National Academies Press: OpenBook

Incorporating Science, Economics, and Sociology in Developing Sanitary and Phytosanitary Standards in International Trade: Proceedings of a Conference (2000)

Chapter: 10 case study 3: genetically modified organisms, 10 case study 3: genetically modified organisms, an overview of risk assessment procedures applied to genetically engineered crops.

PETER KAREIVA and MICHELLE MARVIER

Department of Zoology, University of Washington

The commercial production of genetically engineered crops has prompted countries around the world to adopt risk assessment procedures for evaluating the safety of transgenic cultivars. Most concern has been directed at the risk that a genetically modified crop may itself be made more weedy as a result of its recombinant trait, or may, through hybridization and introgression, contribute genes to a wild relative, consequently making the related plant more weedy (reviewed in Williamson, 1993; Rissler and Mellon, 1996; Bergelson et al., in press). Additional risks include the environmental fate of plant products (such as degradation versus accumulation of novel endotoxins in soils) and altered agricultural practices (such as increased application of herbicides; Rissler and Mellon, 1996). Although these ecological risks are widely thought to be on average minimal, the tremendous variety of plant attributes that are potentially modifiable renders blanket pronouncements of safety untenable. Moreover, because experience with transgenic crops is still limited, the formal development of risk assessment procedures faces the challenge of anticipating problems with traits that have not yet been developed let alone patented or commercialized.

In spite of striking cultural differences regarding willingness to accept risk, countries around the world have converged on three general principles of risk assessment for transgenic crops: containment, the principle of familiarity, and a reliance on small-scale experiments. We discuss each of these approaches and their limitations. Finally, in recognition of the shortcomings of existing screening procedures, we end with a recommendation that greater consideration be given to postrelease monitoring of transgenic plantings.

CONTAINMENT

The most straightforward way to manage the risk of a biological organism would be to simply contain the organism, to somehow prevent it from spreading beyond its intended release site. For instance, the initial experiments with genetically engineered ice-minus bacteria in Northern California were subjected to elaborate security measures, including fences and broad isolation zones. In its 1989 report on the field testing of genetically modified organisms, the National Research Council (NRC) offered the optimistic conclusion that "routinely used methods for plant confinement offer a variety of options for limiting both gene transfer by pollen and direct escape of the genetically modified plant" (NRC, 1989, p. 36). If transgenic plants and genes could in fact be contained, decisions regarding their risks would be greatly simplified. Yet, on the contrary, data from field trials clearly demonstrate that this initial faith in the feasibility of containment was overly optimistic. For some species hybridization and transfer of genes to wild relatives can occur very rapidly (e.g., Mikkelsen et al., 1996). In addition, direct field experiments indicate that, although most pollen moves only short distances from source plants, a measurable quantity of pollen travels vast distances, making containment of transgenic pollen highly unlikely (e.g., Kareiva et al., 1991; Kareiva et al., 1994; Lavigne et al., 1998).

Potential methods of containment include the use of barren zones around crops and plantings of trap plants into border rows. Unfortunately, barren zones may actually cause increases in the mean distance or amount of gene flow out of plots (Manasse, 1992; Morris et al., 1994). Although the use of border rows to trap pollen has proven more successful in reducing the extent of gene movement, the borders must be substantially larger than the transgenic fields, making their use impractical for agronomic-scale plantings (Hokanson et al., 1997).

Even in cases where gene transfer is an extremely infrequent event, the notion that transgenes could ever be completely contained remains indefensible. Furthermore, with large-scale commercial production, the sources of transgenes are so plentiful and opportunities for exchange so widespread, containment can not possibly be considered as a tenable risk management procedure. It is noteworthy that regulations in the United States and in the European Union do not in any way rely on containment as part of their risk management procedure for commercial products. In these countries, containment practices are only required for small-scale experiments during the research and development stage of novel cultivar breeding and genetic modification.

THE PRINCIPLE OF FAMILIARITY

Risk assessments often rely on comparisons between transgenic plants and the more familiar unmodified form of the plant or closely related plant species. The Organization for Economic Cooperation and Development (OECD) describes this principle as follows:

Whether standard cultural practices would be adequate to manage a relatively unfamiliar new plant line or cultivar can be assessed based on familiarity with a closely related line in conjunction with results from laboratory and preliminary field work with the new line (Anonymous, 1993).

This principle is not intended to imply that "familiarity means safety," although implementation of the policy frequently seems to embody such a deduction. For example, it is often assumed that if experiences with familiar plants have been broad and generally positive (e.g., the unmodified plant and its close relatives are not weeds), then the transgenic plant is similarly unlikely to pose a substantial risk. However, field experiments have clearly demonstrated that genetic modification may result in a number of incidental changes to the plant's original traits and that extrapolations from the familiar to the unfamiliar can be severely misguided. For example, the common weed Arabadopsis thaliana is a highly selfing species for which the prospects of gene transfer would generally be considered very low. However, field experiments with transgenic Arabadopsis showed that the transgenic plants, for some unknown reason, actually outcrossed at a rate of 6 percent, nearly 20 times more frequently than unmodified Arabadopsis (Bergelson et al., 1998). The authors concluded (p. 25) that "genetic engineering can substantially increase the probability of transgene escape, even in a species considered to be almost completely selfing." Although regulations in some nations advise that the required degree of scrutiny should depend on the traits of the parent organism (e.g., Genetic Manipulation Advisory Committee, 1998, Appendix 5), transgenic plants may exhibit substantially altered life histories and "familiarity with these [parental] species as useful agricultural and horticultural plants may be irrelevant and misleading" (Williamson, 1994).

A second problem regarding application of the principle of familiarity arises when the risk of a recombinant trait is compared with that of a familiar, seemingly similar trait that occurs naturally in unmodified plants. The assumption is that a novel trait that is similar to traits seen elsewhere is unlikely to pose new risks. The problem is that familiarity with a trait is in the eyes of the beholder. An especially good example involves the gene derived from Bacillus thurengiensis (Bt) for endotoxin production, which provides a "natural" insecticide. Because plants in general produce compounds that act as antiherbivore agents, and plant breeders have a long tradition of selecting plant varieties to increase their resistance to herbivores, some might argue that Bt endotoxin production is "familiar" and therefore probably "safe." On the other hand, when the gene for Bt endotoxin is inserted into canola, the transgenic

canola acquires a trait that it has never before possessed; a trait that protects it, to varying degrees, from a very broad range of caterpillar species. The risks associated with such a trait should not be assessed on the basis of subjective opinions regarding its familiarity or novelty, but rather should rely on data from experimental trials.

A third type of extrapolation that is tenuous concerns the long-term effects of repeated plantings of genetically modified crops on soil ecosystems. For example, although Bt endotoxins have previously been sprayed on crops as a form of organic pest control, we have no experience with large quantities of Bt-laden crops decomposing in soils year after year. Experiments have indicated that Bt-residues in cotton leaves persisted for at least 56 days after burial in the soil (Palm et al., 1996). Similarly, although small-scale laboratory experiments indicate no harmful impacts of proteinase inhibitors (another transgenic trait with insecticidal activity), longer-term experiments using natural soil communities suggests that there might be surprising impacts of these compounds with respect to microbial respiration and soil organisms (Donegan et al., 1997).

Extrapolations from the familiar to the unfamiliar of the type described above are common, but improper, applications of the principle of familiarity. Rather, the intention of the principle is that familiarity should provide a context for measuring risk—for example, the weediness of a genetically modified plant could be compared with that of the familiar, unmodified form. In fact, U.S. regulations require that before a transgenic crop is deregulated, it must be shown that the genetically engineered plant "is unlikely to pose a greater plant pest risk than the unmodified organisms from which it was derived" (U.S. Department of Agriculture [USDA], 1992). Although surprisingly few of the U.S. petitions for nonregulated status approved prior to 1995 performed such a comparison (Purrington and Bergelson, 1995), experiments comparing the performance of transgenic plants with unmodified source plants should be a cornerstone of the risk assessment process. Thus, rather than providing any evidence regarding risk, familiar plants should provide a benchmark or standard to which the risks posed by modified plants can be compared.

SMALL-SCALE RISK ASSESSMENT EXPERIMENTS

Most countries require some degree of "testing" to quantify risks if a crop is modified in a way that seems ecologically significant. In the United States, the earliest petitions to deregulate transgenic crops tended to be deficient on actual field experiments and instead relied upon greenhouse tests or simple literature surveys (Parker and Kareiva, 1996, Table 1). Although disputes have arisen repeatedly between environmental groups and industry over the appropriateness of various experimental designs (e.g., Rissler and Mellon, 1996, comment on Upjohn's transgenic squash petition, Animal and Plant Inspection Service [APHIS] Docket No. 92-127-1) and experimental risk assessments have generally been severely flawed (Purrington and Bergelson, 1995), reliance upon field experiments has grown steadily over recent years. Currently, in the United

States, Europe, and Australia, field experiments aimed at evaluating the potential weediness of transgenic crops are a mandatory part of the approval process (USDA, 1992; European Communities Committee, 1998; Genetic Manipulation Advisory Committee, 1998).

Field experiments are, in fact, a valuable tool: If a transgenic crop behaved like an aggressive weed in these experiments, it would be a clear signal that the plant should be tightly regulated and perhaps not allowed for commercial production. However, while the experimental detection of weediness provides a clear sign of danger, the failure to detect weediness does not lead to such a clear-cut conclusion. Determination of "safety" is more complicated because we must consider the experiment's capacity to detect weediness if it in fact exists. Unfortunately, a one-to two-year field assessment in small plots over a limited region may fail to reveal any enhancement of weediness, when in fact such an enhancement occurs under infrequent but important conditions. Simulations demonstrate that field tests for assessing a plant's enhanced invasiveness are prone to high rates of error unless the trials are repeated at multiple sites and over at least several years (Kareiva et al., 1996). Similarly, the potential risks associated with herbivore resistance genes can only be assessed accurately when trials are performed at multiple sites that offer potentially different environments for plant growth as well as different background densities of herbivores (Marvier and Kareiva, 1999).

A further weakness of short-term experiments is that there will likely be substantial time lags between the introduction of a transgenic plant and the emergence of ecological problems related to its introduction, such as escape of transgenes into wild relatives or the naturalization of transgenic crops. Long time lags are inherent features of many biological invasions. For example, a survey of historical records for past invasions by weeds in the northwestern United States indicated that the median timelag between the first record of a weed and the onset of widespread infestation was on the order of 30–50 years (Marvier et al., 1999). In addition, time lags between the introduction of ornamental woody plants and their escape into the wild in Germany are on the order of 150 years (Kowarik, 1995). Although examples from the "exotic species" literature are often rejected in the biotechnology arena, it is entirely reasonable to expect that invasions of transgenes will entail extensive time lags simply because invasion is such an unlikely event, probably depending on the chance concordance of a suite of favorable conditions. The potential for time lags means that short-term experiments are likely to support a verdict of "safety" when in fact such a determination is not warranted.

MONITORING AND A PRECAUTIONARY APPROACH

Unfortunately, containment of transgenic plants or their genes is not a viable option, "familiarity" with related plants or similar traits cannot be extrapolated accurately to the transgenic plants themselves, and a few experiments under a narrow range of conditions can not provide acceptable

proof of safety. In light of the tremendous uncertainty of risk assessment, the European community has called for amendments to Directive 90/220/EEC on deliberate release of genetically modified organisms that would require vigilant monitoring of transgenic commercial plantings after a marketing consent has been granted (European Communities Committee, 1998), with the idea that dangerous escapes might be detected before undue damage has been done. This approach could prove feasible if populations of problematic transgenic crops (or transgenic weeds) might be sufficiently confined and then controlled with herbicide.

Long-term, large-scale monitoring of transgenic plantings provide both an important research opportunity—we can learn a great deal about temporal and spatial variability as well as the occurrence of rare events—and a valuable means of minimizing risk. Although caution and tenacious monitoring are clearly warranted for certain transgenic crops, it will be hard to exercise that caution given the current pressure to ease regulations on the basis of a safe record to date. It should, however, be considered that, although monitoring is an expensive enterprise, the cost and difficulty of controlling a weed population are greatly exacerbated once a weed becomes well established. Thus, investment in monitoring programs that strive toward the earliest possible detection and elimination of transgenic weeds will likely prove cost effective in the long run. More generally, a reliance on monitoring when uncertainty, in the face of empirical data, is still substantial may be an advisable principle for a wide variety of risk assessments. Because of evolution and the role of chance in biological dynamics, monitoring may need to be a mainstay of any ecological risk assessment.

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APPROACHES TO RISK AND RISK ASSESSMENT 1

PAUL B. THOMPSON

Department of Philosophy, Purdue University

Risk analysis is typically understood as a wholly technical or scientific process. Yet the very concept of risk usually implies that some class of possible events has been judged to be adverse, or that that the very indeterminacy of future events is itself adverse. As such, risk analysis cannot be wholly based on science. At best, science can characterize the mechanisms that would lead to events such as mortality or morbidity, and can assign a probability or likelihood to their occurrence. Still, the badness or adversity that is associated with death and disease is based not on science, but morality. Nature is indifferent to death, and it is only when the perspective of human striving is introduced that it can be understood in terms of risk. Risks to health seem amenable to a purely scientific characterization because the moral judgments that are involved in this issue are among the least controversial. But even these judgments become contested at the margins. Ideas of ''health" shift from "absence of disease" to "enhanced capacities," and the capacity to control (and hence assume responsibility for) future events is reflected in the judgment that a particular practice is "risky." As such, philosophy and ethical theory have an inevitable place in the characterization and evaluation of risks.

Within the social sciences, the normative and philosophical dimensions of risk are often incorporated into the characterization of rationality. For example, cost-benefit analysis (discussed in Chapter 2 ) frames rational choice through evaluating and comparing the likely outcomes from each of two or more options. Cost-benefit analysis takes on ethical significance when rational

  

Author's note: The following is a lightly edited transcript of my workshop presentation, which was an overview of my own research as it bears on the case of genetically modified foods. It was not intended to be a comprehensive or representative discussion of philosophical work on risk assessment or on biotechnology. The orientation of the chapter is thus personal and citations are strongly biased toward my own publications. There has been an on-going discussion of this topic in popular press and on the Internet. Thompson (1997a) provides a more balanced and fully referenced discussion of philosophical work on biotechnology.

optimization of expected values is presumed to be the decision rule that should guide decision making with respect to regulatory standard setting or investment of public resources. Philosophical research on risk has tended to take one of two tacks with respect to this conception of rational optimization. Philosophers who endorse the basic strategy of rational optimization have tended to be critical of scientists' characterizations of probability and uncertainty (see Shrader-Frechette, 1991; Wachbroit, 1991). Other philosophers are critical of rational optimization and cost—benefit analysis, and have argued that public choices should focus on maintaining a basic structure of rights that maintain conditions of fairness among private decision makers (see Sagoff, 1985, MacLean, 1990).

For the case study presented by Peter Kareiva and Michelle Marvier, I will introduce a different set of philosophical concerns that focus on ways of framing (or interpreting) risks involved with genetically engineered food. One of the parameters that I use in my work is not to question the consensus assessment among scientists about the probability and degree of harm associated with genetic engineering. Sometimes it is difficult to figure out exactly what that consensus is, but to the extent that I can discern it, I never question it. That is not my business as a philosopher. What I am interested in is the divergence between that assessment, however it is set it up, and that of the broader public (or at least some segments of the broader public) with respect to the riskiness of genetically engineered food. There are, of course, differing opinions among scientists. Nonetheless, it has been and still is true that the broader public (and particularly if that is extended to the specifically concerned public) understand genetically engineered food to be riskier than the scientific consensus would suggest. My particular project has been to try to understand the rational basis for that difference. I am not interested in irrational bases for difference. I am not interested, for example, in purely nonrational judgments of taste. And in some sense, I am not even interested in culture as an explanatory value of those differences, although I do believe that culture has a tremendous influence in terms of the way that people understand risk and get information about risk.

I have been strongly influenced by cognitive work on risk undertaken by people such as Paul Slovic and, before that, Tversky and Kahnemann (1982). But unlike them, my framework is rational choice, and I am interested in the rational basis for deviations between a benchmark notion of what the risk is, derived from scientific consensus and other notions that might be held by the public. Furthermore, my project is a philosophical rather than an empirical one: I am attempting to make sense of the debate over genetically modified organisms in a manner that exposits and exemplifies a conception of rationality. I am not attempting to make empirical claims about human psychology or motivation. The philosophical work that I have done suggests testable empirical hypotheses, but I do not represent my work as making empirically verified claims.

