GeneWatch Vol. 30 No. 1

Volume 30 Number 1 | Jan-Mar 2017

ISSN 0740-9737

GeneWatch January-March 2017 Volume 30 Number 1

Editor and Designer: Samuel Anderson Editorial Committee: Sheldon Krimsky, Jaydee Hanson Special Thanks: Andrew Kimbrell

GeneWatch is published by the Council for Responsible Genetics (CRG). Founded in 1983, CRG’s mission is to foster public debate on the social, ethical, and environmental implications of new genetic technologies. The views expressed herein do not necessarily represent the views of the CRG or ICTA staff or Board of Directors.

The Council for Responsible Genetics is a project of the International Council for Technology Assessment 660 Pennsylvania Ave Suite 302 Washington, DC 20003 Phone: 202-733-4094 CRG also has a Post Office box address in Cambridge, Massachusetts: Council for Responsible Genetics PO Box 400559 Cambridge, MA 02140 Correspondence can be sent to: CRG@gene-watch.org www.councilforresponsiblegenetics.org

Guest Editor’s Note

Andrew Kimbrell

This is the first issue of GeneWatch since the Council for Responsible Genetics (CRG) merged with the International Center for Technology Assessment. We are proud to continue the legacy of CRG with this special issue on one of the new kinds of genetic engineering: “gene drives.” Most of these articles argue that we should not be using these new kinds of genetic engineering on humans or in organisms to be released into the environment. Gene drives would quickly result in the new genes moving through a population and permanently changing them.

We invited one of the proponents of using gene drives to reduce human and animal diseases to write. Kevin Esvelt argues that with proper controls and complete transparency, CRISPR gene editing could be used safely.

The other authors disagree. Even calling this kind of genetic engineering “editing” misleads; we edit books, not dynamic living things. This makes the entire CRISPR gene “editing” metaphor very wrong headed and counterproductive. Phenotypic traits in plants and animals are not “controlled” by one “gene” or even a series of “genes,” but rather are the result of complex interactions between DNA and countless other elements in the nucleus and other parts of the cell. This includes not only epigenetic agents (histones) and processes (methylation) but much else we do not understand. This also includes all the processes that occur to proteins after they are formed, some of which we understand and many we do not. As such, modern biology is looking at the cell now as more of an ecosystem, where the DNA is a crucial part — not the composer, the conductor, or the whole orchestra, but just one element in the ecosystem. So, for example, every cell in the human body (except red blood cells) has almost the exact same DNA, yet these cells have remarkably different shapes and functions (bone cells, heart cells, toenail cells etc…), so DNA does not even “control” the function of cells.

We also have explanatory gaps in not understanding really how DNA relates to the creation of cells, cells to creation of continued on page 10

staff

comments and submissions

Sheldon Krimsky, Executive Director, Ad Interim Samuel Anderson, Editor of GeneWatch Martin Levin, Senior Fellow Elizabeth Small, Fellow

GeneWatch welcomes article submissions, comments and letters to the editor. Please email editor.genewatch@gmail.com if you would like to submit a letter or any other comments or queries, including proposals for article submissions.

Student submissions welcome!

Cover Design Samuel Anderson

founding members of the council for responsible genetics

Unless otherwise noted, all material in this publication is protected by copyright by the Council for Responsible Genetics. All rights reserved. GeneWatch 30,1 0740-973

Ruth Hubbard • Jonathan King • Sheldon Krimsky Philip Bereano • Stuart Newman • Claire Nader • Liebe Cavalieri Barbara Rosenberg • Anthony Mazzocchi • Susan Wright Colin Gracey • Martha Herbert • Terri Goldberg

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Jan-Mar 2017

Image: ‘Untitled’ by Ruth Hubbard

GeneWatch Vol. 30 No. 1

4 In Memoriam: Ruth Hubbard 5 CRISPR Will Never Be Good Enough to Improve People Even the most precise alteration of a known gene is fraught with uncertainties. By Stuart Newman 7 The Social and Political Dangers of Human Germline Interventions New technologies raise new social justice challenges. By Elliot Hosman and Marcy Darnovsky 10 Letter: No Place for Gene Drives in Conservation 11 Gene Drive and Collective Oversight Powerful technologies are often developed behind closed doors—but we have an opportunity to challenge that. By Kevin M. Esvelt 13 Gene Drives: A Scientific Case for a Complete and Perpetual Ban We have two options for controlling gene drives: A radically novel system of regulation or a complete ban. By Jonathan Latham 17 Sterile Insect Techniques, GE Mosquitoes and Gene Drives The long history and difficult challenge of engineering mosquito fertility. By Jaydee Hanson Volume 30 Number 1

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In Memoriam: Ruth Hubbard

By Sheldon Krimsky Ruth Hubbard will always be remembered as an “Enlightenment Spirit” within the scientific community. Self-reflection is not usually one of the virtues of natural scientists, but Professor Hubbard took the path less traveled. She dedicated a good portion of her career to examining the myopia, sexism, and social implications of scientific claims about what we are and who we are.

She also was an unabashed critic of genetic reductionism. She wrote in the American Scientist in 1995: “Knowing my DNA sequence (my “blueprint”) gives me no insight into how my metabolic function will be integrated into the complex shape of my specific life.”

Even with so-called Mendelian (single-gene) conditions, she correctly noted, the disability varies significantly because of other factors in the individual’s body and living environment that affect the penetrance of the genetic mutation. “Genomania” was the term she used for society’s obsession with genetic causes ignoring proven public health contributions to wellness. In Profitable Promises: Essays on Women, Science and Health she wrote: “It is an enormous waste of talent and resources to try to foresee the potential health hazards that lurk in the genes of each of us while entire segments of the U.S. and world population are exposed to wholly visible threats to their health and well being.”

Professor Hubbard had a profound influence on women in science. She 4 GeneWatch

gave women the confidence to lift their voice over the din of patriarchal hegemony that persisted in so many fields. She was a founding member of the Council for Responsible Genetics at its inaugural year of 1983 and continued to contribute as editor of GeneWatch and Board member well past her retirement as Professor Emerita of Biology at Harvard. She

Professor Hubbard, who at times used the name Ruth Hubbard Wald, loved her walks at Fresh Pond in Cambridge, Massachusetts. She also painted, and she wrote a book of poetry titled Green Sky and Bright Red Grass which had not a trace of science. One poem titled “The Medium and the Message” speaks to the solipsism of technology.

The Medium is the Message Said Marshall McLuhan He is wrong The medium is There is no message cell phones portable phones wall phones plug-ins voicemail press one, press two answering machines with mailboxes stamped mail email webbed wide world ebay talking superstores

was a signatory to the “Genetic Bill of Rights” issued by CRG in 2000. For reasons of logic, later she reformulated Right No. 10: “All people have the right to have been conceived, gestated, and born without genetic manipulation.” She reframed it as: “All people have the right to the integrity of their genome and to refuse to participate in attempts to modify it for any reason or at any point in their lives.”

world shrunk people unreachable leave a message we’ll get back to you Who we?

Who you?

The medium is all No we No you No message.

by Ruth Hubbard Wald

Jan-Mar 2017

CRISPR Will Never Be Good Enough to Improve People Even the most precise alteration of a known gene is fraught with uncertainties.

By Stuart A. Newman The CRISPR/Cas9 (CRISPR) technique has been used to modify genes in animals, plants and fungi, organisms different from and more complex than the bacteria in which the molecular components originally evolved. It has undergone several refinements since its introduction, each iteration proving more accurate, with fewer off-target effects. The Stanford University bioethicist Hank Greely1 contemplates using CRISPR to touch up human embryos, which have been produced by in vitro fertilization and prescreened for overall suitability by gene sequencing. George Church, a Harvard University genetic technologist and entrepreneur, advocates a more aggressive program of CRISPR-mediated genetic improvements to future generations.2 Claims of the near-infallibility of CRISPR may be overstated,3 but even if it could be made to operate perfectly, would using CRISPR to improve humans by altering embryos ever be justified? Since CRISPR acts on genes, not traits (which are presumably the target of any prospective modification), the answer to this question depends on the relationship between them.

