She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (74 page)

James and his colleagues set out to genetically engineer mosquitoes to make the mouse antibody for themselves. The scientists created a gene that encoded the antibody, which they could insert into a mosquito's DNA. James wanted to make the gene safe for the mosquitoes. He worried that if the gene stayed on all the time, the insects would swell up with mouse antibodies and get sick from them. So James and his colleagues connected the antibody gene to a switch. Now the gene would turn on only in response to blood coming into a female mosquito's body.

James and his colleagues inserted the gene and its switch into the DNA
of mosquitoes. When they fed the insects
Plasmodium-
laced blood, they started making antibodies and
wiped out the parasites.

Impressive as this feat might be, it wouldn't put a dent in the worldwide burden of malaria. If James simply released some of his malaria-proof mosquitoes in Africa or India, Mendel's Law would work against him. The engineered mosquitoes would almost always mate with ordinary mosquitoes, and soon their defenses would get diluted in the vast mosquito gene pool.

To spread his malaria-fighting genes, James would need a way to break Mendel's Law. Since the 1960s, scientists had wondered if they could harness gene drives for this purpose. The idea was simple: Link your gene to a gene drive, and with each generation, it would become more common in a population. But no one had yet figured out how to make it work.

James decided to take a crack at the problem. For his gene drive, he picked a piece of DNA called
the P element. Carried by
Drosophila
flies, it spreads by occasionally getting its host cell to make a new copy of itself, which gets inserted at another spot in the fly's DNA. The P element first came to the attention of scientists in the mid-1900s, and over the next few decades it spread like genetic wildfire in North American flies. Margaret Kidwell, a biologist at Brown University, put flies with the P element into tubes with flies that lacked it. Within ten or twenty generations, all her flies carried it.

James and his colleagues thought that if they link their antibody gene to a P element, it could drive resistance to
Plasmodium
into an entire population of mosquitoes, and they would keep passing it down to later generations. That was the idea, at least, but no matter how the scientists adjusted the experiment, it never worked.

In hindsight, James thinks that evolution worked against him. Mosquitoes, like other animals, have probably faced many attacks by gene drives in their long history. And they escaped extinction only because they evolved defenses—defenses that James had no idea how to overcome. “We were probably doomed at the outset on that one,” he told me with a laugh.

When James first heard about CRISPR, he was intrigued. He wondered if he might be able to adapt it to block malaria. But James didn't get much
further than these idle thoughts, when Bier called him. James immediately recognized that the mutagenic chain reaction might be able to spread genes in mosquitoes.

Bier and Gantz drove north up the California coast an hour and a half to visit James and plan out a new experiment. Plastic boxes and shatterproof tubes might be good enough to keep
Drosophila
in check, but for mosquitoes, they'd need much better security. James would need to run the experiment in the safety of his insectarium.

As excited as James was, he knew the odds of success were slim. He and Bier and Gantz would have to design a long piece of DNA containing a number of genes. The DNA would have to carry a gene for the mouse antibody, as well as its switch to turn on during blood meals. It would also have to carry the CRISPR genes to copy all that DNA to other chromosomes. In order to see if they succeeded, the scientists would also need to add a gene that turned the mosquitoes' eyes red.

That was an awful lot to load onto one piece of DNA, especially when the scientists were trying to engineer mosquitoes in a manner no one had ever tried before. James proposed to his colleagues that they break the DNA into smaller chunks. They could then test one chunk at a time, and only later combine them for a final test. Gantz pushed for them to test the whole thing at once. He didn't want to crawl forward when he might leap. When James and Bier agreed to the plan, Gantz worked as fast as he could to assemble all the parts into a single piece of DNA. He then delivered it to James to see if it worked.

During my visit, James took me to the basement of his building, and we walked up to a door marked
A. JAMES TRANSGENIC MOSQU
ITO FACILITY
. He pulled the sleeves of a blue paper smock over his flannel shirt. James had short gray hair, bright big teeth, and broad shoulders that made it hard for him to get the smock on. After a little struggle, he gave up mid-humerus. The smock looked like a newspaper that had slapped against his chest on a windy day.

