Opinion: Standardizing the definition of gene drive

Reaching Consensus

These types of challenges are not new to science. For example, the malaria and immunology fields have recognized and addressed similar challenges in the past (15⇓–17). For instance, the World Health Organization (WHO) Global Malaria Program produced a World Malaria Terminology glossary to prevent confusion in the field given that “medical language must be adaptable so that it can keep pace with the constant increase of our knowledge and with the continual revision and evolution of our concepts” (15). The immunology field standardized its nomenclature of monoclonal antibodies and cluster of differentiation antigens, respectively, because independent laboratories were giving different names for the same entity (16, 17).

To address this challenge in the gene drive community, we reached out to more than 60 researchers and stakeholders on preferred definitions for gene drive and created a glossary of terms. The following definitions have been agreed upon by these signatories and are proposed for widespread use. (Because the field continues to evolve, we have composed a living document for signatories that will be updated periodically.*) For each usage, we include a technical definition as well as a less technical version that may be more accessible to a nonscientific audience.

“Gene drive” is used both to describe a process or phenomenon (the biological activity of gene drive) and to describe an object (“a gene drive”). The term sometimes is also used to describe a management tool or intent for product development or regulatory purposes.

• I. Process or Phenomenon: A gene drive is a phenomenon of biased inheritance in which the prevalence of a genetic element (natural or synthetic) or specific alternate form of a gene (allele) is increased, even in the presence of some fitness cost. This leads to the preferential increase of a specific genotype that may determine a specific phenotype from one generation to the next and potentially spread throughout a population. In other words, a gene drive is a process that promotes or favors the biased inheritance of certain genes from generation to generation.

• II. Material Object: A gene drive is composed of one or more genetic elements that can cause the process of biased inheritance in its favor. The set of necessary elements may be referred to as a gene drive system or simply a “gene drive.” Note that the presence of gene drive elements will not necessarily cause gene drive—many gene drive systems will cause the gene drive phenomenon only under specific circumstances (e.g., if they are present in the population above a certain threshold frequency, or if fitness costs are below a certain threshold, or if all drive componets are present in the organism). Note also that gene drive, when defined as an object, need not always confer preferential transmission. Gene drives must ensure biased inheritance under at least some circumstances but not necessarily all circumstances. For example, some gene drive systems confer preferential inheritance only when present in the population above a threshold frequency. That is, a gene drive is any genetic element able to bias its inheritance within a population.

• III. Intention: A gene drive may be intended as a management tool to achieve a particular goal. A gene drive may include additional “cargo” elements, in addition to the drive components, that are intended to introduce new trait(s) into an interbreeding population so as to effect a change in the characteristics of the population. A gene drive also may cause effects directly, for example by inserting into and disrupting a target gene. Thus, a gene drive is a tool to effect certain changes in a population.

Important Caveats

Additional concepts can help further improve the understanding of gene drives. Again, gene drives are a natural phenomenon. They have arisen through entirely natural processes of mutation and selection; indeed many types exist (transposons, toxin-antidote systems, homing nuclease, and sex distorters), and gene drives and relics of old gene drives are widespread in nature. Naturally occurring gene drives can induce the development of potent suppression systems in response to the selection pressures they impose on the population. Modern molecular biology now allows researchers to mimic various types of natural gene drives in the laboratory. A gene drive system that is created through recombinant DNA techniques is called an “engineered” or “synthetic” gene drive.

A number of basic criteria foster efficient synthetic gene drive. First, the organism must have an inheritance pattern that can be biased; this typically means that it can reproduce sexually. Many plants and some animals that use other means to reproduce cannot be altered in this way. Second, to be practical, the organism must have a short generation time. Gene drive can lead to an increase in the frequency of a specific genetic element from one generation to the next, but speed depends on the generation time of the organism. Consequently, discussions of gene drive applications have focused on species such as tropical/subtropical mosquitoes, with generation times around two weeks to a month, and so multi-generation effects are potentially visible in a few years, rather than organisms for which a similar number of generations might take decades or even centuries.

Gene drive is not a monolithic phenomenon. Just as many forms of gene drive exist in nature, many types of engineered gene drive have been conceived. Gene drives can be subclassified by biologic mechanism, molecular configuration, intended use, and time of action—pregametic versus postgametic. Other classification schemes are possible.

Gene drive is not synonymous with either persistence or spread of a trait through a population. Persistence is the ability of a genotype or phenotype to continue over multiple generations. Spread refers to the ongoing movement of the genotype through increasingly larger segments of the population. Thus, there is a relationship between persistence and spread. Both persistence and spread are possible without gene drive, through natural selection for example. Some gene drive systems have the potential to persist indefinitely. Other forms are not intended or able to persist indefinitely, even in the absence of heritable resistance or genetic change (mutation). Some gene drive systems have the potential to reach fixation in a population (fixation means that no other gene variants of the gene drive are present), whereas researchers predict that others persist at less than 100% frequency. Not all forms of gene drive have the potential to spread widely; high fitness costs, for example, may prevent spread despite strongly biased inheritance. Gene drive systems that have limited persistence also are expected to have limited ability to spread within the environment.

Given that the terms associated with the gene drive field are scattered through the literature, we have compiled a glossary of 78 terms along with their definitions (Dataset S1). This list includes terms that are specialized for the field as well as more standard genetic terms that are foundational to discussion around gene drive concepts. This list is not meant to be exhaustive but rather is intended as a general reference for stakeholders.

Outlining these definitions in detail will be an ongoing process as this area of research continues to develop, and this is only a start. However, achieving broad agreement on the use of basic terminology is fundamental to communicating effectively about this new technology. Only by doing so can we help this important and potentially impactful field progress.