In fact, there is a growing realization that DNA is far from the “code of life” it has long been claimed to be.4,5 Geneticists commonly use terms like “epigenetics” (functional effects from chemical modifications of Volume 30 Number 1

genes), “epistasis” (consequences of interaction between the products of different genes), and “incomplete penetrance” (failure of a gene to have its default effect), to signal their expectation that, apart from such exceptions, a gene, or ensemble of genes will influence a trait in a reliable fashion. But it appears that it is the well-behaved gene that may be the exception. A study in the journal Genome Research reported that the genes of monozygotic (“identical”) twins exhibit different patterns of activity-affecting modification from early stages of development.6 A review article in the journal Human Genetics discussed the implications of the “many known examples of ‘disease-causing mutations that fail to cause disease in at least a proportion of the individuals who carry them.”

The authors noted that in some cases the ability of a “bad” gene to cause disease “appears to require the presence of one or more genetic variants

at other loci.”7 An unstated implication of this is that when a typically pathogenic genetic variant is compensated by a second one, replacing it by its “wild type” or common counterpart would likely cause problems.

Surveying a rash of new data casting doubt on soundness of the received corpus of human genetics, a recent editorial in the journal Nature asserted in that “many [human] genetic mutations have been misclassified as harmful.” This accompanied a news feature that began “Lurking in the genes of the average person are 54 mutations that look as if they should sicken or even kill their bearer. But they don’t.”8 Part of the reason for the disarray in the field is the notion, long rejected by geneticists but difficult to completely dispel, that individual genes map one-to-one to specific traits or diseases. But recent research suggests that the problems of genotypephenotype mapping go much deeper, to the concept of the gene itself. One problem is the fact that genomes have unique evolutionary histories. The genes that helped establish the basic body plans and organ structures of animals around 600 million years ago still operate in present-day species, but they have diverged in their precise functions, partnering with different accessory genes in different kinds of animals, even when making GeneWatch 5

the same structure (an eye, a heart, a limb). Consequently, members of the same species (including individual humans) can use variable genetic means to accomplish the same or similar ends.9 This “rewiring” effect is known to evolutionary biologists as “developmental system drift”.10 Another even more serious difficulty in assigning definite functions to genes is that their protein products do not have fixed identities. For more than half a century molecular biology was dominated by what came to be called “Anfinsen’s dogma,” the doctrine that the polypeptide chains specified by genes fold in unique fashions, and that the resulting proteins therefore perform similarly in all contexts.11 It is now recognized, however, that many proteins have one or more “intrinsically disordered” domains, and the contextdependent interactions among them constitute a protein-based system of inheritance of phenotypic variability that does not depend on changes in DNA.12 Intrinsic disorder is particularly prevalent among gene products that control the expression of other genes in complex, multicellular organisms, undermining standard ideas of how gene regulatory networks regulate embryonic development and organ physiology.13 Thus, even the most precise alteration of a known gene with CRISPR is fraught with uncertainties. This may be worth the risk in an existing person with a disabling or mortal condition for which there is no other effective treatment. But it would never be so in an embryo, where the intention would be to improve a prospective individual’s biological characteristics. Certainly a trait could be altered by gene editing, but not without the possibility of deranging other traits that may well have turned out normally in the unmodified embryo.

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Stated differently, “engineering” an organism, in analogy to engineering a mechanism or machine, is an inapplicable notion.

Commentators writing about reproductive biotechnologies with an ethical orientation often express concerns about the prospects of inequitable distribution or eugenic hazards of the anticipated benefits of gene manipulation – improvements to health, intelligence, physical beauty – while expressing no skepticism at all about the ability of the purveyors to deliver on their promises.14,15 It can be seen from the foregoing that, as with anyone else trying to sell something, it makes sense to find out what they might be hiding. nnn Stuart Newman, Ph.D., is Professor of Cell Biology and Anatomy at New York Medical College.

Endnotes 1. Greely HT (2016) The end of sex and the future of human reproduction. Harvard University Press: Cambridge, Massachusetts.

2. Bohannon J (2011) The life hacker.

Science 333:1236-1237.;Church GM, Regis E (2012) Regenesis : how synthetic biology will reinvent nature and ourselves. Basic Books: New York.

3. Begley S (2016) Do CRISPR enthusiasts have their head in the sand about the safety of gene editing? In: STAT Reporting from the frontiers of health and medicine.

4. Newman SA (2013) Evolution is not mainly a matter of genes. In: Genetic explanations: sense and nonsense. Krimsky S, Gruber J (eds). Harvard University Press: Cambridge, Mass. pp 26-33; 288-290.

5. Bonduriansky R (2012) Rethinking heredity, again. Trends Ecol Evol 27:330336, Moss L (2002) What genes can’t do. MIT Press: Cambridge, Mass.

6. Gordon L, Joo JE, Powell JE, Ollikainen M, Novakovic B, Li X, Andronikos R, Cruickshank MN, Conneely KN, Smith AK, Alisch RS, Morley R, Visscher PM, Craig JM, Saffery R (2012) Neonatal DNA methylation profile in human twins is specified by a complex interplay

between intrauterine environmental and genetic factors, subject to tissue-specific influence. Genome Res 22:1395-1406.

7. Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, Kehrer-Sawatzki H (2013) Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet 132:1077-1130.

8. Hayden E (2016) Seeing deadly mutations in a new light. In: Nature. pp 154-157.

9. Narasimhan VM, Hunt KA, Mason D, Baker CL, Karczewski KJ, Barnes MR, Barnett AH, Bates C, Bellary S, Bockett NA, Giorda K, Griffiths CJ, Hemingway H, Jia Z, Kelly MA, Khawaja HA, Lek M, McCarthy S, McEachan R, O’DonnellLuria A, Paigen K, Parisinos CA, Sheridan E, Southgate L, Tee L, Thomas M, Xue Y, Schnall-Levin M, Petkov PM, Tyler-Smith C, Maher ER, Trembath RC, MacArthur DG, Wright J, Durbin R, van Heel DA (2016) Health and population effects of rare gene knockouts in adult humans with related parents. Science 352:474-477.

10. True JR, Haag ES (2001) Developmental system drift and flexibility in evolutionary trajectories. Evol Dev 3:109-119.

11. Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181:223-230.

12. Chakrabortee S, Byers JS, Jones S, Garcia DM, Bhullar B, Chang A, She R, Lee L, Fremin B, Lindquist S, Jarosz DF (2016) Intrinsically disordered proteins drive emergence and inheritance of biological traits. Cell 167:369-381 e312.

13. Niklas KJ, Bondos SE, Dunker AK, Newman SA (2015) Rethinking gene regulatory networks in light of alternative splicing, intrinsically disordered protein domains, and post-translational modifications. Front Cell Dev Biol 3:8.

14. Singer P (2003) Shopping at the genetic supermarket. In: Asian Bioethics in the 21st Century. Song SY, Koo YM, Macer DRJ (eds). Eubios Ethics Institute: Christchurch, New Zealand. pp 143-156.

15. Comfort N (2015) Can we cure genetic diseases without slipping into eugenics? In: The Nation (August 3-10).

Jan-Mar 2017

The Social and Political Dangers of Human Germline Interventions New technologies raise new social justice challenges.

By Elliot Hosman

and

Marcy Darnovsky

As of this year, the creation of genetically engineered and enhanced future human beings is no longer a scientific hypothetical. It is a social justice challenge.

Human germline modification – that is, altering the genes of gametes or early-stage embryos in order to manipulate the traits of future children and generations – raises hugely consequential safety, social, and ethical concerns. The risks range from irreversible health harms to the introduction of a new era of eugenics, with exacerbated or new forms of social inequality, discrimination, and conflict. For these reasons, human germline modification has been widely considered off-limits, and is formally prohibited in more than 40 countries.

Over the past several years, the development of “gene editing” techniques has triggered renewed debate about human germline modification because they provide a relatively more accurate way to attempt to engineer traits by altering DNA in the nuclei of cells. During the same time period, a different set of biological engineering techniques has also become highly controversial.

