Nat Commun. 2019; 10: 84.

Published online 2019 Jan 8. doi: 10.1038/s41467-018-07964-7

PMCID: PMC6325135

Transforming insect population control with precision guided sterile males with demonstration in flies

Nikolay P. Kandul,1 Junru Liu,1 Hector M. Sanchez C.,2 Sean L. Wu,2 John M. Marshall,2 andOmar S. Akbari corresponding author

1,3

Author information Article notes Copyright and License information Disclaimer

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325135/

From STAT news 07/10/2018

FIRST OPINION

Gene-drive technology must be developed in a safe, ethical way

By ANTHONY A. JAMES

JULY 10, 2018

LAUREN HOLDEN VIA WELLCOME IMAGES

We need powerful tools to take on the deadliest creature in the world: mosquitoes.

Mosquitoes spread malaria, a disease that sickens more than 200 million people each year and kills 430,000. Genetically engineering mosquitoes to stop the spread of malaria offers great promise in saving many of these lives, and could add an estimated $4 trillion to the global economy over the next 14 years.

A new technology known as gene drive can increase the likelihood that desirable engineered traits in a mosquito are passed on to all of its offspring in the next generation, ultimately spreading these traits throughout a target population.

Since only female mosquitoes feed on blood and transmit malaria parasites from person to person, a gene that boosts the inheritance of the male chromosome would reduce the number of females in the target population and cause it to crash, a strategy known as population suppression. Another type of beneficial gene might kill malaria parasites in mosquitoes before they can be transmitted, a strategy known as population modification.

The result of either scenario — or others in the works — would ultimately stop the spread of malaria.

In a remote West African village, a revolutionary genetic experiment is on its way — if residents agree to it

While the potential to control malaria through genetic manipulation represents an opportunity to make significant advances in eradicating the disease, developing a technology designed to spread new genes through populations must be carefully managed. Any new tools must be as safe as they are effective.

A useful rule of thumb for achieving this appears in an important new paper from the Foundation for the National Institutes of Health. It stipulates that the new technologies “will do no more harm to human health than wild-type mosquitoes of the same genetic background and no more harm to the ecosystem than other conventional vector control interventions.” Showing this to be true requires research as well as patience and dialogue.

Explainer: What is a gene drive?

Gene drives have the potential to change the genetic makeup of entire populations, like mosquitos that carry malaria.HYACINTH EMPINADO/STAT

While gene-drive research builds on previous mosquito-control experience and prevailing good practices in biotechnology, this is a new approach with unique aspects. In particular, the genetic modification is designed to spread through wild populations. This poses new questions for how to develop and evaluate gene-drive organisms. The majority of questions fall into two categories: how to limit the spread of genetically engineered mosquitoes to a defined geographical region, and what impact they might have on existing ecosystems.

Population suppression approaches are self-limiting by design — all mosquitoes carrying the genes are sterile or die. Important questions here address the implications of loss of the species from the ecosystem. This is less of a concern in places where the mosquitoes are an invasive species, but some people have expressed opinions that regional success will lead to widespread use and result in global extinction of the target mosquito species.

Gene drive debate must include voices from Africa, elsewhere

Population modification strategies are designed to persist. The major questions here focus on what can be done should we, for one reason or another, no longer want these mosquitoes out in the wild.

Fortunately, there are major research efforts to develop chemical and genetic control or “recall” mechanisms for gene drive (Safe Genes). The first open-field trials of these will likely take place only after regulatory agencies are satisfied that appropriate mitigation procedures are available.

All of the scientists I know working on this technology have adopted a phased approach outlined in the new paper (which was adapted from previous publications) to testing safety and effectiveness complete with “go/no go” decision points before any consideration of releasing any insects into the field.

Included in this approach is time to review the implications and the possible risks described above, to engage the public to address concerns they might have, to develop the necessary safety protocols, and to secure regulatory approval.

Inherent in this process is an understanding that each new gene-drive technology is different. While there are some general principles that apply to all, such as containment of the organism during early testing, the risks and challenges of each must be evaluated on a case-by-case basis.

Much of the research on gene-drive mosquitoes is carried out in countries where the disease is not endemic. Yet control over the use of gene-drive mosquitoes must ultimately rest with scientists, public health authorities, regulators, and the community in affected countries where they will be released. Because insects can cross international borders, such decisions may need to be taken at a multicountry level.

The best way to ensure that gene-drive technology is developed safely is to discuss it openly — in laboratories, within governments, and in public. Engaging nonprofit organizations like the Foundation for the National Institutes of Health contributes to safeguarding public interest in this emerging disease-fighting tool.

With so many people suffering from malaria every year, we cannot afford to leave this potential new tool unexplored. But we must do it the right way.

Anthony A. James, Ph.D., is professor of microbiology and molecular genetics at the University of California, Irvine, School of Medicine and professor of molecular biology and biochemistry at the UCI School of Biological Sciences.

About the Author

Anthony A. James

aajames@uci.edu

Jon Beck
JULY 14, 2018 AT 9:32 PM

BIOETHICS

Principles for gene drive research

Sponsors and supporters of gene drive research respond to a National Academies report

By Claudia Emerson,^{^[1]} Stephanie James,²

Katherine Littler,³ Filippo (Fil) Randazzo⁴

http://science.sciencemag.org/content/358/6367/1135.full

The recent outbreak of Zika virus in the Americas renewed attention on the importance of vector-control strategies to fight the many vector-borne diseases that continue to inflict suffering around the world. In 2015, there were ∼212 million infections and a death every minute from malaria alone (1). Gene drive technology is being explored as a potentially durable and cost-effective strategy for controlling the transmission of deadly and debilitating vector-borne diseases that affect millions of people worldwide, such as Zika virus and malaria. Additionally, its suitability is being evaluated for various potential applications in conservation biology, including a highly specific and humane method for eliminating invasive species from sensitive ecosystems (2, 3).

The use of gene drives is an emerging technology that promotes the preferential inheritance of a gene of interest, thereby increasing its prevalence in a population. A gene drive is distinct from genome editing, in which the genetic change is not preferentially inherited. A variety of gene drives occur in nature that can cause genetic elements to spread throughout populations to varying degrees, and researchers have been studying how to harness these to solve some of society’s most intractable problems (4). Aided by CRISPR gene-editing technology, the rapid pace with which the research is progressing is demonstrated by recent successes in laboratory experiments (5, 6), although observation of resistance developing in one instance highlights the need for further research (7).

In recognition of the rapid advances of research in this field, the U.S. National Institutes of Health (NIH) and the Foundation for the NIH requested that the U.S. National Academies of Sciences, Engineering, and Medicine (NASEM) conduct a study that would “summarize current understanding of the scientific discoveries related to gene drives and their accompanying ethical, legal, and social implications,” which was published in 2016 [(2), p. vii)]. The authors noted that the promise of gene drives is tempered by uncertainties regarding potential for harm from unintended consequences or misuse of the technology. The potential persistence of genetic change in the target population caused by a gene drive is both the source of optimism for a durable and affordable tool to combat a variety of pernicious public health and environmental problems as well as the source of concern about the possibility for irreversible harm to the ecosystem that has prompted some to call for a moratorium on the research (2, 8, 9). This led the authors of the National Academies report to advocate for a precautionary contextual approach to the science—i.e., concluding that currently there is insufficient evidence to support deployment of gene drive–modified organisms into the environment but that the potential benefits justify proceeding with laboratory research and highly controlled field trials (2, 10).

The report issues a number of recommendations aimed at researchers, funders, and policy-makers on actions important for minimizing potential risks, averting preventable harm, and earning the confidence and support of the public. Of the 32 recommendations made, 13 are specific to funders—including one aimed specifically at “United States funders” (2).

Published by AAAS

RESPONDING TO THE NASEM REPORT

Sponsors of scientific research have a responsibility to support innovation that promotes and sustains the public good (11). They share the common goal of advancing knowledge and human well-being, while protecting and promoting societal values that underpin the responsible conduct of science. The 2010 report from The Presidential Commission for the Study of Bioethical Issues, “New Directions: The Ethics of Synthetic Biology and Emerging Technologies,” highlights the important point that the responsibility for ensuring the conduct of quality science is not the exclusive domain of scientists, but is a shared responsibility among research sponsors and policy-makers alike (11). In this Policy Forum, we use the term “science” in its broadest sense, referring inclusively to the life and physical sciences as well as social science, and the humanities, i.e. ethics. Moreover, researchers, sponsors, and policy-makers also share the responsibility of monitoring the progress of science and communicating it effectively to the public (2). Effective public engagement, underpinned by transparent dialogue around both the potential benefits and risks, is critical for enabling well-informed public discussion and debate that is free from the type of sensational hype that has framed new technology in the past (12).

As sponsors and supporters of gene drive research, the signatories to these principles have come together to provide a coordinated response to the NASEM recommendations in the form of commitment to a set of guiding principles (see the box) intended to (i) mobilize and facilitate progress in gene drive research by supporting efforts of the highest scientific and ethical quality; (ii) inspire a transparent atmosphere of conscientiousness, respectfulness, and integrity wherein the research can flourish; and (iii) support existing biosafety requirements and best practices as minimum standards for research. Endorsement of the principles represents a pledge to advance the foundational elements of efficient and responsible research conduct: evidence, ethics, and engagement, which are also important themes represented throughout the NASEM report.

The principles are presented in the box, with references indicating the NASEM recommendation to which the principle responds.

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INSIGHTS | POLICY FORUM

Guiding principles for the sponsors and supporters of gene drive research

Advance quality science to promote the public good

The pursuit of gene drive research must be motivated by, and aim to promote, the public good and social value. Funded research shall embody the highest quality science and ethical integrity, consistent with the current best practice guidance set by the research community and relevant decision-making bodies [(2), p. 106)].

Promote stewardship, safety, and good governance

Researchers and sponsors are stewards of science and the public trust. It is imperative that good governance is demonstrably shown in all phases of the research, and especially in relation to risk assessment and management. This requires compliance with applicable national and international biosafety and regulatory policies and standards. Research conducted with respect and humility for the broader ecosystem in which humans live, taking into account the potential immediate and longer-term effects through appropriate ecological risk assessment, is a hallmark of both good stewardship and good governance [(2), pp. 128; 170–172)].

Demonstrate transparency and accountability

Knowledge sharing is not only essential for the advancement of science, but for transparency to foster public trust in emergent technologies. The timely reporting of results and broad sharing of data shall be the norm in gene drive research, consistent with the tradition of openness established in its parent communities of genetic and genomic science. Measures of transparency and accountability that contribute to building public trust and a cohesive community of practice will be supported [(2), pp. 171; 177–178)].

Engage thoughtfully with affected communities, stakeholders, and publics Meaningful engagement with communities, stakeholders, and publics is critical for ensuring the best quality science and building and sustaining public confidence in the research. Funded research shall include the resources needed to permit robust, inclusive, and culturally appropriate engagement to ensure that the perspectives of those most affected are taken into account [(2), pp. 142–143)].

Foster opportunities to strengthen capacity and education

Strengthening capacities in science, ethics, biosafety, and regulation is essential for enabling agile and steady progress in gene drive research globally. Opportunities to partner, educate, and train shall be supported throughout all phases of the research, from the early stages to deployment. Strengthening capabilities within countries for testing and deploying the technology is essential for informed decision-making [(2), pp. 128; 170–172)].

AN ETHIC OF RESPONSIBILITY

Through alignment with the principles, sponsors of gene drive research aim to contribute to an adaptive and data-informed toolbox of policies that can support the responsible development of gene drive research [(2), p. 172]. Such a toolbox affords the flexibility to respond to new technical advances and knowledge, while ensuring the long-term safety of human health and the environment. Principles serve as a moral compass to “anchor the actionables,” so that only the highest-quality research endeavors, consistent with the best-practice guidance and standards set by the scientific community, will be supported. As the NASEM report notes, “institutions, funders, and professional societies work in concert to encourage professional best practices in research. Such cooperation will be instrumental to maintaining high standards in gene drive research” [(2), p. 8].

