The three work groups each focused on two or three case studies and chose one intervention to propose as a compelling business case, identifying the problem, the proposed solution, the value proposition and strategic opportunities.
In order to hone the arguments for possible application of the discussed genomic tools, each work group narrowed its choices to one or two applications and prepared a 10-minute “pitch” to a panel that provided viewpoints from business, philanthropy and government.
Eradication of Invasive Mosquitoes and Disease
Hawaii has the highest number of endangered birds in the US due in part to avian malaria, a parasite introduced into Hawaii that is causing disproportionate mortality in native forest birds, particularly honeycreepers. The disease will likely lead to extinction of several remnant species of honeycreepers unless something is done to decrease the burden of the parasite to native birds. The parasite is transmitted by a single species of introduced mosquito (Culex quinquefasciatus) in wet forests of Hawaii. Transmission of the parasite occurs at lower elevations where temperatures are warmer and drops off at higher altitudes. The result is that save for a few species of native birds that are tolerant of the parasite, susceptible birds are relegated to higher elevations where parasite transmission and mosquito populations are lower. There is additional concern that with climate change, the elevations where malaria can circulate will rise leading to ever shrinking free refugia.
The most viable solution is to try suppress or preferably eradicate the mosquito that transmits the parasite. A plan to do this would unfold as follows: 1) Initial efforts would focus on developing infrastructure to raise mosquitoes for sterile male release. This is a technology that already has a lot of procedural and regulatory buy-in, it has been shown to effectively eradicate insects over large areas, and would be a good way to get public buy-in to initiate eradication efforts. It would then establish a precedent and infrastructure that could then be used to layer successively more sophisticated off-the-shelf approaches such as Release of Insects with Dominant Lethality (RIDL). Implementing just sterile male and RIDL would take years and would, in the interim, allow development of the gene drive technologies whilst at the same time driving down mosquito populations and thereby reducing the current pressure on threatened bird species.
The Current Landscape
The only other options to address the avian malaria issue are to attack the host (e.g. make birds more resistant) or the agent (e.g. get rid of malaria). Given that multiple species of birds harbor malaria, figuring out ways to make birds resistant to the parasite would probably not succeed given the variation in host immune systems, behaviors, and other unknown factors. Getting rid of the parasite would involve either a vaccine or engineering a parasite that would drive itself out of existence. Developing a vaccine against a parasite that is notorious for hiding from the host immune response would take many years during which several bird species would likely become extinct. Attempts to develop a human malaria vaccine are a good example for why this would not likely work. Even if a vaccine were available, there are currently no effective ways to deliver vaccines to wild birds. Finally, use of pesticides to kill mosquitoes is not an option because delivering these chemicals in remote forests would be difficult and there is the concern of effects of pesticides on non-target native insects.
If we were able to eliminate mosquitoes, the following stakeholder would benefit from successful suppression or elimination of C. quinquefasciatus in Hawaii:
1) Hawaiian public: C. quinquefasciatus is not only a vector of avian malaria but could be a vector of human diseases such as West Nile Virus should it ever be introduced into Hawaii.
2) Conservation agencies
3) Native Hawaiian birds
One big risk would be public perception and resistance to the effort. There is already great public concern about GMOs in Hawaii, primarily in the context of GM crops and it is possible certain organizations could conflate GMO with mosquito eradication efforts, engender a public backlash, and torpedo the project. One way to circumvent this is to engage the public early and often during preparation and implementation of this effort. Another risk (though less likely) would be abject failure of the sterile male release or RIDL to achieve its technical objectives. However, these techniques have been proven to work in other areas, so the likelihood of success is good. A third risk is not developing methods to effectively monitor success.
Developed by Work Group 1.
