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Humans have carved nature to our taste on a small scale for thousands of years. But now, we are looking at much bigger changes, thanks to a growing understanding of genetics.
Reuters / Mariana Bazo
Farmers have always grown plants to improve the chances of replicating the desired results, by growing larger squash or sweeter strawberries, by crossing certain varieties producing new and improved seeds. Farmers have also selectively reared animals for various traits, for example, by making sheep with longer hairs for better wool. These efforts changed nature, but they were slow and focused attempts.
Today, scientists plan to transform nature to an unprecedented level. CRISPR gene modification technology allows scientists to cut and glue DNA fragments, which can target very specific aspects of a species' genome to eliminate or improve them. It is also possible to propagate these changes across an entire species relatively quickly, faster than natural heritage models, with deliberate gene drives, which would alter the DNA of a species over several generations.
Genes are naturally present in some species, such as various fungi, and scientists have been studying selfish genes since the 1960s. Deliberate gene drives have a natural tendency to develop. Instead of having about 50% chance of being passed on to offspring, like most genes, these "selfish genes" are more likely to be inherited, even if they do not. may be harmful to an individual or species, resulting in sterilization.
The advent of CRISPR means that using gene drives to sculpt the evolution – reconfiguring creatures to better meet our needs by forcing a skewed genetic inheritance – is closer to reality than ever before . It could be argued that scientists could rethink the genetics of a species by using CRISPR to edit DNA sequences and to reproduce creatures with these "selfish genes" that have a greater than average chance of being transmitted to the community. offspring. As these selfish genes continue to spread more quickly than others, the entire species may or may not have particular traits based on human preferences.
Theoretically, we could one day live in a world where creatures could not transmit diseases to humans, because certain genetic tendencies had been suppressed. Mosquitoes, for example, would not carry malaria. Realistically, however, there are dangers and one of the major and widely recognized problems with the introduction of genetic drives is that humanity can not accurately calculate what will happen when we begin to tinker with nature. this scale. And there are many reasons to be suspicious.
Given the interdependence of ecological systems and the high probability that we can not predict all the possible consequences of such actions, genetic mechanisms differ from other scientific efforts to eradicate diseases that target humans rather than alter the DNA of a species carrying the disease. They offer dramatic improvements but could also have devastating consequences. Add to this that creatures do not respect national borders and that genomes become a regulatory nightmare. Basically, humanity has to agree on how to proceed before moving forward. International standards must be developed, countries must adopt laws that conform to these standards, and communities where genes are initiated must give their consent to any proposed scientific effort.
How can we accept a process whose consequences are not yet well understood and where it may be impossible to calculate the risks?
This question of consent underlies a profound question that no one is yet able to answer. How can we – humanity in general and the specific individuals involved in a deliberate change and concerned by this change – accept a process whose consequences are not yet well understood, of which it may be impossible to calculate the risks?
Some scientists have argued that we alter nature all the time – we apply pesticides, for example, we drain swamps – and that genes are a "more elegant way of interacting with nature than anything we do. let's do it now. "
Nevertheless, the communities that would be affected by these efforts have expressed serious reservations. "In Africa, we are all potentially affected and we do not want to be lab rats for this exterminator technology," said Mariann Bassey-Orovwuje, president of the Alliance for Food Sovereignty in Africa, at the end of a United Nations conference on biological diversity in Egypt last November. "Farmers have already marched through the streets of Burkina Faso to protest against genetically modified mosquitoes and we will still march if they ignore this decision of the UN. We now report that potentially affected West African communities have not given their consent or approval to this risky technology. "
The scientists who support the genes, and the communities that their work will affect, have valid arguments.
Save lives
To understand the promise, the controversy and the complexity of genetic systems, consider a single case of possible use: carve the evolution of three species of mosquitoes to eliminate malaria, a deadly disease. This mosquito-borne disease kills a child every 30 seconds of every day, according to UNICEF (pdf). Every year, 300 to 600 million people suffer from the disease, mainly in sub-Saharan Africa, and about 1 million people die from it. But if the DNA of mosquitoes could be modified to not contain the parasite responsible for the disease, this deadly disease could theoretically be totally eradicated and the experts are already working on it.
Target Malaria, a project funded in part by the Bill and Melinda Gates Foundation, is a highly publicized initiative to use gene drives to eliminate the disease. And this is an excellent example of the complexity of these efforts. It brings together researchers, regulators, stakeholders and communities from Europe, North America and Africa to reflect on all aspects of an extremely complex and potentially very promising proposal.