James waited for me to slide my smock on, and then opened the door. We stepped into a windowless vestibule. A silvery mesh—fine enough to
block a mosquito—covered the ceiling vents. Once we had both stepped into the vestibule, James closed the outer door and waited a moment until he could open the inner one. We entered the insectarium—a small cluster of rooms in which James and his staff raise tens of thousands of mosquitoes.

The first thing I saw when we stepped inside was a row of yellow movie theater popcorn buckets. They sat on a table, each with a gray cylinder attached to the top, trailing a power cord. When I leaned over the buckets, I could see adult female mosquitoes clinging to the inner walls. Each had a swollen belly. The gray cylinders contained warm calf's blood. James unscrewed an empty cylinder to show me how he lined it with a membrane. The mosquitoes could pierce the membrane with their needlelike mouthparts and drink deeply, filling their tear-shaped abdomens with blood.

Once a mosquito is sated on blood, she will grow hundreds of eggs inside her body. James and his staff of technicians have found that the mosquitoes prefer to lay their eggs in the dark, and so they transfer the insects from the popcorn buckets into a lightless room. After the mosquitoes are done laying, James's technicians gather the eggs and attach them to strips of paper.

Now they can alter the genes of the new generation of mosquitoes. They pierce the soft eggs with fine glass needles, injecting DNA. They have only a few hours to work on the mosquitoes before the eggs tan and harden.

“It's like an assembly line,” James said as he showed me the microscope where his team manipulates the DNA inside the eggs. “You can do three or four hundred, maybe five hundred a day, depending on how good you are.”

In the wild, a mosquito lays her eggs in water, where they float together like a raft. After a few days, the eggs hatch, and the larvae swim away to spend their first stage of life underwater. James has to re-create that stage in his insectarium, too. He led me through a transparent vinyl-strip door into his larva room. Metal shelves reached from the floor to the ceiling, and on many of them were plastic tubs half-filled with water. Each was like a pond filled with hundreds of larvae. They swam about like hairy miniature snakes.

We stopped to look closely at one tub of larvae. There was a tag taped to
the rim, with the number 29 written in thick marker ink. The larvae twirled and twitched. Each one had a pair of pinprick-size eyes. All the eyes were red.

“So these are the famous gene drive ones, here,” James said.

The number 29 referred to the twenty-nine generations of mosquitoes James had reared since beginning his experiment with Gantz and Bier. After Gantz created a new piece of DNA with all the gene drive pieces, James and his team injected them into the soft eggs of mosquitoes. To his delight, the larvae hatched with red eyes, meaning that they carried two copies of the malaria-resistant gene. James and his colleagues mated the male larvae with ordinary females, and the following generation was red-eyed as well. I was now looking at generation twenty-nine, at the end of an unbroken chain of heredity.

In November 2015, James and his colleagues announced that
they had successfully used gene drive in mosquitoes, just seven months after Gantz and Bier had published the original mutagenic chain reaction paper. “People said, ‘That went fast!'” James told me as I looked at his red-eyed mosquitoes. “Well, it didn't really go fast, because we'd been laboring for years.” James had all the tools he needed for the experiment by the time Bier called him. “It was just another piece of DNA for us to inject,” he said.

The mutagenic chain reaction hit the news amidst jolting stories about experiments with CRISPR on human embryos. Human genetic engineering had been the stuff of speculation for more than fifty years, since Rollin Hotchkiss had worried over it. But the idea of overriding heredity to cure diseases with gene drive came as a bigger surprise. Even most scientists who worked on CRISPR hadn't seen it coming.

There were exceptions: George Church and one of his colleagues at Harvard, Kevin Esvelt, had been musing about the idea. In 2014, they and some of their colleagues published a couple of speculative pieces. But they called CRISPR-based gene drive only a “
theoretical technology.”

