A female Aedes aegypti mosquito takes a “blood meal” from Ben Matthews, a postdoctoral fellow at Rockefeller University. Dozens of her offspring, all fathered by a single male, were the source of the DNA needed to create a new genome map with modern sequencing and assembly techniques. Credit Hilary Swift for The New York TimesWith the Zika virus spreading largely unchecked in Latin America and the Caribbean by way of a now-notorious insect, some of the nation’s leading mosquito researchers are striving to assemble a state-of-the-art DNA map that they say will help them fight the disease with the mosquito’s own genetic code.
The quest involves scientists from assorted disciplines who rarely collaborate, often compete for funding and have different ideas about how to genetically manipulate the mosquito, Aedes aegypti.
Some want to hunt for genes that, if altered in mosquitoes released into the wild, could drive the species to extinction. Others are trying to identify genes that control how mosquitoes sense human prey so as to devise better repellents. Still others favor the idea of selectively breeding populations of mosquitoes, like corn or cattle, for desirable — or, at least, less undesirable — traits, such as a preference for biting animals other than humans.
The project took off after a series of frustrated Twitter posts from Leslie B. Vosshall, a mosquito researcher at Rockefeller University. Dr. Vosshall issued a plea for advice on constructing a detailed mosquito DNA map in January, as Brazil began reporting a spike, apparently related to the Zika virus, in newborns with unusually small heads.
“I was worried people would be defensive or paranoid or weird,” she said in the days leading up to the scientists’ first nine-way videoconference call. “For a long time, I think we all thought the map was somebody else’s job.”
The bid to map the genome of the Aedes mosquito has received little attention, perhaps because a map in itself will not yield a fix for Zika, any more than the human genome map has yielded a cure for cancer. It might lead to biological possibilities, moreover, whose ecological consequences are deemed too serious to risk.
But the story of how the Aedes Genome Working Group emerged offers a glimpse at the often ad hoc way science lurches forward, driven by self-interest, new technology and pressing social needs. The pursuits of its members reflect the range of hopes for a new form of genetic combat that may be increasingly called into play as the specter of diseases borne by insects grows along with our ability to parse the details of their DNA.
And the need to control the Aedes mosquito, which also carries yellow fever and other viruses, is not likely to end with this outbreak. Despite the introduction of a vaccine against yellow fever that saved millions of lives, for instance, the virus still kills 30,000 people a year.
“If we’re going to control the creature, we need to know it frontwards and backwards,” said Jeffrey Powell, a mosquito researcher at Yale University, who was among the first to join forces with Dr. Vosshall. “Having a complete genome sequence of the beast will give us a fundamental understanding of its biology that you can’t get any other way.”
A Powerful Tool
Genome mapping, which first captured the public imagination in 2000 with the release of a draft of the human DNA sequence, has become a fundamental tool of modern molecular biology, used to help study how living things evolve, develop, get sick and behave. An Aedes genome map of sorts, too, has existed since 2007, but researchers say it is staggeringly imperfect: fragmented into 36,204 pieces, some of which are themselves misassembled, with hundreds of genes known to be missing and others mistakenly duplicated.
The participants in the Aedes Genome Working Group held a nine-way videoconference call in January, led by Leslie B. Vosshall, top center.For a long time, cost and sheer difficulty made filling in every detail prohibitive for all but a few genome sequences, including our own and those of a handful of laboratory favorites like mice and fruit flies. Even as new techniques have made it easier and more affordable to create better maps, the task has been seen more as a technical feat than a scientific one, which is one reason the Aedes map has remained in its state of disrepair.
“There’s not a lot of glory in it,” Dr. Powell conceded.
Zika, however, has helped galvanize the small community of researchers who already spend most of their time thinking about the insect. The normally mild virus’s apparent link to brain damage in babies whose mothers were infected while pregnant has stirred fears worldwide and led health officials to declare the current pandemic a public health emergency.
An Aedes mosquito in the United States could become a carrier for the virus if the insect bit a traveler who had acquired Zika abroad. Though the use of air-conditioning and screens is likely to limit outbreaks in the United States as the mosquito population swells in the South this summer, stanching Zika’s spread means controlling a mosquito that has grown resistant to previously effective insecticides and requires only minute amounts of standing water to breed.