Reuters / Joseph Okanga
Consider only the considerations of the scientific teams in this project and you will see how much work remains to be done in order to put genetic systems in place. Scientists must determine how to best modify genes and insert them into mosquitoes that carry malaria, study local mosquito and human populations, and determine how the technology could be used if their research is successful.
Then there are all other concerns, such as local and international regulations, the long-term consequences, the ethics of these efforts and the way affected communities and the general public feel that they are falsifying. 39; ecology. There must be widespread agreement and understanding about a project of this magnitude because the consequences will not necessarily be limited to the specific community in which it takes place.
Secret and persuasion
Not everyone is totally sold on this notion, and the Gates Foundation is aware of it. It spent $ 1.6 million on a secret advocacy effort to "fight back" against those who want to stop the development of gene experiments until the tool is better understood. A request for freedom of information legislation published in 2017 on SynthBio revealed that the foundation had paid a private public relations firm in the sector of agriculture and biotechnology, Emerging Ag, to influence experts involved in a UN online forum on synthetic biology that discussed concerns about genetic training. The foundation hopes to convince stakeholders to see the results and underline their promises.
Some people involved in research on controlled genes are considering its use in more than preventing disease. For example, the US Defense Advanced Research Agency (DARPA) funds the development of genetic actors. The agency calls its research program "Safe Genes" and its website explains that it aims to "protect fighters and the country of origin against intentional or accidental misuse of technologies." editing the genome; to prevent and / or reverse undesirable genetic modifications in a given biological system; and facilitate the development of safe, accurate and efficient medical treatments that use gene editors. "
But as shown by SynthBio's requests for documents, DARPA has not been entirely clear about its participation in the development of this technology. He spent about $ 100 million on gene research, 35 million more than previously announced, making the US military "probably the biggest funder of gene research on the planet".
In 2017, the Advanced Intelligence Research Projects Agency (IARPA) also sought to work with scientists. In an exchange between academics involved in induced gene research at North Carolina State University, Todd Kuiken, senior researcher at the school's Genetic Engineering and Society Center, explained why this could be troubling, writing: "I do not know IARPA well. . My limited understanding is that it's essentially the DARPA version of the intelligence agencies, which can be more scary! "
The same tools that can be used for good could in theory be used for bad, too, which is just one of the reasons why one should be careful in developing a gene control technology. And even if everyone involved in its development now has the best possible intentions, it does not necessarily mean that knowledge will always be limited or used by those who have it.
Secret efforts such as these, if they become public, could have the opposite effect to what organizations want – they could make people even more suspicious of gene drives and their supporters. .
Think about the problems
Much is not known about what will happen when gene drives are implemented. This prompted the US National Institutes of Health to request a comprehensive assessment of the technology, processes, considerations, and consequences of these efforts at the National Academy of Sciences, Engineering and Research. of Medicine (NASEM), a consortium of private nonprofit institutions providing the government with expert advice to help shape the policy.
The NASEM committee has met to examine the state of gene reader systems and the ethical issues they raise. "One of the main recommendations of the NASEM report is that we do not have sufficient evidence at the moment to support the release of modified organisms that induce genes into the environment," writes the ecologist of evolution. James Collins of the University of Arizona in a 2018 document summarizing the findings of the committee. Central procedures of BioMed. "It is important to note that the committee has also recognized that the potential benefits of gene drives for basic and applied research are important and warrant continued laboratory research and controlled field trials."
In other words, it is good to experiment with genes in scientific research, but we still do not know enough to say that it is a safe way to deal with major problems like malaria.
Other groups of experts have reached similar conclusions. At a United Nations conference on biodiversity in Egypt (Paywall) last November, government officials from 200 countries with scientific expertise agreed that any field trial could only be conducted if it could be proven that the reconfigured organisms were safe and if the people who live there an area affected by an experiment provide "free, prior and informed consent". But the agreement did not specify exactly how these standards would be established.
The devil is in the details and the details have not been finalized yet.
In principle, everyone theoretically agrees that experiments on inducing genes can only be used if they are safe and that communities need to understand the science, processes and objectives involved before they can agree to future projects. But the devil is in the details and the details have not been finalized yet, which means that there is still no agreement on how to get involved. with communities and on how groups involved in a project can prove that they act with permission if community members are affected to agree to proceed.
Kevin Esvelt, a molecular biologist who leads the "Sculpting Evolution" group at MIT Media Lab, is seeking the consent of the Massachusetts communities for an experiment he planned to eradicate Lyme disease. He argues that gene drive technology can solve ecological problems "by using the language of nature". In his opinion, this tool is risky but less than alternatives. "It's better to use DNA than potentially inhumane pesticides," he told the Washington Post (Paywall) in response to concerns raised at the biodiversity conference in Egypt.