My philosophical approach to the subject hand is non-standard in that I do not assume that probability and harm or probability and negative outcome are essential characteristics of risk. I have built my work on risk by looking at the

way the word risk is actually used in Western languages (Thompson, 1987 and 1991; Thompson and Dean, 1996). I look for the meaning of the word "risk," the things that it could possibly mean in a grammatical sentence. Although in many instances it could and does, in fact, mean something like "the probability of harm," that certainly does not account for all of the legitimate uses of the word risk. So I would argue that we need a broader notion of risk, one that sees it as having multiple dimensions. This is a standard view in risk perception and cognitive science literature (Slovic, 1987).

My hypothesis is that although genetic engineering tends to score fairly low with respect to probability and harm, it tends to score fairly high with respect to some of these additional dimensions of risk. In this paper I discuss two dimensions of risk. One is information reliability and the second is an ambiguity between event-predicting and act-classifying notions of risk (see Thompson, 1997a; 1997b; 1999).

First, is information reliability. Whenever anyone does work on risk, one of the factors to be considered is how reliable the information is. We tend to discount information that we believe to be unreliable. In the first part of this chapter Peter Kareiva and Michelle Marvier discuss the value judgments that scientists apply within their research and within their community for how much discounting to place on information. Here I lay out a spectrum between highly reliable information that is true (although in some respects that is a bad, possibly misleading characterization), to highly unreliable information, which is not just false but also mendacious.

How do people sort out whether information is highly reliable or highly unreliable? Clearly one of the things that people consider in evaluating reliability is the context in which this information is presented to them. As a matter of fact, I would argue that the discourse context—the kind of speech that is being performed, the kind of claims that are being made, the purposes that are behind the making of claims, and the rules under which claims can be put forward and evaluated—all influence the extent to which people regard information as reliable. Corresponding to highly reliable information we can postulate the ideal discourse situation, which is a long story. It is something borrowed from the work of Habermas (1990). In the ideal discourse situation, everyone is trying to figure out what is true. There are rules of arguments and ethics; there are possibilities of reproducing results or testing results that are carried out. So there is a sense, at least, in which the way science is supposed to work that fits the ideal discourse situation, and it is clear that people like Habermas who have worked this out have science in mind when they talk about ideal discourse.

On the opposite extreme, there is strategic discourse, and purely strategic discourse is a situation in which people do not care about whether the claim is true or false. Strategic speakers only want you to believe something or to act on the basis of something or to accept it as true because it happens to suit some particular interest of theirs at the moment. My paradigm example of strategic discourse in some of my writings is buying a used car. Not all used car dealers

are bad, of course, but the metaphor still strikes a chord. The used car dealer is a cultural icon—we just do not believe anything that a used car dealer tells us.

There is a rational tendency to regard a situation as more risky (like buying a used car) to the extent that we see it moving down a scale toward more strategic considerations and toward more circumstances in which the information that we get is expected to be unreliable. My conclusion would be that risk increases to the extent that one is moving down the information reliability scale. We tend to think of this as the risk of buying a car, which is risky. There is some sense in which the objective facts about the probability that the car is going to break down are quite independent of whether the person that is selling us the car is with a firm that we trust and so on. But we will interpret the purchase of the car and the activity of buying the car as more risky based in part on this information reliability factor.

So this is one dimension in which there is a tremendous difference between the public's position and the position of the scientific community, including the regulatory community. The difference is that, for the most part, the scientific community's information about risk comes from an ideal discourse situation. As scientists, we may not get quite as close to an ideal discourse as we might like in large conference settings, but it is far closer to an ideal discourse setting than the circumstance in which members of the public often acquire risk information. Therefore, it is, in fact, quite rational to regard information that filters through strategic channels as questionable. In other words, if genetic engineering is claimed to be safe in a strategic situation, someone might actually interpret that claim to mean that it is therefore more dangerous because it is claimed to be safe. If it is claimed to be dangerous in a strategic situation, one might actually move in the other direction and think that therefore it must be safe.

Again, I will not speculate too much on whether and how much this explains European versus North American considerations. But it may well be that there is a sense in which, partly because of the way in which the issue has come to Europe as part of the strategic trade negotiations, that there is a tendency to see this as a set of more strategic claims than in the United States.

The second issue that I want to point out is a bit more contentious and a bit more complex. There is an ambiguity in the concept of risk that I have characterized here, and I am systemizing it as an ambiguity between event predicting and act classifying. If we look at the way that people talk about risks in real life, in a nonscientific context, often what they mean is exactly what scientists mean, which is that some function of the probability of events, and the value or harm are associated with the events. But there are many other contexts in which that cannot be what is meant. To summarize a long argument (Thompson, 1991 and 1995), remember that the word "risk" is a verb. And words like "risky" and "risking'' pertain much more to the verb form of the word risk than to the noun form of the word "risk". I defy anyone to translate probability and harm into a verb. When someone risks something, they are doing something. There is some connotation of action or activity that is implicit

whenever the word risk is used as a verb. There is no connotation of action that is implicit when the word risk is used as a probability and an outcome.

Furthermore, if you'll perform the thought experiment, you will have a lot of trouble forming a meaningful grammatically correct English sentence in which the subject that risks, the subject of a risk sentence, is not an intentional agent. By that I mean a human being or a group. We attribute intentionality to corporations and countries all the time. Sometimes we attribute it to animals. We do not attribute it too often to plants and trees, and we certainly do not attribute it to mountains and ecosystems; it just does not make sense to say that that a tree risked its livelihood by growing in a particular place. That starts to sound like anthropomorphism. So there is an important part of the grammar of risk that picks out actions that are performed by intentional agents.

I am suggesting that, in the spirit of the kind of heuristics work that has been done by Tversky and Kahnemann and Slovic, we should understand this other sense of risk, what I call the act classifying the sense of risk, as a kind of heuristic. When we use the word risk in these contexts, we are picking out a class of actions. We are picking out a class of things that either people or organizations do. Under this definition, risks are actions that call for some sort of special consideration.

Next I want to discuss heuristics as a kind of cognitive filtering. When we call something a risk, we are saying that this deserves more consideration. We need to give it some thought. We need to do something with respect to it. And when we do not call something a risk, when we do not call it risky, we just go ahead and do it. These would be fairly routine, ordinary, habitual things that pass through the cognitive filter without detection. This cognitive filter may be culturally based or psychologically based. It is a way of telling us when to dedicate more resources, in the sense of time, energy, intellectual activity, or (socially) in terms of money to obtain information, write reports, or have committee meetings. It is a filter that tells us when it is important to do that and when it is not important to do that, because we tend to rely on habit, routine, or ordinary activities. There is a link between the intentionality and the cognitive filtering function because at least historically, but maybe not anymore, there has been very little point to devoting special attention to things that we cannot do anything about. So we look at actions that, if we did something else, then things would be different, or if I did something else, I might avoid a certain type of harm. We do not lump generic natural hazards, earthquakes, floods, tornadoes, and so on into that "could have acted otherwise" category.

So there is a sense in which, in this way of thinking about risk, things such as freak accidents and acts of God—and as well a background of hazards that characterize all of our daily activities—are not considered to be risks. Clearly accidents have some probability of harm associated with them, but they are not picked out by the cognitive filter that is associated with the word risk in an ordinary context.

I want to make a final point. Many times when people say that there is no risk associated with something, scientists interpret that as meaning that there is zero probability of harm. However, few people believe that there is zero

probability of harm associated with any activity. But what is going on is that when someone makes a claim that "there is no risk," they are saying that it is something that has not made it through their cognitive filter. It is something that we do not devote any special attention to. We just keep doing what we have always been doing.

So there is a tension that arises between the way that the scientific risk assessment scientists talk about risk and this other notion of risk that is still very much alive in public discourse. Note that intention is irrelevant to the probability and harm conception of risk. Yet it is highly relevant to the cognitive filtering sense of risk.

When we start out with the event-predicting sense of risks, we are already involved in a process of deliberative optimizing. We want to know the probabilities and the level of harm because we are at least, at some level, making a risk-benefit trade-off decision. By deliberative, I mean that we are consciously thinking about options, we are consciously making a comparison, and we are, at least to some degree, consciously applying a decision rule about which way to go. We are doing very little consciously at the heuristics or the cognitive filtering level. This is the type of thing that happens before something even emerges in our world view as significant.

For the responses to act-classifying risks, there are three strategies that people follow, both individually and collectively, when they have decided that there is a risk in this broad sense of actions that call for special consideration.

The first is to eliminate the perceived source of risk to simplify one's life by saying "I don't even want to think about it. Just don't do it." A second thing someone will do is solve the problem of accountability. Who is going to be responsible in this particular situation? Am I responsible as the risk bearer? Are you responsible as the risk imposer? And if we get that satisfied satisfactorily, that may be the end of the story. We may not have done any work to either quantify or even approximate or estimate probabilities and consequences before we arrive at either of those two solutions. The third thing that we can do in this situation is to undertake a deliberation, to go to the trouble of trying to explicitly articulate—perhaps qualified, perhaps not—but explicitly articulate the dimensions of probability and harm and go through the process of making a deliberate conscious decision. This may be an individual working through a thought process or a group working through a social process. There is a sense in which what is going on in terms of a lot of the public debate is that the risk assessment community, and justifiably so, is already well into the process of deliberation. And the public is still sorting things out and talking about this as being risky in the sense that this is something that calls for a greater look and more care. And it is not clear that the public wants to resolve this problem by a deliberative strategy. They may be more receptive to resolving it by laying down some strict criteria of accountability or by simply eliminating the option from consideration.

What is the rationality that is implicit in this? Basically it would be quite irrational to engage in deliberative optimization with regard to all the potential

choices that we face. If we did that, we would be spending all our time calculating probabilities and benefits and making comparative decisions. One after another there are hundreds of thousands of potential choices that we make every day, and it would be a tremendous waste of our cognitive resources to make deliberative decisions about all of them.

It is clear that there have to be some of these substitute rules that apportion deliberative resources and tell us when we are going to go though the explicit risk comparison. I am suggesting that although there is a clear sense in which deliberative optimizing gives us a very strong characterization of what would be rational behavior in a particular case, we need some type of heuristic operating in the background. This heuristic gives some sense of when it is the right time to get more information, when it is the right time to get a detailed risk assessment or risk calculation.

In looking at genetically engineered foods, I will assume that they score low on the probability and harm levels. That has been the scientific consensus, at least, although that consensus goes back and forth over time. Nevertheless, compared with microbial hazards, genetic engineering is not a serious risk issue with respect to the probability of harm. Compared with risks of global climate change, it is probably not even a serious environmental risk issue. Genetically modified food is not going to score very high on the two parameters of probability and degree of harm.

However, if we look at questions such as "Is it an action that is being undertaken intentionally?," it scores very high. It is not only an intentional (or deliberate) action, but it is very clearly promoted by the people that are undertaking the action as something that is new. The novelty of this activity is, in fact, a big element in the way it has been discussed. How does information on genetic engineering come to people? It often comes to them through channels that are perceived as strategic, meaning that it is through advertising or channels in which people with different points of view are debating one another over issues such as food safety policy or trade issues. Therefore, it is quite rational that it would tend to filter into a relatively high-risk category with respect to both the classifying and the information reliability.

Many people who are concerned about genetically modified organisms see it as an easily eliminable source of risk; they do not understand that there would be important costs associated with foregoing genetically engineered food altogether. Because of this, there has been a tendency to gravitate rather quickly toward the elimination strategy, at least in the minds of many people, and I do not believe that this is an irrational move for people to make. When the science and business communities strive to counter that move, they are perceived as engaging in strategic discourse. This cycle of factors tends to reinforce itself. In some respects, science institutions remain in a self-reinforcing cycle of increasing public skepticism about genetic engineering.

Habermas, J. 1990. Discourse Ethics: Notes on a Program of Philosophical Justification, in The Communicative Ethics Debate, S. Behabib, and F. Dallmayer, eds. Cambridge, MA: Massachusetts Institute of Technology Press.

Kahnemann, D., P. Slovic, and A. Tversky, eds. 1982. Judgment Under Uncertainty: Heuristics And Biases. New York: Cambridge University Press.

MacLean, D. 1990. Comparing values in environmental policies: moral issues and moral arguments. P.B. Hammond and R. Coppock, eds. Pp. 83–106 in Valuing Health Risks, Costs and Benefits for Environmental Decision Making. Washington, D.C.: National Academy Press.

Sagoff, M. 1985. Risk Benefit Analysis in Decisions Concerning Public Safety and Health, Dubuque, IA: Kendall/Hunt.

Shrader-Frechette, K. 1991. Risk and Rationality. Berkeley, California: University of California Press.

Slovic. P. 1987. Perception of Risk, Science 236:280–285.

Thompson, P.B. 1987. Agricultural Biotechnology and the Rhetoric of Risk: Some Conceptual Issues, The Environmental Professional, 9:316–326.

Thompson, P.B. 1991. Risk: Ethical Issues and Values, in Agricultural Biotechnology, Food Safety and Nutritional Quality for the Consumer, J.F. MacDonald, ed. National Agricultural Biotechnology Council (NABC) Report 2, Ithaca, N.Y.: NABC. Pp. 204-217.

Thompson, P.B. 1995. Risk and Responsibilities in Modern Agriculture, in Issues in Agricultural Bioethics, T.B. Mepham, G.A. Tucker, and J. Wiseman, eds. Nottingham: Nottingham University Press. Pp. 31–45.

Thompson, P.B. 1997a. Food Biotechnology in Ethical Perspective. London: Chapman and Hall.

Thompson, P.B. 1997b. Science Policy and Moral Purity: The Case of Animal Biotechnology, Agriculture and Human Values 14(1997):11–27.

Thompson, P.B. 1999. The Ethics of Truth-Telling and the Problem of Risk, Science and Engineering Ethics 5(4):489–511.

Thompson P.B. and W.E. Dean. 1996. Competing Conceptions of Risk, Risk: Health, Safety and Environment 7(4):361–384.

Wachbroit, R. 1991. Describing Risk, M.A. Levin and H.S. Strauss, eds., Risk Assessment in Genetic Engineering, New York: McGraw-Hill. Pp. 368–377.

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The rapid expansion of international trade has brought to the fore issues of conflicting national regulations in the area of plant, animal, and human health. These problems include the concern that regulations designed to protect health can also be used for protection of domestic producers against international competition. At a time when progressive tariff reform has opened up markets and facilitated trade, in part responding to consumer demands for access to a wide choice of products and services at reasonable prices, closer scrutiny of regulatory measures has become increasingly important. At the same time, there are clear differences among countries and cultures as to the types of risk citizens are willing to accept. The activities of this conference were based on the premise that risk analyses (i.e., risk assessment, management, and communication) are not exclusively the domain of the biological and natural sciences; the social sciences play a prominent role in describing how people in different contexts perceive and respond to risks. Any effort to manage sanitary and phytosanitary (SPS) issues in international trade must integrate all the sciences to develop practices for risk assessment, management, and communication that recognize international diversity in culture, experience, and institutions.

Uniform international standards can help, but no such norms are likely to be acceptable to all countries. Political and administrative structures also differ, causing differences in approaches and outcomes even when basic aims are compatible. Clearly there is considerable room for confusion and mistrust. The issue is how to balance the individual regulatory needs and approaches of countries with the goal of promoting freer trade. This issue arises not only for SPS standards but also in regard to regulations that affect other areas such as environmental quality, working conditions, and the exercise of intellectual property rights.

This conference focused on these issues in the specific area of SPS measures. This area includes provisions to protect plant and animal health and life and, more generally, the environment, and regulations that protect humans from foodborne risks. The Society for Risk Analysis defines a risk as the potential for realization of unwanted, adverse consequences to human life, health, property, or the environment; estimation of risk is usually based on the expected value of the conditional probability of the event occurring times the consequence of the event given that it has occurred.

The task of this conference and of this report was to elucidate the place of science, culture, politics, and economics in the design and implementation of SPS measures and in their international management. The goal was to explore the critical roles and the limitations of the biological and natural sciences and the social sciences, such as economics, sociology, anthropology, philosophy, and political science in the management of SPS issues and in judging whether particular SPS measures create unacceptable barriers to international trade. The conference's objective also was to consider the elements that would compose a multidisciplinary analytical framework for SPS decision making and needs for future research.

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November 1, 2021

Four Success Stories in Gene Therapy

The field is beginning to fulfill its potential. These therapies offer a glimpse of what’s to come

By Jim Daley

3d illustration DNA molecules

Design Cells Getty Images

After numerous setbacks at the turn of the century, gene therapy is treating diseases ranging from neuromuscular disorders to cancer to blindness. The success is often qualified, however. Some of these therapies have proved effective at alleviating disease but come with a high price tag and other accessibility issues: Even when people know that a protocol exists for their disease and even if they can afford it or have an insurance company that will cover the cost—which can range from $400,000 to $2 million—they may not be able to travel to the few academic centers that offer it. Other therapies alleviate symptoms but don’t eliminate the underlying cause.

