of the molecular biology, as well as the entomological
and ecological effects of a potential gene drive application.
Both funding agencies and federal regulators can involve themselves in this process to promote the
safe and robust development of gene drive technology. By prioritizing research dollars for projects
in the ecological sciences alongside those for the basic research on the molecular biology of gene
drive, funding agencies can answer the broader questions associated with the impact of ecological
engineering. By supporting the phased trial approach, regulatory agencies can ensure the pre-market
review process is robust and the technology safe.
 Recommendation 4-3: Funders of gene drive research should prioritize funding research
intended to analyze the ecological and environmental impact of potential gene drive
applications alongside projects seeking to develop the molecular biology of gene drive.
Monitoring is essential for providing real-time data on drive spread
Confinement alone is insufficient if there is no means to confirm its success. Consequently, a
secondary issue to confinement and control is the active monitoring of gene drive spread.
Researchers have historically relied on phenotypic markers to differentiate gene drive-modified
organisms from non-gene drive-modified organisms (Gantz et al 2015, Hammond et al 2016).
However, this approach suffers from adding an additional load onto the organism. Specifically, the
more protein-coding genes that are added to the organism the more cumbersome the optimization
strategy to minimize the fitness cost (Catteruccia et al 2003). In cases where possible it is
advantageous to have non-phenotypic means of differentiating organisms within a population to
track gene drive spread.
This requires unique genetic markers that differentiate transgenic organisms from non-transgenic
ones. The insertion of CRISPR/Cas9 gives a clear distinguishing characteristic for monitoring
instruments to target. Functionalization of CRISPR/Cas9 relies on specialized promoter elements
(Deltcheva et al 2011), which can be screened for. Genotypic analysis can clearly differentiate
CRISPR/Cas9-modified organisms from wild-types by searching for either the specific promoter
sequences or the CRISPR/Cas9 sequences themselves19
.
Recent proposals in high-throughput autonomous sequencing offer a potential means for actively
monitoring the spread of a gene drive throughout a population. Microsoft’s Project Premonition
seeks to utilize an unmanned aerial system (drone) capable of delivering a mosquito trap equipped
with an on-site high-throughput DNA sequencing system (MSR 2015). The mosquito trap lures
mosquitoes in, closes the trap door once the mosquito is confirmed inside, and then analyzes the
insect. Originally proposed for epidemiological modeling of vector-borne disease (Jackson 2015), the
system has applications in many areas. Currently, the system is capable only of differentiating various
species of mosquitoes through morphological analysis (McFarland 2016). However, partnerships
with academic researchers (MSR 2015) are allowing the company to develop compact sequencing
19 This would be an effective means for identifying known gene drives where the developer declares the specific guide
RNA and endonuclease they are using. For illicit uses, like those discussed in Section 6, developers could use uncommon
endonucleases or promoter elements could be used, necessitating a wider net to cast for screening.

24
that can be deployed by the drone systems to enable on-site DNA sequencing. While their current
proposal adapts the system for tracking the spread of Zika, equipping the system with sequencing
capabilities would make it an ideal candidate for autonomously monitoring the spread of a gene
drive by searching for gene drive-modified organisms, as indicated by the presence of CRISPR/Cas9
promoters.
Even under current capabilities, Premonition would be useful in tracking the spread of a gene drive.
By including a unique phenotypic marker as part of the gene drive cargo, gene drive-modified
organisms could be analyzed using Microsoft’s current infrared analysis techniques (MSR 2015).
Deploying a fleet of drone monitoring systems, an accurate picture could be developed of gene drive
spread. Mosquitoes with the identifying marker could be geolocated to the trap location and the data
uploaded to cloud servers that would refine predictive models.
Such a strategy would secondarily offer a market for monetizing the monitoring of gene drive
spread. Under contractual agreements, Microsoft (or a relevant subsidiary) could work with those
deploying a locally-confined gene drive to track drive spread and ensure it does not go outside the
bounds agreed to by those licensing the gene drive technology (see Section 6 for discussion).
 Recommendation 4-4: Developers should explore the use of autonomous monitoring
systems to track the spread of gene drives in a population.