To date, 13 organizations have endorsed the principles, and other sponsors and research organizations in both the public and private sector are encouraged to contact the corresponding author if they wish to sign on. The signatories to the principles will cooperate on catalyzing a culture of responsible innovation by encouraging sponsors in the public and private sectors to endorse and implement the guiding principles in funding decisions and research management. Moving forward, the forum of gene drive sponsors and supporters will convene to discuss next steps in operationalizing the principles. Although there are many challenges to address, the forum will start with consideration of harmonized approaches to stakeholder engagement, regulatory oversight, transparency and data sharing to support the research, knowledge sharing, and public discourse on gene drive technology. The forum is in a position to develop a “consensus standard” designed to set an agreed level of good practice or quality to help establish confidence in gene drive innovations, and to continue working with stakeholders and relevant agencies to implement all of the principles. This will ensure progress, efficiency, and a common framework within which to move the field forward.

1136 1 DECEMBER 2017 • VOL 358 ISSUE 6367

Published by AAAS

to discuss next steps in operationalizing the principles. Although there are many challenges to address, the forum will start with consideration of harmonized approaches to stakeholder engagement, regulatory oversight, transparency and data sharing to support the research, knowledge sharing, and public discourse on gene drive technology. The forum is in a position to develop a “consensus standard” designed to set an agreed level of good practice or quality to help establish confidence in gene drive innovations, and to continue working with stakeholders and relevant agencies to implement all of the principles. This will ensure progress, efficiency, and a common framework within which to move the field forward. j

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

References and Notes

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Acknowledgments: Institutions and signatories to the principles for sponsors and supporters of gene drive research (in alphabetical order): Bill & Melinda Gates Foundation, Trevor Mundel; Canadian Institutes of Health Research (CIHR), Paul Lasko; Commonwealth Scientific and Industrial Research Organization (CSIRO), Jack Steele; Foundation for the National Institutes of Health (FNIH), Maria Freire; Fundação Oswaldo Cruz (Fiocruz), Marco Aurélio Krieger; Health Research Council of New Zealand, Kathryn McPherson; Indian Council of Medical Research (ICMR), Soumya Swaminathan; Institut National de la Santé et de la Recherche Médicale (Inserm), Yves Lévy; Institut Pasteur, Christian Bréchot; National Health and Medical Research Council of Australia, Anne Kelso; Open Philanthropy Project, Nick Beckstead and Alexander Berger; Tata Trusts, R. Venkataramanan; Wellcome Trust, Jeremy Farrar.The authors are grateful for valuable feedback received from members of the signatory organizations and representatives from other sponsor and supporter organizations. C.E. is supported by a grant from the Bill & Melinda Gates Foundation, and S.J. is supported by grants from the Bill & Melinda Gates Foundation and the Open Philanthropy Project. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material.

ACKNOWLEDGMENTS

Institutions and signatories to the principles for sponsors and supporters of gene drive research (in alphabetical order): Bill & Melinda Gates Foundation, Trevor Mundel; Canadian Institutes of Health Research (CIHR), Paul Lasko; Commonwealth Scientific and Industrial Research Organization (CSIRO),

Jack Steele; Foundation for the National Institutes of Health

(FNIH), Maria Freire; Fundação Oswaldo Cruz (Fiocruz), Marco

Aurélio Krieger; Health Research Council of New Zealand,

Kathryn McPherson; Indian Council of Medical Research (ICMR), Soumya Swaminathan; Institut National de la Santé et de la Recherche Médicale (Inserm), Yves Lévy; Institut Pasteur, Christian Bréchot; National Health and Medical

Research Council of Australia, Anne Kelso; Open Philanthropy Project, Nick Beckstead and Alexander Berger; Tata Trusts, R. Venkataramanan; Wellcome Trust, Jeremy Farrar.

The authors are grateful for valuable feedback received from members of the signatory organizations and representatives from other sponsor and supporter organizations. C.E. is supported by a grant from the Bill & Melinda Gates Foundation, and S.J. is supported by grants from the Bill & Melinda Gates Foundation and the Open Philanthropy Project. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material.

10.1126/science aap9026

ciencemag.org SCIENCE

Principles for gene drive research

Claudia Emerson, Stephanie James, Katherine Littler and Filippo (Fil) Randazzo

Science 358 (6367), 1135-1136.

DOI: 10.1126/science.aap9026

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Science (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. 2017 © The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. The title Science is a registered trademark of AAAS.

[1] Institute on Ethics and Policy for Innovation, McMaster University, Hamilton, Ontario L8S 4L8, Canada. ²Foundation for the National Institutes of Health, North Bethesda, MD 20852, USA. ³Wellcome Trust, London NW1 2BE, UK. ⁴Bill & Melinda Gates Foundation, Washington, DC 20005, USA. Email: sjames@fnih.org

SCIENCE sciencemag.org

Gene Drives Steer toward Road Tests

PSW 2378 The Mosquito, Synthetic Biology, CRISPR, and Malaria

PSW 2378 The Mosquito, Synthetic Biology, CRISPR

Developing Safety Standards for Germline Use

Richard A. Stein, M.D., Ph.D.

Click Image To Enlarge +

Scientists believe that within a decade CRISPR/Cas9 gene-editing could be used in a gene drive approach in mosquitoes to help fight malaria and other mosquito-borne diseases. [abadonian/Getty Images]

Technologies that would bias the inheritance of a gene or a group of genes in a population have been discussed for decades.

Such technologies, scientists have long proposed, could exploit translocation mechanisms to prevent, contain, and eradicate vector-borne infectious diseases, some of which are global public health emergencies. An especially interesting possibility was introduced back in 2003, when Austin Burt, Ph.D., an evolutionary geneticist at Imperial College London, described how site-specific “selfish genes,” such as homing endonuclease genes, could be engineered to target new host sequences and skew population sex ratios.

At the time, Dr. Burt’s suggestion could not be tested because a convenient means of retargeting selfish elements didn’t exist. Such a means, however, has come to the fore in recent years. It is, of course, the CRISPR/Cas9 genome-editing technology. It is already being used to construct gene drives that could be used to spread desirable mutations through populations in super-Mendelian fashion.

“In CRISPR gene-drive technologies, probably the biggest challenge is making sure that we understand the environmental consequences and the unintended consequences, if any,” George M. Church, Ph.D., professor of genetics at Harvard Medical School and MIT, tells GEN. Several years ago, Dr. Church’s group was the first to create a gene drive in the budding yeast Saccharomyces cerevisiae. In a more recent study on wild and laboratory strains of S. cerevisiae, Dr. Church and colleagues showed that CRISPR/Cas9 gene drive systems can bias inheritance over successive generations at efficiencies over 99%.

Historically, several model organisms have been used to study gene drives, and while each of them provided important lessons, there are key differences between them in terms of the types of information they provide and the challenges they help address. An area of particular concern in gene-drive studies revolves around the accidental escape from the laboratory of even a single organism, and the subsequent consequences over time on wild populations. “Because fruit flies are present outside of every laboratory, escape is easier in this model,” warns Dr. Church.

Dr. Church and colleagues recently developed and validated two molecular confinement methods. One method encodes Cas9 on an unlinked episomal plasmid and ensures that the gene drive element contains only the single guide RNA. (In this arrangement, the single-guide RNA-only gene drive is unable to spread in wild organisms, which lack Cas9.) The other method involves using exclusively synthetic target sequences, which are not encountered in wild-type organisms.

As part of these studies, Dr. Church’s laboratory illustrated the benefits of testing CRISPR/Cas9-based gene drives in the budding yeast before conducting work on multicellular organisms. Additional work with mathematical models led Dr. Church and colleagues to propose the use of alternative designs that could select against resistant alleles and improve the gene drive’s evolutionary stability.

One of the technical challenges in engineering mosquitoes is the need to perform the engineering within or near essential genes. “Engineering genes that are not important to the organism will quickly eliminate the gene drive because the organism does not need the target site,” explains Dr. Church.