“Completely curing patients is obviously going to be a huge success, but it’s not [yet] an achievable aim in a lot of situations,” says Julie Crudele, a neurologist and gene therapy researcher at the University of Washington. Still, even limited advances pave the way for ongoing progress, she adds, pointing to research in her patients who have Duchenne muscular dystrophy: “In most of these clinical trials, we learn important things.”

Thanks to that new knowledge and steadfast investigations, gene therapy researchers can now point to a growing list of successful gene therapies. Here are four of the most promising.

Gene Swaps to Prevent Vision Loss

Some babies are born with severe vision loss caused by retinal diseases that once led inevitably to total blindness. Today some of them can benefit from a gene therapy created by wife-and-husband team Jean Bennett and Albert Maguire, who are now ophthalmologists at the University of Pennsylvania.

When the pair first began researching retinal disease in 1991, none of the genes now known to cause vision loss and blindness had been identified. In 1993 researchers identified one potential target gene, RPE65 . Seven years later Bennett and Maguire tested a therapy targeting that gene in three dogs with severe vision loss—it restored vision for all three.

In humans, the inherited condition that best corresponds with the dogs’ vision loss is Leber congenital amaurosis (LCA). LCA prevents the retina, a layer of light-sensitive cells at the back of the eye, from properly reacting or sending signals to the brain when a photon strikes it. The condition can cause uncontrolled shaking of the eye (nystagmus), prevents pupils from responding to light and typically results in total blindness by age 40. Researchers have linked the disease to mutations or deletions in any one of 27 genes associated with retinal development and function. Until gene therapy, there was no cure.

Mutations in RPE65 are just one cause of inherited retinal dystrophy, but it was a cause that Bennett and Maguire could act on. The researchers used a harmless adeno-associated virus (AAV), which they programmed to find retinal cells and insert a healthy version of the gene, and injected it into a patient’s eye directly underneath the retina. In 2017, after a series of clinical trials, the Food and Drug Administration approved voretigene neparvovecrzyl (marketed as Luxturna) for the treatment of any heritable retinal dystrophy caused by the mutated RPE65 gene, including LCA type 2 and retinitis pigmentosa, another congenital eye disease that affects photoreceptors in the retina. Luxturna was the first FDA-approved in vivo gene therapy, which is delivered to target cells inside the body (previously approved ex vivo therapies deliver the genetic material to target cells in samples collected from the body, which are then reinjected).

Spark Therapeutics, the company that makes Luxturna, estimates that about 6,000 people worldwide and between 1,000 and 2,000 in the U.S. may be eligible for its treatment—few enough that Luxturna was granted “orphan drug” status, a designation that the FDA uses to incentivize development of treatments for rare diseases. That wasn’t enough to bring the cost down. The therapy is priced at about $425,000 per injection, or nearly $1 million for both eyes. Despite the cost, Maguire says, “I have not yet seen anybody in the U.S. who hasn’t gotten access based on inability to pay.”

Those treated show significant improvement: Patients who were once unable to see clearly had their vision restored, often very quickly. Some reported that, after the injections, they could see stars for the first time.

While it is unclear how long the effects will last, follow-up data published in 2017 showed that all 20 patients treated with Luxturna in a phase 3 trial had retained their improved vision three years later. Bennett says five-year follow-up with 29 patients, which is currently undergoing peer review, showed similarly successful results. “These people can now do things they never could have dreamed of doing, and they’re more independent and enjoying life.”

Training the Immune System to Fight Cancer

Gene therapy has made inroads against cancer, too. An approach known as chimeric antigen receptor (CAR) T cell therapy works by programming a patient’s immune cells to recognize and target cells with cancerous mutations. Steven Rosenberg, chief of surgery at the National Cancer Institute, helped to develop the therapy and published the first successful results in a 2010 study for the treatment of lymphoma.

“That patient had massive amounts of disease in his chest and his belly, and he underwent a complete regression,” Rosenberg says—a regression that has now lasted 11 years and counting.

CAR T cell therapy takes advantage of white blood cells, called T cells, that serve as the first line of defense against pathogens. The approach uses a patient’s own T cells, which are removed and genetically altered so they can build receptors specific to cancer cells. Once infused back into the patient, the modified T cells, which now have the ability to recognize and attack cancerous cells, reproduce and remain on alert for future encounters.

In 2016 researchers at the University of Pennsylvania reported results from a CAR T cell treatment, called tisagenlecleucel, for acute lymphoblastic leukemia (ALL), one of the most common childhood cancers. In patients with ALL, mutations in the DNA of bone marrow cells cause them to produce massive quantities of lymphoblasts, or undeveloped white blood cells, which accumulate in the bloodstream. The disease progresses rapidly: adults face a low likelihood of cure, and fewer than half survive more than five years after diagnosis.

When directed against ALL, CAR T cells are ruthlessly efficient—a single modified T cell can kill as many as 100,000 lymphoblasts. In the University of Pennsylvania study, 29 out of 52 ALL patients treated with tisagenlecleucel went into sustained remission. Based on that study’s results, the FDA approved the therapy (produced by Novartis as Kymriah) for treating ALL, and the following year the agency approved it for use against diffuse large B cell lymphoma. The one-time procedure costs upward of $475,000.

CAR T cell therapy is not without risk. It can cause severe side effects, including cytokine release syndrome (CRS), a dangerous inflammatory response that ranges from mild flulike symptoms in less severe cases to multiorgan failure and even death. CRS isn’t specific to CAR T therapy: Researchers first observed it in the 1990s as a side effect of antibody therapies used in organ transplants. Today, with a combination of newer drugs and vigilance, doctors better understand how far they can push treatment without triggering CRS. Rosenberg says that “we know how to deal with side effects as soon as they occur, and serious illness and death from cytokine release syndrome have dropped drastically from the earliest days.”

Through 2020, the remission rate among ALL patients treated with Kymriah was about 85 percent. More than half had no relapses after a year. Novartis plans to track outcomes of all patients who received the therapy for 15 years to better understand how long it remains effective.

Precision Editing for Blood Disorders

One new arrival to the gene therapy scene is being watched particularly closely: in vivo gene editing using a system called CRISPR, which has become one of the most promising gene therapies since Jennifer Doudna and Emmanuelle Charpentier discovered it in 2012—a feat for which they shared the 2020 Nobel Prize in Chemistry. The first results from a small clinical trial aimed at treating sickle cell disease and a closely related disorder, called beta thalassemia, were published this past June.

Sickle cell disease affects millions of people worldwide and causes the production of crescent-shaped red blood cells that are stickier and more rigid than healthy cells, which can lead to anemia and life-threatening health crises. Beta thalassemia, which affects millions more, occurs when a different mutation causes someone’s body to produce less hemoglobin, the iron-rich protein that allows red blood cells to carry oxygen. Bone marrow transplants may offer a cure for those who can find matching donors, but otherwise treatments for both consist primarily of blood transfusions and medications to treat associated complications.

Both sickle cell disease and beta thalassemia are caused by heritable, single-gene mutations, making them good candidates for gene-editing therapy. The method, CRISPR-Cas9, uses DNA sequences from bacteria (clustered regularly interspaced short palindromic repeats, or CRISPR) and a CRISPR-associated enzyme (Cas for short) to edit the patient’s genome. The CRISPR sequences are transcribed onto RNA that locates and identifies DNA sequences to blame for a particular condition. When packaged together with Cas9, transcribed RNA locates the target sequence, and Cas9 snips it out of the DNA, thereby repairing or deactivating the problematic gene.

At a conference this past June, Vertex Pharmaceuticals and CRISPR Therapeutics announced unpublished results from a clinical trial of beta thalassemia and sickle cell patients treated with CTX001, a CRISPR-Cas9-based therapy. In both cases, the therapy does not shut off a target gene but instead delivers a gene that boosts production of healthy fetal hemoglobin—a gene normally turned off shortly after birth. Fifteen people with beta thalassemia were treated with CTX001; after three months or more, all 15 showed rapidly improved hemoglobin levels and no longer required blood transfusions. Seven people with severe sickle cell disease received the same treatment, all of whom showed increased levels of hemoglobin and reported at least three months without severe pain. More than a year later those improvements persisted in five subjects with beta thalassemia and two with sickle cell. The trial is ongoing, and patients are still being enrolled. A Vertex spokesperson says it hopes to enroll 45 patients in all and file for U.S. approval as early as 2022.

Derailing a Potentially Lethal Illness

Spinal muscular atrophy (SMA) is a neurodegenerative disease in which motor neurons—the nerves that control muscle movement and that connect the spinal cord to muscles and organs—degrade, malfunction and die. It is typically diagnosed in infants and toddlers. The underlying cause is a genetic mutation that inhibits production of a protein involved in building and maintaining those motor neurons.

The four types of SMA are ranked by severity and related to how much motor neuron protein a person’s cells can still produce. In the most severe or type I cases, even the most basic functions, such as breathing, sitting and swallowing, prove extremely challenging. Infants diagnosed with type I SMA have historically had a 90 percent mortality rate by one year.

Adrian Krainer, a biochemist at Cold Spring Harbor Laboratory, first grew interested in SMA when he attended a National Institutes of Health workshop in 1999. At the time, Krainer was investigating how RNA mutations cause cancer and genetic diseases when they disrupt a process called splicing, and researchers suspected that a defect in the process might be at the root of SMA. When RNA is transcribed from the DNA template, it needs to be edited or “spliced” into messenger RNA (mRNA) before it can guide protein production. During that editing process, some sequences are cut out (introns), and those that remain (exons) are strung together.

Krainer realized that there were similarities between the defects associated with SMA and one of the mechanisms he had been studying—namely, a mistake that occurs when an important exon is inadvertently lost during RNA splicing. People with SMA were missing one of these crucial gene sequences, called SMN1 .

“If we could figure out why this exon was being skipped and if we could find a solution for that, then presumably this could help all the [SMA] patients,” Krainer says. The solution he and his colleagues hit on, antisense therapy, employs single strands of synthetic nucleotides to deliver genetic instructions directly to cells in the body [see “ The Gene Fix ”]. In SMA’s case, the instructions induce a different motor neuron gene, SMN2 , which normally produces small amounts of the missing motor neuron protein, to produce much more of it and effectively fill in for SMN1 . The first clinical trial to test the approach began in 2010, and by 2016 the FDA approved nusinersen (marketed as Spinraza). Because the therapy does not incorporate itself into the genome, it must be administered every four months to maintain protein production. And it is staggeringly expensive: a single Spinraza treatment costs as much as $750,000 in the first year and $375,000 annually thereafter.

Since 2016, more than 10,000 people have been treated with it worldwide. Although Spinraza can’t restore completely normal motor function (a single motor neuron gene just can’t produce enough protein for that), it can help children with any of the four types of SMA live longer and more active lives. In many cases, Spinraza has improved patients’ motor function, allowing even those with more severe cases to breathe, swallow and sit upright on their own. “The most striking results are in patients who are being treated very shortly after birth, when they have a genetic diagnosis through newborn screening,” Krainer says. “Then, you can actually prevent the onset of the disease—for several years and hopefully forever.”

This article is part of “ Innovations In: Gene Therapy ,” an editorially independent special report that was produced with financial support from Pfizer .

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Article Contents

Introduction, human enhancement, genetic engineering, conclusions.

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Human enhancement: Genetic engineering and evolution

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Mara Almeida, Rui Diogo, Human enhancement: Genetic engineering and evolution, Evolution, Medicine, and Public Health , Volume 2019, Issue 1, 2019, Pages 183–189, https://doi.org/10.1093/emph/eoz026

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Genetic engineering opens new possibilities for biomedical enhancement requiring ethical, societal and practical considerations to evaluate its implications for human biology, human evolution and our natural environment. In this Commentary, we consider human enhancement, and in particular, we explore genetic enhancement in an evolutionary context. In summarizing key open questions, we highlight the importance of acknowledging multiple effects (pleiotropy) and complex epigenetic interactions among genotype, phenotype and ecology, and the need to consider the unit of impact not only to the human body but also to human populations and their natural environment (systems biology). We also propose that a practicable distinction between ‘therapy’ and ‘enhancement’ may need to be drawn and effectively implemented in future regulations. Overall, we suggest that it is essential for ethical, philosophical and policy discussions on human enhancement to consider the empirical evidence provided by evolutionary biology, developmental biology and other disciplines.

Lay Summary: This Commentary explores genetic enhancement in an evolutionary context. We highlight the multiple effects associated with germline heritable genetic intervention, the need to consider the unit of impact to human populations and their natural environment, and propose that a practicable distinction between ‘therapy’ and ‘enhancement’ is needed.

There are countless examples where technology has contributed to ameliorate the lives of people by improving their inherent or acquired capabilities. For example, over time, there have been biomedical interventions attempting to restore functions that are deficient, such as vision, hearing or mobility. If we consider human vision, substantial advances started from the time spectacles were developed (possibly in the 13th century), continuing in the last few years, with researchers implanting artificial retinas to give blind patients partial sight [ 1–3 ]. Recently, scientists have also successfully linked the brain of a paralysed man to a computer chip, which helped restore partial movement of limbs previously non-responsive [ 4 , 5 ]. In addition, synthetic blood substitutes have been created, which could be used in human patients in the future [ 6–8 ].

The progress being made by technology in a restorative and therapeutic context could in theory be applied in other contexts to treat non-pathological conditions. Many of the technologies and pharmaceutical products developed in a medical context to treat patients are already being used by humans to ‘enhance’ some aspect of their bodies, for example drugs to boost brain power, nutritional supplements, brain stimulating technologies to control mood or growth hormones for children of short stature. Assistive technology for disabled people, reproductive medicine and pharmacology, beside their therapeutic and restorative use, have a greater potential for human ‘enhancement’ than currently thought. There are also dual outcomes as some therapies can have effects that amount to an enhancement as for example, the artificial legs used by the South African sprinter Oscar Pistorius providing him with a competitive advantage.

This commentary will provide general ethical considerations on human enhancement, and within the several forms of so-called human biomedical enhancement, it will focus on genetic engineering, particularly on germline (heritable) genetic interventions and on the insights evolutionary biology can provide in rationalizing its likely impact. These insights are a subject often limited in discussions on genetic engineering and human enhancement in general, and its links to ethical, philosophical and policy discussions, in particular [ 9 ]. The rapid advances in genetic technology make this debate very topical. Moreover, genes are thought to play a very substantial role in biological evolution and development of the human species, thus making this a topic requiring due consideration. With this commentary, we explore how concepts based in evolutionary biology could contribute to better assess the implications of human germline modifications, assuming they were widely employed. We conclude our brief analysis by summarizing key issues requiring resolution and potential approaches to progress them. Overall, the aim is to contribute to the debate on human genetic enhancement by looking not only at the future, as it is so often done, but also at our evolutionary past.

The noun ‘enhancement’ comes from the verb ‘enhance’, meaning ‘to increase or improve’. The verb enhance can be traced back to the vulgar Latin inaltiare and late Latin inaltare (‘raise, exalt’), from ‘ altare ’ (‘make high’) and altus (‘high’), literally ‘grown tall’. For centuries human enhancement has populated our imagination outlined by stories ranging from the myths of supernormal strengths and eternal life to the superpowers illustrated by the 20th century comic books superheroes. The desire of overcoming normal human capacities and the transformation to an almost ‘perfect’ form has been part of the history of civilization, extending from arts and religion to philosophy. The goal of improving the human condition and health has always been a driver for innovation and biomedical developments.

In the broadest sense, the process of human enhancement can be considered as an improvement of the ‘limitations’ of a ‘natural version’ of the human species with respect to a specific reference in time, and to different environments, which can vary depending on factors such as, for example, climate change. The limitations of the human condition can be physical and/or mental/cognitive (e.g. vision, strength or memory). This poses relevant questions of what a real or perceived human limitation is in the environment and times in which we are living and how it can be shifted over time considering social norms and cultural values of modern societies. Besides, the impact that overcoming these limitations will have on us humans, and the environment, should also be considered. For example, if we boost the immune system of specific people, this may contribute to the development/evolution of more resistant viruses and bacteria or/and lead to new viruses and bacteria to emerge. In environmental terms, enhancing the longevity of humans could contribute to a massive increase in global population, creating additional pressures on ecosystems already under human pressure.