"Better" may be in the viewer's eye, though.
"A cost to do nothing"
Lyme disease is transmitted to ticks and transmitted to deer populations and humans. But it comes from white-footed mice that carry the Lyme bacteria in their blood. By injecting laboratory mice with the Lyme bacteria that immunizes them against the disease, and then integrating the immune populations in the wild where they will breed and "hunt" the Lyme bacteria over time through reproduction, Esvelt hopes that ticks will no longer affect humans with the disease.
USCDC via Reuters
Esvelt works closely with communities in Massachusetts, Martha's Vineyard Islands and Nantucket, where the experiment will one day (if approved). He sees himself both as a researcher and educator and wants the public to participate in thinking about the issues. To this end, he organized island meetings, where he can explain science and talk to community members about their concerns. He says his proposal is seconded.
"There is always a cost to doing nothing, and we need technology not only to keep the world moving, but to make it better."
With his colleagues, Esvelt hopes to release about 1,000 genetically modified mice on an island to test the effects. But it will still take time, because he still needs to get regulatory approval of the experiment, which he says will take at least eight years before modified mice are released.
Esvelt recognizes that there are risks but thinks that the potential benefits outweigh these. "There is always a cost to doing nothing, and we need the technology not only to keep the world moving, but to make it better," he told CNN last year.
The value of the models
However, it is always possible that playing with ecological systems does not make the world a better place. Even if a gene reader has a desired result, it could result in unforeseen problems elsewhere. Esvelt's own work, which models the results on the basis of "existing empirical evidence" on genetic heritage, has shown that a gene system intended to modify an invasive species in one place presents a high risk of modifying it, even in places where it is not invasive. "Even the least effective [gene drive] The systems reported to date are highly invasive, Esvelt and colleagues told bioRxiv, a biology pre-print server where researchers publish their work before their peer review. "Highly effective training systems should be even more invasive."
Reuters / Toby Melville
Basically, the more scientists know how to use CRISPR, target specific genes and create readers, the more dangerous the effects can be. Not only are the gene drives ending up being as well effective in a targeted species, extending beyond the specific place where it is invasive and where the same species is not problematic, changing a creature type could affect countless other living things .
There is not enough information yet to determine how gene drives will work in nature. Scientists can only make enlightened assumptions. Right now, they think they are not sure. The NASEM report noted that research on responsible genes should be limited to experimental efforts and not be published in the wild, precisely because the available data are not sufficient to determine what will happen. At this point, it is only safe to say that we know we do not know enough.
Having fun with one species could and probably would have effects on other species.
The flora and fauna of an ecosystem are inextricably linked. Having fun with one species might and probably would have effects on other species – there may be reasons why white mice are carriers of certain bacteria, reasons that might not become totally obvious as long as the bacteria is no longer carried by the mice. As Collins points out in his review of NASEM's results, "Because global genetic systems will spread into all populations of a species connected by gene flow and persist, organisms modified with a gene system have the potential to generate great benefits or harmful ecological changes.
You could argue that ecosystems change all the time, and that's true. But the results are not always positive. The introduction of a new species into a particular environment can cause serious damage – just ask the Florida Fish and Wildlife Commission, which is struggling with an increasing number of invasive snakes in the Everglades. In the 1980s, a small number of Burmese pet pythons were released into the wilds of Florida and have since proliferated, attacking populations of birds and mammals, including indigenous creatures endangered. In April, local snake hunters captured a 17-foot pregnant python with 73 eggs, the largest creature of this type found in the region to date. The discovery is simply additional evidence – beyond damage to native species – of how a seemingly minimal change to an ecosystem can have dramatic long-term effects.
A gene drive will not introduce a new species into an environment, but it will change aspects of the affected species – in the case of mosquitoes carrying malaria that can lead them to extinction. And that too could have cascading effects, as noted by NASEM and many environmentalists.
Esvelt is working on methods to limit gene drives, to contain or cancel DNA modifications, limiting their effects to a few generations using "daisy drives". He describes them as "a form of self-extinguishing reader system. Based on mathematical models, he believes that these" integrated and adjustable "limitations prevent genetic effects from spreading beyond a limited geographical area and predetermined. Their effects would be local and temporary. "In the absence of further intervention, a population affected by a daisy system would eventually return to its original state," he wrote in a 2017 article on Medium, explaining:
It is important to note that daisy discs could be safely tested in the field without the risk of unintentional spread, while being effectively scaled to reach large areas without releasing large numbers of daisies. d & # 39; organizations. In short, daisy systems could allow local communities to follow the two main rules of engineering complex systems: make the smallest change possible to solve the problemand sSmall pie before going to scale.
