crispr as a potential tool for malaria eradication

Why avoiding delays to gene-drive based mosquito eradication should be the most

important goal of the global community right now, and why it is not.

CRISPR as a potential tool for malaria

eradication

Asst.-Prof. Mag. Dr. Matthias SamwaldSection for Artificial Intelligence and Decision

Support Medical University of Vienna

Vienna Rationality Meetup 14. 05. 2016

What is malaria?

• Plasmodium falciparium, transmitted by Anopheles spp.

• In 2015:o 214 million cases globallyo 438,000 deaths globallyo 90% of deaths occur in Sub-

Saharan Africao 70% of deaths are children under

fiveo About 3.2 billion people – almost

half of the world’s population – are at risk of malaria

o 97 countries had on-going malaria transmission

What is malaria?

• Since 2000 malaria has cost sub-Saharan Africa US$ 300 million each year for case management alone

• Malaria is estimated to cost endemic countries up to 1.3% GDP

• Malaria can account for up to 40% of public health spending in the most endemic countries

What is malaria?

Speeding up Malaria eradication by a single week could prevent 4,1 million cases of malaria, prevent 8400 deaths, and free up 48 million dollars of international and domestic funding spent on malaria

What is CRISPR?

• Technology for editing genomes arbitrarily

• Evolved for immune defense in bacteria

• Works for both somatic as well as germ-line alterations

• Probably one of the major scientifc breakthroughs of the 21st century

What are gene drives?

Are there scientists in the domain who advocate rapid implementation of gene drives for malaria/mosquito eradication?

Yes.

>> There's a constant effort to educate people to use treated nets and other tactics to avoid being bitten. But would it just be simpler to make an entire species of disease-carrying mosquito extinct?Biologist Olivia Judson has supported "specicide" of 30 types of mosquito. She said doing this would save one million lives and only decrease the genetic diversity of the mosquito family by 1%. "We should consider the ultimate swatting," she told the New York Times. << (3)

Major roadblocks: uncertainty + bureaucracy + biases

>> Even with public support, government approval won’t come easy unless rules change. The whole point of a gene drive is to disperse in the wild, but government regulations are designed to keep genetic engineering out of wild organisms, says Zach Adelman, a molecular biologist at Virginia Tech in Blacksburg. “There is no regulatory pathway that can deal with something that, by definition, can’t be contained.”

It’s not even clear which government agency would have jurisdiction over gene drives, Kenneth Oye of MIT and colleagues wrote in a commentary last year in Science. U.S. Food and Drug Administration regulations require that genetic modifications to animals be safe and effective for the engineered critters. Gene drives designed to wipe out invasive species might be effective, but they certainly would not be “safe” from the target species’ point of view. Then there’s the Department of Agriculture and the Environmental Protection Agency, which have overlapping regulations on the use of toxic substances, pest control and animal and plant health.

Gene drives spreading through wild populations would not respect international boundaries, so they might run afoul of international treaties, such as the Cartagena Protocol on Biosafety that governs cross-border movement of genetically engineered organisms. Nations that release gene drives could also be accused of violating the United Nations Biological Weapons Convention if gene-drive–carrying organisms cause harm to native species in another country.

Gene drives may make getting rid of disease and pests easy, but resolving questions surrounding their use will be anything but. << (2)

Reminder:

Speeding up Malaria eradication by a single week could prevent 4,1 million cases of malaria, prevent 8400 deaths, and free up 48 million dollars of international and domestic funding spent on malaria

What arguments against implementation of gene drives are brought forward?

If the intervention fails to produce lasting eradication of malaria (e.g., resulting only in a transient decline followed by a resurgence), the intervention could have net-negative effects because of loss of acquired immunity. (5)

However, this is a concern with all possible interventions for decreasing malaria, and radical population suppression (‘speciecide’) might protect from such a scenario.


Negative impact on ecosystems if whole mosquito species are eradicated.

>> So are there any downsides to removing mosquitoes? According to Phil Lounibos, an entomologist at Florida University, mosquito eradication "is fraught with undesirable side effects". He says mosquitoes, which mostly feed on plant nectar, are important pollinators. They are also a food source for birds and bats while their young - as larvae - are consumed by fish and frogs. This could have an effect further up and down the food chain.However, some say that the role of mosquito species as food and pollinators would quickly be filled by other insects. "We're not left with a wasteland every time a species vanishes," Judson said. << (3)

Evidence for ecological importance of select mosquito species as pollinators actually seems rather weak.


The ecological niche opened by the eradication of Anopheles spp. might be filled by other species of mosquito that introduce novel diseases.

>> [...] But for Lounibos, the fact this niche would be filled by another insect is part of the problem. He warns that mosquitoes could be replaced by an insect "equally, or more, undesirable from a public health viewpoint". Its replacement could even conceivably spread diseases further and faster than mosquitoes today. << (3)

Anopheles spp. would not be replaced by a completely novel set of species, so this criticism should state more precisely which vectors and which diseases that already exist might become a problem of equal or greater impact as malaria, which evolved as a human pathogen over long time periods.