Two decades ago, the practices of human enhancement have been described as ‘biomedical interventions that are used to improve human form or functioning beyond what is necessary to restore or sustain health’ [ 10 ]. The range of these practices has now increased with technological development, and they are ‘any kind of genetic, biomedical, or pharmaceutical intervention aimed at improving human dispositions, capacities, or well-being, even if there is no pathology to be treated’ [ 11 ]. Practices of human enhancement could be visualized as upgrading a ‘system’, where interventions take place for a better performance of the original system. This is far from being a hypothetical situation. The rapid progress within the fields of nanotechnology, biotechnology, information technology and cognitive science has brought back discussions about the evolutionary trajectory of the human species by the promise of new applications which could provide abilities beyond current ones [ 12 , 13 ]. If such a possibility was consciously embraced and actively pursued, technology could be expected to have a revolutionary interference with human life, not just helping humans in achieving general health and capabilities commensurate with our current ones but helping to overcome human limitations far beyond of what is currently possible for human beings. The emergence of new technologies has provided a broader range of potential human interventions and the possibility of transitioning from external changes to our bodies (e.g. external prosthesis) to internal ones, especially when considering genetic manipulation, whose changes can be permanent and transmissible.

The advocates of a far-reaching human enhancement have been referred to as ‘transhumanists’. In their vision, so far, humans have largely worked to control and shape their exterior environments (niche construction) but with new technologies (e.g. biotechnology, information technology and nanotechnology) they will soon be able to control and fundamentally change their own bodies. Supporters of these technologies agree with the possibility of a more radical interference in human life by using technology to overcome human limitations [ 14–16 ], that could allow us to live longer, healthier and even happier lives [ 17 ]. On the other side, and against this position, are the so-called ‘bioconservatives’, arguing for the conservation and protection of some kind of ‘human essence’, with the argument that it exists something intrinsically valuable in human life that should be preserved [ 18 , 19 ].

There is an ongoing debate between transhumanists [ 20–22 ] and bioconservatives [ 18 , 19 , 23 ] on the ethical issues regarding the use of technologies in humans. The focus of this commentary is not centred on this debate, particularly because the discussion of these extreme, divergent positions is already very prominent in the public debate. In fact, it is interesting to notice that the ‘moderate’ discourses around this topic are much less known. In a more moderate view, perhaps one of the crucial questions to consider, independently of the moral views on human enhancement, is whether human enhancement (especially if considering germline heritable genetic interventions) is a necessary development, and represents an appropriate use of time, funding and resources compared to other pressing societal issues. It is crucial to build space for these more moderate, and perhaps less polarized voices, allowing the consideration of other positions and visions beyond those being more strongly projected so far.

Ethical and societal discussions on what constitutes human enhancement will be fundamental to support the development of policy frameworks and regulations on new technological developments. When considering the ethical implications of human enhancement that technology will be available to offer now and in the future, it could be useful to group the different kinds of human enhancements in the phenotypic and genetic categories: (i) strictly phenotypic intervention (e.g. ranging from infrared vision spectacles to exoskeletons and bionic limbs); (ii) somatic, non-heritable genetic intervention (e.g. editing of muscle cells for stronger muscles) and (iii) germline, heritable genetic intervention (e.g. editing of the C–C chemokine receptor type 5 (CCR5) gene in the Chinese baby twins, discussed later on). These categories of enhancement raise different considerations and concerns and currently present different levels of acceptance by our society. The degree of ethical, societal and environmental impacts is likely to be more limited for phenotypic interventions (i) but higher for genetic interventions (ii and iii), especially for the ones which are transmissible to future generations (iii).

The rapid advances in technology seen in the last decades, have raised the possibility of ‘radical enhancement’, defined by Nicholas Agar, ‘as the improvement of human attributes and abilities to levels that greatly exceed what is currently possible for human beings’ [ 24 ]. Genetic engineering offers the possibility of such an enhancement by providing humans a profound control over their own biology. Among other technologies, genetic engineering comprises genome editing (also called gene editing), a group of technologies with the ability to directly modify an organism’s DNA through a targeted intervention in the genome (e.g. insertion, deletion or replacement of specific genetic material) [ 25 ]. Genome editing is considered to achieve much greater precision than pre-existing forms of genetic engineering. It has been argued to be a revolutionary tool due to its efficiency, reducing cost and time. This technology is considered to have many applications for human health, in both preventing and tackling disease. Much of the ethical debate associated with this technology concerns the possible application of genome editing in the human germline, i.e. the genome that can be transmitted to following generations, be it from gametes, a fertilized egg or from first embryo divisions [ 26–28 ]. There has been concern as well as enthusiasm on the potential of the technology to modify human germline genome to provide us with traits considered positive or useful (e.g. muscle strength, memory and intelligence) in the current and future environments.

Genetic engineering: therapy or enhancement and predictability of outcomes

To explore some of the possible implications of heritable interventions we will take as an example the editing (more specifically ‘deletion’ using CRISPR genome editing technology) of several base pairs of the CCR5 gene. Such intervention was practised in 2018 in two non-identical twin girls born in China. Loss of function mutations of the CCR5 had been previously shown to provide resistance to HIV. Therefore, the gene deletion would be expected to protect the twin baby girls from risk of transmission of HIV which could have occurred from their father (HIV-positive). However, the father had the infection kept under control and the titre of HIV virus was undetectable, which means that risk of transmission of HIV infection to the babies was negligible [ 29 ].

From an ethical ground, based on current acceptable practices, this case has been widely criticized by the scientific community beside being considered by many a case of human enhancement intervention rather than therapy [ 29 , 30 ]. One of the questions this example helps illustrate is that the ethical boundary between a therapy that ‘corrects’ a disorder by restoring performance to a ‘normal’ scope, and an intervention that ‘enhances’ human ability outside the accepted ‘normal’ scope, is not always easy to draw. For the sake of argument, it could be assumed that therapy involves attempts to restore a certain condition of health, normality or sanity of the ‘natural’ condition of a specific individual. If we take this approach, the question is how health, normality and sanity, as well as natural per se, are defined, as the meaning of these concepts shift over time to accommodate social norms and cultural values of modern societies. It could be said that the difficulty of developing a conceptual distinction between therapy and enhancement has always been present. However, the potential significance of such distinction is only now, with the acceleration and impact of technological developments, becoming more evident.

Beyond ethical questions, a major problem of this intervention is that we do not (yet?) know exactly the totality of the effects that the artificial mutation of the CCR5 may have, at both the genetic and phenotypic levels. This is because we now know that, contrary to the idea of ‘one gene-one trait’ accepted some decades ago, a gene—or its absence—can affect numerous traits, many of them being apparently unrelated (a phenomenon also known as pleiotropy). That is, due to constrained developmental interactions, mechanisms and genetic networks, a change in a single gene can result in a cascade of multiple effects [ 31 ]. In the case of CCR5, we currently know that the mutation offers protection against HIV infection, and also seems to increase the risk of severe or fatal reactions to some infectious diseases, such as the influenza virus [ 32 ]. It has also been observed that among people with multiple sclerosis, the ones with CCR5 mutation are twice as likely to die early than are people without the mutation [ 33 ]. Some studies have also shown that defective CCR5 can have a positive effect in cognition to enhance learning and memory in mice [ 34 ]. However, it’s not clear if this effect would be translated into humans. The example serves to illustrate that, even if human enhancement with gene editing methods was considered ethically sound, assessing the totality of its implications on solid grounds may be difficult to achieve.

Genetic engineering and human evolution: large-scale impacts

Beyond providing the opportunity of enhancing human capabilities in specific individuals, intervening in the germline is likely to have an impact on the evolutionary processes of the human species raising questions on the scale and type of impacts. In fact, the use of large-scale genetic engineering might exponentially increase the force of ‘niche construction’ in human evolution, and therefore raise ethical and practical questions never faced by our species before. It has been argued that natural selection is a mechanism of lesser importance in the case of current human evolution, as compared to other organisms, because of advances in medicine and healthcare [ 35 ]. According to such a view, among many others advances, natural selection has been conditioned by our ‘niche-construction’ ability to improve healthcare and access to clean water and food, thus changing the landscape of pressures that humans have been facing for survival. An underlying assumption or position of the current debate is that, within our human species, the force of natural selection became minimized and that we are somehow at the ‘end-point’ of our evolution [ 36 ]. If this premise holds true, one could argue that evolution is no longer a force in human history and hence that any human enhancement would not be substituting itself to human evolution as a key driver for future changes.

However, it is useful to remember that, as defined by Darwin in his book ‘On the Origin of the Species’, natural selection is a process in which organisms that happen to be ‘better’ adapted to a certain environment tend to have higher survival and/or reproductive rates than other organisms [ 37 ]. When comparing human evolution to human genetic enhancement, an acceptable position could be to consider ethically sound those interventions that could be replicated naturally by evolution, as in the case of the CCR5 gene. Even if this approach was taken, however, it is important to bear in mind that human evolution acts on human traits sometimes increasing and sometimes decreasing our biological fitness, in a constant evolutionary trade-off and in a contingent and/or neutral—in the sense of not ‘progressive’—process. In other worlds, differently from genetic human enhancement, natural selection does not ‘ aim ’ at improving human traits [ 38 ]. Human evolution and the so-called genetic human enhancement would seem therefore to involve different underlying processes, raising several questions regarding the implications and risks of the latter.

But using genetic engineering to treat humans has been proposed far beyond the therapeutic case or to introduce genetic modifications known to already occur in nature. In particular, when looking into the views expressed on the balance between human evolution and genetic engineering, some argue that it may be appropriate to use genetic interventions to go beyond what natural selection has contributed to our species when it comes to eradicate vulnerabilities [ 17 ]. Furthermore, when considering the environmental, ecological and social issues of contemporary times, some suggest that genetic technologies could be crucial tools to contribute to human survival and well-being [ 20–22 ]. The possible need to ‘engineer’ human traits to ensure our survival could include the ability to allow our species to adapt rapidly to the rate of environmental change caused by human activity, for which Darwinian evolution may be too slow [ 39 ]. Or, for instance, to support long-distance space travel by engineering resistance to radiation and osteoporosis, along with other conditions which would be highly advantageous in space [ 40 ].

When considering the ethical and societal merits of these propositions, it is useful to consider how proto-forms of enhancement has been approached by past human societies. In particular, it can be argued that humans have already employed—as part of our domestication/‘selective breeding’ of other animals—techniques of indirect manipulation of genomes on a relatively large scale over many millennia, albeit not on humans. The large-scale selective breeding of plants and animals over prehistoric and historic periods could be claimed to have already shaped some of our natural environment. Selective breeding has been used to obtain specific characteristics considered useful at a given time in plants and animals. Therefore, their evolutionary processes have been altered with the aim to produce lineages with advantageous traits, which contributed to the evolution of different domesticated species. However, differently from genetic engineering, domestication possesses inherent limitations in its ability to produce major transformations in the created lineages, in contrast with the many open possibilities provided by genetic engineering.

When considering the impact of genetic engineering on human evolution, one of questions to be considered concerns the effects, if any, that genetic technology could have on the genetic pool of the human population and any implication on its resilience to unforeseen circumstances. This underlines a relevant question associated with the difference between ‘health’ and biological fitness. For example, a certain group of animals can be more ‘healthy’—as domesticated dogs—but be less biologically ‘fit’ according to Darwin’s definition. Specifically, if such group of animals are less genetically diverse than their ancestors, they could be less ‘adaptable’ to environmental changes. Assuming that, the human germline modification is undertaken at a global scale, this could be expected to have an effect, on the distribution of genetically heritable traits on the human population over time. Considering that gene and trait distributions have been changing under the processes of evolution for billions of years, the impact on evolution will need to be assessed by analysing which genetic alterations have been eventually associated with specific changes within the recent evolutionary history of humans. On this front, a key study has analysed the implications of genetic engineering on the evolutionary biology of human populations, including the possibility of reducing human genetic diversity, for instance creating a ‘biological monoculture’ [ 41 ]. The study argued that genetic engineering will have an insignificant impact on human diversity, while it would likely safeguard the capacity of human populations to deal with disease and new environmental challenges and therefore, ensure the health and longevity of our species [ 41 ]. If the findings of this study were considered consistent with other knowledge and encompassing, the impact of human genetic enhancements on the human genetic pool and associated impacts could be considered secondary aspects. However, data available from studies on domestication strongly suggests that domestication of both animals and plans might lead to not only decreased genetic diversity per se, but even affect patterns of variation in gene expression throughout the genome and generally decreased gene expression diversity across species [ 42–44 ]. Given that, according to recent studies within the field of biological anthropology recent human evolution has been in fact a process of ‘self-domestication’ [ 45 ], one could argue that studies on domestication could contribute to understanding the impacts of genetic engineering.

Beyond such considerations, it is useful to reflect on the fact that human genetic enhancement could occur on different geographical scales, regardless of the specific environment and geological periods in which humans are living and much more rapidly than in the case of evolution, in which changes are very slow. If this was to occur routinely and on a large scale, the implications of the resulting radical and abrupt changes may be difficult to predict and its impacts difficult to manage. This is currently highlighted by results of epigenetics studies, and also of the microbiome and of the effects of pollutants in the environment and their cumulative effect on the development of human and non-human organisms alike. Increasingly new evidence indicates a greater interdependence between humans and their environments (including other microorganisms), indicating that modifying the environment can have direct and unpredictable consequences on humans as well. This highlight the need of a ‘systems level’ approach. An approach in which the ‘bounded body’ of the individual human as a basic unit of biological or social action would need to be questioned in favour of a more encompassing and holistic unit. In fact, within biology, there is a new field, Systems Biology, which stresses the need to understand the role that pleiotropy, and thus networks at multiple levels—e.g. genetic, cellular, among individuals and among different taxa—play within biological systems and their evolution [ 46 ]. Currently, much still needs to be understood about gene function, its role in human biological systems and the interaction between genes and external factors such as environment, diet and so on. In the future if we do choose to genetically enhance human traits to levels unlikely to be achieved by human evolution, it would be crucial to consider if and how our understanding of human evolution enable us to better understand the implications of genetic interventions.

New forms of human enhancement are increasingly coming to play due to technological development. If phenotypic and somatic interventions for human enhancement pose already significant ethical and societal challenges, germline heritable genetic intervention, require much broader and complex considerations at the level of the individual, society and human species as a whole. Germline interventions associated with modern technologies are capable of much more rapid, large-scale impacts and seem capable of radically altering the balance of humans with the environment. We know now that beside the role genes play on biological evolution and development, genetic interventions can induce multiple effects (pleiotropy) and complex epigenetics interactions among genotype, phenotype and ecology of a certain environment. As a result of the rapidity and scale with which such impact could be realized, it is essential for ethical and societal debates, as well as underlying scientific studies, to consider the unit of impact not only to the human body but also to human populations and their natural environment (systems biology). An important practicable distinction between ‘therapy’ and ‘enhancement’ may need to be drawn and effectively implemented in future regulations, although a distinct line between the two may be difficult to draw.

In the future if we do choose to genetically enhance human traits to levels unlikely to be achieved by human evolution, it would be crucial to consider if and how our understanding of humans and other organisms, including domesticated ones, enable us to better understand the implications of genetic interventions. In particular, effective regulation of genetic engineering may need to be based on a deep knowledge of the exact links between phenotype and genotype, as well the interaction of the human species with the environment and vice versa .

For a broader and consistent debate, it will be essential for technological, philosophical, ethical and policy discussions on human enhancement to consider the empirical evidence provided by evolutionary biology, developmental biology and other disciplines.

This work was supported by Fundação para a Ciência e a Tecnologia (FCT) of Portugal [CFCUL/FIL/00678/2019 to M.A.].

Conflict of interest : None declared.

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Harvard researchers, others share their views on key issues in the field

Medicine is at a turning point, on the cusp of major change as disruptive technologies such as gene, RNA, and cell therapies enable scientists to approach diseases in new ways. The swiftness of this change is being driven by innovations such as CRISPR gene editing , which makes it possible to correct errors in DNA with relative ease.

Progress in this field has been so rapid that the dialogue around potential ethical, societal, and safety issues is scrambling to catch up.

This disconnect was brought into stark relief at the Second International Summit on Human Genome Editing , held in Hong Kong in November, when exciting updates about emerging therapies were eclipsed by a disturbing announcement. He Jiankui, a Chinese researcher, claimed that he had edited the genes of two human embryos, and that they had been brought to term.

There was immediate outcry from scientists across the world, and He was subjected to intense social pressure, including the removal of his affiliations, for having allegedly disregarded ethical norms and his patients’ safety.

Yet as I. Glenn Cohen, faculty director of the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School, has said, gene editing comes in many varieties, with many consequences. Any deep ethical discussion needs to take into account those distinctions.

