使用基因驱动技术减少疟疾传播蚊子的数量：一种建模方法

Malaria-transmitting mosquitoes pose a serious threat to human health, and numerous approaches to reduce these disease-vectors are currently in use or development – including release of genetically modified mosquitoes. Here, Dr Ace North describes his最近的论文BMC Biology，显示如何使用数学建模来计划和预测这种方法的最大效果的影响。

Ace North

A simulation of the model (the black outline demarks Burkina Faso). There are annual oscillations in mosquito numbers because the dry season occurs at the same time of year across the study area, though its duration and severity varies by location. This simulation supposes 10 driving-Y modified male mosquitoes are released at one in every hundred settlements each year.
GIF provided by author. Ace North

In much of sub-Saharan Africa, malaria is a huge public health burden. Burkina Faso is one of the worst afflicted countries with an estimated 7.9 million clinical cases of malaria in 2017, causing in the region of 28,000 deaths mainly in children under five. Worryingly, despite major investment in malaria control in this country (circa 50 million USD per year), progress has stalled (世卫组织世界疟疾报告2018）。特别是，由于蚊子正在发展抗药性，目前的措施（其中最重要的是使用杀虫剂处理的床头）正在失去效力。

There is a compelling need to develop new tools to complement existing control programs. These might include gene-drive technologies to modify mosquito populations, either to reduce their fitness and cause a drop in population size or to make the mosquitoes unable to transmit disease. Gene drives are genetic constructs that positively bias their own inheritance and thus can spread rapidly through populations, even if they reduce individual survival or fecundity.

Figure 1: Top: Wooden model of a mosquito (from the author). Bottom – An Anopheles gambiae spermathecae, crushed to allow the sperm to come out and be screened for fluorescence to determine which genotype of male the female had mated: courtesy of Rosemary Lees, LSTM

In our最近的研究BMC Biology, we modelled the potential of modifying mosquitoes with a type of gene-drive called a “driving-Y chromosome” to reduce mosquito populations. A driving-Y chromosome has been genetically modified so that the male mosquitoes that carry it produce predominantly male offspring (which also carry the modification). Since only female mosquitoes bite, the spread of this Y-chromosome will result in fewer females to transmit the disease, and fewer mosquitoes overall.

The technology, which is still under development, proposes targeting the most important species of malaria mosquitoes of sub-Saharan Africa. Before modified mosquitoes can be considered for release in the wild, we need to know the likely impact – how much reduction of overall populations might we reasonably expect – which is affected by numerous factors like the timing/extent of release, and the geography of the environment. For example, releasing driving-Y mosquitoes in a region far from human vectors or just prior to the dry season may be less than ideally effective.

The study area centered on Burkina Faso (yellow).
Figure from article.

我们为包括所有布基纳法索（Burkina Faso）在内的100万平方公里区域建模。该模型代表了两个蚊子的生物学，Anopheles gambiae和the closely relatedAnopheles coluzzii。这些可能是世界上两个最有效的疟疾媒介，主要是因为它们与我们人类一起演变，并且对我们的血液特别偏爱。该模型将生物动力学与有关降雨，水文学和人类定居点的外部数据融合在一起。

在轻度干旱季节的地区，消除人口的可能性更大，而在季节性强的地区，减少的可能性更大。

该模型预测在某些地区消除该物种，而其他地区的人口减少。我们发现季节性是基因驱动器局部影响的最关键的预测指标。在轻度干旱季节的地区，消除人口的可能性更大，而在季节性强的地区，减少的可能性更大。但是，即使在最具挑战性的环境中，人口也减少了。总体而言，我们发现，每年重复将转基因蚊子重复引入到一小部分人类定居点中可能足以实质性地减少整个研究区域中疟疾传播蚊子的总数。

蚊子是一种的基因改造novel approach to disease control, and must be subject to rigorous and independent scrutiny to ensure it is safe for humans and for the environment. A crucial component of this process is understanding mosquito population dynamics after the release of a construct. Our model suggests that a driving-Y chromosome could have a major impact in reducing malaria.

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