A few experiments with the mass release of biologically altered mosquitoes, carried out by a biotechnology company and by researchers funded by the Bill and Melinda Gates Foundation, have reportedly had some success. But researchers say other strategies are virtually certain to be needed. With the Obama administration asking for $1.8 billion to combat Zika, it seemed likely to Dr. Vosshall that the budget for a new map — a few hundred thousand dollars, with enough support and volunteer labor from other researchers — could somehow be secured.
And on their first videoconference call in late January, nine far-flung teams of scientists found common cause in their discontent with trying to track down which genes control which traits on a map that often leads them astray.
“I can’t tell you how many meetings I’ve been to where people use four-letter words” to describe the existing map, Anthony A. James, a mosquito researcher at the University of California, Irvine, observed to the group.
Amid different opinions about the best approach and who would pay for what, a consensus emerged. The DNA for the new map would be extracted from the offspring of a very particular mating of Aedes mosquitoes, from the same line mapped a decade earlier.
A few days later, researchers at Virginia Tech shipped the offspring in the form of dried eggs to Dr. Vosshall’s laboratory at Rockefeller, where they were hatched and reared by a postdoctoral fellow, Ben Matthews. Since females will not lay eggs until they are fed, Dr. Matthews took a necessary first step. Inside a humid chamber, behind an airlock and a third heavy door, he offered up his arm for a bite so that the selected Eve could take what is known in the parlance of mosquito researchers as “a blood meal.”
“It’s kind of amazing,” he said cheerfully, “when you think about the amount of money, time and science that’s going to come downstream of this.”
An Age-Old Enemy
That a genome map for Aedes aegypti, however imperfect, was published in 2007 is a testament to the species’ longtime status as a potent human foe. (Its genus name, bestowed by 18th-century naturalists with a penchant for accuracy, means “unpleasant” in ancient Greek; “aegypti” refers to Egypt, where it was first believed to have been collected.)
A visualization of the recently sequenced Aedes aegypti genome. Each of the 3,752 colored lines is a fragment of its three chromosomes that could not be fit together without the additional information that the Aedes Genome Working Group hopes to produce. A 2007 genome map for Aedes aegypti is fragmented into about 10 times as many pieces. Credit Mark KunitomiBesides Zika and yellow fever, the insect carries dengue, which causes a severe and sometimes fatal flulike illness, and chikungunya, which can cause intense joint pain that lasts for years.
Because Aedes is easier to maintain in laboratories, it is simpler to study than its more lethal cousins, certain Anopheles mosquitoes, which kill some 800,000 people a year by infecting them with malaria. The hope that scientists could blunt the threat of both species by learning which genes control what in Aedes was what persuaded the National Institutes of Health to underwrite the initial sequencing of the mosquito’s genome for about $18 million.
The genomes of every living thing consist of four chemical units that function like letters in an alphabet, arranged in sequences, or “words,” that tell its cells what to do. In Aedes’s case, each cell nucleus contains 1.3 billion letters of DNA from each parent, coiled into three chromosomes. Since the order of the words is also important, in an ideal world, a DNA sequence would consist of those same letters, which would then be assembled, or “mapped,” into three long stretches.
But the technology used for the 2007 Aedes map, and many others, could only read relatively short stretches of DNA at a time, which were then pieced together by matching up the sections where they overlapped in a process that often left some areas garbled and riddled with gaps. And since more than half of the Aedes genome consists of sequences that repeat again and again, it has proved more difficult than many genomes to make sense of.
“Have you seen ‘The Shining’?” Dr. Vosshall asked, referring to the classic horror film in which the psychotic Jack Torrance character, played by Jack Nicholson, appears to be writing a novel that turns out to be the same phrase over and over again. “It’s like you have a thousand copies of ‘all work and no play’ and then three sentences of unique text.”
Adam M. Phillippy, an expert in assembling genome maps at the National Institutes of Health, likened the process to doing a puzzle for which the pieces have precisely the same shape, are tiny, “and you’re missing the cover.”