Engineering Parasite-Resistant Mosquitoes

“As part of our efforts focusing on malaria, we are trying to create tools and generate mosquitoes that could be used for rigorous tests including large cage trials and subsequently, if the regulatory approvals are given, for field trials,” says Ethan Bier, Ph.D., professor of cell and developmental biology at the University of California, San Diego. Dr. Bier’s group was the first to show that a gene drive can be created in the fruit fly.
Overall, two competing strategies have been envisioned and developed for using gene-drive technologies. One strategy involves the use of mosquitoes to distribute or disseminate an immunizing gene cassette. If this strategy is implemented correctly, notes Dr. Bier, it would not have much or any impact on the health or fitness of the mosquitoes. The other strategy involves using gene drive to sterilize or reduce the population of mosquitoes. According to Dr. Bier, this is a version of genetic insecticide.
Dr. Bier’s laboratory is pursuing the first strategy in collaboration with a team of scientists based at the University of California, Irvine, and led by Anthony James, Ph.D., a professor of microbiology and molecular genetics, and of molecular biology and biochemistry. The collaboration is focusing on population-level mosquito modifications in which genes that confer a parasite-resistant phenotype are engineered into the mosquitoes that transmit the pathogen.
“The immunizing cassette, originally developed by Dr. James’ laboratory, would just stay in the population and not be subject to evolutionary pressures that try to rid those mosquitoes from the environment,” explains Dr. Bier. “They might therefore be present long enough to have a significant impact on the prevalence of the malaria parasite by blocking its transmission.”
In a recent study using Anopheles stephensi, a malaria vector on the Indian subcontinent, Dr. Bier and colleagues in the Dr. James’ group revealed that CRISPR/Cas9-directed homologous recombination drives gene conversion at a more than 99.5% efficiency in mosquito transgene heterozygotes. The technology to perform this work is based on the mutagenic chain reaction, which Dr. Bier and colleagues previously developed in Drosophila melanogaster, and in which a heterozygous mutation is converted to a homologous loss-of-function mutation in germline and somatic cells.
Gene-drive technologies have applications for other vector-borne diseases, such as leishmaniasis and Chagas disease, as well as for population reduction schemes to control crop pests. “Any scheme that goes after reducing the population of any insect or organism in the wild, even though it may be successful, will at the end, always be an uphill battle,” cautions Dr. Bier. A more desirable alternative involves modifying attributes that are undesirable, such as an organism’s ability to propagate disease or its preference for one type of crop versus another. “One can obtain more of an effect by just changing that characteristic and not trying to kill the organism,” advises Dr. Bier.
In introducing genetic modifications into mosquitoes, Dr. Bier and colleagues extensively rely on the ability to generate effector molecules that bind to parasites and render them unable to transfer to the body of the mosquito. One of the key requirements of these molecules is their ability to bind with high affinity to epitopes on the parasite.
“Technologies that we would value for this work include rapid protein evolution binders, which are molecules that are capable of binding random input peptides,” maintains Dr. Bier. After peptides are provided, genetically encodable binders that interact with them could be used in vivo to tether them to components in the mosquito to either kill the parasites or make them aggregate. “[Using] evolutionary synthetic biology approaches to make novel protein-interacting peptides,” adds Dr. Bier, “would be extremely valuable for our work.”
Sterilizing Populations
“We look at gene drive as something that can bias inheritance and is differentially included in the offspring, and that can be coupled to a trait that might be of use in terms of controlling the mosquito population,” says Tony Nolan, Ph.D., senior research fellow at Imperial College London. In a recent study, Dr. Nolan and colleagues designed a CRISPR/Cas9-based approach to individually target and disrupt three Anopheles gambiae genes that have high ovarian expression and tissue specificity.
“We disrupted key fertility genes,” informs Dr. Nolan. “That allowed us to introduce an element that can cause population reduction, which is viewed as the most successful strategy today to control malaria.” For two of these loci, the constructs were predicted to disappear from the population over time, but for the third one, the gene disruption met the minimum requirements for targeting female reproduction by gene drive in a mosquito population.
One of the challenges related to the implementation of gene drives is intimately related to the emergence of resistance. “Anything that tries to suppress a population would impose a selection pressure on the population,” states Dr. Nolan. An advantage, when using gene drives, is that some of the resistance mechanisms are foreseeable. “Therefore, one can plan in advance and make the emergence of resistance much less likely,” asserts Dr. Nolan.
Another challenge is the need to demonstrate that gene-drive technology, which is still new, can be trusted. Large amounts of data are needed to confirm that gene drive works and is safe. “There is a lot of testing that should happen between building something in the laboratory and making something the field,” advises Dr. Nolan. “This is going to be a very long process.”
Comparing Alternative Strategies
“We think of gene drives as having three categories of challenges or issues,” says Austin Burt, Ph.D., professor of evolutionary genetics at Imperial College London. The challenges, Dr. Burt suggests, are technological (the ability to “generate constructs that do what we want them to do”); regulatory (the ability to “obtain permission to use the technology that we develop”); and in a sense, communal (the ability to “broaden stakeholder acceptance in terms of people wanting to have this technology”).
Almost 15 years ago, Dr. Burt was the first investigator to propose the use of gene drives based on homing endonuclease genes. Homing endonuclease genes encode highly specific endonucleases with recognition sequences that occur only once in a genome and can activate recombination repair systems by inducing double-stranded chromosomal breaks in the homologous chromosome. As a result of the homology-directed repair process, the endonuclease gene is copied to the broken chromosome. This process can be used to spread the gene through a population.
In a recent modeling analysis, Dr. Burt and colleagues evaluated three different strategies—population suppression through dual-germline fertility disruption, population suppression with a driving-Y chromosome, and mosquito population replacement—to predict how each strategy would perform in a real-life setting from sub-Saharan Africa. Each strategy, despite presenting a unique set of challenges, was highly effective at reducing malaria transmission.
“The point of this work is to help define what it is that would constitute technical success,” declares Dr. Burt. A broader understanding of success, he adds, would encompass the gene-drive attributes that “need to be in place to predict the successful transition of the work from the laboratory to the field.”
Gene Drive in Practice
Many different techniques have been developed, and many more could be developed, to incorporate gene drives, says Zach N. Adelman, Ph.D., associate professor of entomology at Texas A&M University. What these techniques have in common, he suggests, is the need to address the issue of specificity.
The blessing of specificity is that off-target effects are minimized with a highly specific nuclease. The curse of specificity is that when sequence variation is pronounced in a natural population, or when new changes arise, a very specific nuclease will lack or come to lose the ability to recognize the genomic region that needs to be targeted. “This is what investigators have come up against recently,” insists Dr. Adelman.
Even though sequence variations may naturally occur at low levels in a population, such variations could quickly become more prevalent if a gene drive were to bring with it any kind of fitness cost. “We are trying to develop nucleases that are so specific that they do not cause undesirable changes, but are not so specific that it takes only a single change, one that might already occur in nature, to make them nonfunctional,” explains Dr. Adelman.
Dr. Adelman and colleagues recently proposed a two-step approach for gene editing in organisms that are difficult to manipulate genetically, such as mosquitoes. In this approach, the first step is to evaluate candidate site-specific nucleases. (Many synthetic guide RNA molecules are initially examined in vivo.) The second step is to carry out germline-based editing while constraining the choice of DNA repair response. (RNA interference is used to suppress components of the nonhomologous end-joining response.) Suppression of the Ku70 component substantially improved the rates of homology-directed repair and resulted in gene insertion frequencies of around 2–3%.
“The regulatory agencies are still coming to grips with what it means to have a technology that will be used in an environment that is beyond a containment barrier,” says Dr. Adelman. In the case of previous initiatives to generate genetically engineered products, such as salmon and crops, these were confined to a contained environment, did not move beyond where they were breeded (salmon) or planted (crops), and did not admix intentionally with wild population.
“But the goal in gene drive is to admix, and we are still working out the pathways,” declares Dr. Adelman. The pathways from the laboratory to the field will have to be constructed de novo at the same time that the regulatory frameworks are constructed, he suggests.

http://www.genengnews.com/gen-articles/gene-drives-steer-toward-road-tests/6135

How Humans Are Shaping Our Own Evolution

Like other species, we are the products of millions of years of adaptation. Now we're taking matters into our own hands.

This story appears in the April 2017 issue of National Geographic magazine

When I met the cyborg Neil Harbisson, in Barcelona, he looked like any local hipster, except for the black antenna arching impressively from the back of his skull over his mop of blonde hair.

It was December, and Harbisson, 34, was wearing a zippered grey shirt under a black peacoat, with narrow grey pants. Born in Belfast and raised in Spain, he has a rare condition called achromatopsia; he cannot perceive colour. His antenna, which ends in a fiber-optic sensor that hovers right above his eyes, has changed that.

Harbisson never felt that living in a black-and-white world was a disability. “I see longer distances. Also I memorise shapes more easily because colour doesn’t distract me,” he told me, in his careful, neutral English.
But he was deeply curious about what things looked like in colour too. Having trained as a musician, he had the idea in his late teens of trying to discover colour through sound. After some low-tech false starts, in his early 20s he found a surgeon (who remains anonymous) who was willing to implant a device, a cybernetic enhancement to his biological self.

The fibre-optic sensor picks up the colours in front of him, and a microchip implanted in his skull converts their frequencies into vibrations on the back of his head. Those become sound frequencies, turning his skull into a sort of third ear. He correctly identified my blazer as blue and, pointing his antenna at his friend Moon Ribas, a cyborg artist and dancer, said her jacket was yellow—it was actually mustard yellow, but as he explained, in Catalonia “we didn’t grow up with mustard.”

When I asked Harbisson how the doctor had attached the device, he cheerfully parted the hair at the back of his head to show me the antenna’s point of entry. The pinkish flesh was pressed down by a rectangular plate with two anchors. A connected implant held the vibrating microchip, and another implant was a Bluetooth communication hub, so friends could send him colours through his smartphone.
The antenna has been a revelation for Harbisson. The world is more exhilarating for him now. Over time, he said, the input has begun to feel neither like sight nor hearing but a sixth sense.

12,500 YEARS AGO: EVOLVED TO LIVE AT HIGH ALTITUDES Until recently it was thought that our species had stopped evolving far in the past. Our ability to peer inside the human genome has shown that in fact our biology continues to change to suit particular environments. Most of us feel breathless in high mountain air because our lungs must work harder to capture the reduced level of oxygen there. But Andeans have a genetically determined trait that allows their haemoglobin to bind more oxygen. Tibetan and Ethiopian populations independently adapted to their high elevations, showing that natural selection can take us on different paths to reach the same outcome: survival.

The most intriguing part of the antenna, though, is that it gives him an ability the rest of us don’t have. He looked at the lamps on the roof deck and sensed that the infrared lights that activate them were off. He glanced at the planters and could “see” the ultraviolet markings that show where nectar is located at the centres of the flowers. He has not just matched ordinary human skills; he has exceeded them.

He is, then, a first step toward the goal that visionary futurists have always had, an early example of what Ray Kurzweil in his well-known book The Singularity Is Near calls “the vast expansion of human potential.” Harbisson hadn’t particularly meant to jump-start Kurzweil’s dream—his vision of the future is more sylvan than silicon. But since he became the world’s first official cyborg (he persuaded the British government to let him wear the antenna in his passport photo, arguing that it was not an electronic device, but an extension of his brain), he has also become a proselytizer. Ribas soon followed him into what is sometimes called transhumanism by having a seismic monitor in her phone connect to a vibrating magnet buried in her upper arm. She gets real-time reports of earthquakes, allowing her to feel connected to the motions of the Earth and interpret them through dance. “I guess I got jealous,” she says.

“We will transcend all of the limitations of our biology,” Kurzweil promised. “That is what it means to be human—to extend who we are.”

Clearly Harbisson’s antenna is merely a beginning. But are we on the way to redefining how we evolve? Does evolution now mean not just the slow grind of natural selection spreading desirable genes, but also everything that we can do to amplify our powers and the powers of the things we make—a union of genes, culture, and technology? And if so, where is it taking us?

8,000 YEARS AGO: ADAPTED TO A DESERT CLIMATE The desert presented an evolutionary challenge for the inhabitants of Sahul, the continent that once united Australia, New Guinea, and Tasmania. After the ancestors of modern Aboriginals made the crossing to Sahul, around 50,000 years ago, they developed adaptations that allowed them to survive below-freezing temperatures at night and days often exceeding 100 degrees Fahrenheit. A genetic mutation in a metabolism-regulating hormone provides this survival advantage, especially for infants, by modulating the excess energy that’s produced when body temperature rises.

Conventional evolution is alive and well in our species. Not long ago we knew the makeup of only a handful of the roughly 20,000 protein-encoding genes in our cells; today we know the function of about 12,000. But genes are only a tiny percentage of the DNA in our genome. More discoveries are certain to come—and quickly. From this trove of genetic information, researchers have already identified dozens of examples of relatively recent evolution. Anatomically modern humans migrated from Africa sometime between 80,000 and 50,000 years ago. Our original genetic inheritance was appropriate for the warm climates where we first evolved from early hominins to humans, from knuckle-walkers to hunters and gatherers. But a lot has happened since that time, as humans have expanded around the world and the demands posed by new challenges have altered our genetic makeup.

Recent, real-life examples of this process abound. Australian Aboriginals living in desert climates have a genetic variant, developed in the past 10,000 years, that allows them to adjust more easily to extreme high temperatures. Prehistorically, most humans, like other mammals, could digest milk only in infancy—we had genes that turned off the production of the milk-digesting enzyme when we were weaned. But around 9,000 years ago, some humans began to herd animals rather than just hunt them. These herders developed genetic alterations that allowed them to continue making the relevant enzyme for their whole lives, a handy adaptation when their livestock were producing a vitamin-rich protein.

In a recent article in the Scientist, John Hawks, a paleoanthropologist at the University of Wisconsin–Madison, wrote how impressed he was at the speed with which the gene was disseminated: “up to 10 percent per generation. Its advantage was enormous, perhaps the strongest known for any recent human trait.”

Similarly, the ancestors of all non-Africans came out of Africa with dark skin. Indeed even 10,000 years ago, according to researchers, European and African skin looked much the same. But over time humans in darker northern climates evolved less heavily pigmented skin, which helped absorb the sun’s ultraviolet rays and synthesize vitamin D more efficiently. The Inuit of Greenland have an adaptation that helps them digest the omega-3 fatty acids in fish far better than the rest of us. An indigenous population near the Argentine town of San Antonio de los Cobres has evolved to be able to drink the high levels of arsenic that have occurred naturally in their groundwater.
Evolution is relentless; when the chance of survival can be increased, it finds a way to make a change—sometimes several different ways. Some Middle Eastern populations have a genetic variation that’s different from the one northern Europeans have to protect them from lactose intolerance. And there are a half dozen distinct genetic adaptations that protect Africans against malaria (one has the significant drawback of also causing sickle-cell anemia, if the altered form of the gene is inherited from both parents). In the past 50 years researchers have uncovered a variety of adaptations in Andeans, Ethiopians, and Tibetans that allow them to breathe more efficiently at high altitudes. Andean populations retain higher levels of oxygen in their blood. Among Tibetans there is evidence that a gene was introduced through interbreeding with Denisovans, a mysterious branch of the human lineage that died out tens of thousands of years ago. All these adaptations give indigenous people living at high altitudes an advantage over the woozy visitor gasping for oxygen in the mountain air.