Once Bier and Gantz revealed the mutagenic chain reaction, the technology was no longer theoretical. Esvelt and his colleagues reported that
they could use CRISPR in yeast to override Mendel's Law as well. The technology might conceivably work in just about any sexually reproducing species scientists might want to alter.

As Jennifer Doudna and her colleagues grappled with CRISPR's use on people, Bier, Gantz, Esvelt, and other scientists began working through the implications of gene drives. At conferences and in scientific reviews, they laid out some of the ways the technology could make life better. Making mosquitoes malaria-proof could save thousands, or even hundreds of thousands, of lives every year. Esvelt traveled to Nantucket to propose to its residents that he use CRISPR on the island's mice. It might be possible to render them resistant to Lyme disease, breaking the disease's cycle. Plant scientists speculated about fighting the evolution of herbicide-resistant weeds. They could use gene drive to eradicate the genes that made them resistant, replacing them with genes that make the plants vulnerable once more.

It might even be possible to use CRISPR to drive a population, or even an entire species, extinct. Scientists could give genes to an undesired animal that made it less fertile. The animals inheritng these genes would have fewer offspring, but thanks to CRISPR, they would end up in a growing fraction of the population. Eventually, the population would cross a tipping point and collapse.

Conservation biologists had long dreamed of this kind of power to fight invasive species. When snakes and rats are introduced to remote islands, for example, they can wipe out local bird species by eating their eggs. A team of Australian scientists calculated that the introduction of a hundred CRISPR-altered rodents to an island could
wipe out a population of fifty thousand. It would take only five years.

But gene drive might also wreak havoc. If scientists unleashed a gene drive in the wild, it might not work as they had planned. If it caused harm, it might be impossible to undo the damage. A committee organized by the National Academy of Sciences issued a report in 2016 in which it warned that gene drives had the potential to cause “
irreversible effects on organisms and ecosystems.”

Artificial gene drives represent a profound ethical quandary—arguably a bigger one than using CRISPR to genetically engineer human embryos.
They may be able to alter heredity not just in the genetic sense of the word but in other senses as well. We might drastically alter the genes that animals or plants inherit far into the future. We would also leave an ecological inheritance to our descendants that they might curse us for. To judge the wisdom of this tool, we would do well to look back at how the tools we've already invented have altered
our ecological inheritance over the past ten thousand years.

Human cumulative culture allowed hunter-gatherers to learn over generations how to harvest plants and control animals. Mostly without knowing it, some of them engineered new environments where agriculture could arise. Their descendants became farmers, sowing crops and raising livestock. Each new generation inherited more than just the knowledge required to farm. Humans now left an ecological inheritance to their descendants.

Before about ten thousand years ago, children were born into a world sculpted by fire, hunting, and foraging. Farmers began reworking the land on a greater scale, and at an accelerating pace. By clearing fields to plant, they could grow enough food to feed their families, with surplus they could sell to others. Farmers stopped moving, settling into villages with sturdy houses and granaries where they could store their extra food. A farmer could now pass down this accumulated wealth to his children, along with the land that he used to generate it.

But this new form of inheritance created an inescapable tension: A family's land could be divided among the children in small portions, or passed on to just one of them, leaving the rest to find other kinds of work. That tension drove some members of the family to find more land to clear. It also drove them to discover and adopt new cultural practices that let them get bigger harvests out of a given parcel, such as
plows drawn by horses or oxen. By the Bronze Age, kilns were invented. Their fires reached temperatures humans had never managed before. Miners could smelt ores, and smiths could work metals. They discovered that coal was a better fuel than wood.
Out of these intense fires came new metal tools, including axes that farmers could use to clear more forests, and plows to plant more crops.

Yet these advances did not free farmers from the feedback loop between their culture and the environment. The short-term benefits they got from new farming equipment came at the long-term expense of the land's fertility. As fields eroded and became less productive, people cleared forests to work soils that would have previously been considered too poor to bother with. This feedback continued to raise the world's population, fostering more cultural innovations. And those innovations allowed people to convert even more wildlands to farms and cities.