Human genome editing: somatic vs. germline

The germline editing He claimed to have carried out is quite different from the somatic gene therapies that are currently changing the frontiers of medicine. While somatic gene editing affects only the patient being treated (and only some of his or her cells), germline editing affects all cells in an organism, including eggs and sperm, and so is passed on to future generations. The possible consequences of that are difficult to predict.

Somatic gene therapies involve modifying a patient’s DNA to treat or cure a disease caused by a genetic mutation. In one clinical trial, for example, scientists take blood stem cells from a patient, use CRISPR techniques to correct the genetic mutation causing them to produce defective blood cells, then infuse the “corrected” cells back into the patient, where they produce healthy hemoglobin. The treatment changes the patient’s blood cells, but not his or her sperm or eggs.

Germline human genome editing, on the other hand, alters the genome of a human embryo at its earliest stages. This may affect every cell, which means it has an impact not only on the person who may result, but possibly on his or her descendants. There are, therefore, substantial restrictions on its use.

Germline editing in a dish can help researchers figure out what the health benefits could be, and how to reduce risks. Those include targeting the wrong gene; off-target impacts, in which editing a gene might fix one problem but cause another; and mosaicism, in which only some copies of the gene are altered. For these and other reasons, the scientific community approaches germline editing with caution, and the U.S. and many other countries have substantial policy and regulatory restrictions on using germline human genome editing in people.

But many scientific leaders are asking: When the benefits are believed to outweigh the risks, and dangers can be avoided, should science consider moving forward with germline genome editing to improve human health? If the answer is yes, how can researchers do so responsibly?

CRISPR pioneer Feng Zhang of the Broad Institute of Harvard and MIT responded immediately to He’s November announcement by calling for a moratorium on implanting edited embryos in humans. Later, at a public event on “Altering the Human Genome” at the Belfer Center at Harvard Kennedy School (HKS), he explained why he felt it was important to wait:

“The moratorium is a pause. Society needs to figure out if we all want to do this, if this is good for society, and that takes time. If we do, we need to have guidelines first so that the people who do this work can proceed in a responsible way, with the right oversight and quality controls.”

Comparison of somatic vs. germline editing.

Professors at the University’s schools of medicine, law, business, and government saw He’s announcement as a turning point in the discussion about heritable gene therapies and shared their perspectives on the future of this technology with the Gazette.

Here are their thoughts, issue by issue:

Aside from the safety risks, human genome editing poses some hefty ethical questions. For families who have watched their children suffer from devastating genetic diseases, the technology offers the hope of editing cruel mutations out of the gene pool. For those living in poverty, it is yet another way for the privileged to vault ahead. One open question is where to draw the line between disease treatment and enhancement, and how to enforce it, considering differing attitudes toward conditions such as deafness.

Robert Truog , director of the Center for Bioethics at Harvard Medical School (HMS), provided context:

“This question is not as new as it seems. Evolution progresses by random mutations in the genome, which dwarf what can be done artificially with CRISPR. These random mutations often cause serious problems, and people are born with serious defects. In addition, we have been manipulating our environment in so many ways and exposing ourselves to a lot of chemicals that cause unknown changes to our genome. If we are concerned about making precise interventions to cure disease, we should also be interested in that.

“To me, the conversation around Dr. He is not about the fundamental merits of germline gene editing, which in the long run will almost certainly be highly beneficial. Instead, it’s about the oversight of science. The concern is that with technologies that are relatively easy to use, like CRISPR, how does the scientific community regulate itself? If there’s a silver lining to this cloud, I think it is that the scientific community did pull together to be critical of this work, and took the responsibility seriously to use the tools available to them to regulate themselves.”

When asked what the implications of He’s announcement are for the emerging field of precision medicine, Richard Hamermesh, faculty co-chair of the Harvard Business School/Kraft Precision Medicine Accelerator, said:

“Before we start working on embryos, we have a long way to go, and civilization has to think long and hard about it. There’s no question that gene editing technologies are potentially transformative and are the ultimate precision medicine. If you could precisely correct or delete genes that are causing problems — mutating or aberrant genes — that is the ultimate in precision. It would be so transformative for people with diseases caused by a single gene mutation, like sickle cell anemia and cystic fibrosis. Developing safe, effective ways to use gene editing to treat people with serious diseases with no known cures has so much potential to relieve suffering that it is hard to see how anyone could be against it.

“There is also commercial potential and that will drive it forward. A lot of companies are getting venture funding for interesting gene therapies, but they’re all going after tough medical conditions where there is an unmet need — [where] nothing is working — and they’re trying to find gene therapies to cure those diseases. Why should we stop trying to find cures?

“But anything where you’re going to be changing human embryos, it’s going to take a long time for us to figure out what is appropriate and what isn’t. That has to be done with great care in terms of ethics.”

George Q. Daley  is dean of HMS, the Caroline Shields Walker Professor of Medicine, and a leader in stem cell science and cancer biology. As a spokesperson for the organizing committee of the Second International Summit on Human Genome Editing, he responded swiftly to He’s announcement in Hong Kong. Echoing those remarks, he said:

“It’s time to formulate what a clinical path to translation might look like so that we can talk about it. That does not mean that we’re ready to go into the clinic — we are not. We need to specify what the hurdles would be if one were to move forward responsibly and ethically. If you can’t surmount those hurdles, you don’t move forward.

“There are stark distinctions between editing genes in an embryo to prevent a baby from being born with sickle cell anemia and editing genes to alter the appearance or intelligence of future generations. There is a whole spectrum of considerations to be debated. The prospect includes an ultimate decision that we not go forward, that we decide that the benefits do not outweigh the costs.”

Asked how to prevent experiments like He’s while preserving academic freedom, Daley replied:

“For the past 15 years, I have been involved in efforts to establish international standards of professional conduct for stem cell research and its clinical translation, knowing full well that there could be — and has been — a growing number of independent practitioners directly marketing unproven interventions to vulnerable patients through the internet. We advocated so strongly for professional standards in an attempt to ward off the risks of an unregulated industry. Though imperfect, our efforts to encourage a common set of professional practices have been influential.

“You can’t control rogue scientists in any field. But with strongly defined guidelines for responsible professional conduct in place, such ethical violations like those of Dr. He should remain a backwater, because most practitioners will adhere to generally accepted norms. Scientists have a responsibility to come together to articulate professional standards and live by them. One has to raise the bar very high to define what the standards of safety and efficacy are, and what kind of oversight and independent judgment would be required for any approval.

“We have called for an ongoing international forum on human genome editing, and that could take many shapes. We’ve suggested that the national academies of more countries come together — the National Academy of Sciences in the U.S. and the Royal Society in the U.K. are very active here — because these are the groups most likely to have the expertise to convene these kinds of discussions and keep them going.”

Cohen , speaking to the legal consequences of germline human genome editing, said:

“I think we should slow down in our reaction to this case. It is not clear that the U.S. needs to react to Dr. He’s announcement with regulation. The FDA [Food and Drug Administration] already has a strong policy on germline gene editing in place. A rider in the Consolidated Appropriations Act of 2016 — since renewed — would have blocked the very same clinical application of human germline editing He announced, had it been attempted in the U.S.

“The scientific community has responded in the way I’d have liked it to. There is a difference between ‘governance’ and ‘self-governance.’ Where government uses law, the scientific community uses peer review, public censure, promotions, university affiliations, and funding to regulate themselves. In China, in Dr. He’s case, you have someone who’s (allegedly) broken national law and scientific conventions. That doesn’t mean you should halt research being done by everyone who’s law-abiding.

“Public policy or ethical discussion that’s divorced from how science is progressing is problematic. You need to bring everyone together to have robust discussions. I’m optimistic that this is happening, and has happened. It’s very hard to deal with a transnational problem with national legislation, but it would be great to reach international consensus on this subject. These efforts might not succeed, but ultimately they are worth pursuing.”

Professor Kevin Eggan of Harvard’s Department of Stem Cell and Regenerative Biology said, “The question we should focus on is: Will this be safe and help the health of a child? Can we demonstrate that we can fix a mutation that will cause a terrible health problem, accurately and without the risk of harming their potential child? If the answer is yes, then I believe germline human genome editing is likely to gain acceptance in time.

“There could be situations where it could help a couple, but the risks of something going wrong are real. But at this point, it would be impossible to make a risk-benefit calculation in a responsible manner for that couple. Before we could ever move toward the clinic, the scientific community must come to a consensus on how to measure success, and how to measure off-target effects in animal models.

“Even as recently as this past spring and fall, the results of animal studies using CRISPR — the same techniques Dr. He claimed to have used — generated a lot of confusion. There is disagreement about both the quality of the data and how to interpret it. Until we can come to agreement about what the results of animal experiments mean, how could we possibly move forward with people?

“As happened in England with mitochondrial replacement therapy, we should be able to come to both a scientific and a societal consensus of when and how this approach should be used. That’s missing.”

According to Catherine Racowsky, professor of obstetrics, gynecology and reproductive biology at Brigham and Women’s Hospital, constraints on the use of embryos in federally funded research pose barriers to studying the risks and benefits of germline editing in humans. She added:

“Until the work is done, carefully and with tight oversight, to understand any off-target effects of replacing or removing a particular gene, it is inappropriate to apply the technology in the clinical field. My understanding of Dr. He’s case is that there wasn’t a known condition in these embryos, and by editing the genes involved with HIV infection, he could also have increased the risks of susceptibility to influenza and West Nile viruses.

“We need a sound oversight framework, and it needs to be established globally. This is a technology that holds enormous promise, and it is likely to be applied to the embryo, but it should only be applied for clinical purposes after the right work has been done. That means we must have consensus on what applications are acceptable, that we have appropriate regulatory oversight, and, perhaps most importantly, that it is safe. The only way we’re going to be able to determine that these standards are met is to proceed cautiously, with reassessments of the societal and health benefits and the risks.”

Asked about public dialogue around germline human genome editing, George Church , Robert Winthrop Professor of Genetics at HMS, said:

“With in vitro  fertilization (IVF), ‘test tube babies’ was an intentionally scary term. But after Louise Brown, the first IVF baby, was born healthy 40 years ago, attitudes changed radically. Ethics flipped 180 degrees, from it being a horrifying idea to being unacceptable to prevent parents from having children by this new method. If these edited twins are proven healthy, very different discussions will arise. For example, is a rate of 900,000 deaths from HIV infection per year a greater risk than West Nile virus, or influenza? How effective is each vaccine?”

Science, technology, and society

Sheila Jasanoff , founding director of the Science, Technology, and Society program at HKS, has been calling for a “global observatory” on gene editing, an international network of scholars and organizations dedicated to promoting exchange across disciplinary and cultural divides. She said:

“The notion that the only thing we should care about is the risk to individuals is very American. So far, the debate has been fixated on potential physical harm to individuals, and not anything else. This is not a formulation shared with other countries in the world, including practically all of Europe. Considerations of risk have equally to do with societal risk. That includes the notion of the family, and what it means to have a ‘designer baby.’

“These were not diseased babies Dr. He was trying to cure. The motivation for the intervention was that they live in a country with a high stigma attached to HIV/AIDS, and the father had it and agreed to the intervention because he wanted to keep his children from contracting AIDS. AIDS shaming is a fact of life in China, and now it won’t be applied to these children. So, are we going to decide that it’s OK to edit as-yet-to-be children to cater to this particular idea of a society?

“It’s been said that ‘the genie is out of the bottle’ with germline human genome editing. I just don’t think that’s true. After all, we have succeeded in keeping ‘nuclear’ inside the bottle. Humanity doesn’t lack the will, intelligence, or creativity to come up with ways for using technology for good and not ill.

“We don’t require students to learn the moral dimensions of science and technology, and that has to change. I think we face similar challenges in robotics, artificial intelligence, and all kinds of frontier fields that have the potential to change not just individuals but the entirety of what it means to be a human being.

“Science has this huge advantage over most professional thought in that it has a universal language. Scientists can hop from lab to lab internationally in a way that lawyers cannot because laws are written in many languages and don’t translate easily. It takes a very long time for people to understand each other across these boundaries. A foundational concept for human dignity? It would not be the same thing between cultures.

“I would like to see a ‘global observatory’ that goes beyond gene editing and addresses emerging technologies more broadly.”

To learn more:

Technology and Public Purpose project, Belfer Center for Science and International Affairs, Harvard Kennedy School of Government, https://www.belfercenter.org/tapp/person

Concluding statement from the Second International Summit on Human Genome Editing. http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=11282018b

A global observatory for gene editing: Sheila Jasanoff and J. Benjamin Hurlbut call for an international network of scholars and organizations to support a new kind of conversation. https://www.nature.com/articles/d41586-018-03270-w

Building Capacity for a Global Genome Editing Observatory: Institutional Design. http://europepmc.org/abstract/MED/29891181

Glenn Cohen’s blog: How Scott Gottlieb is Wrong on the Gene Edited Baby Debacle. http://blog.petrieflom.law.harvard.edu/2018/11/29/how-scott-gottlieb-is-wrong-on-the-gene-edited-baby-debacle/

Gene-Editing: Interpretation of Current Law and Legal Policy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651701/

Forum: Harvard T.H. Chan School of Public Health event on the promises and challenges of gene editing, May 2017: https://theforum.sph.harvard.edu/events/gene-editing/

Petrie-Flom Center Annual Conference: Consuming Genetics: Ethical and Legal Considerations of New Technologies: http://petrieflom.law.harvard.edu/events/details/2019-petrie-flom-center-annual-conference

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Legal reflections on the case of genome-edited babies

  • Shuang Liu 1  

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Human genome-editing is banned by guidelines, laws and regulations in most countries. However, the first criminal case on genome-edited babies was sentenced in China in 2019. In this commentary we discuss our legal reflections on this case. Genome-editing on healthy embryos of human may lead to irreversible mutations and serious consequences on the heredity of future generations, while its long-term safety is unpredictable. A full set of laws, regulations along with the guidelines should be formulated to penalize genome-editing behaviors and prevent similar negative events in the future. More effective and binding mechanisms should be constructed and implemented among different countries. A collaborative network should be strengthened for better global registry and surveillance of human genome-editing technologies and research.

Introduction

On December 30, 2019, a Chinese researcher, Jiankui He, was sentenced by Chinese local Court in Shenzhen City to 3 years of imprisonment with a fine of 3 million RMB Yuan for committing the crime of “Illegal Medical Practice”, and the other two defendants in the same case were also sentenced. One was sentenced to imprisonment of 2 years with a fine of 1 million RMB Yuan, another was sentenced to imprisonment of 1 year and 6 months (with probation of 2 years) with a fine of 0.5 million RMB Yuan [ 1 ]. The court concluded that each of the three defendants did not have a doctor’s practice license, and they applied the genome-editing technology (known as Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR) to human assisted reproductive medicine, which caused the genetic changes of babies. In this case, the fathers are HIV positive and the mothers are HIV negative. Eggs were extracted from their body and the twin pregnancy gestated after the genome-edited embryos were transferred to their uterus. Genome-editing was undertaken to remove the CCR5 gene which allows the HIV to infect cells. The birth of babies represented a controversial leap in genome editing [ 2 ]. One day later when He announced the research of his team, more than 100 Chinese scientists and scholars signed a joint statement to denounce the trial. They reasserted that both the accuracy of the CRISPR and the potential off-target effects are controversial in the scientific community. Any attempt to directly transform human embryos and produce babies before rigorous tests poses tremendous risks. Such experiment is forbidden by the international biomedical community.

Genome-editing technology can bring great positive influence to the human being. It can be used to treat certain genome-related diseases [ 3 ]. However, it can also lead to some problems, such as how to (1) use it ethically and legally; (2) acquire the real consent from the experimental subjects; (3) how to penalize the genome-editing research for non-medical reasons, etc. Specific laws and regulations are important to resolve these problems because they are the last line of defense for social governance.

Current laws and regulations of genome-editing in different countries

Human genome-editing is largely forbidden by laws or guidelines even in countries permissive to human embryonic stem cell research [ 4 ]. Many countries have banned human genome-editing. Thirty nine countries were surveyed and categorized as “Ban based on legislation” (25 countries), “Ban based on guidelines” (4), “Ambiguous” (9) and “Restrictive” (1). China, India, Ireland, and Japan forbid genome-editing based on guidelines which are less enforceable than laws and are subject to amendment [ 3 ]. In the USA, Human genome-editing is not banned, but a moratorium is imposed under vigilance of the Food and Drug Administration (FDA) and the guidelines of the National Institutes of Health (NIH). Any clinical trial proposals for germline alterations will be rejected by the Recombinant DNA Advisory Committee (RAC) of the NIH. Clinical studies are regulated by FDA [ 5 ]. In the UK, the legislation of medical use of mitochondrial replacement is likely to lead to legal permission for the modification of germline nuclear genome that can be readily changed by genome-editing technology [ 6 ].

