Woolly

by Ben Mezrich

  Lyme disease is a particularly nasty bacterial infection that affects around three hundred thousand people a year, mostly in the northeastern United States. Symptoms can start off like a mild flu with fever, joint pain, fatigue, and sometimes a distinctive bull’s-eye-shaped rash. It is difficult to treat, and if it isn’t caught early, can cause years, or decades, of systemic, chronic health problems. People and dogs contract Lyme from the bite of a certain type of tick: Ixodes scapularis, more commonly known as a deer tick.

  Nantucket and its sister island, Martha’s Vineyard, were at the center of the epidemic. According to the Nantucket board of health, more than 40 percent of the year-round population of Nantucket had been infected with Lyme disease, and during the summer, hundreds of new cases were seen every week.

  For an economy that lived on tourism—the population in Nantucket swelled from its base of ten thousand year-round occupants to more than sixty thousand during the summer months—the tick-borne disease was a growing, existential threat. In previous years, drastic steps to fight the disease had been discussed, such as mass spraying for the insect, which was tactically difficult, given the island’s dense population mixed in with thick foliage, and a culling of the deer population, an idea met with fierce opposition. People chose to live on Nantucket to be closer to nature, not to destroy it.

  But two weeks ago, Esvelt had offered a third solution, one pulled directly from Church’s playbook. Indeed, although Ting and Church had missed the presentation, they had spent part of their weekend on the island getting feedback from those who had attended, and Esvelt himself.

  Esvelt’s plan was to attack the disease earlier in its food chain than when it latched on to and was carried around by deer. The insect acquired the infectious disease as larvae from feeding on white-footed mice, four-inch rodents that live all over the contiguous United States. Esvelt’s plan was to genetically engineer white-footed mice that were either immune to Lyme disease, and thus couldn’t spread it to the tick larva, or resistant to the tick’s saliva, which allowed the tick to attach to and feed on the infected mice, thus cutting off the disease cycle before it began.

  Esvelt believed that around three hundred thousand genetically modified mice released on Nantucket would make a serious dent in the incidents of Lyme disease by overtaking the indigenous rodent population, interbreeding, and eventually becoming the dominant, and perhaps the only, mouse living on the island. Ting admitted, the visual image—more than a quarter million genetically altered mice skidding along the cobblestones on their tiny feet, disappearing into basements, rain gutters, into the underbrush to combat Lyme disease—was a little troubling, but to her surprise, the general mood of the meeting had been open and accepting. Esvelt had been careful to explain that his team planned to test the idea on an uninhabited island first—akin to Church’s genetically enhanced mosquitoes being tested under domed villages. Only then, when it was proven they’d fit in with the island’s ecosystem, would the mice be released onto Nantucket. But even still, the implementation of the program had ethical implications.

  In recent years, Ting had dedicated herself to community outreach such as this. She’d traveled to cities all over the country speaking to people, often in impoverished communities, about genetics and the possibilities of genomic engineering. Going out into the civilian population to connect with people about the changes that would affect every one of us had become as important as any of the scientific work she was pursuing. As Church had said many times, science doesn’t take place in a vacuum; scientists need to be open about their work and communicate.

  The transgenic mouse that Esvelt was proposing had implications far beyond the little island of Nantucket. The transgenic mouse was really the first step toward a “gene drive” to rid the entire Northeast, and the rest of the world, of Lyme. Eventually, it wouldn’t just be changing a gene in a few hundred thousand white-footed mice to make them immune to the disease; the next step would be to insert the genetic change into the species line, to change the entire species.

  Gene drives—a change in a gene that was passed to all of a living thing’s heirs—were controversial. Changing genes that were inherited meant changing a species, and gene drives could just as easily be used to end a species. Rather than making the white-footed mice unable to carry Lyme disease, Esvelt could have proposed to make the mice unable to reproduce.

  In the realm of mosquitoes, that exact solution was being worked on by multiple private companies. In fact, in Brazil one such project was already being tested in the field to combat dengue fever and, eventually, the Zika virus: A quarter million Aedis aegypti mosquitoes created by a UK company called Oxitec had been released into a village in São Paulo; these particular mosquitoes had been created using a gene drive that led to highly competitive males who could live only four days, and whose larvae couldn’t survive to adulthood. The genetically altered mosquitoes had overwhelmed the local natural population, and cases of dengue had dropped to a tenth of what had previously been reported.

  In short, the genetic modification had been successful, and in that local area, the Aedis aegypti species was on its way to being gene-driven to extinction. Although most people would argue that the elimination of disease-carrying mosquitoes was for the greater good, there were still questions about the ethics of using such a powerful scientific tool. In fact, U.S. intelligence officials had recently determined—causing much controversy in the science world—that CRISPR and gene drives should be considered potential weapons of mass destruction: Altering genes in a species line could cause almost immediate genocide of entire species.