Early in origin of species, Charles Darwin comes out fighting: “Natural Selection, as we shall hereafter see, is a power incessantly ready for action, and is immeasurably superior to man’s feeble efforts, as the works of Nature are to those of Art.” The book was published in 1859. Is what was true then still true today? Was it true even in Darwin’s lifetime? Biological evolution may be implacable, and indeed more skilful than the genetic evolution humans can effect with crossbreeding in plants and animals, but how important is it, measured against the adaptations we can devise with our brains? To paraphrase the paleoanthropologist Milford Wolpoff, if you can ride a horse, does it matter if you can run fast?

In our world now, the primary mover for reproductive success—and thus evolutionary change—is culture, and its weaponized cousin, technology. That’s because evolution is no match for the speed and variety of modern life. Despite what evolution has accomplished in the recent past, think of how poorly adapted we are to our computer screens and 24-hour schedules, our salty bags of corn chips and pathogen-depleted environments. Why are our internal clocks so rigid? Why can’t our seemingly useless appendix, which may have once helped us digest grass, shift to break down sugars instead? If human genetics were a tech company, it would have gone bankrupt when steam power came along. Its business plan calls for a trait to appear by chance and then spread by sexual reproduction.

This works nimbly in mice, which can produce a new litter in three weeks, but humans go about things more slowly, producing a new generation only every 25 to 35 years or so. At this rate, it can take thousands of years for an advantageous trait to be spread throughout a population. Given genetic evolution’s cumbersome protocols, it’s no surprise technology has superseded it. Technology now does much of the same work and does it far faster, bolstering our physical skills, deepening our intellectual range, and allowing us to expand into new and more challenging environments.

“People get hung up on Darwin and DNA,” says George Church, a molecular engineer with a joint appointment at Harvard and MIT. “But most of the selection today is occurring in culture and language, computers and clothing. In the old days, in the DNA days, if you had a pretty cool mutation, it might spread in the human race in a hundred thousand years. Today if you have a new cell phone or transformative manufacturing process, it could spread in a week.”

PRESENT DAY: TECHNOLOGY VERSUS NATURAL SELECTION We big-brained humans have done much to neutralize the power of natural selection. With our tools, medicine, and other cultural innovations, we have started a potentially deadly race—one we could lose to a highly evolved superbug. Given the speed with which we can spread disease around the globe, “we are in a new pandemic era and must take action now to stop it,” says Kevin Olival, a disease ecologist at EcoHealth Alliance. Shifts brought about by habitat destruction and climate change are also bringing more people into contact with pathogens previously isolated from human hosts.

To be sure, the picture is more complicated. As the cyberpunk writer William Gibson has pointed out: “The future is already here. It’s just not evenly distributed yet.” Some of us live in Church’s world of jet travel and intersociety marriage, of molecular medicine and gene therapy, and seem to be heading toward a time when our original genetic makeup is simply a draft to be corrected. But outside the most developed parts of the world, DNA is still often destiny.

Not all trends are irreversible, however. There are scenarios under which natural selection would return to centre stage for the rest of us too. If there were a global disease outbreak, for instance, along the lines of the great influenza pandemic of 1918, those with a resistance to the pathogen (because of a robust immune system or protective bacteria that could render such a pathogen innocuous) would have a huge evolutionary advantage, and their genes would carry forward into subsequent generations while the rest of us died out.

We have medicines today to combat many infectious diseases, but virulent bacteria have recently evolved that do not respond to antibiotics. Jet travel can send an infectious agent around the world in a day or two. Climate change might prevent cold temperatures from killing off whatever animal carried it, as winter may have once killed the fleas that harboured the plague.

Elodie Ghedin, a microbiologist at New York University, says, “I don’t know why people aren’t more scared.” She and I discussed the example of AIDS, which has killed 35 million people worldwide, a death toll roughly equal to that of the 1918 pandemic. It turns out that a small percentage of people—no more than one percent—have a mutation of the gene that alters the behaviour of a cellular protein that HIV, the virus that causes AIDS, must latch on to, making it nearly impossible for them to become infected. If you live in New York City’s Greenwich Village, with access to the best antiviral drugs, this may not decide if you live or die. But if you are HIV-positive in rural Africa, it very well might.

There are many more scenarios by which genes could return to centre stage in the human drama. Chris Impey, a professor of astronomy at the University of Arizona and an expert on space travel, foresees a permanent Martian settlement within our grandchildren’s lifetimes, stocked by the 100 or 150 people necessary to make a genetically viable community. A first, smaller wave of settlement he regards as even closer at hand: “When Elon Musk is glue-sniffing, he might say 10 to 15 years,” Impey says, “but 30 to 40 doesn’t seem that radical.” Once the settlement is established, he adds, “you’re going to accelerate natural evolutionary processes. You’re going to have a very artificial and physically difficult environment that’s going to shape the framework of the travellers or colonists in a fairly aggressive way.” The optimal Earthling turned Martian, he says, would be long and slender, because gravity on the red planet has about one-third the force of Earth’s. Over generations, eyelashes and body hair might fade away in an environment where people never come directly into contact with dust. Impey predicts—assuming that the Martian humans did not interbreed with terrestrial ones—significant biochemical changes in “tens of generations, physical changes in hundreds of generations.”

One human trait with a strong genetic component continues to increase in value, even more so as technology grows more dominant. The universal ambition of humanity remains greater intelligence. No other attribute is so desirable; no other so useful, so varied in its applications, here and on any world we can imagine. It was indispensable to our forebears in Africa and will come in handy for our descendants on the planet orbiting the star Proxima Centauri, should we ever get there. Over hundreds of thousands of years, our genes have evolved to devote more and more resources to our brains, but the truth is, we can never be smart enough.

PRESENT DAY AND NEAR FUTURE: DO-IT-YOURSELF EVOLUTION Pairing in vitro fertilization with another process allows us to test embryos for mutations that could lead to serious medical conditions. Now we’re developing powerful new gene-editing tools that could bring about human-directed evolution. Most research has been on other organisms—for instance, attempting to change a mosquito genome so that the insect cannot transmit Zika or malaria. We could harness the same techniques to “design” our babies—simply to choose a preferred hair or eye colour. But should we? “There’s definitely a dark side,” says bioethicist Linda MacDonald Glenn, “but I do think humanity-plus is inevitable. We are, by our nature, tinkerers.

Unlike our forebears, we may soon not need to wait for evolution to fix the problem. In 2013 Nick Bostrom and Carl Shulman, two researchers at the Future of Humanity Institute, at Oxford University, set out to investigate the social impact of enhancing intelligence, in a paper for Global Policy. They focused on embryo selection via in vitro fertilization. With IVF, parents can choose which embryo to implant. By their calculations, choosing the “most intelligent embryo” out of any given 10 would increase a baby’s IQ roughly 11.5 points above chance. If a woman were willing to undergo more intensive hormone treatments to produce eggs faster—“expensive and burdensome,” as the study notes with understatement—the value could grow.

The real benefit, though, would be in the compound gain to the recipient’s descendants: After 10 generations, according to Shulman, a descendant might enjoy an IQ as much as 115 points higher than his or her great-great-great-great-great-great-great-great-grandmother’s. As he pointed out to me, such a benefit is built on extremely optimistic assumptions, but at the least the average recipient of this genetic massaging would have the intelligence equal to a genius today. Using embryonic stem cells, which could be converted into sperm or ova in just six months, the paper notes, might yield far faster results. Who wants to wait two centuries to be the scion of a race of geniuses? Shulman also mentioned that the paper omitted one obvious fact: “In 10 generations there will likely be computer programs that outperform even the most enhanced human across the board.”

There’s a more immediate objection to this scenario, though: We don’t yet know enough about the genetic basis for intelligence to select for it. One embryo doesn’t do advanced calculus while another is stuck on whole numbers. Acknowledging the problem, the authors claim that the ability to select for “modest cognitive enhancement” may be only five to 10 years off.

At first glance this would seem improbable. The genetic basis of intelligence is very complex. Intelligence has multiple components, and even individual aspects—computational ability, spatial awareness, analytic reasoning, not to mention empathy—are clearly multigenetic, and all are influenced by environmental factors as well. Stephen Hsu, vice president for research at Michigan State University, who co-founded the Cognitive Genomics Lab at BGI (formerly Beijing Genomics Institute), estimated in a 2014 article that there are roughly 10,000 genetic variants likely to have an influence on intelligence. That may seem intimidating, but he sees the ability to handle that many variants as nearly here—“in the next 10 years,” he writes—and others don’t think you’d need to know all the genes involved to start selecting smarter embryos. “The question isn’t how much we know or don’t know,” Church says. “It’s how much we need to know to make an impact. How much did we need to know about smallpox to make a vaccine?”

If Church and Hsu are right, soon the only thing holding us back will be ourselves. Perhaps we don’t want to practice eugenics on our own natural genomes. Yet will we pause? If so, for how long? A new technology called CRISPR-Cas9 has emerged, developed in part in Church’s lab that will test the limitations on human curiosity. First tried out in 2013, CRISPR is a procedure to snip out a section of DNA sequence from a gene and put a different one in, quickly and accurately. What used to take researchers years now takes a fraction of the time. (See “DNA Revolution,” in the August 2016 issue of National Geographic.)

No technology remotely as powerful has existed before for the manipulation of the human genome. Compare CRISPR and IVF. With IVF you select the embryo you want from the ones nature has provided, but what if none of the embryos in a given set is, for instance, unusually intelligent? Reproduction is a crapshoot. A story, likely apocryphal, illustrates the point: When the dancer Isadora Duncan suggested to the playwright George Bernard Shaw that they have a baby together so it would have her looks and his brains, he is said to have retorted: “But what if it had your brains and my looks?” CRISPR would eliminate that risk. If IVF is ordering off a menu, CRISPR is cooking. In fact, with CRISPR, researchers can insert a new genetic trait directly into the egg or sperm, thus producing, say, not just a single child with Shaw’s intelligence and Duncan’s looks but an endless race of them.

So far many experiments using CRISPR have been done on animals. Church’s lab was able to use the procedure to reengineer pig embryos to make their organs safer for transplant into humans. A colleague of Church’s, Kevin Esvelt at the MIT Media Lab, is working to alter the mouse genome so the animal can no longer host the bacterium that causes Lyme disease. A third researcher, Anthony James of the University of California, Irvine, has inserted genes in the Anopheles mosquito that prevent it from carrying the malaria parasite.

NEAR FUTURE: SCIENCE FICTION BECOMES REALITY More than 50 years ago two scientists coined the word “cyborg” for an imaginary organism—part human, part machine. It seemed science fiction, but today around 20,000 people have implants that can unlock doors. Neil Harbisson, who can perceive colours only by transforming them into sounds he can hear through an antenna implanted in his head, sees a future vastly improved by widening our senses with such technology. “Night vision,” he says, “would give us the ability to adapt to the environment: design ourselves instead of the planet. Designing the planet is harming it.”

Around the same time, however, researchers in China surprised everyone by announcing that they had used CRISPR in nonviable human embryos to try to fix the genetic defect that causes beta-thalassemia, a potentially fatal blood disorder. Their attempt failed, but moved them closer to finding a way to fix the defect. Meanwhile there is an international moratorium on all therapies for making heritable changes in human genes until they are proved safe and effective. CRISPR is no exception.

