GMOs Against Malaria? OECD Weighs the Risks

Genetically modified organisms have been discussed extensively regarding crop plants, but this is not the only class of species that researchers are manipulating in the hope of producing new characteristics, beneficial to humans. The fight against infectious, insect-borne diseases, like malaria, may finally find solutions here via the contributions of modified bacteria. This week in Paris, the OECD held a conference on the Environmental Uses of Micro-Organisms to consider the risks associated with the release of such altered microorganisms into the environment. Some can be assessed today, but others may be impossible to evaluate until the organisms are already out there.

Genetically modified organisms have been discussed extensively regarding crop plants, but this is not the only class of species that researchers are manipulating in the hope of producing new characteristics, beneficial to humans. The fight against infectious, insect-borne diseases, like malaria, may finally find solutions here via the contributions of modified bacteria. This week in Paris, the OECD held a conference on the Environmental Uses of Micro-Organisms to consider the risks associated with the release of such altered microorganisms into the environment. Some can be assessed today, but others may be impossible to evaluate until the organisms are already out there.

 

Last fall a team of researchers at pharmaceutical company GlaxoSmithKline announced the promising results of a malaria vaccine trial. The study reported a 50% success rate in blocking this disease responsible for an estimated 655,000 deaths in 2010, mostly among children under five. Still, some were asking if 50% success made the vaccine worth pursuing, worth further funding by the Bill and Melinda Gates Foundation. Dr Regina Rabinovitch, from the Foundation, was quoted by The Guardian newspaper as saying they would need to see the final data before making a decision. "Would I prefer to see a 100% effective vaccine? Certainly."

Clinical burden of malaria globally, 2007. Source: The Malaria Atlas Project
Malaria burden world map

The fight against malaria, and other insect-borne diseases like dengue fever and chikungunya, badly needs new weapons. Today, treated bed nets and insecticides to kill disease-carrying mosquitoes are the primary defense. This is problematic, though, as their extensive use provides a selective pressure for the insects to evolve resistance to the chemicals used. A very different approach, currently under study, is to genetically modify (GM) species involved in the chain of transmission. Many are leery of such tinkering with genomes, but scientists are simultaneously working to understand the consequences and assess the risks involved. This week, the OECD Working Group on Harmonisation of Regulatory Oversight in Biotechnologybrought together researchers and policy makers to discuss the science and how best to evaluate the consequences of releasing GM micro-organisms into the environment.

One method to stop the spread of malaria, presented by Marcelo Jacobs-Lorena of the Johns Hopkins Malaria Research Institute (Baltimore, USA), involves engineering bacteria naturally found in the gut of the mosquito to produce specific proteins naturally found in mammals or scorpions. These proteins bind to the malaria-causing parasite Plasmodium and prevent its maturation. Unable to advance through its lifecycle, it is also unable to cause disease.

Some advantages of the system, Dr. Jacobs-Lorena explains, are that it attacks the parasite at the most vulnerable step of its reproductive cycle, without depending on the mosquito’s own reproduction. It is relatively low-tech, too, requiring only the culture of the engineered bacteria. He also notes that, importantly, this system of paratransgenesis is compatible with other methods of malaria suppression, such as the continued use of insecticides. “The important thing is to maintain a variety of approaches,” to block the parasite from as many angles as possible.

Jacobs-Lorena feels quite confident about the safety of using this tool, for one, because the bacteria they use are already present in mosquitoes. One major question is what will happen to the new genes once they are released into the environment and whether they could be passed to other bacterial species. To minimize the chances of this horizontal gene transfer, the Johns Hopkins team inserted the genes in question directly into the genome of the bacterium. Furthermore, Jacobs-Lorena explains that the anti-malarial proteins produced from them are highly specific in binding to the parasite, and remain innocuous to the host.

Malaria is transmitted by the bite of the Anopheles mosquito. Source: CDC
Malaria transmitted Anopheles mosquito

A second approach for blocking insect-borne disease, also presented at the OECD meeting, proved challenging for regulators seeking to classify the method. Not precisely genetic modification, it makes use of Wolbachia, a truly remarkable bacterium with the ability to manipulate reproduction in its insect and arthropod hosts. These bacteria are transmitted vertically from female insects to their eggs, and are not passed horizontally between individuals. Wolbachia gives infected females a reproductive advantage and in this way ensures its own efficient spread throughout a population – an interesting characteristic for a vector control system, if it could be introduced into disease-carrying mosquitoes.