Esvelt nevertheless speculates on the effectiveness of model-based daisy controls. Nobody has tested them in the wild yet, and no one will, legally, for a while, because there is a lot of uncertainty surrounding gene drives.
Avoid the disaster
There will never be two identical genetic genes, because no ecosystem is ever exactly the same, and the way a generic will evolve in a given affected species will vary from one species to another. The NASEM Committee, in its recommendations to the government, which will develop the policies for this work, described the specific steps to be followed by the researchers before embarking on a potential project and evaluating the risks associated with a given activity. They must trace the causal pathways; identify sources of uncertainty; quantify the probability of the results; integrate the concerns of relevant audiences; compare the advantages and disadvantages; and compare alternative approaches.
This list gives a misleading appearance to the process. It may be impossible to determine in advance what causes a certain effect, because we humans do not perfectly master the "language of nature". A constant source of uncertainty will always be the fact that we do not know perfectly all the species in an ecosystem are related. Researchers can only make enlightened assumptions about what can happen and nature will act on its side, whatever.
In particular, the NASEM committee emphasized the importance of comparing alternatives to gene readers when considering solutions precisely because this was a very risky activity. The parties to the United Nations conference on biodiversity concluded the same thing. As The Economist (paywall) wrote in November, "Genetic readers promise big gains and great dangers." The recommendation of the publication concerning genetic readers, based on the available evidence and their absence at present, was: "Do not prohibit. Do not rush. And that also seems to be the subject of consensus among the experts.
At this stage, regulators and scientists are only defining a research framework. And even a hyper-conscientious researcher like Esvelt, who wants to do what is right and is not afraid to admit to being wrong, may not take all the necessary steps described by NASEM, although he is the promoter.
In 2017, for example, Esvelt wrote a post on Medium assuming responsibility for "mistakes" and attempting to "repair" the failure to allow Maori partners in New Zealand, with whom he had discussed the potential of genetic mechanisms for the protection of natural resources from invasive species, to work to revisions in a paper that he had published in Reactive Sciences. Even though he pleaded for community participation in decision-making, he ignored the fact that the Aboriginal population might want to bring their views to his document. "It was inexcusably wrong for me to publish … without thinking of inviting my new Maori partners to make suggestions during the review phase," he admitted. "Acknowledging mistakes is painful, but honesty demands it: it is better to publicly admit wrongdoing and reinforce our resolve than to continue doing bad things."
Proceed with caution
Maybe it's a good idea to change the mosquito-carrying malaria mosquitoes. But if this is not the case, we will not know that it is too late. Before gene readers can move beyond the laboratory, there is a need to rethink existing governance mechanisms. NASEM concluded that the current framework for considering ethics and the stakes of the experiments is "inadequate". Collins writes: "They do not take into account the intentional propagation of the inducing genes and their possible irreversible effects on the ecosystems".
Reuters / Katrina Manson
To approach such projects as ethically and as safely as possible, regulators need to establish new rules at the national level, and they need to be aware of all the international implications and relevant regulations. "When we think about the future of driver gene research, the challenge is to integrate the scientific freedom that allows research to act responsibly and conduct research that encompasses more ethical, legal and societal values. wide, "concludes Collins.
This is, of course, easier said than done. When a solution to a problem can have consequences far beyond the place of origin of the problem, reaching a consensus may be an impossibility. And some problems may not be solved with a given new technology, if only because we do not know exactly how to calculate the impact.
In 2016, a coalition of more than 160 civil society organizations on six continents called for a moratorium on gene drives, precisely for this reason. "We do not have the knowledge and understanding to integrate genes into the environment, we do not even know what questions to ask," said Ricarda Steinbrecher, representative of the Federation of German Scientists. "It is essential that we pause to allow the scientific community, local communities and society at large to debate and reflect."
Esvelt agrees with critics while developing his experiences. He has always called for more thought and believes that we should question the work that he and other scientists around the world are doing. And with regard to genes, concerns abound, even among enthusiasts. As he told the New Yorker (paywall) in 2016, "my biggest fear is that something terrible will happen before something wonderful happens. This keeps me awake at night more than I would like to admit.
Should this exist? is a podcast, organized by Caterina Fake, who discusses the impact of emerging technologies on humanity. Listen here for a more in-depth conversation about assessing the human side of technology.
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