These “mitochondrial manipulation” (or “three-person IVF”) techniques involve removing and recombining components of cells – more specifically, transferring the nucleus of one egg affected with mitochondrial mutations (or of an early-stage embryo Volume 30 Number 1

created with it) into an unaffected, enucleated egg or embryo, in an effort to produce a reconstructed egg or embryo with non-mutated mitochondria.

Although mitochondrial manipulation techniques do not make targeted changes to DNA sequences, they do constitute a form of germline modification. Many scientists are deeply concerned about their safety for any resulting children, and dispute the adequacy of the limited evidence from animal models. After a hotly contested policy process, mitochondrial manipulation was approved in 2015 by Parliamentary vote in the UK (required in order to carve out an exception to the country’s prohibition on human germline modification). It has not yet been attempted in clinics there. In the U.S., a policy process is under way.

Several fertility doctors have decided to simply ignore these scientific and policy deliberations. In late September and early October of this year, fertility clinics in Mexico1 and in the Ukraine2 announced human experiments with mitochondrial manipulation. A New York City-based doctor, who said he took his work to Mexico where “there are no rules,” reported that a child born on April 6, conceived with this technology, appears healthy. Two women in the Ukraine are believed to be pregnant via mitochondrial manipulation, even though they are not affected by

mitochondrial disease – the doctor there is using the technique to treat general infertility. There are rumors of additional pregnancies and/or births in China.

It is difficult to escape the conclusion that some fertility doctors are rushing to stake a claim to being the “first” to make a baby in a novel way. David King, PhD, director of the UK watchdog group Human Genetics Alert, issued a press statement condemning the news from Mexico, stating: This is entrepreneurial reproductive technology at its most unethical and irresponsible. It is outrageous that [these fertility doctors] simply ignored the cautious approach of US regulators and went to Mexico, because they think they know better….

These scientists have used an experimental technique that many scientists still think is unsafe, in order to create a world first. When are the world’s governments going to stop rogue scientists crossing crucial ethical lines?

In contrast, much of the media coverage in the U.S. and the UK seemed to celebrate the creation of the world’s first “three-parent baby.”

And unfortunately, similar hyperbolic and celebratory rhetoric has accompanied media accounts of gene editing. Since early 2015, an imminent “genetic revolution” of “editing humanity” has been featured on GeneWatch 7

cover after cover of magazines and newspapers.3 With the door to high-risk embryo engineering techniques in fertility clinics now ajar, some are pointing to the UK’s policy debate around mitochondrial manipulation techniques as a model for moving forward with germline editing using CRISPR and similar tools.4 In fact, the controversy over “three-person IVF”5 holds many lessons for the ongoing discussion of “germline gene editing”6 – as a cautionary tale rather than an instruction manual.

Market-Drive Mission Creep In the extended policy conversations about mitochondrial manipulation, researchers depicted it as a preventative medical technology for parents at risk of passing on serious mitochondrial disease to their children. On that basis, the techniques would be indicated for only a very small number of people, given that some 85% of mitochondrial disease involves mutations in nuclear DNA that these methods would not address.

However, if they were to be used for infertility, the potential uptake would be very large indeed. The almost immediate adoption of these risky embryo engineering procedures for a purpose never seriously considered in the risk assessments seems to demonstrate that market forces will drive fertility clinics to widen their customer demographic to the greatest extent possible.

In fact, the medical justification for germline techniques of any kind is dubious. People at risk of transmitting genetic diseases to their children have a number of alternatives. In every case, they could be guaranteed unaffected children by using thirdparty eggs or sperm. And in nearly 8 GeneWatch

every case (though not quite as reliably for mitochondrial DNA conditions), the embryo screening method known as pre-implantation genetic diagnosis or PGD would provide children who were unaffected by the condition in question and fully genetically related to both parents.

Dangerous Risk-Benefit Imbalance for Future Generations Children born via embryo engineering methods – whether mitochondrial manipulations or germline editing – would face not just the high risk of biological complications, but also compromises to their privacy both in terms of media coverage, and medical display and tracking. Both procedures would involve a dangerous imbalance between medical and social risks to future children on the one hand, and the benefit to parents in pursuit of a genetic connection on the other.

Germline editing, with its potential ability to engineer specific traits, presents even greater dangers to children, familial relationships, and society. Children would risk being broadly defined by an engineered trait: Regardless of the germline intervention’s actual biological impact or the value that the child placed on that trait in relation to their forming sense of self, it could deeply affect the way the child is treated. This could be particularly disconcerting for children who grow up and find their values differ significantly from their parents.

Reinforcing Inequalities and Introducing Novel Forms of Discrimination We know that zip code is more important than genetic code when it comes to shaping health and longevity. But what if the affluent were given

the ability to choose not only their zip codes but also their children’s genetic codes? Today elite groups pour money and resources into making their neighborhoods upscale and exclusive. Tomorrow will they be working to define their progeny’s costly modified genes as markers of prestige and privilege? We run the risk of programming slippery notions of desirable traits, conditions, and bodies into the biological makeup of future generations. A “biologization” of inequity could prove to be even more recalcitrant to change than existing social structures of power. Further, the social and commercial dynamics that would constitute the context for human reproductive germline modification could easily exacerbate global disparities and take structural inequality to a new (molecular) level.

Unenforceable Policy Distinctions Some who advocate pursuing germline genome editing say they would support using it only to prevent serious disease, and not for other improvements. In practice, however, there is no clear distinction between medical and enhancement uses. Indeed, there is no objective way to draw clear lines among “difference,” “disorder,” and “disease.”

The therapy/enhancement distinction is also untenable from a policy perspective. In many countries, including the United States, it would simply not be possible to restrict the purpose of an approved procedure. If the Food and Drug Administration were to approve germline interventions for serious disease, immediate off-label usage would be completely legal.

The only meaningful policy line is the one that has been consistently and repeatedly drawn up to now: a ban on genetic engineering Jan-Mar 2017

for human reproduction using intentional germline modifications.

Germline modifications are considered medically unnecessary human experimentation by the Council of Europe’s Convention on Human Rights and Biomedicine, as well as by UNESCO, which called for a moratorium on such interventions in the 2015 update to the UN’s Universal Declaration on the Human Genome and Human Rights.7 Undemocratic Strides toward a Brave New World?

At the conclusion of the December 2015 International Summit on Human Gene Editing, a statement issued by the organizing committee stated that “it would be irresponsible to proceed” with human germline editing for reproduction unless and until “there is broad societal consensus about the appropriateness of the proposed application.”8 Unfortunately, there have been few efforts to encourage public engagement on anything like the level that is clearly needed. Most of the meetings and consultation processes that have taken place are monopolized or dominated by scientific and technical experts, with selected individuals who are known supporters of a “full speed ahead” approach to new biotechnologies.

A wide range of publics are in fact being “edited out” of stakeholder meetings and policy debates, including advocates (for disability rights and justice; racial justice; environmental justice; public health; reproductive health rights and justice; and sex and gender minorities including intersex and transgender communities), artists, and scholars from the social sciences and humanities.

These groups’ values, traits, identities, and perceived “inferiorities” risk ending up on the cutting room floor.

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In fact, public opinion studies show wide support for a “don’t go there” approach to human germline modification. Opinion in the United States in particular has been consistent over recent decades.9 Although polls on this issue are highly sensitive to framing bias, their results, along with data from focus groups, show a rich range of articulated concerns that belie techno-enthusiast efforts to dismiss public concern as stemming from religious ideologies or a lack of scientific understanding.

Preventing a New Era of High-Tech Eugenics From a U.S. policy perspective, the needed steps are clear, if far from simple: establishing a federal ban on germline modifications for human reproduction, and joining in international agreements that put such human experimentation off-limits.

In addition, we need a broad international dialogue about establishing scientific and medical norms that observe human rights and prevent practitioners from forum-shopping until they find a jurisdiction lax enough to proceed.

We also need to build a domestic dialogue that includes the range of unheard voices beyond the standard “stakeholder” models. Among the themes that need to be explored in these conversations: commercial and status incentives in biomedicine and biotechnology; the history of human experimentation in vulnerable populations for government, academic, and corporate research; the history of eugenics; and how social inequities warp the distribution of benefits and risks in research and development.