But over the last few years, technology has emerged that allows the DNA letters to be read in stretches of tens of thousands at a time, making for bigger puzzle pieces and prompting biologists to revisit older genome maps.
Remapping the supposedly complete human genome with the new technique has yielded several previously unknown genes active in the brain that scientists say may hold clues to how we differ from other apes. The United States Agriculture Department is in the process of remapping pig, goat and cattle genomes in the expectation of finding genes that make for healthier and more efficient farm animals.
Evan E. Eichler, a human geneticist at the University of Washington who recently led a team in assembling a new gorilla genome, called the new information that scientists had been able to glean “mind-blowing.”
“There’s a strong case to be made for going back to the mosquito and redoing it,” he said, “like there is for any genome that still has lots of gaps.”
Dr. Matthews separated male and female Aedes aegypti mosquito larvae at Rockefeller University. Credit Hilary Swift for The New York TimesAware of the new technology, Dr. Vosshall floated the idea of a new Aedes map on Twitter: “The Aedes aegypti mosquito is infecting millions with #Zika and #Dengue,” she wrote on Jan. 28, “but we still haven’t put all the pieces of its genome together.”
Ultimately, she received over a dozen replies from the cast who would make up the group, including a virologist, a population geneticist, several molecular biologists and experts in assorted aspects of the art of genome assembly.
One came from Mark Kunitomi, a postdoctoral fellow at the University of California, San Francisco. “Hi Leslie,” his email started. “I follow you on Twitter.”
Dr. Kunitomi and his adviser, the virologist Raul Andino, believe that the key to what makes some populations of Aedes mosquitoes resistant to viruses like Zika lies in bits of viral code embedded in their DNA. Such information might allow researchers to predict where in the world outbreaks are most likely to arise and, in effect, to vaccinate a mosquito population by releasing mosquitoes with the requisite viral DNA inserted.
To pursue the idea, Dr. Andino and Dr. Kunitomi produced a new version of an Aedes map in collaboration with Pacific Biosciences, the company that has pioneered the new sequencing technology. This version yielded many hundreds of genes not found in the 2007 map. But, while better, it is still short of what scientists are looking for because it comes from an Aedes cell line with many mutations.
Dr. Kunitomi mentioned that Dr. Vosshall might want to reach out to Dr. Powell, the mosquito researcher at Yale, who Dr. Kunitomi had learned was working with the same company. Dr. Powell, too, was in search of the genes that control the mosquito’s ability to transmit viruses. But a truly complete map would require paying for more sequencing with the Pacific Biosciences technology, and several other steps that he could not afford.
Dr. James of the University of California, Irvine, also voiced support. His interest in the map came from his work on a technology called gene drive, in which a trait engineered into a few individuals in a species — sterility, say, or an altered immune system — is made to spread rapidly through a population as a result of a trick that ensures it is transmitted to all descendants, bypassing the normally random process of inheritance.
While that technology might be used to stop the Zika virus, gene drive is controversial because of fears that an altered gene might “escape” into another species. Dr. James argued that such concerns could be mitigated if the gene were unique to Aedes, or at least to mosquitoes. (“They do something fruit flies don’t do,” he noted. “They feed on blood.”) But to have any hope of that, he needed a map to compare Aedes genes against others.
“For me, it’s an extension of the engineering principle that you want to be as targeted as you can,” he said.
Researchers at Colorado State and at the University of Bristol in England also weighed in. At the University of Notre Dame, David W. Severson, who had orchestrated the making of the original map, offered to help. On Twitter, Dr. Phillippy, of the National Institutes of Health, responded with advice on the best approach to creating a new mosquito map and volunteered his services.
The N.I.H. came through with a $15,000 emergency grant, and Eric S. Lander, the director of the Broad Institute of M.I.T. and Harvard, called Dr. Vosshall with an offer to devote the institution’s considerable resources to the project. “It was like getting a call from the pope,” Dr. Vosshall recalled.
Though it is still short by some $250,000 required for the finishing touches, by late last month, the group had a plan that involved three types of DNA sequencing and enough funding to start. And so Dr. Matthews extracted the DNA from the pupae that the Eve had produced. It is now being sequenced.