Although genome-editing is banned in many countries, necessary and practical laws, regulations and guidelines should be developed, and appropriate penalty should be applied in proportion to the crime. Preventive measures should also be stipulated in a specific law. Early embryo genome-editing for fertility purposes violates the ethical principles provided in the “Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects” (hereafter referred to as “Declaration of Helsinki”), which has been widely accepted by the international community. In He’s case, early human embryos were edited artificially. Consequently, the genome-editing babies not only face the risk of uncertainty, but also are deprived of the right to an open future. The Article 9 of “Declaration of Helsinki” states that the responsibility for the protection of research subjects must always rest with the physicians or other health care professionals and never with the research subjects, even though they have been given consent. He and his team violated the provisions of both Article 9 of Declaration of Helsinki and the Chinese criminal law, and their misconducts should be punished.

The sentence of genome-editing babies in China

Current Chinese laws are insufficient to deal with new challenges posed by new expertise and technologies. The regulations prohibit the development of genome-editing embryos beyond 14 days. The Chinese Guideline on Human Assisted Reproductive Technologies stipulates that the use of human egg plasma and nuclear transfer technology for the purpose of reproduction, and manipulation of the genomes in human gametes, zygotes or embryos for the purpose of reproduction are prohibited. In He’s case, it is unknown whether his team had acquired the true informed consent and they were convicted the crime of “Illegal Medical Practice”. The local court concluded that their behaviors deliberately violated the National Regulations on Scientific Research and Medical Management, crossed an ethical bottom line, and rashly applied genome-editing technology. Genome-editing on embryos with existing technologies and methods is not the only way to prevent mother-to-child transmission of AIDS [ 7 ]. Besides, the experimental procedure was unclear and nontransparent, but the consequence is full of risks. However, according to the Chinese Criminal Law, three-year imprisonment and below is regarded as misdemeanor. In contrast, the punishment of similar behavior could be 10 years of imprisonment in the UK and 20 years in France at maximum [ 8 ]. It is obvious that He and his team were eager for quick success, and their misconducts were irresponsible and dangerous. Moreover, their genome-editing behavior may cause irreversible damage to the entire human genome chain. Therefore, He’s case is very typical to warn other scientists not to commit similar misconducts. Fortunately, on May 28, 2019, the Chinese government promulgated the Regulation of the People’s Republic of China on the Administration of Human Genetic Resources, which aims to protect public health, national security, and public interest through effective protection and rational use of China’s human genetic resources.

Human genome-editing technology is a two-sided sword. The advantage of its benefit can be explored. However, further legislation is required to punish misconducts and avoid potential risks.

A specific crime and more severe penalty should be formulated in the Chinese Criminal Law. Civil responsibility should be assumed if a medical institution or a person in charge do not truthfully and fully informed patients of potential risks.

Better governance is needed. According to the Administrative Penalty Law, local government and other administrative agencies should assume responsibilities if they fail to carry out their duties in ethical review, supervision and management.

More effective and binding mechanisms to constrain the use of genome-editing technology should be developed. More specific guidelines and preventive measures should be formulated in consistent with the international regulations.

A collaborative network should be strengthened for better global registry and surveillance of human genome-editing technologies and research, led by the World Health Organization (WHO) Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing.

Availability of data and materials

Not applicable.

Abbreviations

Clustered Regularly Interspaced Short Palindromic Repeats.

Food and Drug Administration

National Institutes of Health

Recombinant DNA Advisory Committee

World Health Organization

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Acknowledgements

The author would like to thank the comments and advices of reviewers in improving the quality of the article.

This work is supported by a project Research on the Recent Expansion of Chinese Criminal Law and Its Reasonable Limits funded by National Social Science Fund Project of China (grant No.: 16BFX056).

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case study of genetic engineering

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Biotech potatoes: A case study of how genetic engineering can improve our food supply

case study of genetic engineering

To help demonstrate the power of biotechnology, consider the following analogy: Imagine you have two decks of cards, one red and one blue, and each deck contains all the genes of a potato. The red deck makes a great potato, but lacks resistance to late blight disease. The blue deck has late blight resistance …. but these potatoes are unmarketable.

To get the blue ace of spades (LB resistance) together with the rest of the red deck (good potatoes), you could shuffle the two together and divide the deck in two …. You can keep shuffling this new deck with more red cards, but imagine how many times you would have to shuffle the cards to get a perfect deck ….

Compare this with simply picking out the blue ace of spades and placing it into the red deck. Wouldn’t that be easier? …. This is essentially the difference between using traditional breeding (shuffling) and biotechnology (stacking the deck). …

Together with new breeding technologies …. genetic modification remains a useful tool in the genetic improvement of potatoes. The 100-plus wild species relatives of potato provide a virtually endless source of traits that can be incorporated into elite varieties relatively easily and quickly.

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case study of genetic engineering

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Transgenic and genome-edited fruits: background, constraints, benefits, and commercial opportunities

  • Maria Lobato-Gómez   ORCID: orcid.org/0000-0002-2589-6216 1 ,
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  • Metabolic engineering
  • Molecular engineering in plants

Breeding has been used successfully for many years in the fruit industry, giving rise to most of today’s commercial fruit cultivars. More recently, new molecular breeding techniques have addressed some of the constraints of conventional breeding. However, the development and commercial introduction of such novel fruits has been slow and limited with only five genetically engineered fruits currently produced as commercial varieties—virus-resistant papaya and squash were commercialized 25 years ago, whereas insect-resistant eggplant, non-browning apple, and pink-fleshed pineapple have been approved for commercialization within the last 6 years and production continues to increase every year. Advances in molecular genetics, particularly the new wave of genome editing technologies, provide opportunities to develop new fruit cultivars more rapidly. Our review, emphasizes the socioeconomic impact of current commercial fruit cultivars developed by genetic engineering and the potential impact of genome editing on the development of improved cultivars at an accelerated rate.

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Introduction.

The conventional breeding of fruit crops can take more than two decades due to the long juvenile period of woody species 1 . Genetic engineering allows improved varieties to be developed more quickly, and the vegetative propagation of fruit trees allows the engineered cultivars to achieve coverage of larger areas than crops that depend on sexual reproduction 2 . All genetically engineered fruit crops have been produced either by Agrobacterium -mediated transformation or direct DNA transfer. In each case, the efficiency of transformation is highly dependent on the species and even cultivar, requiring the development of bespoke optimized methods consisting of efficient gene delivery, selection, and regeneration from transformed explants 2 . Most fruit tree species are highly heterozygous, and to maintain the characteristics of the original variety the transgenic events should be derived from mature tissue (such as leaves) rather than embryogenic explants 3 .

The first genetically engineered fruit product (Flavr Savr™ tomato) was deregulated in 1992 and introduced into the market in 1994 4 . A gene that triggers pectin solubilization was downregulated in the transgenic fruits, resulting in delayed fruit softening and an extended shelf-life 5 . Several additional fruit crops with traits improved by genetic engineering have received regulatory approval for commercialization in different parts of the world, and are intended for cultivation either as human food or animal feed. These are tomato ( Solanum lycopersicum ) 6 , 7 , 8 , 9 , papaya ( Carica papaya L.) 10 , 11 , pepper ( Capsicum annuum ) 12 , plum ( Prunus domestica ) 13 , eggplant ( Solanum melongena L.) 14 , apple ( Malus domestica Borkh.) 15 , melon ( Cucumis melo L.) 16 , and pineapple ( Ananas comosus L. Merr.) 17 . Most of the transgenic fruits were developed to improve agronomic productivity by conferring pest or disease resistance, or delayed ripening. However, more recent products have addressed quality traits by eliminating fruit browning or adding new visual traits such as flesh color. Some engineered fruit crops have been withdrawn from the market because they were not commercially viable (Flavr Savr™ tomato 4 , 18 ) or were never commercialized (Melon A and B 16 , 19 ).

Advances in genetic engineering, particularly the development of genome editing technologies have provided new tools for the generation of improved fruit varieties. Many proof-of-concept examples involving fruit crops have been reported and the further development and marketing of such varieties could have a major socioeconomic impact. Here we discuss the history and current status of genetically engineered fruit crops and the promise offered by genome editing. In recent years, several countries have amended their current regulations or have developed new guidelines to regulate genome-edited plants and its products 20 . This may make it possible that genome-edited fruits, similarly to all other genome-edited crops, reach the market faster in countries with a genome editing friendly policy 20 , 21 . Here, we first discuss fruit varieties that have already been approved for commercialization, focusing on those that are on the market. We then consider fruit varieties developed more recently using genetic engineering or genome editing, and their potential socioeconomic impact.

Genetically engineered fruits approved for commercialization

Trait description and drivers.

Genetically engineered fruits have been developed with unique agronomic characteristics that are often difficult to achieve by conventional breeding, and are designed to meet the specific needs of growers and/or customers. Fruits that have been developed by genetic engineering are shown in Fig. 1 . Some varieties were approved but not ultimately commercialized, or were launched but subsequently removed from the market, and these are not considered in detail.

figure 1

Year indicates the year of first approval. Currently on the market indicated as light blue boxes

Papaya resistant to papaya ringspot virus

In 1992, papaya ringspot virus (PRSV) was detected in Puna, the major papaya-producing district in Hawaii. PRSV resistance was not found in papaya germplasm or in wild Carica species suitable as candidates for interspecific hybridization. Furthermore, insecticides failed to control the aphid vectors responsible for virus transmission 22 , and many orchards were therefore abandoned due to PRSV infestation 10 . The widely cultivated ‘Sunset’ papaya was transformed with a gene derived from a Hawaiian strain to produce the transgenic papaya ‘SunUp’, which is completely resistant to PRSV in Hawaii 10 . ‘SunUp’ papaya was crossed with ‘Kapoho’, a non-engineered cultivar, to obtain the yellow-flesh ‘Rainbow’ papaya, which is also resistant to PRSV 23 .

In China, PRSV has threatened the papaya industry for 50 years 24 . Similarly to the ‘SunUp’ variety, transgenic Huanong No. 1 papaya is resistant to the four predominant PRSV strains found in South China (Hainan, Guangdong, Guangxi, and Yunnan provinces), namely Ys, Vb, Sm and Lc 24 . Additionally, Huanong No. 1 produces bigger fruits with thicker flesh than the original cultivar 24 . In 2012, some Huanong No. 1 papayas grown in Hainan exhibited PRSV-like symptoms, suggesting that resistance is beginning to break. Phylogenetic analysis revealed the presence of a new virus lineage in Hainan and Guangdong papaya plantations, which may pose a threat to Huanong No. 1 papaya cultivation 25 .

Tomato and sweet pepper resistant to cucumber mosaic virus

In 1990, tomato crops in Fujian province (China) were affected by a virulent strain of cucumber mosaic virus (CMV) causing severe necrosis 26 . CMV is a major threat to tomato and sweet pepper and thus the tomato line PK-TM8805R and the sweet pepper line PK-SP01 were developed 24 . Both fruits express a CMV protein gene, conferring resistance to CMV, but data concerning the performance of these cultivars have not been published 26 .

Squash resistant to potyviruses

Like CMV, zucchini yellow mosaic virus (ZYMV) and watermelon mosaic virus 2 (WMV 2) are potyviruses transmitted by aphids. Together, these viruses can reduce the yields of squash by up to 80% 27 . Resistance to these viruses is not found in squash germplasm, and cannot be introduced by interspecific hybridization due to hybrid incompatibility and the concomitant transfer of undesirable traits 28 . In 1995, several transgenic inbred squash lines were developed by transformation with single or multiple viral protein genes from ZYMV, WMV2, and CMV. Transgenic lines ZW-20 and CZW-3 showed complete resistance to ZYMV and WMV2, line CZW-3 showed additional resistance to CMV 28 .

Eggplant resistant to eggplant fruit and shoot borer

In Bangladesh, eggplant is the second most important fruit crop and a major source of income for small, resource-poor farmers 29 . Eggplant fruits are unmarketable when infested with eggplant fruit and shoot borer (EFSB) larvae ( Leucinodes orbonalis ) but effective prevention requires the application of more than 100 sprays of insecticide each season. In addition to the detrimental impact on the environment, this accounts for more than a quarter of production costs, and there are still losses due to the prevalence of EFSB 30 . Resistant cultivars have not been developed by conventional breeding 31 , but a transgenic variety producing Bacillus thuringiensis (Bt) toxins is resistant to EFSB has been commercialized 30 . Infestations of the Bt variety occur at a frequency of 0.04–0.88% compared to 48–57% for the equivalent non-transgenic cultivar. In 2019, the average yield of Bt eggplant in Bangladesh was 19.8 t/ha, compared to 16.6 t/ha for the non-transgenic cultivar 29 .

Non-browning apple

Fruit quality is affected by the activity of polyphenoloxidases (PPOs), which oxidize phenolic compounds and cause gradual browning in fleshy fruits such as apple. PPOs are activated by exposure to oxygen, resulting in browning when fruits are damaged, peeled, or cut. Enzymatic browning can be prevented by storage in an air-free environment, the inactivation of PPOs by irradiation, or through the use of chemical inhibitors and natural antioxidants 32 . The Arctic ® apple concept was developed by silencing of PPOs 33 , 34 . Currently, there are three commercial varieties of Arctic ® apple: Arctic ® Golden Delicious, Arctic ® Granny Smith, and Arctic ® Fuji. Commercial harvest of Arctic ® Golden Delicious and Arctic ® Granny Smith started in 2016, and Arctic ® Fuji will be on the market in 2021 35 .

Pink-fleshed pineapple

Fruits with different skin and flesh colors have been developed by conventional breeding 36 and in proof-of-concept engineering experiments 37 . In 2005, the Pinkglow™ transgenic pineapple was developed, in which the pink flesh accumulates lycopene due to the modification of the carotenoid pathway 17 . The skin of the Pinkglow™ pineapple also has a combination of green, yellow, orange, and red colors, whereas conventional pineapple is green and yellow. In addition to the modulation of carotenoid accumulation, an endogenous ethylene biosynthesis gene was suppressed to control flowering, but this trait has yet to be evaluated 17 .

Development of commercial transgenic fruits (currently on the market)

In 1986, the coat protein of a Hawaiian PRSV isolate was cloned at Cornell University in collaboration with the Asgrow Seed Company. The USDA Section 406 grant program supported the development of transgenic PRSV-resistant papaya with the aim to control PRSV in Hawaii. In 1992, the first PRSV-resistant papayas were developed through a collaboration involving Cornell University, University of Hawaii and the Asgrow company 10 . The University of Hawaii established the protocol for papaya transformation by particle bombardment using zygotic embryos as the starting material 10 , 38 , whereas Huanong No. 1 papaya was generated using an Agrobacterium -mediated procedure established by an independent laboratory 11 . Transgenic papaya resistant to PRSV were developed using a pathogen-derived resistance approach, in which the resistance is mediated via RNA post-transcriptional gene silencing. The underpinning mechanism involves the expression of a partial or full pathogen gene sequence in the host to disrupt the pathogen’s replication 39 . ‘SunUp’ and ‘Rainbow’ papaya contain the coat protein gene from the mild PRSV HA 5-1 isolate 10 . The coat protein is required for virus survival outside the cell and for aphid transmission 40 . The required RNA specificity explains why PRSV-resistant transgenic papaya shows a narrow spectrum of resistance to particular PRSV isolates 41 . Huanong No.1 contains the replicase protein domain (NIb) from the PRSV Ys isolate, the most prevalent strain in China in 1994 24 . The N1b and N1a proteins are needed for virus replication 40 .

Seminis Vegetable Seeds and Monsanto Company developed transgenic virus-resistant squashes in 1995 27 . ZW-20 and CZW-2 virus-resistant squashes were generated using an Agrobacterium -mediated transformation protocol 28 PTGS has been also used to produce ZW-20 and CZW-3 squash. Specifically, these lines contain the coat protein gene from FL isolates of ZYMV and WMV2, and line CZW-3 contains in addition the coat protein gene from CMV strain C 28 .