  But the people of Nantucket saw that the science of gene drives, applied in a beneficial way, could rid them of a disease that threatened their health and their bank accounts.

  “I’m the first person to say if you go tinker with Mother Nature, we’re going to break it,” one of the gathered towns-people, as reported by the New York Times, had told the floor, encapsulating the mood. “But you know what? Even I want to see where you go with this.”

  Everything about the presentation—the openness, the involvement of the community, the methodical plan laid out for implementing the idea—was exactly what Ting considered science done right. Science in secret was dangerous, difficult to regulate, and people who relished secrecy usually had something to hide. Her husband had proven that it was possible to be competitive, to break new ground, without locking down your lab behind opaque walls, towers with armed guards, and fences of barbed wire.

  And in science such as this, it was especially necessary to involve the greater public. Every person had a stake in something as powerful as gene drives, whether in mosquitoes or in mice.

  Though she knew Church felt similarly, she guessed he was much more excited about the results of the town hall meeting than about the process. A fleet of transgenic mice ending Lyme disease was the sort of real-world solution to a health problem with genetic science that his lab aimed to provide. He also felt that the ethics, safety, and communication had to be done very well.

  Certainly, he did not fault the community for initially being wary; there were real dangers behind such powerful uses of genetic engineering. The general public had a right to ask questions. Church himself was no stranger to such debate.

  During his appearance on the Colbert Report in 2012, the host had asked him point blank: “How do you think your work will eventually destroy all mankind? Do you think it’s going to be like a killer virus, or more like a giant mutant killer squid man?”

  Although Colbert had obviously been joking, the sort of science Church did on a daily basis pushed boundaries, and sometimes when one moved beyond boundaries, one ended up in realms brimming with significant risks.

  Only recently, Church and a team in his lab had created a mostly synthetic life-form: They had created the first “recoded” or “genetically synthetic” organism, a strain of E. coli with a radically changed genome. It was the first example of genome-scaled engineering—not just the
addition of genes.

  The experiment had taken place in a sterile environment with highly redundant safety precautions. From air filtration to sterile, contained work spaces, the environment was completely controlled, and throughout their work Church and his team wore the requisite biosafety gear—gloves, masks, and sealed scrubs. This wasn’t a Hot Zone, and the work didn’t involve Racal bodysuits with oxygen tanks, but everyone involved understood the inherent danger.

  Contamination in any lab could happen quite simply. Lean over to pick up a dropped pipette or Petri dish, tear your gloves or your sleeve on the edge of a cabinet; a microscopic sample touches skin, and a brand-new, synthetic bacteria begins its journey to the outside world. Stop in a coffee shop on the way home, go see a movie, and suddenly a form of E. coli that doesn’t exist in nature—because, as Colbert foresaw, it was invented in a lab—has entered the biosystem of the City of Boston. It travels from a movie theater seat or a poorly washed coffee mug to a stranger, who takes it home via the subway.

  No immune system in the city, in the state, in the country, in the world has any built-in defense against a synthetic bacteria, because it hasn’t existed before. Maybe, most likely, it’s harmless; but maybe it’s not.

  Church understood that no matter how perfectly safe a physical environment felt, no matter how powerful a reverse ventilation system was or how many gloves and bodysuits a scientist wore, there was always the possibility that something could go wrong. A test tube could shatter, a ventilation system could break down. The key to true safety was to build measures into the work itself, a process called “biocontainment.” Church had often likened it to putting in seat belts and air bags when one manufactured a car.

  In the case of Church’s E. coli, he had implanted a synthetic amino acid in the microbe’s genome, which it simply could not survive without. Since the amino acid did not exist naturally, and wasn’t something the bacteria could ever create on its own, the E. coli could live and propagate only where the amino acid existed—which was within Church’s lab. To Church, it was an even more effective method than the more commonly used precaution of engineering a “kill switch” into the microbe—usually some sort of susceptibility to a readily available toxin, so that in the case of an accident, the microbe could be quickly eliminated. Church believed a microbe might find a way around such a kill switch, by evolving to tolerate whatever toxin was chosen, but it was not feasible that a microbe could somehow get around an existential need for a synthetic amino acid built into its genetic structure.

  Church and his colleagues had gone to extreme lengths to test and perfect their biocontainment strategy. He and colleague Dan Mandell had gone through huge stacks of Petri square plates in order to get to “zero in a trillion” escapes. Another colleague, Michael Napolitano, had built an automated “morbidostat,” with big reservoirs of fresh growth media in which they slowly lowered the amounts of the “addicting” chemical. As time passed, the cells in the growth chamber became more and more capable of growing with lower levels of the amino acid, but were never able to grow without some level of the synthetic chemical, proving they could not live on their own.