Will such a halt last? No one I spoke to seemed to think so. Some pointed to the history of IVF as a precedent. It was first touted as a medical procedure for otherwise infertile couples. Soon its potential to eradicate devastating genetic diseases was clear. Families with mutations that caused Huntington’s or Tay-Sachs diseases used the technique to choose disease-free embryos for the mother to carry to term. Not only was the child-to-be spared much misery, but so were his or her potential offspring. Even if this was playing God in the nursery, it still seemed reasonable to many people. “For this sort of technology to be banned or not used,” notes Linda MacDonald Glenn, a bioethicist at California State University, Monterey Bay, “is to suggest that evolution has been benign. That it somehow has been a positive. Oh Lord, it has not been! When you think of the pain and suffering that has come from so many mistakes, it boggles the mind.”

As IVF became more familiar, its accepted purpose spread from preventing disease to include sex selection—most notably in Asia, where the desire for sons has been overwhelming, but also in Europe and America, where parents talk about the virtues of “family balancing.” Officially, that’s as far as the trend toward nonmedical uses has gone. But we are the species that never knows when to stop. “I have had more than one IVF specialist tell me that they can screen for other desirable traits, such as desired eye and hair colour,” Glenn told me. “It is not advertised, just via word of mouth.” In other words, a green-eyed, blond child, if that’s your taste, could already be yours for the asking.

CRISPR is a vastly more powerful technology than IVF, with a far greater risk of abuse, including the temptation to try to engineer some sort of genetically perfect race. One of its discoverers, Jennifer Doudna, a professor of chemistry and molecular biology at the University of California, Berkeley, recounted to an interviewer a dream she’d had in which Adolf Hitler came to learn the technique from her, wearing a pig’s face. She emailed me recently to say she still hoped the moratorium would last. It would, she wrote, “give our society time to research, understand, and discuss the consequences, both intended and unintended, of changing our own genome.”

On the flip side, the potential benefits of applying CRISPR to humans are undeniable. Glenn hopes at least for “thoughtful discussions” first on how the technique will be used. “What becomes the new norm as we try to improve ourselves?” she asks. “Who sets the bar, and what does enhancement mean? You might enhance people to make them smarter, but does smarter equal better or happier? Should we be enhancing morality? And what does that mean?”

Many other scientists don’t think everyone will wait to find out; as soon as CRISPR is shown to be safe, ethical questions will recede, just as they did with IVF. Church thinks this still misses the point: The floodgates are already open to genetic reengineering—CRISPR’s but one more drop in the river. He notes that there are already 2,300 gene therapy trials under way. Last year the CEO of a company called BioViva claimed to have successfully reversed some of the effects of aging in her own body with injections from a gene therapy her company devised. “Certainly,” Church notes, “aging reversal is just as augmentative as anything else we were talking about.” Several gene therapy trials for Alzheimer’s are also in progress. These won’t likely produce any objections, because they are to treat a devastating medical condition, but as Church points out, “whatever drugs work to prevent Alzheimer’s will probably also work for cognitive enhancement, and they will work in adults almost by definition.” In February 2016 the boundary crumbled a bit more when the United Kingdom’s independent fertility regulator gave a research team permission to use CRISPR to explore the mechanisms of miscarriage with human embryos (all embryos used in the experiments will ultimately be destroyed—no pregnancies will result).

Church can’t wait for the next chapter. “DNA was left in the dust by cultural evolution,” he says, “but now it’s catching up.”

DISTANT FUTURE: CAN HUMANS ADAPT TO THE RED PLANET? Large-scale evolutionary divergence from the human norm requires a population to be isolated for thousands of years—unlikely on Earth. But it’s possible we could have a small settlement on Mars before a half century passes. Then would come a larger community—100 to 150 people, with members of reproductive age to sustain and increase its numbers. Could we evolve into ideal Martians? Space travel expert Chris Impey, a professor of astronomy at the University of Arizona, foresees a colony of Martians among whom scientists could accelerate natural evolutionary processes. Bodies would become tall and thin in response to an atmosphere with less than 40 percent of Earth’s gravity, and hairless in a controlled environment where there is no dust.

Our bodies, our brains, and the machines around us may all one day merge, as Kurzweil predicts, into a single massive communal intelligence. But if there’s one thing natural evolution has shown, it’s that there are many paths to the same goal. We are the animal that tinkers ceaselessly with our own limitations. The evolution of evolution travels multiple parallel roads. Whatever marvellous skills CRISPR might provide us 10 years from now many people want or need now. They follow Neil Harbisson’s example. Instead of going out and conquering technology, they bring it within themselves.

Medicine is always the leading edge in these applications, because using technology to make someone well simplifies complicated moral questions. A hundred thousand Parkinson’s disease sufferers worldwide have implants—so-called brain pacemakers—to control symptoms of their malady. Artificial retinas for some types of blindness and cochlear implants for hearing loss are common. Defence Department money, through the military’s research arm, the Defence Advanced Research Projects Agency (DARPA), funds much of this development. Using such funding, a lab at the University of Southern California’s Centre for Neural Engineering is testing chip implants in the brain to recover lost memories. The protocol might one day be applied to Alzheimer’s patients and those who have suffered a stroke or traumatic brain injury. Last year, at the University of Pittsburgh, a subject was able to transmit electrical impulses from his brain, via a computer, to control a robotic arm and even sense what its fingers were touching. That connecting the human brain to a machine would produce a matchless fighter has not been lost on DARPA. “Everything there is dual purpose,” says Annie Jacobsen, whose book The Pentagon’s Brain chronicles such efforts. “You have to remember DARPA’s job isn’t to help people. It’s to create ‘vast weapon systems of the future.’ ”

Human enhancements needn’t confer superhuman powers. Hundreds of people have radio-frequency identification (RFID) devices embedded in their bodies that allow them to unlock their doors or log on to their computers without touching anything. One company, Dangerous Things, claims to have sold 10,500 RFID chips, as well as do-it-yourself kits to install them under the skin. The people who buy them call themselves body hackers or grinders.

Kevin Warwick, an emeritus professor of engineering at Reading and Coventry Universities, in England, was the first to have an RFID device implanted in his body, back in 1998. He told me the decision had been a natural emanation of working in a building with computerized locks and automatic sensors for temperature and light: He wanted to be as smart as the structure that housed him. “Being a human was OK,” Warwick told a British newspaper in 2002. “I even enjoyed some of it. But being a cyborg has a lot more to offer.” Another grinder had an earbud implanted in his ear. He wants to implant a vibrator beneath his pubic bone and connect it via the web to others with similar implants.

It’s easy to caricature such things. The practitioners reminded me of the first men who tried to fly, with long arm paddles fringed with feathers. But it was when I asked Harbisson to show me where his antenna entered his skull that I realized something else. I wasn’t sure whether the question was appropriate. In Philip K. Dick’s novel Do Androids Dream of Electric Sheep? (the book that became the movie Blade Runner) it’s considered rude to ask about the mechanisms powering an android. “Nothing could be more impolite,” the narrator opines. But Harbisson was eager to show me how his antenna worked. He reminded me of how happily people show off their new smartphones or fitness trackers. I began to wonder what the difference really was between Harbisson and me—or any of us.

Nielsen reported in 2015 that the average adult over 18 spent roughly 10 hours a day looking at a screen. (By comparison, we spend 17 minutes a day exercising.) I still remember the home phone number of my best friend from childhood, but not the numbers of any of my good friends now. (This is true of seven of 10 people, according to a study published in Britain.) Seven out of 10 Americans take a prescription drug; of these, one in four women in their 40s or 50s takes an antidepressant, though studies show that for some of them anything from therapy to a short walk in the woods can do as much good. Virtual reality headsets are one of the hottest selling gamer toys. Our cars are our feet, our calculators are our minds, and Google is our memory. Our lives now are only partly biological, with no clear split between the organic and the technological, the carbon and the silicon. We may not know yet where we’re going, but we’ve already left where we’ve been.

Like any other species, we are the product of millions of years of evolution. Now we’re taking matters into our own hands.

UC San Diego researchers selected for DARPA project against mosquito-borne diseases

Wednesday, July 26, 2017 by Alex Murtha

The Defense Advanced Research Projects Agency (DARPA) recently selected the University of California – San Diego (UCSD) to be part of a research team on a project aimed at curbing the spread of infectious diseases like Zika virus and dengue fever.

UCSD’s selection by DARPA now entitles it to a $14.9 million award to assist in research-related efforts.

Through a technique known as gene drive, the research teams will focus their efforts on spreading desirable genes and suppress harmful ones throughout wild mosquito populations that are known to spread deadly infectious diseases.

Gene drives have received increased attention after the recent discovery of the CRISPR/Cas-9 gene-editing technique, which enables scientists to edit parts of the genome by altering sections of the DNA sequence.

In addition, UCSD Professor Ethan Bier and research scientist Valentino Gantz, collaborators on the new DARPA project, recently partnered to create a gene drive technology known as Active Genetics, which helps control the transmission of genetic traits.

“Mosquito species that spread dengue fever and Zika have recently crossed into California,” Bier said. “As the viruses these mosquitoes carry are poised to invade California it is essential to consider all possible strategies to combat these devastating diseases.”

UCSD researchers will now work to control a complementary group of mosquitoes of the Aedes genus, which are the most common species of mosquitoes that spread Zika, dengue, and yellow fever throughout the state of California.

“The gene-drive systems that we have developed at UC San Diego in collaboration with Professor Anthony James at UC Irvine provide a potentially game-changing technology that may eventually contribute to the goal of keeping California safe from these impending health threats,” Bier said.

A social component, led by UCSD Assistant Professor of Medicine Cinnamon Bloss, will also be launched to assess and clarify public concerns regarding gene drives in the United States.

“Our goal is to revolutionize and modernize the way we control the mosquito,” Omar Akbari, a professor at UC-Riverside who is also working on the project, said. “If we succeed with our plan we will be a lot further along in reducing the threat mosquitoes pose to human health.”

Dengue fever, Zika virus, West Nile virus, yellow fever and chikungunya are all part of the flavivirus family of viruses and are a leading cause of illness in tropical and subtropical climates throughout the world. In 2016 alone, more than 700 million people worldwide were infected with malaria or dengue fever, resulting in more than 400,000 deaths.

Small Pest, Big Battle

Researchers use gene editing to control disease-causing mosquitoes, thanks to a multimillion-dollar DARPA contract

By Julie Cohen

Wednesday, July 19, 2017 - 11:00

Santa Barbara, CA

The Aedes aegypti mosquito may be tiny but it can wreak major havoc on human health, spreading diseases such as Zika, dengue fever and yellow fever.

Those little suckers are about to face the fight of their life.

The Defense Advanced Research Projects Agency (DARPA) of the U.S. Department of Defense has awarded up to $14.9 million to a team of researchers from six University of California campuses, including biologist Craig Montell at UC Santa Barbara, to study how to use gene editing as a way to control disease-spreading mosquitoes.

Insects that carry disease represent one of the greatest worldwide threats to human health, with billions of people currently at risk of infection. Last year, more than 700 million people were infected with malaria or dengue fever, resulting in 440,000 deaths. And the prevalence of Zika virus is rising.

“Protecting the public from these diseases is difficult,” said Montell, the Patricia and Robert Duggan Professor of Neuroscience in UCSB’s Department of Molecular, Cellular, and Developmental Biology , whose lab works with Aedes aegypti. “Vaccines to prevent the diseases either don’t exist or are not very effective, and current mosquito control methods are inadequate. Therefore, there is a critical need for a transformative, species-specific, safe and effective method to control mosquitoes.”

Called Safe Genes, the DARPA project will focus on a technique pioneered by two team members, Ethan Bier of UC San Diego and Anthony James of UC Irvine. Known as gene drive, it can spread desirable genes in wild populations or suppress harmful organisms. Gene drive has been discussed and studied for decades, but the recent discovery of the CRISPR/Cas9 gene editing technique has revolutionized the development of gene drive systems, offering an increasingly inexpensive, efficient and more reliable way to make precise, targeted changes to the genome.