We can and should stand in the way of an era driven by eugenic upgrades and increased genetic surveillance. We can and should preserve for future generations the right of

self-determination. We can and should promote democratic debates that shield publics from a cohort of elites bent on the individualistic technological transcendence of human “limits.” We need not risk a never-ending repro-genetic upgrade cycle that threatens to split human society even more dramatically than our current tolerance for social inequality already allows. nnn Elliot Hosman, JD, Senior Program Associate at the Center for Genetics and Society, is an investigative writer on law and policy and a social justice advocate.

Marcy Darnovsky, PhD, Executive Director of the Center for Genetics and Society, speaks and writes widely on the politics of human biotechnology, focusing on their social justice and public interest implications.

Endnotes 1. http://www.geneticsandsociety. org/article.php?id=9697 2. http://www.geneticsandsociety. org/article.php?id=9730 3. http://www.geneticsandsociety. org/article.php?id=9618 4. http://www.biopoliticaltimes. org/article.php?id=9757 5. http://www.geneticsandsociety. org/article.php?id=6527 6. http://www.geneticsandsociety. org/article.php?id=8711 7. http://unesdoc.unesco.org/ images/0023/002332/233258E.pdf 8. http://www.nationalacademies.org/geneediting/Gene-Edit-Summit/index.htm 9. http://www.geneticsandsociety. org/article.php?id=9367

GeneWatch 9

Letter: No Place for Gene Drives in Conservation From a longer letter, “A Call to Conservation With a Conscience,” initiated by the Civil Society Working Group on Gene Drives.

New technologies have played an important role in protecting life on earth, and we the undersigned support innovation and science in conservation. However, we believe that a powerful and potentially dangerous technology such as gene drives, which has not been tested for unintended consequences nor fully evaluated for its ethical and social impacts, should not be promoted as a conservation tool.

From the climate impact of the

internal combustion engine to the synthetic chemicals that have poisoned the web of life, we have learned some lessons. We now understand the serious need for precaution when radical new technologies arise, especially with gene drives, which change the rules of genetics and inheritance and have consequences beyond our comprehension.

Gene drives have the potential to dramatically transform our natural world and even humanity’s

relationship to it. The invention of the CRISPR-CAS9 tool and its application to gene drives (also known as a “mutagenic chain reaction”) gives technicians the ability to intervene in evolution, to engineer the fate of an entire species, to dramatically modify ecosystems, and to unleash largescale environmental changes, in ways never thought possible before. The assumption of such power is a moral and ethical threshold that must not be crossed without great restraint.

Full text and more information: www.synbiowatch.org/gene-drives-letter

Editor’s Note continued from page 2

tissues, tissues to organs, organs to whole organism systems and then all of that functioning as one organism.

There must be a larger organizing principle somewhere, but it certainly is not DNA. That said, another myth is that these new techniques are very precise. This also is not the case as more and more articles discuss the problems with “off-target” effects from CRISPR. Adding to this complexity is the biome. We have 30 trillion or so cells, but the microbiome in us (bacteria) has 40 trillion cells. And that is crucial not just for digestion but for cognition and other functions. This is also true of other animals, not to mention the microbiome on the roots of plants. So CRISPR (borrowed from how bacteria slice up viruses that invade them), which allows for quicker and somewhat more accurate (but not completely accurate) slicing and dicing of DNA, is only dealing with one part of a far, far more complex 10 GeneWatch

puzzle. The hype about it has a lot more to do with public relations and patents and investment than real science or the potential to transform organisms in a reliable and consistent way. Not to say you cannot create a lot of unintended mischief by playing with these techniques, which is its real danger.

So I do take issue with the Science PR machine, the gullible media and even some of our friends in the environment and genetics watchdog community who repeat the hype and fears about these techniques being “successful” without really understanding the biology. This simply advances the “gene myth” and does a disservice to the public. Again, CRISPR scientists can do a lot of harm because they will be slicing and dicing in the dark, but not because they will create the perfect high IQ baby, more nutritious pork chops for all or plants that can get nitrogen from the air. That is all science fiction, not

science fact. These new techniques need to be regulated and controlled not because they will work as well as the hype, but because they won’t, and they will damage the environment and human health when they don’t work well.

Finally, we also include a tribute to our long time board member and friend, Ruth Hubbard, who died in 2016. Ruth was one of the scientists who early on understood that we needed to develop a cadre of scientists and ethicists who monitored closely the development of new genetic technologies. It was largely because of her vision that the Council for Responsible Genetics and GeneWatch magazine were born. We miss her clear voice deeply in this time of rapid change of genetic techniques.

nnn Andy Kimbrell is Executive Director of the International Center for Technology Assessment.

Jan-Mar 2017

Gene Drive and Collective Oversight Powerful technologies are often developed behind closed doors — but we have an opportunity to challenge that.

By Kevin M. Esvelt

As one of the scientists who first described how CRISPR could create gene drive systems capable of altering wild populations, I am morally responsible for the consequences.

I’m writing to you in the hope that the people most critical of the very idea can help. Bluntly, gene drive is an example of how the current scientific enterprise causes our technological power to grow faster than our ability to ensure it is developed wisely. But because it affects the shared environment, gene drive may also be the key to improving the system – namely, by causing it to favor collective oversight. And to do that, we need your help.

To be clear: I am not asking you to change your views on gene drive or any other technology. I certainly don’t expect you to support any realworld deployments, nor even continued research. Unlike what you might have heard, CRISPR-based drive systems cannot cause any species to go extinct unless everyone in the world deliberately chooses that outcome.

But there’s no question that they give entirely too many people the ability to unilaterally alter wild populations.

Just because natural forms of gene drive are present in every species doesn’t mean it’s right for us to harness the phenomenon.

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After all, many people hold the natural world sacred. They may believe that any attempt to change it – even to preserve the remainder – is immoral. Others believe that ecosystems are so complex and potentially fragile that the risk of accidentally causing a catastrophic and irreversible change is too great. I’ve met extremely gifted people who maintain that all technologies increase the ability of the powerful to oppress the powerless, and consequently work to halt them whenever possible.

I respect the intent behind each of these positions, although my own values and assumptions differ. I may be the leading scientific skeptic of our ability to develop gene drives with wisdom and humility, but I continue my research on local drive systems because I’d rather try to solve ecological problems with biology, not bulldozers. The smallest possible change capable of solving a serious problem may be genetic. If so, we should start small, have independent groups study the consequences, and scale up if appropriate.

I say all of this not to change your mind, but to make it clear that a total ban on gene drive research would be tremendously damaging to my own laboratory. Even so, if you decide to call for such a ban, I will understand.

I won’t agree, but I will publicly stand up for your right to share your views and criticize my research. More, I hope you will carefully scrutinize everything that my colleagues and I are doing.1 After all, the more people who try to imagine what might go wrong, the better our chances of avoiding mistakes. You might think of something that we’ve missed.

And since I am morally responsible for the consequences, I will listen to your concerns.

The problem is that many key decisions aren’t similarly advised by others. They’re made by small groups of elites behind closed doors. Even though these people cannot reliably anticipate the consequences of their actions, no one can check their logic or suggest alternatives because no one else knows a decision is being made.

This isn’t a new state of affairs, of course; the same sad description sums up most of human history. The difference is that technology is now powerful enough that some of those decision-making elites are scientists.

That’s a particular shame because doing research behind closed doors violates the central tenet of science.

The “scientific method,” such as there is one, simply involves constructing societal systems to reward GeneWatch 11

people who carefully scrutinize and challenge existing models of the world. Get enough people to look for flaws in the predictions of a theory, and eventually they’ll find some – and by doing so, help improve our understanding.

But why restrict that encouragement to professional scientists? We don’t have a monopoly on insight.

The more people who participate, the greater our understanding.

Sadly, the scientific enterprise began before we could share our research proposals and results with everyone in the world. And it evolved to punish scientists who do. Anyone who shares a good idea is ipso facto allowing other laboratories to throw more money and hands at it, publish first, and claim all of the credit. So no one does.

Everyone would be better off if we all knew what everyone else was doing, because then we wouldn’t be searching blind. We could rationally decide to collaborate or compete depending on the interests and capabilities of others. Doing science would also be much more fun, because we wouldn’t have to live with the nagging worry that we might be wasting years of our lives pursuing a project that someone else would do anyway.