Loss of protection of rainforests that were previously off-limits to deforestation because of high Malaria risk

>> Science writer David Quammen has argued that mosquitoes have limited the destructive impact of humanity on nature. "Mosquitoes make tropical rainforests, for humans, virtually uninhabitable," he said.Rainforests, home to a large share of our total plant and animal species, are under serious threat from man-made destruction. "Nothing has done more to delay this catastrophe over the past 10,000 years, than the mosquito," Quammen said.<< (3)


Another argument points to the unknown long-term impact of gene drives in the wild. Could the gene drives leave the confines of a species and become a major problem?

>> Genetic escape is the idea that the extinction gene might somehow get into a species other than the target and inadvertently wipe it out as well. In principle, this could happen in either of two ways. Anopheles mosquitoes might not be fussy about whom they mate with; if they engage in sex with mosquitoes of other species, the gene could spread into those species and eliminate them, too. Most animals avoid sex with members of different species, so a priori, the likelihood of hybridization seems small; all the same, this is something that should be investigated experimentally before the technology is put in place.<< (6)


Ethical reservations about making Anopheles spp. go extinct

>> But destroying a species isn't just a scientific issue, it's also a philosophical one. There would be some who would say it is utterly unacceptable to deliberately wipe out a species that is a danger to humans when it is humans that are a danger to so many species."One argument against is that it would be morally wrong to remove an entire species," says Jonathan Pugh, from Oxford University's Uehiro Centre for Practical Ethics. << (3)

This stance seems extremely hard to defend Potential solution: confined biospheres full of mosquitos…

What could be done to minimize preventable delays?

Research on ecological impact of Anopheles spp. eradicationo Further field studies

Problem: Takes long until new results are generated Problem: How generalizable are findings at limited scale and without total species eradication? Do ecosystems exist that are isolated enough so that population-supressing gene drives could be

tested without threat of global spread?o Further analysis of existing field studies (e.g., eradication without gene drives such as Oxitec system)o Simulations of global impact?

Improve ethical discourseo Argue against status-quo bias, naturalist fallacy

Improve biomedical discourseo Especially: which standards should be accepted for ecological safety?

Speeding up clarification of international regulatory framework for implementing gene driveso Need to identify relevant institutionso Probably most promising here would be lobbying by pro-gene-drive academics?o Given high morbidity, would it be ethical to push ahead without such a framework?o Would consensus among few local governments suffice?

Might be quicker to achieve than international regulations

Campaining

Bio-vigilantes?!

• It would be possible for an independent group to unleash a gene drive without waiting for development of broad consensus

• Deontological stance: obviously not right

• Consequentialist stance: ?!?o Negative impact on public opinion on future interventions based

on gene drives if hasty implementation has negative outcomes

Summary

Malaria bad

CRISPR gene drives amazing potential

Transnational, trans-bureaucratic collaboration for swiftly and safely implementing cutting-edge technologies and wholly novel ethical problems the jury is still out

Future work lobbying and outreach to minimize unnecessary delays of a potential implementation

Questions?

References1. World Malaria Day 2016 » Key Facts [Internet]. [cited 2016 Mar 11]. Available from: http://www.worldmalariaday.org/about/key-facts2. Gene drives spread their wings | Science News [Internet]. [cited 2016 Feb 7]. Available from: https://www.sciencenews.org/article/gene-drives-spread-their-wings3. Magazine CBBN. Would it be wrong to eradicate mosquitoes? [Internet]. BBC News. [cited 2016 Feb 7]. Available from: http://www.bbc.com/news/magazine-354088354. With This Genetic Engineering Technology, There’s No Turning Back [Internet]. MIT Technology Review. [cited 2016 Feb 7]. Available from: https://www.technologyreview.com/s/543721/with-this-genetic-engineering-technology-theres-no-turning-back/5. David AS, Kaser JM, Morey AC, Roth AM, Andow DA. Release of genetically engineered insects: a framework to identify potential ecological effects. Ecol Evol. 2013 Oct 1;3(11):4000–15.6. A Bug’s Death - NYTimes.com [Internet]. [cited 2016 Feb 10]. Available from: http://www.nytimes.com/2003/09/25/opinion/a-bug-s-death.html7. Esvelt KM, Smidler AL, Catteruccia F, Church GM. Concerning RNA-guided gene drives for the alteration of wild populations. eLife [Internet]. 2014 Jul 17 [cited 2016 Feb 7];3. Available from: http://elifesciences.org/lookup/doi/10.7554/eLife.034018. Oye KA, Esvelt K, Appleton E, Catteruccia F, Church G, Kuiken T, et al. Regulating gene drives. Science. 2014 Aug 8;345(6197):626–8.

What are the alternatives for decreasing the impact of malaria without resorting to population suppressing gene drives?

• Further increasing use of insecticide-treated bed nets

• Increasing availability of rapid-diagnostic tests for confirming malaria cases in remote settings, ensuring that people get the treatment when and where needed.

• Increasing availability of treatment (e.g., artemisinin-based combination therapies).

• Driving the development of vaccines and their availability in the developing world (still under research)

• Devise gene drives that modify mosquitos so as to acquire (partial) immunity to the disease-causing agent.

crispr as a potential tool for malaria eradication

Health & Medicine