人類數千年來都在發明殺死蚊子的新方法。羅馬人通過清排沼澤地來滅蚊。如今，你可能會在院子裡安置一個捕蟲器。在中低收入國家，你經常可以看到人們噴灑殺蟲劑，或者設置用糖作誘餌的粘性陷阱。
然而進化相當聰明。它通過誕生出更難被殺死的蚊子，始終跑在我們的前面。在撒哈拉以南非洲、南美部分地區和東南亞，我們看到了數量驚人的能夠抵抗殺蟲劑的蚊子。
這尤其給防治瘧疾等蚊媒疾病帶來了麻煩。為了根除這些疾病，我們需要新的工具與已有的工具進行互補。
我們的基金會正在支持許多不同的嘗試。其中一個項目令我格外的興奮，那是一組對蚊子進行基因改造的技術，可以顯著減少某些地區攜帶疾病的蚊蟲數量。
這些基因技術最酷的地方在於它們的精確程度。精確與否至關重要，因為在3000多種蚊子裡，造成絕大多數瘧疾病例的只是其中的五種。並且在這些蚊子中，只有雌蚊會傳播疾病，因為它們是唯一會咬人的（當它們需要額外的蛋白質來繁殖時，它們就會這樣做。專家稱之為“吃一頓血液餐”）。而雄蚊隻喝花蜜。
基因編輯帶給我們的希望是，我們可以只在特定區域消滅具有危險性的蚊子，而不是隨意地殺死蚊子。這將為我們贏得治療當地所有瘧疾患者的時間，然後在無寄生蟲的條件下恢復蚊子的種群數量。
一種令人興奮的基因編輯技術被稱為基因驅動（Gene Drive）。這一術語包含幾種不同的方式，但其基本原理是使用CRISPR 技術來重寫遺傳規則。通常情況下，對於任何一個基因，父母中的一方有50% 的幾率將該基因遺傳給孩子（它會與雙親中另一位的基因競爭，且只有一個能夠勝出）。利用基因驅動技術，這一概率可以達到100% 。你將一個編輯過的基因帶給一些蚊子，這個基因將植入——或驅動——它們所有的後代。當這些蚊子與野生蚊子交配時，它們所有的後代都將攜帶編輯過的基因，並且隨著時間的推移，該基因會穿透整個種群。
想象一下，不管伴侶的眼睛是什麽顏色，藍眼睛的蚊子都會有藍眼睛的後代。最終，這個種群中的每一隻蚊子都將有藍色的眼睛。
下面這張圖向你展示了基因驅動是如何最終將某個基因擴散到整個種群的：
我們沒理由認為可以將基因驅動應用在人類身上，更不用說提倡這樣做了。關於這項技術在昆蟲身上的應用也存在著一些嚴重的問題，我稍後會談到這個問題。但首先我想給你們舉兩個例子來說明它是如何起作用的。
其中一個是名字花哨的X-shredder。或許你能回憶起生物課講過的一些內容，一隻蚊子是雌是雄，部分取決於它從父母那裡繼承到了什麽性染色體。雌蚊從雙親分別得到一條X染色體，而雄蚊則從母親那裡得到一條X染色體，從父親那裡得到一條Y染色體。
2014年，倫敦帝國理工學院和西雅圖弗雷德 · 哈欽森中心的科學家們得以編輯雄性蚊子體內的一種蛋白質，從而破壞其精子中的X染色體。於是大部分雄性蚊子將Y染色體傳遞給後代，所以它們後代中的大部分也將是雄性。在基因驅動的作用下，這些後代也將攜帶編輯過的蛋白質，所以它們後代中的大多數也將是雄性。
不出幾代，雌雄比例將會失衡，最終導致該物種在這一地區滅絕。
另一個例子涉及到雙性基因（Doublesex Gene）。這種基因在蚊子體內與性染色體一起發生作用，決定後代是雄性還是雌性。去年，倫敦帝國理工學院的研究人員發現，攜帶經過編輯的雙性基因的雌蚊會長出雌雄混搭的器官，包括雄性生殖器和一個脆弱到無法刺透人類皮膚的喙。它們不能繁殖，所以種群數量會減少；它們不能吸食血液，所以它們不會傳播寄生蟲。
雙性基因編輯不會影響雄蚊，雖然在基因驅動的作用下，它們會將基因傳遞給後代，使得雙性基因編輯能在種群中持續傳播。
我們知道基因驅動技術在實驗室條件下可行。當帝國理工學院的研究人員把150隻攜帶雙性基因編輯副本的雄蚊同450隻野生蚊子放進一個小籠子裡時，所有蚊子在幾個月內（大約10代）就都死光了。基於性別差異的編輯也產生了類似的結果。
下一步是在更大的籠子裡進行試驗，並最終獲得政府的許可在戶外進行試驗。我們還需要了解幾件事情：如果某種蚊子開始死亡，這對食物鏈有什麽影響？我們需要引進多少變異的蚊子？我們需要蚊子消失多長時間？去年，布基納法索政府許可在野外釋放不育的、非基因驅動的蚊子，這科研人員便可以開始研究一些上述的問題。
正如我所提到的，社會問題和監管問題也會產生影響。例如，由於蚊子不會受國界的限制，這就需要鄰國在對待基因編輯技術的使用上具有一致意見。政策制定者和科學家們一直在像世界衛生組織和非盟發展機構的平台上就這些問題進行辯論，並正朝著一個共識邁進。
我認為我們可以在2024年前獲得監管部門的批準，並在2026年前讓第一批基因驅動的蚊子整裝待發。雖然這項技術永遠不會取代其他已有的抗瘧工具，但我樂觀地認為，它可以成為一個更重要的武器來消滅瘧疾。
Test-tube mosquitoes might help us beat malaria
Humans have spent thousands of years inventing new ways to kill mosquitoes. The Romans did it by draining swamps. Today you might have a bug zapper in your back yard. In low- and middle-income countries, it’s common to see people spraying insecticides or setting up sticky traps baited with sugar.