Iñaki Iturbe-Ormaetxe, of Monash University (Australia), explained that, for the most part, Wolbachia is symbiotic with the species it infects. What makes it a potentially powerful tool in the fight against infectious disease is the discovery of a strain in Drosophila melanogaster with the virulent property of cutting the fruit flies’ lifespan in half.  Most pathogens transmitted by mosquitoes require quite a long period of incubation within the insect vector —two weeks for the dengue fever virus. It is primarily old mosquitoes, then, that are responsible for transmitting these diseases. If their lives could be cut short by the introduction of Wolbachia, the opportunities for transmission would also be greatly reduced. After several false starts and four years spent allowing the bacteria to adapt to mosquito cells in culture, researchers succeeded in infecting the species that carries the dengue virus.

The Wolbachia bacterium is therefore a strong candidate for a biocontrol system against infectious diseases spread by insects. On the other hand, intentionally releasing into wild populations mosquito species infected with a new microorganism comes with safety and ethical concerns. Before carrying out a field test releasing Wolbachia-infected mosquitoes into the environment, Dr. Iturbe-Ormaetxe and colleagues at the University of Queensland conducted social research studies and engaged intensively with the community in order to determine the concerns and assess the risks associated with such a program, for a period of 30 years to come. “You can’t go to a region where there’s dengue and tell people you’re going to release more mosquitoes to control dengue…” he points out. “We had meetings, went door to door, and constantly kept people informed by newsletter. People were supportive. They don’t want to see more and more insecticides sprayed.”

In the end, only five of the 30 risks identified were determined to be non-negligible. And these five were considered low-risk. The number one potential hazard was found to be a change in human behavior, such as discontinuing use of important insecticides.

Still, the researchers addressed experimentally certain biological concerns raised by their system. Although Wolbachia has never been found in humans or any other vertebrate, they tested whether the bacteria could be passed to people through the bite of a mosquito. Their results showed that Wolbachia, too large to fit through the insect’s proboscis, is not even found in mosquito saliva. Nevertheless, they examined samples from human volunteers who had fed experimental mosquitoes, receiving thousands of bites over a four-year period. These showed no immunological evidence for the presence of Wolbachia.

In addition to human health concerns, worries exist about the well-being of the ecosystem when a new element is introduced. Whether Wolbachia could be passed to the mosquitoes’ predators was addressed with two species of spiders, fed on Wolbachia-infected insects for extended periods. To represent a more complete ecosystem, samples were collected from the fully enclosed, greenhouse-style lab where the mosquito work was conducted. Soil samples, leaves, roots, earthworms and millipedes were all analyzed.  None of the above samples indicated any transmission of Wolbachia to the environment.

These preliminary studies are encouraging, both regarding the potential efficacy of the Wolbachia system for blocking disease transmission, and for the anticipated innocuousness of introducing the bacteria into new species. The questions that apply to species altered for the fight against infectious disease also apply more generally to all applications of genetically modified microorganisms. Scientists working on biofertilizers, microalgae for food, feed, fuel or bioremediation, microbes in cleaning products and much more must all ask themselves what will happen to the modified organisms once they’re released. What will be the fate of the genes themselves, and what impact will there be on the environment? How should “potential adverse effects” be defined for different settings? As Hans Bergmans, of the Netherlands’ National Institute of Public Health and the Environment, and chair of the OECD special working group, puts it, “We’re trying to think of all the possible questions now, to stay ahead, so that after four years of work, when scientists ask permission to release something, they aren’t told ‘You need to address these questions’, and it takes another four years.”

Some of these questions, participants of the OECD meeting agreed, cannot be answered until an eventual release has taken place. The Wolbachia researchers, for instance, will not be able to say in advance how the dengue virus might evolve in the presence of this bacterium it had not previously encountered.  At the same time, there was consensus that “released is released”; once an organism is let into the environment, there can be no taking it back.

The dilemma is significant. But, as Hiroshi Yoshikura, of the National Institute of Infectious Diseases in Japan, suggested, the community can move forward using the OECD’s concept of familiarity: start from something you know, and scale up the processes to gain familiarity with the system or organism under study. He also recommends demonstrating “substantial equivalence”: that a new genetically modified product or method is at least as safe as a conventional counterpart with a history of safe use, because “uncertainty can be reduced only through experience.” As Marcelo Jacobs-Lorena commented, compared to DDT-based insecticides, the effects of GM approaches to blocking malaria may be minor. According to the WHO World Malaria Report 2011, there were 216 million cases of the disease in 2010; significantly reducing this number may be a compelling reason to try.

  Find out more: World Health Organization, Malaria Fact Sheet http://www.who.int/mediacentre/factsheets/fs094/en/ Centers for Disease Control and Prevention, Malaria Map Applicationhttp://cdc-malaria.ncsa.uiuc.edu/ European Union legislation on Contained use of genetically modified micro-organisms http://europa.eu/legislation_summaries/other/l21157_en.htm European Food Safety Authority, Panel on Genetically Modified Organisms (GMO) http://www.efsa.europa.eu/en/panels/gmo.htm About Wolbachia https://www.wolbachiawebsite.org/about.cfm