Advances in genetics and molecular biology will allow the UC researchers to understand the potential risks and benefits of using the technique to introduce genetic elements into laboratory mosquito populations to enforce the continued inheritance of selected genes. These elements function by biasing their transmission frequencies at rates significantly greater than the normal 50 percent, resulting in rapid spread throughout a population.

With the DARPA contract, the scientists aim to develop and test several approaches and integrate novel effectors to the gene drives. Effectors are elements that increase utility and safety and enable complex mathematical modeling to identify the most effective approaches. This effort seeks to answer many of the unknowns that still surround this novel approach for consideration by scientists, policymakers and the public.

UCSB’s contribution to the four-year project focuses in part on callback measures, which ensure that transgenic mosquitoes extinguish themselves. “Our approach is to suppress the population of Aedes aegypti,” Montell explained. “Although we will not release transgenic animals within the scope of this contract, our design nevertheless includes safeguards to make sure that the animals are not capable of persisting in the environment.”

The team will also integrate ecological data by sampling and sequencing wild mosquitoes captured from locations throughout California. This knowledge will help inform the designs of the drives and help predict how they might behave in a natural setting.

While the initial research will focus on Aedes aegypti, the technologies the UC team develops are meant to be general enough that they can be applied later to different mosquito species that spread other diseases, such as malaria and West Nile virus.

“Our primary goal is to safely test and innovate these technologies strictly in the laboratory,” said Safe Genes team leader Omar Akbari, an assistant professor at UC Riverside. “We hope our efforts will broaden our fundamental understanding of the potency of gene drives to help better understand how they may behave in the natural environment if ever released.”

Other team members are Valentino Gantz, Sergey Kryazhimskiy, Justin Meyer and Cinnamon Bloss at UC San Diego; Gregory Lanzaro at UC Davis; and John Marshall at UC Berkeley.

Craig Montell (center) and the researchers in his lab that will be working on the "Safe Genes" Zika mosquito project. (Photo Credit: Matt Perko)

UC Santa Barbara Targets Zika

Part of Six-UC DARPA Research Project

Sunday, July 23, 2017

By Jean Yamamura (Contact)

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Anxiety over the Zika virus has grown in fits and starts since it broke out dramatically in Brazil in 2015, with widespread reports of infected pregnant women bearing infants suffering microcephaly, a condition in which the brain fails to grow fully. The U.S. had more than 5,000 cases of Zika infection, and California reported more than 500 by April 2017. Santa Barbara County had eight positive cases of Zika, including two pregnant residents; according to County Public Health, all were travel related.

UCSB researchers have joined the effort to suppress Zika-virus-bearing mosquitoes under a contract with the Defense Department’s R&D powerhouse DARPA, the Defense Advanced Research Projects Agency. Using a technique pioneered by two members of the project team — Ethan Bier of UC San Diego and Anthony James of UC Irvine — they will work on aspects of spreading desirable genes in the wild and suppressing harmful organisms. The recently perfected CRISPR/Cas9 gene-editing technique has made genome changes more efficient and well targeted. No mosquitoes will be released as part of this work.

The $14.9 million contract with DARPA is spread across six UC labs, including Professor Craig Montell’s at Molecular, Cellular, and Developmental Biology at UC Santa Barbara. Dr. Montell’s portion of the four-year research project will concentrate on “callback measures” that ensure the genetically altered mosquitoes will not “persist in the environment.” His lab will collect the stinging bugs throughout California and use the ecological data they gather to predict how altered mosquitoes might behave in the wild. The focus of this research is Aedes aegypti, which spreads Zika, but the scientists hope the results will also apply to mosquitoes that spread West Nile and malaria.

UC San Diego Researchers Join $14.9 Million Fight Against Disease-transmitting Mosquitoes

As disease-carrying mosquitos threaten California, scientists leading cutting-edge gene-editing technologies take part in DARPA’s new Safe Genes project

An adult Aedes aegypti mosquito. Photo by Michelle Bui (Akbari Lab)

http://ucsdnews.ucsd.edu/pressrelease/uc_san_diego_researchers_join_14.9_million_fight_against_disease

University of California San Diego scientists have been selected by The Defense Advanced Research Projects Agency (DARPA) to be part of a “Safe Genes” research team that will receive up to $14.9 million to study an innovative genetic research technique as a way to control disease-causing mosquitoes.

Led by UC Riverside’s Omar Akbari, assistant professor of entomology, the project will focus on a technique known as gene drive, which can spread desirable genes in wild populations and suppress harmful organisms.

The researchers want to understand the potential risks and benefits of using gene drives to control mosquitos that carry diseases including Zika, chikungunya, dengue and yellow fever. Gene drives have received broad attention because the new CRISPR/Cas9 gene-editing technique has the potential to create, streamline and improve the development of gene drives. This effort seeks to develop new tools which should aid in the assessment of the effectiveness and safety of the technology by scientists, policy makers and the public.

Ethan Bier. Photo by Erik Jepsen/UC San Diego Publications

UC San Diego Professor Ethan Bier and research scientist Valentino Gantz, collaborators on the new DARPA project, recently developed a breakthrough gene-drive technology called Active Genetics, which controls the transmission of genetic traits. The technology is a driving force behind the new Tata Institute for Genetics and Society (TIGS), established last year to focus on immunizing mosquitoes in the Anopheline genus against malaria disease transmission in India.

“Mosquito species that spread dengue fever and Zika have recently crossed into California. As the viruses these mosquitoes carry are poised to invade California it is essential to consider all possible strategies to combat these devastating diseases,” said Bier, a professor in UC San Diego’s Division of Biological Sciences. “The gene-drive systems that we have developed at UC San Diego in collaboration with Professor Anthony James at UC Irvine provide a potentially game-changing technology that may eventually contribute to the goal of keeping California safe from these impending health threats.”

The UC San Diego effort will focus on controlling a complementary group of mosquitoes (Aedes genus) that transmit viral diseases (dengue, Zika, chikungunya and yellow fever) in California. The effort also includes a social component, led by Cinnamon Bloss, an assistant professor at UC San Diego’s School of Medicine and affiliate of the Qualcomm Institute, which aims to assess and clarify public concerns regarding gene drives in the U.S. (California).

“The parallel pursuit of gene-drive solutions to vector borne disease problems of global significance in both the U.S. and India will help define the scientific and ethical framework for possible implementation of this technology for practical applications,” said Bier.

“One daunting question many researchers have about gene drives is what their long-term effects will be,” said Justin Meyer, a UC San Diego Biological Sciences assistant professor and project collaborator. “Will mutations eventually develop in the drives or mosquito genomes to stop them from working? This type of question is difficult to answer because targeted populations must be monitored over long time periods and hundreds of generations.”

UC San Diego researchers including Meyer and Sergey Kryazhimskiy will aim to answer these questions by studying gene drives in baker’s yeast, a microorganism that undergoes multiple generations in a day and hundreds within months. These studies will help the researchers design gene drives that may be better able to withstand the test of time, said Meyer.

Valentino Gantz. Photo by Erik Jepsen/UC San Diego Publications

Bier and Gantz are also part of a separate DARPA Safe Genes project to test conditionally active forms of Cas-9 (such as drug-regulated forms of the Cas9 enzyme), which could be used to help restrict gene-editing activity to specific cell types at particular times to achieve greater control over the system and potentially to limit unwanted side-effects such as off-target mutations.

Insects that carry disease represent one of the greatest worldwide threats to human health with billions of people currently at risk of infection. Last year, more than 700 million people were infected with malaria or dengue fever, resulting in 440,000 deaths. Now the prevalence of Zika virus is rising.

“Our goal is to revolutionize and modernize the way we control the mosquito,” Akbari said. “If we succeed with our plan we will be a lot further along in reducing the threat mosquitoes pose to human health.”

Protecting the public from these diseases is difficult. Vaccines to prevent the diseases either don’t exist or are not effective. Current mosquito control methods are inadequate as many mosquito populations have become resistant, leading to a critical need for a transformative, species-specific, safe and effective method to control mosquitoes.

Recent advances in genetics and molecular biology have allowed researchers to use the gene drive technique to introduce genetic elements into enclosed populations to enforce the continued inheritance of selected genes. These elements function by biasing their transmission frequencies at rates significantly greater than the normal 50 percent, resulting in rapid spread throughout a population.

Larvae mosquitos of the species Aedes aegypti. Photo by Michelle Bui (Akbari Lab)

Although gene drives have been discussed and studied for decades, the CRISPR/Cas9 gene editing technique, which relies on a Cas9 protein targeted to a specific genomic location by guide RNAs, has recently revolutionized the development of gene drive systems because it offers an inexpensive, efficient and reliable way to make precise, targeted changes to the genome.

With the DARPA project, the researchers aim to develop and test several innovative gene drive approaches, including potential neutralization strategies to halt the unwanted spread of such systems. The team will also integrate ecological data by sampling and sequencing wild mosquitoes captured from locations spanning California. This data will help inform the designs of the drives and help predict how gene drives might behave in a natural setting.

The initial research will focus on the Aedes aegypti mosquito, which spreads diseases including Zika, dengue and yellow fever. But the technologies they develop are meant to be generalizable so they can be later applied to other mosquito species that are responsible for spreading other diseases, such as malaria and West Nile virus.

In addition to Akbari, Bier, Bloss, Gantz, James, Kryazhimskiy and Meyer, team members include Craig Montell (UC Santa Barbara); Gregory Lanzaro (UC Davis) and John Marshall (UC Berkeley).

Mother Jones Magazine

This Technology Could Stop the World’s Deadliest Animal

The capabilities of “gene drive” are thrilling—and also terrifying.

Michael MechanicAug. 14, 2017 6:00 AM

A gene drive currently in development could render Anopheles stephensi mosquitoes unable to spread malaria. JamesGathany/AP

Not long ago, Bill Gates, whose family foundation has spent billions of dollars battling diseases around the globe, noted in his blog that the deadliest animals on the planet are not sharks or snakes or even humans, but mosquitoes. Technically, the bloodsuckers merely host our most dangerous creatures. Anopheles mosquitoes can incubate the protozoae responsible for malaria—a stubborn plague that inspired the DDT treatment of millions of US homes and the literal draining of American swamps during the 1940s to shrink the insects’ breeding grounds. Malaria is now rare in the United States, but it infected an estimated 212 million people around the world in 2015, killing 429,000—mostly kids under five.

Mosquito-borne diseases kill hundreds of thousands of people every year. What if we could make them go away?

Dengue, which infects up to 100 million people worldwide each year, is spread largely by Aedes aegypti mosquitoes, which thrive along our Gulf Coast and also are capable of transmitting the related viruses Zika, chikungunya, and yellow fever. Of the millions infected, roughly 500,000 dengue victims develop an excruciatingly painful “break-bone fever”—according to Laurie Garrett’s The Coming Plague, “dengue” derives from the Swahili phrase ki denga pepo, “it is a sudden overtaking by a spirit”—and tens of thousands die.

West Nile virus, spread by Culex mosquitoes, has killed more than 2,000 Americans since 1999, primarily in California, Colorado, and Texas. Our latest headache, Zika, produces ghastly brain defects in the infants of infected mothers and neurological symptoms in some adults. Puerto Rico has been ravaged by more than 35,000 mosquito-borne Zika cases since 2015, not to mention periodic dengue outbreaks that afflict tens of thousands of people.

What if we could make all of this go away?

We do, in fact, have a weapon that could end the mosquito’s reign of terror. It’s called “gene drive,” and its implications are thrilling—and also kind of terrifying.

Evolution is a numbers game. Say you were to engineer a lab-modified gene into an animal embryo. By the rules of inheritance, that anomaly would be passed along to roughly half the creature’s offspring. Assuming the new gene didn’t offer any survival advantage (or disadvantage), it would be inherited by about a quarter of the subsequent generation and then an eighth and a sixteenth, and so on—until it became the genetic equivalent of radio static.