In 2000, the Maharashtra Hybrid Seeds Company (Mahyco) started to develop Bt eggplant with the collaboration of Monsanto, in India. In 2003, the Agricultural Biotechnology Support Project II (ABSPII) funded a partnership between Mahyco, Cornell University, the US Agency for International Development (USAID), and public-sector partners in India, Bangladesh, and the Philippines to develop and commercialize Bt eggplant. Under the ABSPII agreement, the EE-1 eggplant event, resistant to EFSB, was donated to the public Bangladesh Agricultural Research Institute (BARI) by Mahyco via a public–private partnership 30 . EFSB resistance was incorporated into nine local eggplant lines by BARI. The ASBPII project ended in 2014 and the distribution of Bt eggplant to farmers in Bangladesh was funded by the South Asia Eggplant Improvement Partnership (SAEIP), which comprises BARI, Cornell University, USAID, the University of the Pihilippines Los Banos, and Allience for Science 14 , 30 . Mahyco also set up its own eggplant transformation pipeline. Cotyledons from eggplant seedlings were used as explants for Agrobacterium -mediated transformation with the Bt cry1Ac gene, producing the EE-1 transgenic variety 42 .

Okanagan Specialty Fruits developed Arctic ® Apple events GD743 (Golden Delicious), GS784 (Granny Smith) 33 and GS784 (Fuji) 35 using their patented method to limit quinone biosynthesis 43 . Quinones are produced from diphenols in a reaction catalyzed by PPO, and their condensation with amino acids and proteins generates lignin-like compounds that cause browning. Cell damage is needed for plastidial PPO to act on vacuolar substrates, which is why browning only occurs in cut or otherwise damaged fruit 43 . RNA interference (RNAi) technology was used to target four apple PPO genes by expressing a chimeric sense RNA containing partial coding sequences of PPO2 , GPO3 , APO5 and pSR7 , leading to the generation of dsRNA and the suppression of homologous genes by post-transcriptional silencing 32 .

Del Monte started to develop the Pinkglow™ pineapple by modulating the carotenoid pathway 44 . ‘MD2’, also known as the Del Monte Gold pineapple, is a commercial variety developed by the company and was used as starting material. Ten years later, this transgenic pineapple was patented in the US 17 . Del Monte also patented the transformation method, which involved the cultivation of organogenic pineapple cells with A. tumefaciens . Conventional pineapple on the market has yellow flesh, reflecting the β-carotene content. The Pinkglow™ pineapple expresses the tangerine ( Citrus reticulata ) PSY gene, which is a rate-limiting enzyme in carotenoid biosynthesis during fruit development 17 . In addition, the endogenous lycopene β and ε cyclase genes ( βLYC and εLYC ) were suppressed by RNAi 17 . Ethylene promotes flowering in pineapple, and 1-aminocyclopropane-1 carboxylic acid (ACC) is the immediate ethylene precursor in plants 45 . A meristem-specific ACC synthase (ACS) was suppressed by RNAi in the Pinkglow™ pineapple to inhibit flowering 17 .

Regulatory approval and commercialization of improved fruit crops

The USA has issued the most approvals for transgenic fruit cultivation either for human consumption or as animal feed. Like other genetically engineered crops, three government agencies are responsible for the oversight of transgenic fruit cultivation and import: the US Department of Agriculture (USDA) Animal and Plant Health Inspection Service (APHIS), the US Environmental Protection Agency (EPA), and the US Food and Drug Administration (FDA), which is part of the Department of Health and Human Services. Depending on its characteristics, a genetically engineered fruit may fall under the jurisdiction of one or more of these agencies 46 . APHIS regulates the environmental release of genetically engineered organisms that may pose a risk to plant health, the EPA oversees pesticides, including genetically engineered plants expressing plant incorporated protectants (PIP), and the FDA ensures the safety of all human food and animal feed (also from plant origin).

In 2020, APHIS published a revision of its 1987 biotechnology regulations 47 . The new framework, known as the SECURE rule (Sustainable, Ecological, Consistent, Uniform, Responsible, and Efficient) differs from the previous regulatory framework by focusing on an organism’s properties and not on the production method 47 .

Flavr Savr™ tomato developed by Monsanto Company was the first genetically engineered fruit to gain non-regulated status from APHIS and approval by the FDA 5 , 18 . Flavr Savr™ was also approved for import into Mexico in 1995 by the Federal Commission for the Protection against Sanitary Risk (COFEPRIS), a decentralized organ of the Mexican Secretariat of Health that oversees the safe release and import of genetically engineered plants 48 . COFREPIS also permitted the import of the engineered tomato varieties Da, B, F, and Endless summer. Similarly, in 1995 Health Canada and Agriculture and Agri-food Canada determined that the Flavr Savr™ tomato was safe for human consumption and did not pose risks as a plant pest 49 . In Canada, the Flavr Savr™ tomato was marketed under the brand name MacGregor, allowing consumers to make an informed choice 49 . Flavr Savr™ was removed from the market in 1997 because the fruits were less firm than expected and the costs of production were uncompetitive 18 .

APHIS deregulated additional engineered tomato lines in the 1990s, namely Da, B, F developed by Zeneca and Petoseed Company; 35-1-N developed by Agritope, Inc; and 5345 and 8338 “Endless summer” developed by the Monsanto Company 6 , 7 , 8 , 9 , 50 . These lines were also approved as food and feed. The Da, B, and F lines were intended for processing 4 . Between 1996 and 1999, more than 1.8 million cans derived from hybrids of the F line were sold in the UK 18 , but from 1998 onwards were no longer used as food ingredients 18 . In 2000 Health Canada also approved line 5345, which was resistant to insect pests, but it has not been released onto the market 51 .

In 1999, Agritope was granted FDA approval of the Melon A and B lines for use as food 16 . The company also requested the deregulation of these lines, but withdrew the APHIS petition the same year 19 , and neither line has been commercialized.

The Pinkglow™ pineapple received FDA approval in 2016 and was marketed for the first time in October 2020 by Fresh del Monte 52 , 53 . This cultivar is grown on a single farm in Costa Rica. The C5 plum (HoneySweet) developed by the US Department of Agriculture, which is resistant to plum pox virus (PPV), has also been deregulated by APHIS, approved by the FDA and registered by the EPA 54 . It was patented in the US in 2004, but no trees have been planted thus far and it is therefore not on the market. On request, the Agricultural Research Service (the research branch of the USDA) can freely provide a limited number of heat-treated bud wood samples to be used as a genetic resource for the breeding of PPV-resistant varieties 55 .

Genetically engineered squash has been on the US market for 25 years. CZW3 squash is also approved for import as food by Health Canada 56 . The cultivation of genetically engineered papaya in the US began in 1996, and the current predominant variety is ‘Rainbow’ because it has yellow fruit flesh favored by consumers 4 . Canada and Japan are the major importers of genetically engineered papaya produced in the US, although it is also approved for cultivation in Japan 57 . Two additional papaya lines resistant to PRSV were approved for cultivation by APHIS: 63-1 developed by Cornell University and the University of Hawaii 58 , and X17-2 developed by the University of Florida, respectively 59 . Neither lines have been commercialized 4 .

Arctic ® apples were developed by Okanagan Specialty Fruits Company in Canada, and the Golden Delicious, Granny Smith, and Fuji varieties have received approval for cultivation, human consumption and use as animal feed in both Canada and the US 15 , 60 , 61 , 62 . However, Arctic ® apples are only grown in the US, and it is unclear if Artic varieties are among the 206,259 tons of apples (including dried apples) imported to Canada, most of which are grown in the US 63 , 64 .

In China, the commercialization of all genetically engineered crops is regulated by the Ministry of Agriculture (MOA) 65 , with safety advice provided mainly by the Biosafety Management Division of the Center for Science and Technology Development (CSTD) and the National Biosafety Committee (NBC). The NBC can recommend safety certification based on product testing and field trials, but only the MOA can formally provide regulatory clearance 25 . After registration, genetically engineered crops can be cultivated and commercialized but approval for commercialization is only granted at the province/region level and not nationwide.

Huafan No. 1 tomato developed by Huazhong Agricultural University was the first genetically engineered fruit to be approved for cultivation, human consumption and use as animal feed in China, followed by Da Dong No. 9 (Institute of Microbiology, CAS) and PK-TM8805R (Beijing University) tomatos 26 . Huafan No. 1 and Da Dong No. 9 are no longer cultivated in China, and the status of PK-TM8805R is unclear 26 . Similarly, the genetically engineered sweet pepper PK-SP01 developed by Beijing University was approved for cultivation and for human consumption, but the extent of its cultivation is unclear 26 . PRSV-resistant papaya Huanong No. 1 was approved for cultivation in 2006 and is commercially available in China.

In Bangladesh, the National Committee on Biosafety (NCB) grants regulatory approvals for all genetically engineered crops, assisted by a Biosafety Core Committee (BCC) 66 . The eggplant varieties Bari Bt Begun 1, 2, 3, and 4 were approved for cultivation and food use in Bangladesh, and in 2020 they are the only genetically engineered fruit commercialized in this country 29 , 30 .

Socioeconomic impact of commercialized fruits with improved traits

The socioeconomic impact of genetically engineered fruits is growing with the scale of cultivation, although less than 0.01% of the 185.43 million ha cultivated with genetically engineered crops in 2018 was represented by fruits 67 . Production and adoption rate details are provided in Table 1 . PRSV-resistant papaya is the most widely cultivated genetically engineered fruit, followed by Bt eggplant, virus-resistant squash, Arctic ® apples, and Pinkglow™ pineapple.

Virus-resistant fruits

China grew 9600 ha of PRSV-resistant papaya in 2018. Initial plantings took place in the southern Guangdong Province in 2006, but Hainan Island became the leading location for PRSV-resistant papaya production in 2017 (46%), followed by Guangdong (36%) and Guangxi (18%) provinces 57 . CMV-resistant sweet pepper and tomato have been cultivated in China since 1998 and 1999, respectively, in Beijing municipality and in Fujian and Yunnan provinces, but the scale of cultivation is unclear 26 . Data on the profitability of PRSV-resistant papaya have not been published by the Chinese authorities, so the socioeconomic impact is difficult to judge 68 .

In the US, PRSV-resistant papaya has been commercially grown in Hawaii since 1999 and it has prevented the collapse of the Hawaiian papaya industry due to the prevalence of PRSV in orchards of conventional varieties 23 . In 1992, when PRSV was first detected on Hawaii, the Puna district produced 95% of all Hawaiian papaya grown (~24,000 tons) but yields had fallen to ~12,000 tons in 1998. Two years after the introduction of the resistant variety, yields recovered to ~18,000 tons 23 . Although lower than 1992 levels, the lack of production was not caused by the virus but by the falling demand from Japan, resulting in the papaya cultivation area in Hawaii declining from more than 500 ha in 2015 to only 250 ha in 2018 4 , 67 . The shrinking Japanese market partly reflected the reluctance of retailers to handle genetically engineered products and partly the increased competition from Philippine papaya growers 4 . Nevertheless, the yield of genetically engineered papaya in 2018 was 17% higher than conventional papaya, with a net farm income gain of $2623/ha. Overall, the accumulated farm income benefit between 1999 and 2018 was $38.4 million 67 . Cultivation of PRSV-resistant papaya in Hawaii has also reduced the threat of PRSV in the Puna district, allowing papaya growers to cultivate non-transgenic varieties alongside the genetically engineered crop 23 .

Virus-resistant squash has been commercially grown in the US since 2004, mainly in Florida and Georgia. In 2018, virus-resistant squash was planted on 1000 ha, representing 6% of total squash production in the US 67 . The genetically engineered varieties achieve higher yields than conventional squash, resulting in a net gain to farmers of $10.1 million. Overall, the cumulative farm income benefit between 2004 and 2018 was $310.9 million 67 .

Insect-resistant fruit crops

Bt eggplant was first grown commercially in Bangladesh in 2014, and was cultivated on 2975 ha in 2018 67 . Eggplant is mostly grown by resource-poor farmers, who can obtain seed at no or minimal cost from three organizations: BARI, the Department of Agricultural Extension, and the Bangladesh Agricultural Corporation. Accordingly, the cost of this technology to the farmers is near zero 29 . The Bt eggplant was initially provided to 20 farmers, but by 2018, the variety had been adopted by 20,695 farmers 29 . Bt eggplant achieved 20% higher yields than conventional eggplant in 2018, and the enhanced quality resulted in a 10% increase in price. As a result, farm income has increased by $616–704/ha 29 , 67 .

As well as the direct income gains, Bt eggplant also helps to reduce pesticides. In 2016, farmers in 35 districts cultivating Bt eggplant spent 61% less on pesticides compared to farmers growing conventional varieties 69 . This difference solely represents the cost of pesticides to control EFSB because different chemicals are used to control other pests. However, the prevention of damage caused by EFSB also reduces infestations by secondary pests such as leaf-eating beetles, thrips, whitefly, mites, leaf wing bugs, and leaf roller, by 42–60% 70 .

Fruits with enhanced quality traits

Arctic ® apples were first planted in 2016 (70,000 trees planted over 80 ha). This had grown to 300,000 trees over 101 ha by 2018 and in 2019 the cultivated area exceeded 500 ha 71 . Although the profitability of growing this variety has not been made public, Okanagan Specialty Fruits states that Arctic ® apples are more suitable for mechanical harvesting and suffer less impact from finger bruising, bin rubs and other superficial damage, which results in higher packouts (an industry measure of fruit suitable for market) and therefore less waste, and similar benefits for retailers 72 . Furthermore, the Arctic ® Golden variety does not require warm packing, reducing the cost of production. Del Monte commercialized the Pinkglow™ pineapple in October 2020 so the socioeconomic impact of this variety will not be known until market data are available.

Technological advances in gene functional analysis and genetic modification of fruits

Genetic engineering can be used to investigate the functions of genes and to exploit these functions for the improvement of traits such as biotic and abiotic stress tolerance, flowering time, ripening, fruit flavor, and nutrient content. In this section, we discuss genetic engineering and genome editing technologies that have been used for the enhancement of target traits in fruit crops, which may facilitate commercialization in the future (Table 2 ). Use of CRISPR and associated genome editing technologies for the development or enhancement of fruit crops may open the door to new commercial opportunities, potentially circumventing restrictions on GM crops in many parts of the world 20 . While marketability will vary by country, additional, transgene-free cultivars may be accessible to consumers in the near future 20 , 73 , 74 .

Pathogen and pest resistance

Pathogens and pests are severe constraints affecting the growth and development of fruit trees, the development and ripening of fruits, and the quality of fruit products. In 2017 up to 30% of the fruit and vegetables losses worldwide were pre-harvest, mainly caused by pests and pathogens 75 . In many cases, conventional breeding for resistance is not possible because strong resistance is not present in available germplasm and the introgression process would take too long 2 . One strategy to enhance disease resistance in fruit crops is the modification of receptors that directly interact with or perceive the presence of a specific pathogen. In apple, overexpression of the HcrVf2 gene encoding such a receptor resulted in near-complete resistance to fungal scab ( Venturia inaequalis ) 76 . Recently, CRISPR/Cas9-mediated inactivation of the susceptibility-associated gene DspA/E-interacting protein ( DIPM4 ), also encoding a receptor, significantly reduced bacterial fire blight ( Erwinia amylovora ) symptoms by 50% in apple 77 .

Another strategy for the mitigation of pathogen symptoms is the targeting of response pathways (innate immunity) in the host. For example, the nonexpressor of pathogenesis-related 1 ( NPR1 ) gene encodes a transcriptional regulator of pathogenesis-related (PR) protein genes as part of the salicylic acid-dependent systemically acquired resistance (SAR) pathway. Sweet orange trees ( Citrus sinensus ) overexpressing NPR1 under the control of the phloem-specific SUC2 promoter exhibited enhanced resistance to huánglóngbìng (citrus greening disease), and up to 46% of the engineered plants remained disease-free for 2 years 78 . These findings highlight the importance of promoter selection in overexpression studies and indicate that NPR1 possesses a conserved role among tree fruit species in the response to pathogens.

Other PR-associated proteins have been targeted for modification in banana, chili pepper, and citrus in order to mitigate the effect of bacterial and fungal pathogens. In banana, the induction of a hypersensitive response (HR) by the overexpression of genes encoding an HR-assisting protein and a plant ferredoxin-like protein conferred resistance to banana Xanthomonas wilt, with 50–60% of the transgenic plants displaying no disease symptoms following inoculation 79 . Overexpression of the pepper carboxylesterase gene in chili pepper reduced infections by anthracnose fungus from 70% in wild-type plants to 20% 80 . Similarly, expressing the J1-1 gene encoding an antifungal defensin reduced the frequency of anthracnose lesions by up to 90% 80 , 81 . CRISPR/Cas9 was used to inactivate the grapefruit lateral organ boundary domain family protein 1 and orange WRKY22 genes, which regulate immunity responses, improving resistance to canker caused by Xanthomonas citri subsp. citri ( Xcc ) in Duncan grapefruit ( Citrus ✕ paradisi ) and Wanjincheng orange ( Citrus sinensis (L.) Osbeck) 82 , 83 , 84 , 85 . The CRISPR-induced mutation rate in grapefruit was 23–89%, and Xcc resistance was correlated with the mutation rate, as shown by the corresponding range of canker symptoms 85 . Similar findings were reported for orange plants with mutations in the WRKY22 gene 83 .