Using autonomous monitoring systems would have an added benefit of providing a means for
verifying the rate of spread during field testing. A current challenge for researchers has been
ensuring field trials are restricted to target sites given gene drives intent to spread (Akbari et al 2015).
While monitoring technology would not aid in confining the gene drives themselves, monitoring
does aid in knowing whether more stringent molecular confinement strategies are required.
Monitoring technology can further assist in understanding the broader ecosystem effects, but only to
the extent that it captures the requisite information. If, for example, a gene drive transfers via
horizontal gene transfer to another species, and the monitoring equipment is not designed to study
other species, it may miss a critical development. This could be avoided in part by designing
monitoring equipment that is overly broad (e.g., mosquito traps that capture and sequence multiple
species of mosquitoes). Equipment designers would then have the challenging task of delimiting
their technology, so that monitoring can be more broad than strictly necessary, but not broad to the
extent that it diminishes the ability to quickly gather accurate information.
By confining and monitoring gene drive spread, developers can work with local communities to
ensure its safe and ethical use. Controlling against the illicit deployment or misuse of drive
technology will require more active management. As these systems are being developed, it is
necessary to consider strategies for securing these devices.

25
5. Biosecurity: Preventing Misuse
As with many technologies, gene drives can be used for good or ill. Two related questions underlie
gene drive biosecurity: what is the potential for dual-use and what is the potential for misuse? Dual-
use traditionally refers to technology that can be used for both licit and illicit applications. Misuse
denotes specific applications of technology outside the agreed upon use. While gene drives have
dual-use potential, it seems unlikely state or non-state actors would seek to weaponize a gene drive.
It is more likely a scenario will arise in which a drive is used outside its intended use. When weighing
the benefit alongside the consequences, dual-use and misuse potential must be considered and
options for control (discussed in Section 4) actively pursued.
Gene drives are impractical bioweapons
Five points would seem to suggest gene drives are impractical bioweapons.
1. Gene drive elements are conspicuous
2. Gene drive research has proven difficult to optimize
3. Edits propagated by gene drives are reversible
4. Gene drives are not effective in directly affecting human populations
5. There are easier alternatives for weaponizing biotechnology
This is not to say there are no dual-use concerns, nor that the concerns are insignificant. The
possibility of combining gene drive with research intended to increase the virulence of a disease or
the susceptibility of a vector to carrying or transmitting disease is cause for attention. However, the
specific characteristics of gene drives suggest the technology would be impractical as a bioweapon.
1. Gene drive elements are conspicuous
CRISPR/Cas9 is an adaptive immune system native to many bacterial species. In 2011, researchers
adapted this system to eukaryotes (Deltcheva et al 2011). However, CRISPR/Cas9 is non-native to
eukaryotic cells; a screen for the endonuclease would return positive for any CRISPR/Cas9-
modified organism. The development of various CRISPR-compatible endonucleases (Zetsche et al
2015, Deltcheva et al 2011, Jinek et al 2012) would appear to suggest actors could develop new
endonucleases that would escape analysis, but development of new proteins involves a laborious
process of protein isolation, characterization, and optimization. It is theoretically possible, but, as
discussed later, unlikely. Additionally, CRISPR/Cas9 requires specialized promoters (Ran et al 2013),
which are optimized to initiate transcription of the non-native elements in eukaryotic cells. There are
a fairly limited set of promoters used for genetic engineering (Morgan 2014). Screening for these
promoters in combination with known CRISPR-compatible endonucleases makes it difficult to
conceal the use of gene editing techniques.
2. Gene drive research has proven difficult to optimize
Gene drives are theoretically elegant systems. However, implementing these in candidate species is
more difficult. Each proof of concept (discussed in Section 2) has revealed unexpected challenges
that will have to be overcome on a case-by-case basis. Gantz et al found sex-dependent
discrepancies associated with when and where the gene drive activated in vivo. Early activation led to
higher rates of non-homologous end joining (Gantz et al 2015). Subsequent papers have not solved
this specific issue in An. stephensi and it is unclear the extent to which this would be a problem in

26
other species. Subsequently, Hammond et al noted leaky expression in their suppression drive that
imposed prohibitively high fitness costs to An. gambaie that were heterozygous for the drive.
Optimizing the frequency of homology directed repair relative to non-homologous end joining and
preventing leaky drive expression in organisms heterozygous for the drive are non-trivial problems.