The current state of affairs is a tragedy for science. But why should you care?

Because a world in which ever more powerful technologies are developed in secret by people who cannot reliably anticipate the consequences is a disaster waiting to happen.

Worse, it’s a world in which ever more people lack a voice in decisions that could affect them. Gene drives are a perfect example. Even though most CRISPR-based drive systems pose few — if any — ecological risks, that’s small consolation when some 12 GeneWatch

researchers can single-handedly loose constructs that could eventually alter entire wild populations. They might even do so accidentally while trying to do something else, entirely ignorant of the consequences for the social fabric.

That’s not a world I particularly want to live in, but none of us has much of a choice. We decided to publicly detail CRISPR-based drives precisely to raise awareness of this risk. We let people know before running experiments in order to encourage outside scrutiny, and my group is now working on ways of precisely restoring populations to their original state. But even if we succeed, it won’t be enough.

Because gene drive is just one powerful technology. There will be more. The problem is systemic: we are encouraging scientists to open boxes without allowing anyone else to take a look or offer an opinion.

That’s not a system anyone would rationally design. Sadly, it’s now easier to engineer biology than culture. And it’s particularly difficult to change a system from the inside.

You are not on the inside. In fact, you’re already engaged with the one issue that could help change the system: gene drive technology itself. As the U.S. National Academies’ report stated, “The best course of action is to ensure that the people who could be affected by a proposed project or policy have an opportunity to have a voice in decisions about it. Experts acting alone will not be able to identify or weigh the true costs and benefits of gene drives.”

doors. That means they’re a lever capable of changing the system… but only if enough people on the outside grab on.

So oppose gene drive research if you feel that you must. But please help use its very existence to change the system. The path is clear: pressure scientific journals, funders, and policymakers to require all research proposals involving any kind of gene drive to be made public. Give everyone a chance to voice concerns and make suggestions before experiments begin, when we can still change the design to improve safety.

If that sounds like a good idea for other fields, I couldn’t agree more.

But as with all things ecological, we should begin by making the smallest possible change – in this case, to the one field that demands it – and see if it works. Success will create a precedent that could then spread to other technologies with shared impacts, and perhaps far beyond. A few extra voices could make all the difference.

So help science be true to itself.

Use gene drive to open its doors, and let the daylight in.

nnn Kevin M. Esvelt is an assistant professor at the MIT Media Lab, where he leads the Sculpting Evolution Group.

Endnotes 1. http://www.sculptingevolution.org/genedrives http://www.sculptingevolution.org/daisydrives http://www.sculptingevolution. org/genedrives/current

In short, the status quo cannot hold. Simply building a drive system capable of spreading in the wild risks affecting others in the event of an accident. Hence, gene drives cannot be ethically developed behind closed Jan-Mar 2017

Gene Drives: A Scientific Case for a Complete and Perpetual Ban We have two options for controlling gene drives: A radically novel system of regulation or a complete ban.

By Jonathan Latham One of the central issues of our day is how to safely manage the outputs of industrial innovation. Novel products incorporating nanotechnology, biotechnology, rare metals, microwaves, novel chemicals, and more, enter the market on a daily basis. Yet none of these products come with an adequate data set of scientific information. Nor do they come with a clear intellectual framework within which their risks can be placed, as disputes over the precautionary principle show. The majority of products receive no regulatory supervision at all. How will the product be disposed of? What populations and which ecosystems will be exposed in the course of its advertised uses? What will be the consequences of accidental, offlabel or illegal uses? Typically, none of these kinds of questions are adequately asked by government regulatory agencies unless citizens actively prod them to do so.

In consequence of these defects, we expose our world to unique hazards with every product launch. In comparison with its tremendous importance, this is surely one of the least discussed issues of our day.

The spectrum of regulation Regulation of the products of industrial processes comes in quite diverse forms. At one extreme is the U.S. airline industry. Commercial airplanes are intensively regulated throughout their lives, from design to production, maintenance and Volume 30 Number 1

operation. When plane accidents occur, an intensive and independent investigation is carried out and little expense is spared searching for the parts, which may even be retrieved from the bottom of the ocean. When the investigation is concluded, recommendations are made. Not infrequently, aircraft design or maintenance is subsequently altered and planes already manufactured may be recalled.

This regulatory process is thus characterized by extensive and continuous feedback between all parts of the system: aircrew, regulators, maintenance crews, manufacturers, etc. This iterative type of regulatory supervision is widely viewed as successful and uncontroversial. Indeed, the airline industry has proportionately few deaths given the inherently hazardous and unnatural nature of flight.

In significant contrast is the regulation of the products of the chemical industry. The standard model for those synthetic chemicals that do not evade regulation entirely is to release them in a single decision. This decision is typically referred to as the ‘approval’ or ‘deregulation’ event.

After the approval decision is made, further data are sometimes collected and chemical re-registration may sometimes be required, but the approval decision is in many senses irreversible — for example, because recall is a practical impossibility. This type of regulation, which applies also

to pharmaceuticals, crop biotechnology, and medical devices is thus characterized by only a minimal iterative component. The contrast with airplane safety, with its numerous systematized and formalized opportunities for feedback and learning with respect to each product, is significant.

The question of endpoints A further contrast between airplane safety and chemical (or GMO) safety is in the number of endpoints — that is, potential specific hazards — that need to be taken into account.

The relative simplicity and success of airline safety follows significantly from the fact that the number of potential negative outcomes are few and well defined. With the exception of hijacking, a plane crash is almost the sole endpoint of airplane safety.

Each product of the chemical and biotech industries, on the other hand, has a close to infinite list of potential negative outcomes. In 2007 the French government was presented with a report by professor Dominique Belpomme into the health of the population of the Caribbean islands of Martinique and Guadeloupe.

According to that report, the 800,000 inhabitants faced a “health disaster” as a result of the spraying of the banana pesticide chlordecone. Half the male population would develop prostate cancer, infertility on the islands is rising, and all children on the islands are contaminated. Chlordecone will GeneWatch 13

remain in the soil for up to a century.1 Chlordecone was part of a pattern.

Beginning with Lead-Arsenate, via DDT and other chlorinated hydrocarbons, and continuing successively through organophosphates and neonicotinoids, a long line of chemical insecticide families have entered widespread use only to be discarded or banned for their broad negative ecological and health consequences.

The primary reason for this pattern of insufficient foresight by regulators and experts is that any single synthetic chemical, such as a pesti-

cide, may potentially cause an enormous number and diversity of harms.

They may result in reproductive toxicity, neurotoxicity, or carcinogenicity, for example, to any of a very large (often unknown) number of species.

Moreover, these harms may vary according to life stages, with environmental or dietary conditions, the presence of other pollutants, and so forth. Furthermore, these harms may occur near to or far from the places and times where the chemical was used. Even pharmaceuticals, where negative endpoints have historically been considered to be limited to individual patients, can yield surprises.

14 GeneWatch

For example, contraceptives entering sewage systems may later contaminate water bodies and so disrupt the endocrine systems of fish.2 A few authors have argued that the history of chemical regulation, from the point of view of protecting public health and ecological health, is better described as a long line of failure brought on unavoidably by the fact that such a myriad of endpoints greatly exceeds the practical and financial limitations of science. This is both because of the potential diversity and number of harmful endpoints,

and because each endpoint requires a specific scientific experiment—or at least specific data collection.3,4 Thus, endpoints as exotic as the reproductive consequences for fish of contraceptive hormones filtered by the human kidney (and by a sewage system) need to be explicitly considered and experimentally measured as part of the regulatory system, in order to avoid major health and ecological harms. Yet regulators are faced with the genuine unavoidable conundrum of the sheer number of such potential outcomes. Listing them all is impossible and investigating them is inconceivable. There

are, by many orders of magnitude, too many. The number of possible toxicological endpoints of a single chemical is enormous, yet failure to explicitly consider and measure each and every one of them could potentially lead to a public health disaster on the scale of Martinique and Guadeloupe or an ecological one on the scale of neonicotinoids.5 In short, one can show that regulations covering industrial products vary along two main parameters.