In addition to the knockout of host genes to improve pathogen and pest resistance, pathogen-derived transgenes (or other heterologous genes) serve as additional routes for the improvement of fruit traits. In pear, the expression of a bovine lactoferrin gene, which encodes a bactericidal glycoprotein, reduced fire blight symptoms by 78% compared to controls 86 . In sweet orange, expression of the E. amylovora hairpin protein triggered HR in the host plants and reduced susceptibility to citrus canker by up to 79% 87 . The expression of a synthetic insect antimicrobial peptide (cecropin B) in blood orange improved long-term resistance to huánglóngbìng by 85–100% 88 .

An important strategy in the fight against viral diseases is the expression of non-translatable pathogen genes to elicit a PR response or to silence viral components essential for replication, packaging, or systemic spreading. RNAi-mediated silencing of viral components has been achieved in banana, resulting in the complete absence of bunchy top virus disease symptoms in transgenic plants 6 months after challenge 89 . Similarly, transgenic melon and watermelon ( Citrullus lanatus ) lines displayed up to 100% resistance when challenged with several cucurbit viruses 90 , 91 , and grafted transgenic plum lines remained resistant to PPV for more than 9 years 92 . In cucumber, the CRISPR/Cas9 system was used to mutate the eukaryotic translation initiation factor 4E gene, which is associated with CMV susceptibility, resulting in 100% virus-free fruits in the T3 generation 93 . Bt cry genes have been expressed in kiwifruit ( Actinidia chinensis ) and walnut ( Juglans regia ) to protect them against insect pests, resulting in 75–100% insect pest mortality 94 .

Abiotic stress tolerance

Abiotic factors, such as drought, are also among the main factors causing pre-harvest losses of fruit and vegetables 75 . The engineering of abiotic stress tolerance in fruit trees allows them to be grown in environments where temperatures are sub-optimal, water is scarce, or high concentrations of salt and/or heavy metals in the soil are toxic and prevent the uptake of water and nutrients. Overexpression of the Na + /H + cation antiporter gene NHX1 in apple and kiwifruit prolonged survival in saline conditions by allowing the accumulation of higher concentrations of antioxidant flavonoids (60% more than normal) as well as sodium and potassium (2x more than normal) thus delaying the stress response 95 , 96 . In chili pepper, the expression of a tobacco osmotin gene increased yields by 31% accompanied by higher levels of proline, chlorophyll and reactive oxygen species (ROS) scavengers, as well as a higher relative water content 97 . Transgenic citrumelo ( Citrus paradise × Poncirus trifoliata ) plants overexpressing the enzyme Δ1-pyrroline-5-carboxylate synthase, required for proline synthesis, showed a 2.5-fold increase in drought tolerance, as determined by turgor pressure maintenance, stomatal conductance, photosynthetic rate, and transpiration rate 98 .

Fruit crops are often threatened by cold temperatures, which affect plant growth as well as the quality of maturing and ripening fruits. Cold tolerance is therefore an important target in commercial fruit development programs. In apple, overexpression of the transcription factor MYB4, which regulates cold-induced dormancy and stress pathways, allowed the transgenic plants to tolerate cold temperatures for long periods while maintaining normal water content, reflecting the accumulation of glucose, fructose, and sucrose to levels 30–38% higher than normal 99 . Overexpression of the Arabidopsis dehydration response element-binding 1b protein in grapevine reduced cold-induced wilting by 73% 100 . Similarly, the expression of a Poncirus trifoliata basic helix-loop-helix protein in pumello ( Citrus grandis ) enhanced cold tolerance, reduced electrolyte leakage by 13% and increased proline levels by up to 67% compared to wild-type plants 101 .

Flowering time and dormancy release

Flowering time is a very important trait targeted for improvement in fruit crops because of its close association with the timing of fruit development. This trait is under strict genetic regulation and is dependent on environmental conditions, particularly temperature and day length, which limits the geographical regions in which crops can be cultivated 102 . Genetic engineering has been used to express floral activators or repressors, allowing the specification of floral transition and dormancy requirements in major fruit tree species. In transgenic apple, plum, and citrus trees, the overexpression of FT family floral activators needed to trigger bud breaking promoted early flowering (by up to 45 weeks in apple and 12 weeks in orange), and reduced dormancy requirements, eliminating them completely in plum 103 , 104 , 105 . Recently, CRISPR/Cas9 was used to inactivate the self-pruning 5G gene in tomato, which abolished sensitivity to day length and reduced the time to harvest by 2 weeks, translating to a greatly accelerated flowering stage and early fruit yield 102 . In kiwifruit, CRISPR/Cas9-mediated repression of the CEN-like genes also led to rapid and early terminal flowering 106 . These experiments provide insights into the genetic and environmental control of flowering time in different fruits and form the basis for additional engineering strategies to develop early or late-flowering cultivars adapted to specific growing regions.

Fruit ripening and sensory attributes

The modulation of fruit ripening is one of the major strategies by which flavor, aroma, and nutrient profiles can be adjusted, and by which the shelf-life can be extended to improve marketability and reduce waste. In climacteric fruits such as apple, banana, and tomato, the key targets are genes associated with ethylene biosynthesis and degradation. In apple, the silencing of ACS and ACC oxidase ( ACO ) by expressing antisense RNA generated fruit that produced 60% less ethylene, increasing firmness by 20% and allowing cold storage for up to 3 years 107 . Although the synthesis of volatile esters was suppressed, sugar and organic acid accumulation were unaffected. Co-suppression and knockdown of ethylene-biosynthetic genes achieved similar results in pear, kiwifruit, and papaya 108 , 109 , 110 .

Sugar and organic acid content can be modified to enhance fruit flavor. In strawberry, the suppression of ADP-glucose pyrophosphorylase by expressing antisense RNA under the control of a fruit-specific promoter inhibited the conversion of sugar to starch and reduced the starch content of transgenic fruits by up to 47% while increasing the soluble sugar content by up to 37% 111 . Plant pigments such as anthocyanins and carotenoids are also major targets for metabolic engineering in fruits because they provide health benefits and allow the production of fruits with unique colors. The overexpression of MYB family transcription factors in apple, grapevine, and strawberry enhanced the production and storage of anthocyanins, with transgenic fruits accumulating up to 50% more than normal 36 , 112 , 113 . The accumulation of carotenoids has been achieved by the RNAi-mediated silencing of β-carotene hydroxylase in sweet orange, preventing conversion of β-carotene to xanthophylls and thus increasing the β-carotene content in the fruit pulp by 26-fold. Caenorhabditis elegans adults fed with diets supplemented with β-carotene-enriched orange pulp were 20% more resistant to hydrogen peroxide-induced oxidative stress than those fed with control diet 114 . These studies demonstrate how genetic engineering and genome editing can be used to produce fruits with enhanced flavor, texture, and nutrient levels.

Trans-grafting

Grafting is widely used during the propagation of fruit trees to allow the selection of rootstock and scions with different favorable characteristics that may be difficult or laborious to combine in one cultivar (such as high fruit yields paired with resistance to root pests). The rootstock and scion still influence each other by exchanging soluble signals, but the two components maintain their genetic integrity 115 . Trans-grafting refers to grafting of a non-transgenic scion onto a transgenic rootstock. Some desirable characteristics of the rootstock, such as dwarfing or disease resistance, are conferred upon the scion by the vascular transport of RNA, hormones or signaling proteins, but the shoot, leaves, and fruits remain transgene-free 116 , 117 . Although the specific regulations vary by country, trans-grafting can be used to circumvent restrictions on the marketing of GM products in certain jurisdictions 118 . This technology has been used in apple, by grafting non-transgenic scions onto rootstock expressing the Agrobacterium rhizogenes rolB gene, which confers dwarfing characteristics on the scion 119 . In grapevine, non-transgenic scions were grafted onto rootstocks engineered to produce an antimicrobial peptide and a protein that inhibits cell wall degradation. These proteins were transported to the scion through the xylem, resulting in the enhanced mobilization of water and nutrients and a 30–95% reduction in pathogen-induced mortality 120 . Transgenic rootstocks can therefore improve the production of commercially important fruit trees but the fruits and seeds do not carry any exogenous DNA 79 .

Moving beyond transgenesis—genome editing technologies

Genome editing is perhaps the most important recent development in crop breeding, and protocols based on the versatile CRISPR/Cas9 system have been optimized for several fruit species to increase the editing efficiency. In apple, CRISPR/Cas9 produced transgene-free edits 121 . In cucumber, wild strawberry, and watermelon, CRISPR/Cas9 constructs were integrated as part of the T-DNA but segregation was then achieved through back-crossing 122 , 123 , 124 , 125 . A major challenge to the commercial development of edited varieties is the successful transmission of targeted mutations through the germline 126 . This is particularly difficult in woody species, including fruit trees, because they are propagated vegetatively. Back-crossing could take decades (depending on the species) and could result in the unintentional outcrossing of the edited gene. It is also difficult to achieve homozygosity at the edited locus within the desired genetic background because most fruit trees are self-incompatible and thus require obligate outcrossing. Such characteristics hinder the introduction of genome edits that are stable and heritable 127 , 128 , 129 . Several new derivatives of the original CRISPR/Cas9 editing platform have been proposed, including CRISPR/Cas9 ribonucleoprotein (RNP) technology, CRISPR cytidine and adenosine base editors (CBEs/ABEs), CRISPR flippase, and new CRISPR-associated nucleases such as Cas12a/Cpf1, which may help to address these challenges and accelerate the development and commercialization of genome-edited crops 77 , 126 , 129 , 130 , 131 , 132 .

CRISPR RNP technology

Transgene-free genome editing improves the commercialization potential of modified crops (including fruits) because the CRISPR/Cas9 cassette is not inserted into the genome and, in many jurisdictions, the resulting variety is regulated in the same manner as a conventional crop, with certain caveats 21 . CRISPR/Cas9 RNP technology avoids transgene integration by delivering purified RNPs containing the Cas9 protein and gRNA into plant protoplasts and the subsequent regeneration of plants 133 , 134 . This approach has already been used in apple and grapevine to introduce mutations that confer resistance to fire blight and powdery mildew, respectively 129 . In addition to Cas9 RNPs, CRISPR/Cpf1-RNPs have also been employed successfully for gene editing in protoplasts of soybean and tobacco, paving the way for future use in other crops, including fruits and vegetables 134 . Subsequent optimization experiments permitted plant regeneration from protoplasts and improved the transformation protocol for grape protoplasts, reducing the amount of time needed for RNP delivery and genome editing to less than 3 weeks 131 . It is likely that species- and even cultivar-specific protocol optimization will be necessary to achieve satisfactory editing efficiencies because the major hurdle is not the delivery of RNPs across the protoplast membrane, but the subsequent recovery and regeneration of fertile plants.

CRISPR base editing

Whereas conventional CRISPR/Cas9 editing tends to introduce short insertions or deletions at the target locus, cytidine and adenosine base editing facilitates the targeted introduction of single nucleotide replacements by direct C-to-T or A-to-G base conversion, respectively. Base editors have been used to introduce herbicide resistance traits in fruit crops in proof-of-concept experiments. For example, CBE in the watermelon ALS gene resulted in a single amino acid substitution that was sufficient to confer broad-spectrum and heritable resistance to commercial sulfonylurea herbicides 122 .

CRISPR flippase

Flp/ FRT is a yeast site-specific recombinase system in which the recombinase Flp (flippase) catalyzes recombination between two copies of the 34-bp FRT site, resulting in the excision or inversion of the intervening DNA, depending on the relative orientation of the FRT sites. The Flp/ FRT system has been used to remove selectable markers in T1 apple, apricot, citrus, and grapevine plants, leaving a single FRT site behind as a footprint 2 . These studies laid the foundations for more recent work in which the FLP/FRT system was placed under the control of a heat-shock promoter and incorporated into the CRISPR/Cas9 plasmid, allowing the editing of a disease susceptibility gene in apple and subsequent removal of the CRISPR/Cas9 components 77 . This technology has yet to be applied in other fruit crops, but it shows great promise given the efficiency of editing and T-DNA excision.

New CRISPR nucleases

Most CRISPR studies thus far have used the endonuclease Cas9 from Streptococcus pyrogenes (SpCas9). In its native form, SpCas9 requires a trans-activating CRISPR RNA (tracrRNA) and a CRISPR-RNA (crRNA) to induce blunt double-strand breaks in target DNA. These functions were combined into a single gRNA for the development of CRISPR/Cas9 as an engineering tool. But SpCas9 is only one of a large family of CRISPR-associated nucleases with diverse properties, some of which may be advantageous for genome editing in fruit crops by improving efficiency, specificity, or versatility, or by reducing costs 135 . For example, Cas9 from Staphylococcus aureus (SaCas9) differs from SpCas9 in terms of protospacer adjacent motif (PAM) specificity but has a similar editing efficiency. It has been used in several model plant species and also recently in citrus, and provides greater versatility by extending the range of potential genomic targets 126 .

Cas12a/Cpf1 from Prevotella and Francisella spp. recognizes a T-rich PAM and generates compatible cohesive ends with overhangs of 4–5 nt, differing from the blunt ends introduced by Cas9, and increasing the efficiency of DNA integration (knock-in) 136 . Cas12a/Cpf1 is also a smaller protein than Cas9, which improves the efficiency of multiplex editing. CsmI is also smaller than Cas9 136 , and recognizes AT-rich PAM sites thus improving the accuracy of genome editing in AT-rich regions 135 . This approach has been employed to edit the PDS gene in citrus, establishing the feasibility of Cpf1-mediated, DNA-free editing in fruit crops 137 .

Conclusions

Genetic engineering facilitates the development of fruits with useful agronomic or quality traits that are difficult or laborious to achieve by conventional breeding, either due to the lack of suitable germplasm or the long breeding cycles and need for multiple rounds of back-crossing. The same traits can be introduced by genetic engineering in one generation, often directly into elite varieties. Some genetically engineered fruits have been on the market for more than 25 years, and have achieved a remarkable positive socioeconomic impact by reducing pests and diseases and increasing the quality of the end product, both of which help to increase income for farmers. Further benefits to farmers, consumers, and the environment reflect the reduced use of pesticides. The development of new molecular breeding technologies such as trans-grafting and genome editing not only offer the promise of further commercial fruit varieties with resistance to biotic and abiotic stresses, improved flavor and nutrient content, and modified flowering and ripening times, but also help to address some of the regulatory constraints that limit the cultivation of first-generation transgenic crops. In particular, the development of transgene-free genome editing methods based on CRISPR/Cas9 and other nucleases offers a way to introduce precise changes at preselected genomic sites with no genetic footprints and no off-targets. In many jurisdictions, some varieties generated through genome editing are exempt from GMO regulations. These tools and techniques are available for the accelerated development of fruit crops with properties that satisfy the needs of producers, retailers, and consumers, in a sustainable and environmentally friendly manner.

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Acknowledgements

M.L.-G., P.S.G.-C., P.C., and T.C. would like to acknowledge funding from MINECO, Spain (PGC2018-097655-B-I00 to P Christou), Generalitat de Catalunya Grant 2017 SGR 828 to the Agricultural Biotechnology and Bioeconomy Unit (ABBU). P.S.G.-C. was supported through an Agrotecnio postdoctoral fellowship. A.D. acknowledges the support from Washington State University Agriculture Center Research Hatch grant WNP00011.

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Department of Crop and Forest Sciences, University of Lleida-Agrotecnio CERCA Center, Lleida, 25198, Spain

Maria Lobato-Gómez, Teresa Capell, Paul Christou & Patricia Sarai Girón-Calva

Department of Horticulture, Washington State University, PO Box, 646414, Pullman, WA, USA

Seanna Hewitt & Amit Dhingra

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Paul Christou

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P.C and A.D. conceived the idea. M.L.-G. and P.S.G.-C. planned the outline. M.L.-G., S.L.H., and P.S.G.-C. collected the literature and wrote the paper. M.L.-G. and P.S.G.-C. prepared the figure and tables. P.C., T.C., and A.D. critically reviewed and improved the paper. All authors approved the final version.

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Correspondence to Patricia Sarai Girón-Calva .

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Lobato-Gómez, M., Hewitt, S., Capell, T. et al. Transgenic and genome-edited fruits: background, constraints, benefits, and commercial opportunities. Hortic Res 8 , 166 (2021). https://doi.org/10.1038/s41438-021-00601-3

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Published : 17 July 2021

DOI : https://doi.org/10.1038/s41438-021-00601-3

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