Understanding the specifics of the problem and devising effective workarounds require advanced
training in molecular biology, and remain pressing problems in the literature today. Whether the
determined solutions will work as intended in all species is unclear, as is the chance that any solution
will reveal deeper problems associated with drive functionality.
On the other hand, implementation may be only a fleeting problem. Present challenges do not
always dictate future outcomes. History is replete with technologies being adapted for dual-use
following scientific progress on the basic research questions (for a more complete discussion, see
(NRC 2010)). Given current capabilities it seems unlikely that state or non-state actors will seek to
develop weaponized gene drives. However, as Director of National Intelligence James Clapper
noted in his 2016 Worldwide Threat Assessment to Congress, gene editing is an emerging threat that
must be carefully monitored (Clapper 2016). Gene drives are one application of gene editing
technology that will need to be continuously assessed for its potential to cause harm to populations.
3. Edits propagated by gene drives are reversible
In the event of a runaway drive, researchers have outlined (Esvelt et al 2014) and designed (DiCarlo
et al 2015) gene drives intended to overwrite the activity of a previous drive. These so-called reversal
drives could protect against illicit use or unanticipated effects. After identifying the unwanted drive,
a reversal drive that “edits the edit” could be engineered and released. As this spread throughout the
population, it would overwrite the activity of the earlier drive to restore the original allele to the
population. Such drives have been tested in yeast and shown to function (DiCarlo et al 2015), but at
present researchers are unable to fully remove the effect of gene editing; the CRISPR/Cas9 markers
would still remain, but would be functionally inactive in drive-affected cells.
It has yet to be fully considered what would happen if two drives were active in a population at
once. Presumably the earlier drive could overwrite the second drive independent of the effect. The
two gene drives would compete, as it were, entering into some steady state where a certain fraction
of the population would remain edited by the first drive. Therefore, it would be necessary to
synchronize the release of the reversal drive in such a way as to prevent the illicit drive from
overwriting the reversal drive. Technology would need to be developed alongside models to assess
when a drive has ceased spreading or where it would be safe to release a drive, so as to maximize the
effect of dispersal.
 Recommendation 5-1: Developers and biosecurity researchers should evaluate the
effectiveness of deploying a reversal drive in environments where undesirable gene drives are
already active.
4. Gene drives are not effective in directly affecting human populations
As discussed in Section 2, gene drives function effectively in fast-breeding sexually reproducing
species. Humans have long generation times, which means a gene drive could not be effectively
applied to human populations. Gene drives could indirectly affect human populations, however,

27
through unanticipated environmental effects or targeted use in crops or pest populations (NAS
2016a). For example, rather than engineering a drive to spread resistance to herbicides, a drive could
be engineered to silence alleles that promote herbicide resistance, thereby increasing the vulnerability
of crops to pesticides. This would cause indirect harm to humans by damaging the food supply, but
would not cause direct harm to individuals or populations.
5. There are more profound or easier alternatives for weaponizing biotechnology
An important aspect of any conversation regarding biosecurity is the threat an emerging technology
poses in relation to other technologies. Resources to address biosecurity challenges are finite, so
threats must be prioritized relative to the potential harm a technology causes to human health or the
environment. As written about elsewhere (see Lipsitch 2014), there are emerging biotechnologies
that pose an acute risk to human health. Gain of function research, which attempts to understand
the specific characteristics of pathogenicity by engineering novel viruses in the laboratory, poses an
acute risk to society. The release of a laboratory strain could cause significant unintended
consequences, as vaccines are less likely to exist for these engineered strains (Lipsitch 2013). There is
the additional possibility an illicit actor may use gain of function research to increase the
pathogenicity of already virulent strain, making viruses more capable of infecting or transmitting
disease.
By contrast, gene drive research centers around the inheritance of alleles at above-average rates.
While gain of function research produces a product (namely, the engineered strain), gene drive
research develops a process for spreading the product. The specific products spread by gene drives
may be either harmful or beneficial to humans and the environment, but the process of spreading is
neutral outside the fitness costs associated with carrying the CRISPR/Cas9 system. Attention should
be paid to the products of research, which could cause exacerbated harm if combined with the
process of gene drive. However, the process of gene drive should be considered agnostic as to its
dual-use concerns for the purposes of prioritizing threat potential.
