Tropane alkaloids from nightshade plants are neurotransmitter inhibitors that are used for treating neuromuscular disorders and are classified as essential medicines by the World Health Organization1,2. Challenges in global supplies have resulted in frequent shortages of these drugs3,4. Further vulnerabilities in supply chains have been revealed by events such as the Australian wildfires5 and the COVID-19 pandemic6. Rapidly deployable production strategies that are robust to environmental and socioeconomic upheaval7,8 are needed. Here we engineered baker's yeast to produce the medicinal alkaloids hyoscyamine and scopolamine, starting from simple sugars and amino acids. We combined functional genomics to identify a missing pathway enzyme, protein engineering to enable the functional expression of an acyltransferase via trafficking to the vacuole, heterologous transporters to facilitate intracellular routing, and strain optimization to improve titres. Our integrated system positions more than twenty proteins adapted from yeast, bacteria, plants and animals across six sub-cellular locations to recapitulate the spatial organization of tropane alkaloid biosynthesis in plants. Microbial biosynthesis platforms can facilitate the discovery of tropane alkaloid derivatives as new therapeutic agents for neurological disease and, once scaled, enable robust and agile supply of these essential medicines.

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Biosynthesis of medicinal tropane alkaloids in yeast.

Gene drive has become a hot topic in the popular press and the scientific literature, yet little consensus vocabulary on the subject exists. As members of the gene drive community, we have developed a core set of definitions to help stakeholders discuss the topic and communicate using a common understanding of terms. A standard consensus definition of gene drive and a glossary of terms, noted here, will be of great practical use to a field that has implications for both researchers and the general public. If we don’t clarify these terms, we risk hampering the field, confusing the public, and possibly losing a technology that may help solve some of the world’s most intractable problems in public health, conservation, and food security.



We need to clarify gene drive terms, or we risk hampering the field, confusing the public, and losing a technology that may help solve otherwise intractable problems in public health, conservation, and food security. Image credit: Stephanie Gamez (University of California San Diego, La Jolla, CA).



Loosely, gene drive refers to a phenomenon whereby a particular heritable element biases inheritance in its favor, resulting in the gene becoming more prevalent in the population over successive generations. Thus, the gene is being “driven” to progressively increase its frequency in the population. Biasing inheritance may involve, for example, more than the familiar Mendelian 50:50 inheritance chance or reducing the fitness of alternative genotypes without directly distorting Mendelian inheritance. Highly efficient gene drives can bias inheritance so heavily in their favor that the heritable element can rapidly reach high frequency, close to doubling its frequency from one generation to the next. The speed of this process is inversely correlated with generation time of the organism (for example, mosquitos have a generation time of 2–4 weeks and rats have a generation time … 

[↵][1]1To whom correspondence may be addressed. Email: oakbari{at}ucsd.edu.

 [1]: #xref-corresp-1-1

https://www.pnas.org/content/pnas/117/49/30864.full.pdf

Opinion: Standardizing the definition of gene drive.

Developments in CRISPR-based gene-editing technologies have generated a growing number of proposals to edit genes in wildlife to meet conservation goals. As these proposals have attracted greater attention, controversies have emerged among scientists and stakeholder groups over potential consequences and ethical implications of gene editing. Responsible governance cannot occur without consulting broader publics, yet little effort has been made to systematically assess public understandings and beliefs in relation to this new area of applied genetic engineering. We analyzed data from a survey of U.S. adults (n = 1600), collected by YouGov, and that examined respondents' concerns about gene editing in animal and plant wildlife and how those concerns are shaped by cultural dispositions toward science and beliefs about the appropriateness of intervening in nature at the genetic level. On average, respondents perceived more risk than benefit in using these tools. Over 70% agreed that gene editing in wildlife could be "easily used for the wrong purposes." When evaluating the moral acceptability of gene editing in wildlife, respondents evaluated applications to improve survival in endangered wildlife as more morally acceptable than applications to decrease abundance in a population or eliminate a population. Belief in the authority of scientific knowledge was positively related to favorable views of the benefits, risks, and moral acceptability of editing genes in wildlife. The belief that editing genes in wildlife inappropriately intervenes in nature predicted relatively more concern about risks and moral acceptability and skepticism about benefits. Given high levels of concern and skepticism about gene editing in wildlife for conservation among the U.S. public, a take-it-slow approach to making decisions about when or whether to use these tools is advisable. Early opinions, including those uncovered in this study, are likely to be provisional. Thus, consulting the public should be an ongoing process.

Public views about editing genes in wildlife for conservation

Synthetic gene drive approaches are nascent technologies with potential applicability for pest control for conservation purposes. Responsible science mandates that society be engaged in a dialogue ...

https://www.tandfonline.com/doi/pdf/10.1080/17524032.2019.1702568

Public Opinion Towards Gene Drive as a Pest Control Approach for Biodiversity Conservation and the Association of Underlying Worldviews

Advances in molecular and synthetic biology are enabling the engineering of gene drives in insects for disease vector/pest control. Engineered gene drives (that bias their own inheritance) can be designed either to suppress interbreeding target populations or modify them with a new genotype. Depending on the engineered gene drive system, theoretically, a genetic modification of interest could spread through target populations and persist indefinitely, or be restricted in its spread or persistence. While research on engineered gene drives and their applications in insects is advancing at a fast pace, it will take several years for technological developments to move to practical applications for deliberate release into the environment. Some gene drive modified insects (GDMIs) have been tested experimentally in the laboratory, but none has been assessed in small-scale confined field trials or in open release trials as yet. There is concern that the deliberate release of GDMIs in the environment may have possible irreversible and unintended consequences. As a proactive measure, the European Food Safety Authority (EFSA) has been requested by the European Commission to review whether its previously published guidelines for the risk assessment of genetically modified animals (EFSA, 2012 and 2013), including insects (GMIs), are adequate and sufficient for GDMIs, primarily disease vectors, agricultural pests and invasive species, for deliberate release into the environment. Under this mandate, EFSA was not requested to develop risk assessment guidelines for GDMIs. In this Scientific Opinion, the Panel on Genetically Modified Organisms (GMO) concludes that EFSA's guidelines are adequate, but insufficient for the molecular characterisation (MC), environmental risk assessment (ERA) and post-market environmental monitoring (PMEM) of GDMIs. While the MC,ERA and PMEM of GDMIs can build on the existing risk assessment framework for GMIs that do not contain engineered gene drives, there are specific areas where further guidance is needed for GDMIs.

/pdf/adequacy-and-sufficiency-evaluation-of-existing-efsa-4hjhjye793.pdf

Adequacy and sufficiency evaluation of existing EFSA guidelines for the molecular characterisation, environmental risk assessment and post-market environmental monitoring of genetically modified insects containing engineered gene drives.

In recent years synthetic biology has emerged as a suite of techniques and technologies that enable humans to read, interpret, modify, design and manufacture DNA in order to rapidly influence the forms and functions of cells and organisms, with the potential to reach whole species and ecosystems. As synthetic biology continues to evolve, new tools emerge, novel applications are proposed, and basic research is applied. This assessment is one part of IUCN’s effort to provide recommendations and guidance regarding the potential positive and negative impacts of synthetic biology on biodiversity conservation; it comprises a full assessment and a short synthesis report.

/pdf/genetic-frontiers-for-conservation-an-assessment-of-2d79ecjbah.pdf

Madeline van Oppen

Papers

Genetic frontiers for conservation:An assessment of synthetic biology and biodiversity conservation