Work Group 1 Participants
Team Leader: Dr. Margaret Wild, Lead Vet, Wildlife Management and Health Program Leader, Biological Resource Management Division, National Park Service, Fort Collins
Luke Alphey, The Pirbright Institute
Drew Endy, Assistant Professor, Bioengineering Stanford
Kevin Esvelt, Research Associate, Wyss Institute, Harvard University
Robert Fleischer, Center Head, Center for Conservation and Evolutionary Genetics, Smithsonian Conservation Biology Institute, National Zoological Park
Ken Gage, Chief, Entomology and Ecology Activity, CDC Fort Collins
Bruce Hay, Professor of Biology, California Institute of Technology
Jennifer Kuzma, Co-director, Genetic Engineering and Society Center, North Carolina State University
Dee McAloose, Head of Pathology, Zoological Health and Chief Pathologist, Wildlife Conservation Society
Jack Newman, Chief Scientific Officer, Amyris
Ben Novak, Lead Researcher, The Great Passenger Pigeon Comeback, Revive & Restore
Ryan Phelan, Executive Director and Co-founder, Revive & Restore
Oliver Ryder, Director of Genetics, San Diego Frozen Zoo
Toni Rocke, National Wildlife Health Center, USGS
Linus Upson, Vice President, Engineering, Google
Thierry Work, National Wildlife Health Center, USGS
Fungal diseases are an emerging problem worldwide for plants, animals, and humans. Fungal diseases destroy staple food crops, like rice and wheat, threaten food security and are serious threats to many wild species. The American Chestnut tree, once an icon of the Eastern US, essentially disappeared from the landscape following the introduction of a fungus to North America. Another fungus has caused extinction of more than 120 amphibian species in little over a decade.
More recently, a fungus introduced to North America has caused the most precipitous decline in mammals ever recorded. This fungus, Pseudogymnoascus destructans, infects bats during hibernation causing a disease called white-nose syndrome. Infected bat populations of several species have declined over 90% and a few species may become regionally extirpated or extinct in the next decade.
We currently have no effective and scalable solutions for white-nose syndrome or most other fungal diseases that threaten food security, human health, and global biodiversity.
We aim to tackle this problem using new genomic approaches and focus on bat white-nose syndrome as a model disease representing the global fungal crisis.
Our solution focuses on the fungal pathogen. P. destructans is an invasive species to North America, its genome is sequenced, and it can be easily grown in the laboratory. These characteristics make it a good target for intervention. Our approach blends new genomic technologies with established ecological principles. We will aim to weaken the fungus, not eliminate it. This will allow the fungus to persist in the environment and on bats, but will reduce the pathogenic potential and mortality rate in bats.
We will accomplish our objective using two strategies to reduce the virulence of P. destructans. One strategy will be genetically based and involve identifying less virulent strains of the fungus. These may be naturally occurring isolates or isolates genetically modified using RNAi or CRISPR. The other strategy will involve identifying or genetically engineering a virus that can infect the fungus (a mycovirus) and cause reduced fitness or virulence. The resulting isolates will be screened for virulence in the laboratory using a waxworm model and bat tissue explants. From these tests, we will identify candidate strains for testing on hibernating bats in controlled laboratory infection trials. All safety testing and assessment of effects on non-target species will be completed at this stage. Based on the results of these experiments, the less virulent strains (either genetically-based or viral-mediated) will then be deployed at select hibernation sites for initial field-testing. Fungal loads in the environment, intensity of infection in bats, and severity of white-nose syndrome will be monitored over the duration of the field trial using established tools and methods. This information will be used to assess and refine our initial approach.
Our approach is unique in that it leaves space for the fungus to survive and allows for co-existence with bats and other organisms within cave ecosystems. Animals and plants have been living with fungi for thousands of years and there is a strong selection pressure for more peaceful coexistence. By reducing virulence of the fungus, we may help facilitate natural evolution of resistance in bats to this disease. Additionally, this approach is consistent with modern evolutionary medicine.
The Current Landscape
Controlling disease in free-ranging wildlife populations is challenging and tools to effectively combat fungal diseases are extremely limited. This is true across species, including humans. Chemotherapeutics and bio-control agents are currently being tested for treatment of white-nose syndrome in bats. But, all of these treatments are labor intensive, temporary fixes with questionable long-term utility.
Genomic tools have been successfully used against fungal disease of plants and may soon allow for restoration of the American Chestnut to our backyards and forests across the eastern US. So this approach has precedence in other species, but has not yet been applied to fungal diseases of animals, such as white-nose syndrome.
Response to white-nose syndrome is strongly supported by a coordinated, international framework that includes Federal agencies in the US, Canada, and Mexico, state and provincial agencies, and a broad network of academic institutions and NGOs. All stakeholders have been actively engaged in response to this epidemic and are driving the research forward. The research that has been completed over the past seven years has led us to this point. As a community, we are ready to develop and deploy treatments for this disease to protect bats across North America…and time is running out.
We need an effective, scalable, long-term solution. We think our approach is that solution. Additionally, the tools and methods we develop for combating white-nose syndrome will likely have broader applications for other species threatened by fungal diseases worldwide, including humans.