 Recommendation 5-2: Defense and intelligence analysts should focus threat assessments
on the products spread by gene drives, rather than the process of gene drive itself.
Even in considering the process of gene drive, there appear easier methods for causing terror by
bioweapons. Gene drives spread agnostically, meaning an actor that deploys a bioweapon with the
intent of terrorizing a population cannot themselves guarantee the technology will not in turn impact
their own populations. This may not deter a non-state actor, but the aforementioned difficulties
associated with optimizing drives for weaponization pose significant barriers for such actors.
Alternatively, naturally occurring toxins, such as anthrax, or chemical weapons offer an already-
proven means of causing harm and can be targeted with much greater precision than a gene drive.
Minimizing the threat of misuse
A more likely threat is the potential for misuse of the technology. Misuse in this context is
characterized as any use outside the intended or agreed upon function. Misuse, therefore, depends
upon the specific consent local populations give to use the technology.
For example, consider a hypothetical gene drive deployed in Florida to interrupt Ae. aegypti’s ability
to transmit Zika. The drive has been locally confined, so that it operates for a number of

28
generations. This has then been correlated to the geographic spread to delimit the expected range of
the gene drive. Sometime after the drive has been deployed, public health officials note an uptick in
Zika-resistant mosquitoes in Texas. Upon investigation, it is discovered the gene drive-modified
organisms have been somehow transported to Texas and are spreading there. The local population
has not consented to the use of gene drive, and is opposed to genetic engineering. Who is
responsible, and how do we prevent this from occurring? It is possible someone inadvertently
transported the mosquito there. It is also possible the transport was done intentionally.
In either case, it is unclear how this type of misuse might be stopped. Conceivably, a reversal drive
could be deployed in the area in which the unwanted drive is operating or an intense eradication
effort could be undertaken to eliminate all gene drive-modified organisms. Phenotypic markers
would make this process easier by clearly differentiating the wild-types from engineered mosquitoes.
However, absent active monitoring of gene drive-modified organisms, it may be impossible to fully
guard against potential misuse. It is also unclear whether authorities would allow a reversal drive to
be deployed if the first fails. This creates complex ethical questions about the potential deployment
of any gene drive, questions that fall outside the scope of this paper. Responsibility and ways to
incentivize monitoring are discussed in Section 6.
Incorporating threat and risk assessment
The recent gene drive report by the National Academy of Sciences (NAS 2016a) focused on the
need for environmental risk assessments (ERA), in contrast to the commonly used environmental
impact statements (EIS). Under NEPA, regulators can either require an EIS, which details the
limited natural and ecological consequences of a proposed technology, or a more expansive ERA
(SCOPE 1980). ERAs weigh natural and ecological consequences against the potential benefits, and
can secondarily consider public opinion and feedback. Such assessments are ideal for emerging
biotechnologies, which face uphill battles in the court of public opinion after the much heated
debates over genetically modified food, most recently reflected in Senator Lisa Murkowski’s
successful amendment barring AquAdvantage Salmon from entering the marketplace (Dennis 2016).
It may be advantageous to expand NAS’s recommendation to additionally include threat assessors in
conversations regarding risk assessment. Risk assessors, such as those at FDA and EPA, are trained
to evaluate the sustainability of a proposed technology and its risks to human health and the
environment (EPA 2016b), but threat assessors across the national security community are trained
specifically to assess the impact of emerging technology on U.S. national security (CBB 2015). As
researchers develop gene drives, the biosecurity challenges may shift as new information emerges.
Early communication by threat and risk assessors can mitigate potential unforeseen side effects. The
White House could take advantage of intergovernmental policy coordinating groups to bring threat
analysts into conversation with federal regulatory, trade, and funding agencies around gene drive
research and application. This would offer a place for the attendant cost/benefit analyses to be
evaluated alongside potential threats to U.S. national security to guide the safe and sustainable
development of gene drive technology.
 Recommendation 5-3: The White House should consider taking advantage of
intergovernmental policy coordinating groups to bring threat analysts into conversation with
federal regulatory, trade, and funding agencies around gene drive research and application.

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