Gene drive upends that calculus. Lab-tested so far in yeast, fruit flies, and mosquitoes, this powerful new technique guarantees that a modified genetic trait is inherited by virtually all a creature’s offspring and all their offspring. After a while, every individual in the population carries the modification.

Courtesy of Kevin Esvelt

This wouldn’t work in people, thankfully—a short reproductive cycle and plenty of offspring are required for gene drives to spread effectively. But one could build, for instance, a drive targeting Aedes mosquitoes that leaves their offspring unable to reproduce, or one that makes Anopheles mosquitoes unable to transmit malaria. You could design a drive to control a stubborn crop pest or to render white-footed mice incapable of acting as a vessel by which ticks pick up and spread Lyme disease.

If used with care, gene drive could save millions of lives and billions of dollars. It could reduce pesticide use, help weed out nasty invasive species, and prevent tremendous human suffering. Then again, it could have unintended social and ecological consequences—or be hijacked for malevolent purposes.

The concept of a gene drive has been around for decades. In a 2003 paper, the British geneticist Austin Burt—inspired by naturally occurring “selfish” genes that copy themselves around the genome with the aid of enzymes that cut the DNA at precise locations—suggested that harnessing this ability and improving upon it would allow scientists to engineer natural populations, with an eye, for instance, toward preventing the spread of malaria.

Burt’s insight wasn’t practical, though, prior to the fairly recent invention of a breakthrough technique called CRISPR-Cas9 gene editing. With this innovation, a scientist uses customized ribonucleic acid (RNA) guide sequences to deliver a molecular scissors (an enzyme called Cas9) to a precise spot on a chromosome. The enzyme snips the double helix, prompting the cell’s DNA-repair machinery to kick in and patch things up—and in the process replacing the wild-type gene at that location with a lab-engineered DNA sequence. (Here’s one simple diagram.)

One spring day in 2013, about a decade after Burt’s paper appeared, a 30-year-old researcher named Kevin Esvelt was out walking in the Boston-area greenbelt known as the Emerald Necklace, pondering his next move. Esvelt, a post-doctoral fellow working with the renowned Harvard geneticist George Church, had ruled out working on the development of new CRISPR techniques. “The field had become so crowded,” he recalls via email, “it seemed likely almost anything I tried would be pursued by at least three other labs.”

Kevin Esvelt in his laboratory.

MIT Media Lab

As he walked along, Esvelt idly wondered whether any of the greenbelt’s wild creatures would end up being gene-edited in the decades to come. You could do it, of course, by introducing the CRISPR elements into wild-animal embryos. But why bother? The modified genes would become less and less prevalent with each generation of offspring. Natural selection would eventually weed them out of the population entirely.

And that’s when it hit him: Scientists had been putting the CRISPR tools into their target cells as separate pieces. What if you introduced them into the embryos as a single, heritable element? Those creatures and their descendants—all of them—would retain the gene-editing ability in their DNA. The system would be self-propagating. In short, you could rig nature’s game so your gene would win every time!

Esvelt was practically giddy with the possibilities. “The first day was total elation,” he told me. He found Burt’s paper and began fantasizing about all the lives gene drive might save. But the elation didn’t last long. A mistake—or a deliberate act—he soon realized, would alter an entire species. An experimental drive could escape into the wild before society agreed that it was okay. Perhaps gene drive could even be used as a weapon of sorts—a means for sowing havoc. “Once it hit me,” he recalls, “well, there was a flash of pure terror, followed by an obsessive evaluation of potential misuses.” Like Enrico Fermi, the scientist who demonstrated the first nuclear chain reaction back in 1942—Esvelt would be letting a very big cat out of the bag.

He took his ideas and concerns to his mentor, George Church. A scientist’s usual first instinct is to test an exciting hypothesis right away to see whether it’s viable, and then be the first to press with a blockbuster paper. This felt different. “We decided not to immediately test it in the lab—not because we couldn’t do it safely, but because we felt that no technology like this should be developed behind closed doors,” Esvelt says. “The question was whether it was safe to tell the world.” At Church’s urging, they brought on Jeantine Lunshof, an ethicist, and Ken Oye, a social scientist and policy expert: “Ken’s first words after I described the probable capabilities were not publishable.”

The researchers determined that their best course was to go public before doing any experiments. They solicited feedback from fellow molecular biologists, ecologists, risk analysts, public policy and national security experts, and representatives of environmental nonprofits. Only then, in July 2014, did they publish a pair of papers on gene drive’s uses and policy implications.

“The right question to ask is whether a hypothetical gene-drive-based bioweapon would afford any specific advantages.”

This summer, a group of researchers that consults for the federal government was tasked with analyzing the technique’s potential risks—including the possibility that it could be used for biowarfare. “The range of nefarious possibilities based on genetically engineered microorganisms is already vast,” Steven Block, an expert in bioterror defense at Stanford University, told me in an email. “The right question to ask is whether a hypothetical gene-drive-based bioweapon, which is based on multicellular organisms, would afford any specific advantages over something based on microorganisms. Would it be more powerful? Cheaper? Easier to construct? Would it be more accessible to an adversary? Would it afford any special ‘desirable’ properties as a weapon, from either a strategic or tactical perspective? I’d argue that, at least for the time being, gene drive seems to have done little to change the lay of the land.”

Accidents, mistakes, and unsanctioned releases are a separate concern. But Esvelt and his peers realized, to their great relief, that gene drives can be overwritten; they spread slowly enough through a population and are easy enough to detect, Esvelt says, that researchers should be able to stop a rogue drive using something called an “immunizing reversal drive” that can cut up the engineered sequence and restore the original genes. (He and Church have demonstrated the reversal process in yeast.) In any case, he says, it would be “difficult to imagine any possible combination of side-effects worse than a disease like malaria.”

Over the past couple of years, several labs have proved that gene drives work as hypothesized. The next step is to convince society they can be tested safely. Each drive is different, so potential risks and benefits have to be weighed on a case-by-case basis. But one big-picture problem is that wild creatures don’t respect human boundaries. A drive could easily scamper or fly or tunnel across borders and into areas where it hasn’t been sanctioned by local authorities. And that, Esvelt says, could trigger “international disputes or even wars.”

In his new position as head of the Sculpting Evolution group at the Massachusetts Institute of Technology’s Media Lab, Esvelt is working on gene-drive variations that can limit the spread of the engineered genes to a given number of generations. But diplomacy will be needed regardless. “For malaria, the case for an international agreement is obvious,” Esvelt says. Ditto the New World screwworm, whose “existence in the wild is an atrocity from an animal welfare perspective—it literally exists by eating higher mammals alive, causing excruciating agony.”

Mosquitoes have become tolerant of insecticides—and the deadliest malaria strain is resistant to “nearly all” available drugs.

In 2015, Austin Burt and his collaborators unveiled a gene drive designed to decimate populations of the African malaria mosquito Anopheles gambiae by rendering all female offspring sterile, although for statistical reasons, it is “quite implausible” for a gene drive system to completely wipe out a problematic species, Esvelt says. “Suppress a population, sure. Locally eliminate, possibly. But extinction? Not by itself.”

Anthony James, a geneticist at the University of California-Irvine, opted to target the disease directly. In 2015, he and his colleagues lab-tested a drive that enlists a pair of synthetic antibodies to disable malaria in the gut of the South Asian mosquito Anopheles stephensi. The dual attack—which targets two distinct phases of the parasite’s life cycle—should be all but impossible for the organism to overcome. In the highly unlikely event that these antibodies were to get into another insect species, they shouldn’t cause any problems. And because the mosquito population remains intact, their predators won’t lack for food.

James says his malaria drive will be ready for field tests within two years—either in huge outdoor cages or within a naturally confined environment such as an island. But is humanity ready to allow it? “It’s all new stuff. This is the problem. There’s no pathway,” he says. Securing permission to move forward with testing will depend entirely on the local mood and regulatory situation. As for deploying gene drive on a species-wide scale? Esvelt is skeptical that nations would accept wild releases without constraints in place that would limit their scope.

One way or the other, something has to change on the mosquito front. Conventional control methods—monitoring and education, poisons, door-to-door efforts to eliminate standing water—aren’t working. Poor countries in particular lack the resources to keep the bugs at bay, and because insects and microorganisms evolve so rapidly, our chemical weapons are rapidly losing their effectiveness. According to Bill Reisen, a retired UC-Davis mosquito expert, California mosquitoes can now tolerate compounds from three major families of insecticides that were once used to kill them: “The opportunities for control are becoming progressively limited.” The Centers for Disease Control and Prevention reports that Plasmodium falciparum, the world’s deadliest malaria parasite, has developed resistance to “nearly all” antimalarial drugs.

A mishap that delays the development of gene drive “would likely result in the otherwise preventable deaths of millions of children.”

A Zika vaccine seems to be on the horizon, but dengue remains a frustratingly elusive target for vaccine developers. UC-Davis geneticist Greg Lanzaro told me last year that, were it solely up to him, he would deploy gene drive as soon as scientifically feasible to beat back the Aedes mosquitoes that spread these diseases. Esvelt has heard similar sentiments from peers in several fields. “As a scientist, it’s hard to accept nontechnical limitations, especially when we could seemingly save so many lives if those constraints somehow magically vanished,” he says. “But they won’t.”

One thing is for sure: “The first effort has to be an unqualified success,” James says. “If there’s a trial and it’s a disaster—meaning it doesn’t prevent an epidemic—the technology is going to be set back.” Esvelt points to Jesse Gelsinger, an 18-year-old whose death during a 1999 gene therapy trial stifled progress in that field for a decade or more. “An accident involving a CRISPR gene drive—which would be viewed as reckless scientists accidentally turning an entire species into GMOs—would almost certainly have similar effects,” he says. And in the case of malaria, the delay “would likely result in the otherwise preventable deaths of millions of children.”

So he’s willing to wait to get it right. Indeed, in Esvelt’s view, gene drive is so existentially powerful that it demands a new era of scientific transparency. If researchers don’t rethink their longtime custom of competing behind closed doors, “we are likely to open extremely dangerous technological boxes without even realizing it.” A deeply collaborative approach with preregistered experiments, he says, would help scientists identify unforeseen dangers and ensure that those “boxes remain closed until we can develop countermeasures.” Such a radical departure from the current culture of secrecy would require nothing short of a sea change in the scientific community. But it might be worth the effort. As Esvelt puts it, “The greatest potential application of gene drive is to engineer the scientific ecosystem.”

This story has been corrected to more accurately describe when the concept of gene drive originated.

UC Riverside-led Team Wins $14.9 Million to Battle Disease-carrying Mosquitoes

DARPA award is largest ever for a UCR researcher

RIVERSIDE, Calif. (www.ucr.edu) — A University of California, Riverside scientist is leading a team of researchers that will receive up to $14.9 million dollars from The Defense Advanced Research Projects Agency (DARPA) to be part of the “Safe Genes” program to study innovative genetic techniques to control disease-causing mosquitoes. With the contract, the largest ever received by a UC Riverside researcher, Omar Akbari, an assistant professor of entomology, and his team will focus on a technique known as “gene drive.” It has the potential to spread desirable genes in wild populations and suppress harmful organisms. “Our primary goal is to safely test and innovate these technologies strictly in the laboratory,” said Akbari, who led the collaboration of six UC campuses. “We hope our efforts will broaden our fundamental understanding of the potency of gene drives to help better understand how they may behave in the natural environment if ever released.”