Our solution will save millions of bats across North America. Bats are keystone species for cave ecosystems and provide important ecological services. Bats are voracious insect predators; a single bat can consume up to 5,000 insects a night. This pest control service translates to $25 billion savings annually for US agriculture.
The solution we propose would provide valuable tools for federal and state land management agencies and conservation NGOs. These groups are eager for solutions that will help them protect and conserve important bat populations.
The tools we develop for white-nose syndrome may be translated to treating fungal infections in other species. This will broaden our market and opportunities to have substantial impacts on global biodiversity, food security, and human health.
We acknowledge there are risks in our approach. Ecologically, this fungus is invasive and has no established niche in the ecosystem of North America. So, altering the fungus is unlikely to have substantial ecological impacts.
There are technical challenges inherent in identifying or creating an effectively less virulent strain of the fungus. However, our multi-pronged approach will help protect against this risk and improve chances of finding one or more potential solutions.
A delay in regulatory approval for deployment of our solution would reduce our ability to protect bat populations from this disease. White-nose syndrome continues to spread across North America with new states confirmed with the disease every year – we don’t have much time. Through the White-nose Syndrome National Response Framework we have created a partnership with regulatory agencies and are prepared to address treatment options as they become available. These relationships have established a pathway for white-nose syndrome treatment options and will allow us to move quickly on implementation in a structured manner.
Public perception is an important consideration and will influence our ability to implement solutions on a broad scale. Communications, education, and outreach have been key components of the White-nose Syndrome National Response. We will continue to actively engage diverse stakeholders through this network.
Developed by Work Group 2.
Work Group 2 Participants
Team Leader: Dr. Billy Karesh, Executive Vice President for Health and Policy at EcoHealth Alliance
Stewart Brand, Cofounder, Revive & Restore. President, The Long Now Foundation
Claudio Campagna, Wildlife Conservation Society Marine and Argentina Programs; Adjunct Professor, UC Santa Cruz; Steering Committee member, IUCN Species Survival Commission
George Church, Platform Lead, Synthetic Biology, Wyss Institute, Harvard University
Jeremy Coleman, National White-Nose Syndrome Coordinator; Northeast Regional Wildlife Disease Coordinator, U.S. Fish and Wildlife Service
James Collins, Professor of Natural History and the Environment, Arizona State University
Tim Doran, Senior Research Scientist and Group Leader for Advanced RNA Technology, CSIRO Biosecurity Flagship
Alicia Jackson, Deputy Director of the DARPA Biological Technologies Office (BTO)
Wendy Kiso, Research and Conservation Scientist, Ringling Bros. and Barnum & Bailey Center for Elephant Conservation
Paul Ling, Department of Molecular Virology and Microbiology, Baylor College of Medicine
Eleonore Pauwels, Public Policy Scholar, Science and Technology Innovation Program, Woodrow Wilson Center
William Powell, American Chestnut Research & Restoration Project
Edward Schulak, Private Investor
Dennis Schmitt, Chair of Veterinary Services and Director of Research, Ringling Bros. and Barnum & Bailey Center for Elephant Conservation
Lee Skerratt, James Cook University, Australia
Michele Verant, Veterinarian, Postdoctoral Research, School of Veterinary Medicine, University of Wisconsin-Madison
Vance Vredenburg, Associate Professor, Department of Biology, San Francisco State University
Applying Genetic Technologies to Eradicate Mice as a Model for Benefiting Human Health, Agricultural Production and Biodiversity
Introduced rodents caused approximately half of all known extinctions in the last 500 years. Islands are rich in species found nowhere else and harbor a fifth of all species. Unfortunately, invasive rodents now impact over 150,000 islands. Rodents are also agricultural pests on islands and all continents, impacting food security. Subsistence farmers are particularly impacted. The cost to US agriculture alone is $19 billion per year. Single mouse plagues in Australia cost farmers $60 million. In Asia alone, the rice loss every year caused by rodents could feed about 200 million people. Invasive rodents are also major vectors or critical hosts of disease, like leptospirosis, that impact people and livestock.
A multi-year horizon scan for innovative ways to eradicate rodents on islands revealed genetic tools as a transformative innovation. They are safe, species-specific and able to be implemented with today’s technologies. A gene that naturally occurs on the mouse’s sex chromosome can be moved to another chromosome where it results in all-male offspring. When released into a mouse population, mice with these genes can theoretically drive populations to extinction. This methodology has been used to effectively control insect pests for decades but this is the first time it has been proposed for use for conservation purposes.