Those two parameters are: 1) the iterative nature (or otherwise) of the regulatory process applied to them, and 2) the number of potential negative endpoints needing to be explicitly considered.

Combining these two parameters with some relatively uncontroversial estimates of regulatory success suggests a simple hypothesis: that products having fewer endpoints and subjected to regulatory processes with more iterations are those most likely to be safe.

The underlying logic to this position is straightforward: Iterations allow mistakes to be corrected while fewer endpoints make regulation simpler and more manageable.

The endpoints biotechnology

of

agricultural

In comparison to synthetic chemicals, GMOs intended for agricultural use have a similarly large, perhaps greater, number of potential hazardous endpoints. They may harm human and other intended consumers, soils, other crops, non-target insects, and so forth. Nevertheless, agricultural GMOs are in some sense relatively contained with respect to the harms they can cause for the reason that many GMO varieties used in Jan-Mar 2017

agriculture are restricted in their reproductive potential. Most commonly by virtue of their frost sensitivity.

Such crops include maize and soybeans in most of the United States.

This natural biological containment acts as a severe restriction on the possibility of harm by eliminating most long term interactions outside of the agriculture/food system. Thus, the number of endpoints needing to be considered in risk assessment is greatly reduced.

There are some GMO crop varieties, however, which are not subject to such natural containment.

Creeping bentgrass (Agrostis stolonifera) is a turf grass for which the Scotts corporation (in collaboration with Monsanto) has created a GMO version resistant to the herbicide glyphosate.

The Scotts GMO bentgrass was open field-tested by the company in preparation for marketing between 2001 and 2003. However, it escaped from several company test sites.

Whether mainly by pollen flow or by seed dispersal is not known, but glyphosate-tolerant A. stolonifera can currently (as of 2016) be found in several Oregon counties and in neighboring Idaho.6 The escape of this GMO grass has created problems for weed management of waterways. Since A. stolonifera is a windpollinated species, we can anticipate that, in the absence of a dramatic intervention, GMO A. stolonifera transgenes will spread globally to wherever this grass grows wild.

GMO herbicide-tolerant canola (Brassica napus) has been approved for agricultural use in Canada, the US, and Australia. Within those countries, herbicide-tolerant canola GMO populations have been found growing as feral populations. Feral GMO canola populations have also been found in Great Britain, Japan Volume 30 Number 1

and France.7 The third example of an uncontained GMO is corn in Mexico.8 The above countries might consider themselves lucky that creeping bentgrass and feral canola are (so far) largely agricultural annoyances. GMO corn often contains one or more members of the Cry family of insecticidal proteins. In much of Mexico, unlike most of the U.S., corn growth is not restricted by frost — which means that, in essence, self-

most GMO crops is that gene drive organisms are explicitly designed to live and reproduce in the wild.

Conventional understanding is that gene drives can be regulated within standard frameworks.9 If we consider gene driven organisms in the terms of the framework outlined here, however, gene drive organisms approximate a perfect storm. They are ‘products’ that will likely not be able to be recalled, so any approval decision point must be presumed to

Each product of the chemical and biotech industries has a close to infinite list of potential negative outcomes. replicating insecticides are spreading across the landscape. This corn arguably represents a degree of risk to ecological and food systems that exceeds the threat from chemical pesticides.

Application to gene drives Gene drives, as currently envisaged, and as explained elsewhere in this issue, are techniques to promote the inheritance of specific alleles.

Gene drives typically rely on the introduction of CRISPR RNA and Cas9 type proteins from integrated transgenes to drive gene frequencies. Their ultimate goal is to alter the genetic composition of populations, including for the purposes of engineering population crashes or extinctions.

Because they rely on in vitro techniques to introduce foreign gene sequences, gene drives are technical extensions of biotechnology. From the present point of view of risk, however, the main distinction between gene driven organisms and

be final and irreversible; and their reproductive and dispersal abilities imply the need to test a great number of endpoints, perhaps even more than either synthetic chemicals or agricultural GMOs. Some sample questions can illustrate diversity of endpoints relevant to gene drive organisms.

For example, will gene driven organisms, such as mice or mosquitoes, be hazardous to the predators that eat them, either as the prey species drive their own population extinct (if that is their intention), or if they fail to do so? The scientific grounds for posing this question are substantial. One is the documented unpredictability of genetic engineering processes. This unpredictability is especially a concern in the pest organisms for which gene drives are presumably intended since they are largely uncharacterized in comparison to the agricultural varieties that are the standard objects of genetic engineering.

The second scientific grounds for concern about the toxicity of gene drive organisms are the specific gene GeneWatch 15

sequences that will be added. For instance, Oxitec’s GMO (but not gene drive) diamond back moth (Plutella xylostella), already planned for experimental releases in New York State, contains DNA from several viral pathogens including Herpes Simplex Virus (HSV).10,11 Whether genes from viral pathogens can ever be safely inserted and used in other organisms is still an open question.12 Other key questions center around whether gene drives will spread from the original species to others with which it may sometimes interbreed.

The importance of this is firstly that the gene drive is likely to negatively impact these other species. More than that, any unwanted and unanticipated impacts of the gene drive will be felt outside the predicted impact zone if gene drives spread beyond the original species.

A third set of questions surely must center around whether the evolutionary trajectory of gene drive components can be adequately controlled and predicted given the complex assorting and mutating inherent in the concept of gene drives.

Posing such questions foregrounds the crucial underlying point: that the number of potential hazardous endpoints needing to be investigated to establish the safety of a gene drive in the numerous conditions it will inevitably encounter will be vast. This is especially so when each question cannot be considered alone since none of them exist in isolation. The consequence is that no nation is financially or otherwise capable of operating such a science program, especially when these three questions represent the tip of an iceberg.

Compounding this main issue is that a large proportion of such endpoints cannot be credibly investigated outside of ecologically realistic environments, and such experiments 16 GeneWatch

are invariably expensive and laborious. Ideally, one would need a planet B to do such experiments.

It needs also to be considered that answering such questions would require unique and unprecedented scientific protocols. Imagine we wanted to test the toxicity of gene driven mosquitoes to bats, or test the behavioral characteristics of gene driven mosquitoes. There are unlikely to be scientific precedents, in terms of techniques and expertise, for such experiments.

These are the harsh realities that regulatory systems have long ignored. Having failed to protect the population against synthetic chemicals and failed to protect the environment from GMOs, it is illogical to expect that regulation organized on conventional lines will protect us from gene drives or any other wild GMO organisms.

This leads to just one conclusion. Unless a radically novel system of regulation can be invented, we should forget about gene drives.

Just as we would have been better off foregoing agricultural pesticides and fungicides. Because regulatory systems lacked the rigor to oversee them, gene driven organisms equally must never be released.

nnn Jonathan Latham, PhD, is Executive Director of The Bioscience Resource Project.

Endnotes 1. http://www.independent.co.uk/ news/world/europe/health-disaster-in-french-caribbean-linkedto-pesticides-402816.html 2. Fick J et al. (2010) Therapeutic Levels of Levonorgestrel Detected in Blood Plasma of Fish: Results from Screening Rainbow Trout Exposed to Treated Sewage Effluents. Environ. Sci. Technol., 2010, 44 (7), pp 2661–2666. (http://pubs.

acs.org/doi/abs/10.1021/es903440m).

3. Thornton J. (1999) Pandora’s Poison: Chlorine, Health, and a New Environmental Strategy. The MIT Press 4. Latham JR (2016) Unsafe at any Dose?