Omar Akbari

The researchers want to understand the potential risks and benefits of using gene drives to control mosquitoes that carry diseases including Zika, chikungunya, dengue, and yellow fever. Gene drives have ever greater promise because the recently discovered CRISPR/Cas9 gene editing technique has the potential to create, streamline, and improve the development of gene drives. Insects that carry disease represent one of the greatest worldwide threats to human health, with billions of people at risk of infection. Last year, more than 700 million people were infected with malaria or dengue fever, resulting in 440,000 deaths. And the prevalence of the Zika virus is rising. Protecting the public from these diseases is difficult. Vaccines to prevent the diseases either don’t exist, or are not effective. And current mosquito control methods are inadequate, as mosquitoes have become resistant. That creates a critical need for a transformative, species-specific, safe, and effective method to control mosquitoes. Recent advances in genetics and molecular biology allow researchers to use the gene drive technique to introduce genetic elements into a population to enforce the inheritance of selected genes. These elements increase transmission by more than 50 percent, resulting in rapid spread throughout a mosquito population.

The UC Riverside-led effort seeks to answer many of the unknowns that surround this novel approach, and will offer data for consideration by scientists, policy makers, and the public. Although gene drives have been discussed and studied for decades, the CRISPR/Cas9 gene editing technique, which relies on a Cas9 protein targeted to a specific genomic location by guide RNAs, has revolutionized the development of gene drive systems because it offers an increasingly inexpensive, efficient, and more reliable way to make precise, targeted changes to the genome. With the DARPA contract, the researchers aim to develop and test several innovative, safe, gene drive approaches, integrate novel effectors to the drives, which are elements that can increase their utility and safety, and to use complex mathematical modeling to identify the most effective approaches. The team will also integrate ecological data by sampling and sequencing wild mosquitoes captured from locations spanning California. This data will help inform the designs of the drives and help predict how gene drives might behave in a natural setting. There will also be a public engagement component, an essential ingredient to establish public trust if field studies are to be considered. The initial research will focus on the Aedes aegypti mosquito, which spreads diseases including Zika virus, dengue fever and yellow fever virus. But the technologies developed are meant to be later applied to other mosquito species, responsible for spreading diseases such as malaria and West Nile virus.

In addition to Akbari, the other team members are: Craig Montell (UC Santa Barbara); Anthony James (UC Irvine); Ethan Bier, Valentino Gantz, Sergey Kryazhimskiy, Justin Meyer and Cinnamon Bloss (UC San Diego); Gregory Lanzaro (UC Davis) and John Marshall (UC Berkeley).

Draft World Health Organization Global Vector Control Response 2017-2030

Se busca aplicación práctica para revolucionarias tijeras genéticas

En 2015, Science designaba a la la tecnología CRISPR/Cas como el progreso científico del año. En junio de 2016, la revista TIME la llevaba a su portada. Descrita como “uno de los avances más fascinantes de la ciencia”, esta herramienta molecular, cuya andadura comenzó en Alicante de la mano de Francisco Mojica ( el científico español que caracterizó y dio nombre a CRISPR), permite editar el ADN con “una precisión notable”. Según las citadas publicaciones estadounidenses, tiene el potencial de cambiar las vidas humanas para siempre.

http://www.eldiario.es/hojaderouter/ciencia/CRISPR-edicion_genetica-aplicaciones-ciencia_0_658634615.html

CRISPR Gene Editing Controversy: Does It Really Cause Unexpected Mutations?

https://www.forbes.com/sites/stevensalzberg/2017/07/10/crispr-gene-editing-problems-does-it-really-cause-unexpected-mutations/#362b65c66a1a

Children's Hospital Los Angeles asks blood donors to step up

"Another challenge? Newly emerging diseases like Zika and West Nile virus pose a risk to the local blood supply. There are also restrictions for donors who have traveled to a country where they may have been exposed to malaria."

http://www.scpr.org/news/2017/07/05/73530/children-s-hospital-los-angeles-asks-blood-donors/

Officials report Pennsylvania's first case of Zika found by testing donated blood

http://lancasteronline.com/news/local/officials-report-pennsylvania-s-first-case-of-zika-found-by/article_d1038f6c-5e6a-11e7-9b26-a3914ff074d3.html

We Need Other Options to Fight Zika

http://time.com/4833467/mosquitos-zika-incesticide-danger/

The UCI Malaria Kickoff meeting is scheduled for August 4th 2017! See you there.

CRISPR Applications:Life changer NBC News filmed in James lab

https://youtu.be/rjeRKoyAGBg

TATA Institute Web Site - http://tigs.ucsd.edu/

NBC News - Sunday Night with Megyn Kelly - June 11, 2017

A breakthrough in gene editing, CRISPR, gives humans unprecedented access to the source code of life. ... Up the coast at the University of California, Irvine, they are trying to rid the world of a disease that kills a child every two minutes. Dr. Anthony James is using CRISPR to bred malaria free mosquitoes. [starts at 3:52]

Bier Lab website UCSD - http://bierlab.weebly.com/

Molecular and population biology of mosquitoes and other disease vectors: vector and disease control

24 – 28 July 2017 | Kolymbari, Greece

http://meetings.embo.org/event/17-vector-control

Genetic Engineering and Diseases – Gene Drive & Malaria

Kurzgesagt channel youtube

Resistance complicates use of gene drive to control dangerous pests

A feeding female Anopheles stephensi mosquito. Note the red-colored abdomen that had become enlarged due to its blood meal contents, so full, in fact, that droplets of blood had been expelled from its distal tip. (James Gathany/CDC)

https://www.nature.com/news/gene-drive-mosquitoes-engineered-to-fight-malaria-1.18858

UCI mosquito project receives $2 million from Gates Foundation to fight malaria

UCI Professor Anthony James in Irvine on Tuesday, May 9, 2017. James, a vector biologist, will lead a multimillion-dollar effort to cultivate new strains of mosquitoes to fight malaria in Africa. (Photo by Paul Rodriguez, Orange County Register/SCNG)

UCI establishes Malaria Initiative to fight deadly disease in Africa

Acclaimed vector biologist Anthony James will lead multi-campus effort

on May 8, 2017

"Working hand in hand with thought leaders, scientists, public health personnel and government officials, we expect to lay the foundation for eliminating a disease that affects hundreds of millions of people globally," says Anthony James, UCIs Donald Bren Professor of Microbiology & Molecular Genetics and Molecular Biology & Biochemistry. Steve Zylius / UCI

Fighting malaria (OC Register news and events 05/05/2017 5:38 pm)

UC Irvine vector biologist Anthony James will lead a multimillion-dollar effort to cultivate new strains of mosquitoes to fight malaria in Africa.

A pioneer in creating genetically altered mosquitoes, James will direct the UCI Malaria Initiative, which will bring together experts in molecular biology, entomology, public health, community engagement and regulatory control to further develop and one day test these insects in the field.

The Bill & Melinda Gates Foundation is providing $2 million for the generation of sustainable, genetics-based approaches to controlling malaria parasite transmission by the vector mosquito Anopheles gambiae. Grants from the National Institutes of Health and other funding sources will also support the collaborative work involving scientists from other University of California campuses.

Anthony A. James Mosquitoes Al Jazeera America

https://ajam.app.box.com/s/6b9z7rqd7gp67w9g7gri4fsf1byooz9o

UCSD gene drive technology offers life-transforming power

Ethan Bier, UCSD professor of cell and developmental biology, helped apply gene drive technology to produce a malaria-resistant mosquito. (Howard Lipin)

Gene drive' mosquitoes engineered to fight malaria

The Anopheles stephensi mosquito can spread the malaria parasite to humans.

Panel Endorses ‘Gene Drive’ Technology That Can Alter Entire Species

https://nyti.ms/2jBwjq3

Female mosquitoes that have been altered as part of a gene drive experiment. Credit Anthony James

Editing the Genome of Mosquitoes

Published on Jan 5, 2016

(Visit: http://www.uctv.tv/) How should we balance the benefits of limiting or possibly eliminating a disease that kills 1000 people a day against the possible disruption of an ecosystem? Valentino Gantz, and Ethan Bier recently published a Science paper describing a new mechanism of "gene drive." This is not just a matter of editing the genes of a single individual, but an opportunity to make a change that will drive that change into all descendants of the original individual. Their publication resulted in international interest because of the broad potential applications of this new technology, which could rapidly produce beneficial genetic changes. Others have argued that because of the risks and implications of such research the work should not even have been published. Series: "Exploring Ethics" [1/2016] [Science] [Show ID: 30009]

Chain reaction' spreads gene through insects

http://www.sciencemag.org/news/2015/03/chain-reaction-spreads-gene-through-insects

Southern California scientist creating mutant mosquitoes

https://www.youtube.com/watch?v=jvSWQ5n1ppg

Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi

Abstract PNAS.org

http://www.pnas.org/content/112/49/E6736.abstract

Engineered Mosquitoes Could Eliminate Deadly Malaria Strain

NOVA NEXT

http://www.pbs.org/wgbh/nova/next/evolution/engineered-mosquitoes-could-eliminate-deadly-malaria-strain/

How we can eliminate malaria by 2040

How we can eliminate malaria by 2040 | Martin Edlund | Full Talk

UC, Davis PopI - Population Genomics Database, Gregory Lanzaro and Yoosook Le e

https://popi.ucdavis.edu/PopulationData/

WHO: Global Malaria Progress and Challenges in 2016

The President’s Malaria Initiative and Other U.S. Government Global Malaria Efforts

http://kff.org/global-health-policy/fact-sheet/the-u-s-government-and-global-malaria/

World Health Organization (WHO) 2016 World Malaria Report

http://apps.who.int/iris/bitstream/10665/252038/1/9789241511711-eng.pdf?ua=1

Malaria in South Africa (CDC)

https://wwwnc.cdc.gov/travel/notices/alert/malaria-south-africa

Transgenic Clustered Regularly Interspaced Short Palindromic Repeat/Cas9-Mediated Viral Gene Targeting for Antiviral Therapy of Bombyx mori Nucleopolyhedrovirus

http://escholarship.org/uc/item/3h7441fp#page-1

https://genomebiology.biomedcentral.com/articles/10.1186/s13059-014-0459-2

Transforming insect population control with precision guided sterile males with demonstration in flies

Gene-drive technology must be developed in a safe, ethical way

About the Author

Principles for gene drive research

RESPONDING TO THE NASEM REPORT

1 DECEMBER 2017 • VOL 358 ISSUE 6367 1135

1136 1 DECEMBER 2017 • VOL 358 ISSUE 6367

References and Notes

ACKNOWLEDGMENTS

Gene Drives Steer toward Road Tests

PSW 2378 The Mosquito, Synthetic Biology, CRISPR, and Malaria

Developing Safety Standards for Germline Use

Engineering Parasite-Resistant Mosquitoes

Sterilizing Populations

Comparing Alternative Strategies

Gene Drive in Practice

UC San Diego researchers selected for DARPA project against mosquito-borne diseases

Small Pest, Big Battle

UC Santa Barbara Targets Zika

Sunday, July 23, 2017

UC San Diego Researchers Join $14.9 Million Fight Against Disease-transmitting Mosquitoes

As disease-carrying mosquitos threaten California, scientists leading cutting-edge gene-editing technologies take part in DARPA’s new Safe Genes project

Mother Jones Magazine

UC Riverside-led Team Wins $14.9 Million to Battle Disease-carrying Mosquitoes

Se busca aplicación práctica para revolucionarias tijeras genéticas

CRISPR Gene Editing Controversy: Does It Really Cause Unexpected Mutations?

Children's Hospital Los Angeles asks blood donors to step up

Officials report Pennsylvania's first case of Zika found by testing donated blood

We Need Other Options to Fight Zika

The UCI Malaria Kickoff meeting is scheduled for August 4th 2017! See you there.

TATA Institute Web Site - http://tigs.ucsd.edu/

Bier Lab website UCSD - http://bierlab.weebly.com/

Genetic Engineering and Diseases – Gene Drive & Malaria

Fighting malaria (OC Register news and events 05/05/2017 5:38 pm)

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