But evolution is smart. It is one-upping us by creating mosquitoes that are harder to kill. In sub-Saharan Africa and parts of South America and southeast Asia, we are seeing an alarming number of mosquitoes that can withstand insecticides.
This is especially problematic for the fight against mosquito-borne diseases like malaria. To eradicate these diseases, we need new tools to complement the ones we already have.
Our foundation is backing a lot of different advances. One that I’m especially excited about is a set of techniques for genetically modifying mosquitoes that could dramatically reduce the number of disease-carrying insects in certain areas.
What is cool about these genetic techniques is how precise they can be. Precision matters because out of more than 3,000 species of mosquitoes, only five are responsible for causing most cases of malaria. Of those, only females spread the disease, because they’re the only ones that bite humans. (They do it when they need extra protein for reproduction. Experts call it “taking a blood meal.”) The males just drink nectar.
The promise of gene editing is that, instead of killing a bunch of mosquitoes indiscriminately, we could eliminate only the dangerous ones in a particular area. That would buy us time to cure all the people there of malaria. Then we could let the mosquito population return without the parasite.
One exciting gene-editing technique is calledgene drive. The term covers several different approaches, but the basic idea is to use theCRISPR methodto rewrite the rules of inheritance. Normally, for any given gene, there’s a 50 percent chance that a parent with that gene will pass it on to a child. (It is competing with one from the other parent, and only one of the two can win.) With gene drive, the odds go up to 100 percent. You give a few mosquitoes an edited gene that inserts—or drives—itself into all their offspring. When those mosquitoes mate with wild mosquitoes, all their children will have the edited gene, and over time it will make its way through the entire population.
Imagine if blue-eyed mosquitoes had only blue-eyed children, no matter what color their partners’ eyes were. Eventually, every mosquito in that population would have blue eyes.
This chart shows you how gene drive eventually spreads a gene throughout an entire population:
There’s no reason to think gene drive is even feasible in humans, let alone advisable. There are also serious questions surrounding the use of this technology on insects, which I will get to in a moment. But first I want to give you two examples of how it works.
One is the colorfully namedX-shredder. As you might remember from biology class, the sex of a mosquito is determined partly by the sex chromosomes it inherits from its parents. Females got one X chromosome from each parent; males got an X from their mother and a Y from their father.
In 2014, scientists at Imperial College London and the Fred Hutchinson center here in Seattle were able toedit a protein in male mosquitoesso that it shreds the X chromosomes in their sperm. As a result, the males pass along mostly Y chromosomes, so most of their offspring will be males. Thanks to gene drive, those offspring will also have the edited protein, so most of their children will be males.
Within a few generations, the male/female ratio gets out of whack, and eventually the species dies off in that area.
Another example involves thedoublesex gene, which in mosquitoes works along with the sex chromosome to determine whether an insect turns out male or female. Last year, researchers at Imperial College Londonfoundthat females with edited doublesex genes develop a mix of male and female organs, including male genitalia and a proboscis that is too flimsy to break human skin. They can’t reproduce, so the population shrinks; and they can’t take a blood meal, so they won’t spread the parasite.
The doublesex edit doesn’t affect males, although thanks to gene drive, they will pass it to their offspring, which is how it keeps spreading through the population.
We know gene-drive technology works in the lab. When the Imperial College researchers put 150 males carrying a copy of the doublesex edit in a small cage with 450 wild-type mosquitoes, the population died off within a few months (about 10 generations). The sex bias edit produced similar results.
The next step is to run tests in larger cages and, eventually, get permission from governments to do them outdoors. We need to understand things like: What’s the impact on the food chain if a certain species of mosquito starts dying off? How many altered insects would we need to introduce? How long do we need the mosquitoes to be gone? Last year, the government of Burkina-Faso agreed to allow the release of sterile, non-gene-drive mosquitoes in the wild so researchers could begin to study some of these questions.
As I mentioned, social and regulatory issues also come into play. For example, because mosquitoes don’t exactly respect national boundaries, neighboring countries will probably need to agree on the rules surrounding the use of gene-editing technology. Policymakers and scientists have been debating these questions in forums like the World Health Organization and the African Union’sdevelopment agency, and they are moving toward a consensus.
I think we can have the regulatory approvals in place by 2024 and the first gene-drive mosquitoes ready for use by 2026. Although this technique will never replace the other tools we have for fighting malaria, I’m optimistic that it could become one more important weapon in eradicating the disease.
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