We selected mice as the rodent species with which to prove this concept as they are a major agricultural, health and conservation pest, they are the most sophisticated animal model, and this knowledge base can be leveraged, and naturally occurring genetic elements known in mice but not other species can be exploited. Once this approach is demonstrated to be safe, reliable and effective in mice, replication could occur in rat and other pest species. The first phase of developing this methodology for rodents involves proof-of-concept trials under controlled simulated field conditions.
On islands, rodents have been entirely eradicated from >400 islands as a response to their threats to biodiversity values. Once rodents are removed from islands, the ecosystems and species recover, often spectacularly. To eradicate rodents, the only effective strategy is to use anticoagulants, particularly the toxicant brodifacoum. However, a major disadvantage is that these toxicants are not species-specific. The use of toxicants creates adversity, and the toxicant itself has animal welfare issues.
The current rate of rodent eradications is 10-20 islands/year, which is plausible but it doesn’t match the scale of the problem with >150,000 islands having invasive rodents. Further, failure rate in mice is approximately 25%, and this technology has effectively reached its limits.
More than $600 million was spent on rodenticide products in 2012 globally, and by 2019 this market is expected to be $900 million. Rodents are major pests of agriculture worldwide, impacting food security. Rodents are vectors and critical hosts of diseases that impact people and livestock health. Biodiversity, particularly on islands is also impacted, with rodents being responsible for half of all the known recent extinctions. A transformative technology such as the daughterless mouse project has the potential to rapidly increase global food production, reduce the use of rodenticides, improve human health and protect biodiversity around the world.
We have identified three major risks:
1. Translating laboratory success into the field: will the genes spread at a population level? We know the approach works in laboratory settings. We need to demonstrate that this success can translate into field efficacy. Evidence suggests this is possible. For example, on a small Orkney island, mice released into the local population successfully altered the entire population’s genetic makeup within 18 months. The work we propose in the next five years aims to determine how we can realize this potential. Simulated field trials will generate data on select mouse types, enabling mathematical models to be generated to predict outcomes and identify optimum release numbers and the most appropriate mouse type.
2. Navigating the regulatory environment. Our overall strategy is in-line with international guidelines, and our staged approach allows us to anticipate and assess risk. To provide effective oversight and potential implementation options we will work simultaneously with US, Australian and Brazilian regulatory agencies with early and frequent consultation throughout the process. This provides benefits and implementation options that a single regulatory agency cannot provide.
3. Public acceptance will be key to influencing regulatory agencies and political support. Incorporating lessons learned from previous work and employing consultation processes we will identify and inform potential champions within interest groups, while learning of their concerns and adapting accordingly.
Developed by Work Group 3.
Work Group 3 Participants
Team Leader: Josh Donlan, Advanced Conservation Strategies
Karl Campbell, Island Conservation, Galapagos
Rob Carlson, Principal, Biodesic
Robert Cook, Program Director of the Conservation Program and the Basic Medical Research Program, Helmsley Charitable Trust
Owain Edwards, Program Leader, Commonwealth Scientific and Industrial Research Organisation (CSIRO)
Neil Gemmel, Professor and Gemmel Lab Lead, Department of Anatomy, University of Otago
Fred Gould, Professor of Entomology, North Carolina State University
Ben Hoffman, Senior Research Scientist, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Australia
Gregg Howald, Island Conservation, Canada
David Lang, Co-founder of OpenROV
Kent H. Redford, Principal, Archipelago Consulting.
Phil Seddon, Professor, Department of Zoology, Director, Postgraduate Wildlife Management Programme, University of Otago, New Zealand
Ronald Thresher, Research Scientist, CSIRO / Wealth from Oceans Research Flagship, Australia
Neil D. Tsutsui, Professor, Vice Chair for Instruction Policy & Management, Department of Environmental Science, UC Berkeley
Marcela Uliano da Silva, Federal University of Rio de Janeiro
W. Ian Lipkin, Director, Center for Infection and Immunity, Columbia University
Toni Piaggio, Research Scientist, Wildlife Genetics, National Wildlife Research Center
David Threadgill, Texas A&M University
Tanja Zabka, Veterinary Pathologist and Lead in the Safety Assessment Group, Genentech