Diagnosing Chemical Safety Failures, from DDT to BPA. (https://www. independentsciencenews.org/health/ unsafe-at-any-dose-diagnosing-chemicalsafety-failures-from-ddt-to-bpa/) 5. IUCN Taskforce on Systemic Pesticides 2015 (http://www.tfsp.info/) 6. Zapiola ML et al., (2008) Escape and establishment of transgenic glyphosate-resistant creeping bentgrass Agrostis stolonifera in Oregon, USA: a 4-year study J. Appl. Ecology 45: 486–494. (http://onlinelibrary.wiley.com/ doi/10.1111/j.1365-2664.2007.01430.x/ full) 7. Schafer, M G. Ross A A., Londo J P., Burdick C A., Lee E. H, Travers S E., Van de Water P K., Sagers C L. (2011) The Establishment of Genetically Engineered Canola Populations in the U.S. (http://journals.plos.org/plosone/ article?id=10.1371/journal.pone.0025736) 8. D Quist & I H. Chapela (2001) Transgenic DNA introgressed into traditional maize landraces in Oaxaca, Mexico Nature 414, 541-543 doi:10.1038/35107068; Received 26 July 2001; Accepted 31 October 2001 9. de Andrade, Paulo Paes; Aragão, Francisco José Lima; Colli, Walter; Dellagostin, Odir Antônio; Finardi-Filho, Flávio; et al. 2016) Use of transgenic Aedes aegypti in Brazil: risk perception and assessment. Bulletin of the World Health Organization 94.10 (Oct 2016): 766-771. http://www.who.int/entity/bulletin/ online_first/BLT.16.173377.pdf 10. https://www.washingtonpost. com/news/energy-environment/ wp/2015/11/20/this-tiny-moth-is-stirring-up-the-gmo-debate-in-new-york/ 11. Wallace, H. GeneWatch (Nov 2015) Oxitec’s genetically modified moths: summary of concerns (http://www.genewatch.org/uploads/ f03c6d66a9b354535738483c1c3d49e4/ DBMbrief_fin.pdf ).

12. Latham JR, and AK Wilson (2008) Transcomplementation and Synergism in Plants: Implications for Viral Transgenes?

Molecular Plant Pathology 9: 85-103.

Jan-Mar 2017

Sterile Insect Techniques, GE Mosquitoes and Gene Drives The long history and difficult challenge of engineering mosquito fertility.

By By Jaydee Hanson

One of the great temptations in any field is to promote your solution to a problem as the only solution.

The recent application of gene drives to sterilize mosquitoes that transmit malaria or viruses like dengue and zika is an example of this tendency to first develop a technology and then look for applications that might justify its use.

For at least 70 years, scientists have been trying to sterilize insects to prevent them from spreading disease, especially mosquito-borne diseases like malaria, dengue and zika, an approach known as “sterile insect technique.” Sterilizing some insects with irradiation has been successful in preventing their reproduction.1 In the 1950s, it was used to rid the southeastern U.S. of the New World screwworm Cochliomyia hominivorax (Coquerel), a deadly parasite of livestock. During the next 43 years the technique was used to eradicate this screwworm from the U.S., Mexico, and Central America. Currently, the largest use of Sterile Insect Technique in the U.S. is for the control of Mediterranean fruit fly. Irradiated bollworms are also being released to control cotton boll weevils, and irradiated coddling moths are being released to help protect apples and pears.2 Interestingly, Rachel Carson, in Silent Spring, warned that using the Sterile Insect Technique to control a population of insects that could rebuild from neighboring islands or Volume 30 Number 1

other populations was especially challenging. Talking about a SIT effort to control houseflies in the Florida Keys, she wrote: “In a test on an island in the Florida Keys in 1961, a population of flies was nearly wiped out within a period of only five weeks. Repopulation of course followed from nearby islands, but as a pilot project the test was successful….

One of the problems of sterilization by radiation is that this requires not only artificial rearing but the release of sterile males in larger number than are present in the wild population. This could be done with the screw-worm, which is actually not an abundant insect. With the housefly, however, more than doubling the population through releases could be highly objectionable [to the local people].”3

Genetically Engineered Mosquitoes as a Sterile Insect Technique It seems a bit ironic that the first effort to use genetically engineered insects as a sterile insect technique is occurring in the Florida Keys near where the house fly experiment occurred more than 50 years ago. Rachel Carson’s observation about the need to release huge numbers of the altered insects has proven to be a big challenge for the company planning to release its genetically engineered mosquitoes. Oxitec, a company that grew out of research by Oxford

scientists, has genetically engineered mosquitoes, flies, diamond back moths, and cotton bollworms to become sterile in the next generation.

They planned to release their GE mosquitoes on the Key Haven, just north of Key West. The U.K. company (now owned by U.S. biotech giant, Intrexon), has a contract with the Monroe County Mosquito Control Board. However, local groups in Monroe County, led by the Florida Keys Environmental Coalition, organized an effort to block the release of the mosquitoes in Key Haven and forced the Mosquito Control Board to hold a referendum. On Nov. 8, the people of Key Haven voted against the release of mosquitoes on their island.4 The coalition effort may have been one of the few places in the U.S. where supporters of Donald Trump and supporters of Hillary Clinton worked alongside each other and won. The Mosquito Control Board agreed on Nov. 19 that they would respect the vote in Key Haven. On Dec. 5, the U.S. Food and Drug Administration confirmed to lawyers at the Center for Food Safety that the FDA’s approval only applied to Key Haven. If Oxitec wants to release its mosquitoes in the Keys, it will have to resubmit its application to the FDA.5 The problems of the Oxitec mosquito are likely a template for many of the problems that could come from using the gene drive technology to make mosquitoes sterile. The lack GeneWatch 17

of independent scientific research on the release of GE mosquitoes constitutes a most troubling factor in the initiative to release billions of these insects. While the desire to control viral diseases like zika and dengue is understandable, Oxitec, the company manufacturing the GE mosquitoes, has not demonstrated that its release of the mosquitoes in Panama, Brazil, Cayman Islands and Malaysia has reduced disease.

No studies have been done to understand the unintended evolutionary effects of introducing new genes into a species. GE mosquitoes are intended to be sterile, but not all are.

Eliminating Aedes aegypti, the yellow fever mosquito engineered by Oxitec, may open ecological space for Aedes albopictus, the Tiger Mosquito which carries the same diseases. Additionally, mosquitoes provide a food for animals and help pollinate plants.

18 GeneWatch

At least one orchid species depends on mosquito pollination. Genetically engineering mosquitoes to die off could put at risk species that rely on them, including threatened amphibians, bats and birds. The company only studied one of the many endangered species in the Keys to determine what effect that releasing the GE mosquito would have on the ecosystem. Prior to the cancelation of the GE releases on Key Haven, the Center for Food Safety and other groups filed a notice of a planned lawsuit on the failure to follow the strictures of the Endangered Species Act.6 In addition to potential threats to sensitive ecosystems and a lack of evidence to support the GE mosquitoes’ efficacy at minimizing the spread of disease, there is little information about what ingesting these insects could do to people. So many mosquitoes are released in the Oxitec

trials (millions are released multiple times a week) that people complain of being forced to breathe in and eat mosquitoes.

The Oxitec mosquitoes are designed to cause a die off of the local mosquito population, and if new mosquitoes move into areas treated by the GE mosquitoes, then the company makes its money selling more of its GE mosquitoes. Gene drive mosquitoes, however, are intended to keep spreading their genes until ALL of the mosquitoes die off. This is one of the huge ecological challenges of the gene drive technique which will be discussed next.

Gene Drives as a Sterile Insect Technique The largest spending to create a mosquito-killing technology that

Jan-Mar 2017

relies on CRISPR Cas9 gene editing is coming from the Bill and Melinda Gates Foundation, which has dedicated more than $75 million to developing the technique. This sterile insect technique is designed to go through wild populations of mosquitoes and make them sterile with the intention of driving them extinct.

The Gates funded project is based at Imperial College, London and is attempting to put “gene drives” in to the DNA of mosquitoes that transmit malaria and make them sterile.

Interestingly, locating the research in London is considered a geographical bio-control, as the mosquitoes do not naturally live in the UK.7 Gene drives are an experimental genetic engineering technique intended to overwrite Mendelian evolution by assuring that specific traits spread into every offspring in a population. Normally, only half of the population would inherit the traits from its parents.8 If a gene drive were successful, the chosen traits would become dominant in a wild population in a few generations. A successful sterilization drive could push a population to extinction. Most of these artificial gene drives are developed using the gene editing system known as CRISPR cas9.9 While some of the more cautious CRISPR researchers argue that adequate environmental and human health safeguards need to in place before any gene drive organism is released into the wild,10 other researchers insist that gene drives organisms (not necessarily mosquitoes) could be released as early as 2020.11 As tempting as it might seem to try to completely eliminate the mosquitoes that cause human malaria in Africa, which is now killing 450,000 people a year (mostly in Central African countries that have faced years of war and dire poverty), one must Volume 30 Number 1

consider all of the possible consequences. Likewise, to eliminate bird malaria carried by Culex mosquitoes in Hawaii, the longer-term effects need to be fully considered.

The ecological effects of gene drives are at present unknown and hard to predict. Eradicating a single species of mosquito, moreover, as noted in the GE Oxitec mosquito, does not necessarily eliminate the disease, as other mosquitoes capable of moving into the niche of the first mosquito can also transmit many of the same diseases. The next mosquito might carry varieties of malaria less treatable with current medicines.

In the case of bird malaria in Hawaii, the Culex mosquitoes are believed to have originated in Latin America and came to Hawaii in the drinking water of whaling ships. We don’t know the effect of causing the extinction of that species in Latin America where presumably there are birds, bats and other creatures that eat the adults, larvae or eggs of the mosquito. If the mosquito can get to Hawaii on whaling ships, it is likely that the gene driven form can get back to Latin America on a plane or ship.

Gene drives can thus undermine most of the principles of biological control. Previous biosafety practice encouraged testing GMOs in remote places like Hawaii to prevent environmental persistence. Gene drives are designed to override local conditions and supplant pre-existing species. Once the gene drive organism hops on a plane or ship, it can spread its genes beyond the isolated area into which it was released.

Some researchers, including Esvelt, have posited that it may be possible to reverse the gene drive effects, but this should not be tested after the organism is released into the environment.

No Release of Gene Drive Mosquitoes until containment and monitoring procedures are in place Elsewhere in this issue of GeneWatch, Jonathan Latham argues that it may not be possible to control these gene drives, so we should ban their use. I share a lot of his concern that we may not be able to do this right, but would suggest a moratorium on the environmental release of gene drive mosquitoes to attempt to control human disease and provide for wild life conservation.

The Principles for the Oversight of Synthetic Biology12 suggest that new organisms should be subject to a moratorium until rules are in place assuring that a “precautionary approach” is being taken, and until regulations are in place that address the ecological and human health implications of the release of the organism. Moreover, local people should be involved in a participatory review of the technique. Alternative techniques should also be examined as a part of the review of the techniques used to make the new organism. Hypothetical claims about the reversibility of a technique need to be carefully tested. Strict international rules for the containment and handling of gene drive research on mosquito species must be in place even before laboratory testing begins. Mosquito eggs can survive long distance travel.

The Asian Tiger mosquito is believed to have arrived in the U.S. as eggs attached to tires shipped across the Pacific. No mosquitoes should be able to escape the laboratory and hop aboard a ship or a plane.

There must also be adequate monitoring procedures in place to detect accidental releases of these gene drive mosquitoes.

Only after these international rules are in place should testing move GeneWatch 19

to the next phase, which is testing in large mesocosms that mimic the environment into which they might eventually be released. But these structures must be designed to effectively prevent the release of the mosquito until control strategies can be fully researched.

Alternatives to Gene Drive Mosquitoes Bacterial “gene drives” At the same time that the above research is being done, research on the alternatives must be advanced.

Nature has already designed some “natural” ways of controlling mosquito fertility. One of these ways is by infection with the Wolbaccia bacteria.

The EPA has already approved tests of two Wolbaccia infected mosquitoes in the Central Valley in California13 and a test in Florida is expected soon.

Vaccines Since most of the problems we are trying to solve are actually the diseases being carried by the mosquitoes, not the mosquitoes themselves, attention needs to be paid to other ways of eliminating the disease than by eliminating the mosquito. Yellow fever vaccines have been reducing the number of people who contract yellow fever from the so-called “yellow fever mosquito” for many years.

Recently dengue fever vaccines have been developed and are now approved in some of the countries where dengue is most endemic. Last April, the World Health Organization recommended that any country where dengue is endemic use the first approved commercial vaccine, Sanofi’s Dengvaxia.14 Malaria vaccines have proven more difficult to develop, but are being tested.

20 GeneWatch

Sanitation and medicines Finally, it is important to remember that a good part of avoiding malaria or dengue or zika includes basic public sanitation strategies. Last year, I visited a woman in Managua, Nicaragua who is the de facto mayor of her shantytown slum. She and a group of women go from house to house making sure that any standing water is dumped so mosquitoes can’t breed. She then takes the temperatures of the home’s residents. If anyone has a temperature, she and her team make sure that they are enclosed in a mosquito net, so mosquitoes can’t bite them and transmit their illness. Through such rigorous monitoring of her community, she has eliminated malaria, dengue and other mosquito borne diseases from her slum. This is an old fashioned but effective low-technology method for eliminating the disease. El Salvador saw 20,000 new cases of malaria at the peak of its civil war, but after more than 20 years, both liberal and conservative governments have made sure that everyone had access to the drugs that cure malaria. Two years ago, they no longer had endemic cases of malaria.

The world community needs to put its money in these proven alternatives and maintain a moratorium on gene drives as a way to control mosquito borne diseases until international regulations are in place.

By that time, these other strategies may have completed the job without the help of GE and gene drive mosquitoes. nnn Jaydee Hanson is Policy Director, International Center for Technology Assessment.

1. See http://www-naweb.iaea.org/ Nafa/ipc/public/Sterile_Insect_ Technique_book.pdf#page=14 2. Ibid. page 16.

3. Rachel Carson, Silent Spring, 1962. Available on-line at: https:// archive.org/stream/fp_Silent_SpringRachel_Carson-1962/Silent_SpringRachel_Carson-1962_djvu.txt 4. http://www.centerforfoodsafety.org/ press-releases/4568/this-election-keysresidents-vote-no-on-ge-mosquitoes 5. http://www.centerforfoodsafety.org/press-releases/4593/ victory-ge-mosquitoes-will-not-belet-loose-on-florida-community 6. http://www.centerforfoodsafety.org/ press-releases/4580/advocates-challengefda-on-first-ever-ge-mosquito-release 7. Antonio Regalado, “The Extinction Invention” Technology Review, April 13 2016, available at: https://www. technologyreview.com/s/601213/ the-extinction-invention/ 8. National Academies of Science, Engineering, and Medicine (NASEM).

“Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values, Washington DC: National Academies Press 2016 available at: https:// www.nap.edu/download/23405 9. Andre Hammond, et al. “A CRISPR Cas9 gene drive system targeting female reproduction in the malaria mosquito vector, Anopheles gambiae,” Nature Biotechnology 34, no. 1 (2016): 78-83 10. See Kevin Esvelt article in this issue.

11. GBIRd Project (Genetic Biocontrol of Invasive Rodents) led by Island Conservation International) Available at www.islandconservation.org/programcoordinator 12. International Center for Technology Assessment, Friends of the Earth, and ETCgroup. Principles for the Oversight of Synthetic Biology available at: http://www.icta.org/ files/2016/09/ICTA_Principles_ Oversight-Synthetic-Biology.pdf 13. See https://www.epa.gov/pesticides/ epa-grants-extension-experimentaluse-permit-wolbachia-mosquito 14. Dengue vaccine research”. World Health Organization. Retrieved 18 April 2016. Available at: http://www. who.int/immunization/research/ development/dengue_vaccines/en/

Endnotes

Jan-Mar 2017

From the Council for Responsible Genetics

The GMO DecepTiOn What You Need to Know about the Food, Corporations, and Government Agencies Putting Our Families and Our Environment at Risk

edited by Sheldon Krimsky and Jeremy Gruber Foreword by Ralph nader

“If you do not understand why there is so much opposition to GMOs, nationally and internationally, this book is the place to start.”

—Marion Nestle, professor of nutrition, food studies, and public health at New York University and author of Eat Drink Vote: An Illustrated Guide to Food Politics “The GMO Deception is the most comprehensive resource covering all areas of this complex topic.”

—Ken Roseboro, editor and publisher, The Organic & Non-GMO Report

ON SALE NOW Volume 30 Number 1

GeneWatch 21

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