  Would all scientists conduct their experiments with such an unwavering sense of responsibility? Church couldn’t be sure. More and more, Church’s sort of science didn’t require the state-of-the-art labs found at Harvard. At some point, genetic engineering would be possible in garages and attics—if it wasn’t already.

  Esvelt was going to make his genetically engineered mice in a safe lab at MIT, but one day, Church could imagine, there would be twentysomethings making transgenic mice in the basements of their suburban homes.

  All the more reason, Church believed, that it was important for scientists to reach out to the general public, to explain what they were doing, and that the world needed to take notice, to understand.

  Church’s thoughts on the return ferry were not only about Esvelt’s mice. Among other things, he was picturing the town hall meeting he’d one day pull together to unveil the first baby Woolly Mammoth. He intended to be as open and public with the project as he could. Especially as he moved closer and closer to his goals.

  He’d recently received his grant to attempt to build a synthetic womb. And Luhan and Bobby were on the verge of implanting synthetically sequenced Mammoth genes into immortalized elephant cells. They had put together fourteen in all—ten more than the original four they had planned—and would soon be attempting to stimulate the cells to make them iPSCs, so they could create organoids and test their results. If they succeeded, there would be a clear path to that first Woolly Mammoth.

  But right now, he was on the ferry, and another animal had come into view.

  The seagull had reappeared, once again suspended in the air in front of them.

  “Your friend is back,” Church said, touching Ting’s shoulder with his big hand.

  Perhaps, Ting thought, he saw it now as a gull, not as a sum of its parts.

  Church always had his feet in both the present and the future, and only he knew for sure which was reality, and which was still just a dream.

  CHAPTER TWENTY-EIGHT

  Today

  77 AVENUE LOUIS PASTEUR, BOSTON.

  Ten minutes past two in the morning.

  “It’s alive,” Luhan said, as she watched Church step back from the Petri dish filled with altered hemoglobin cells. The condensation from the cryogenic device swirled around their corner of the lab, only adding to the atmosphere.

  Luhan didn’t understand why Bobby, standing next to Church in the dim light from the fluorescent tubes high above the work hoods, seemed to be having difficulty holding back a smile at her words; she wasn’t aware that she’d referenced the classic 1930 horror film Frankenstein, and she hadn’t meant to imply that they had just created life. Because they hadn’t. Nor was “alive” really the proper description.

  “I mean, they’re functioning properly. Releasing oxygen.”

  If the cells had been traveling through the highways and byways of a mammalian circulatory system, rather than floating in a culture trapped in a plastic Petri dish, they would have been feeding the oxygen they carried to peripheral limbs and organs, to skin wrapped around the little bones that made up a tail, a trunk, ears, and padded toes.

  “So now we’ve got an elephant who can live in the Arctic Circle,” Bobby said, finally letting his smile grow.

  “We’ve got a lot more than that,” Luhan said.

  She watched as Church shifted his attention to the row of other Petri dishes that they’d just removed from the sterile refrigeration unit near their work space. Lined up together along the counter, it was a collection that, in Luhan’s opinion, ought to have been in a display case front and center at the Smithsonian, or perhaps more appropriately in the offices of National Geographic.

  Fourteen organoids (ideally as accurate as possible in three-dimensional shape and molecular details) made up of living, immortalized, and chemically rendered “stemlike” Asian elephant cells originally donated by Ringling Brothers Conservation Center, implanted with synthetically created Woolly Mammoth genes by means of CRISPR. Each of the organoids, representing an isolated Mammoth gene, cells dividable beyond the Hayflick limit and ready for testing for the traits those genes were designed to generate.

  Woolly Mammoth hemoglobin, Woolly Mammoth subcutaneous fat, Woolly Mammoth ear cells, Woolly Mammoth tail cells—fourteen of the twentysomething traits they eventually hoped to code for. Church was looking through them one by one, going over the testing procedures they’d developed to check their work; in some ways, though the hemoglobin was one of the more difficult genes to sequence, it had been one of the easier to test. You didn’t need to grow an ear to see if you’d gotten hemoglobin right.

  Luhan and Bobby had been over their test protocols many times in recent weeks. Working without Quinn and Margo hadn’t been easy, and they were hopeful that at least Quinn would return at some point in the near future. Soon, Luhan knew, her trans
genic pigs would take her away from the Church Lab as well; the company she and Church had founded was already raising significant money, and would be beginning trials with liver material that could lead to their first actual transplantation.

  It was bittersweet to think about. To Luhan, graduating from the Church Lab was like stepping off a cloud and into the real world. She knew the Woolly Mammoth Revival project would be in good hands with Bobby, who was still continuing with his aging work as well, but day to day, she would be running a business as much as she’d be challenging the boundaries of science.

  Church somehow managed to keep pushing those boundaries ever farther; the postdocs who would undoubtedly take Luhan’s place would find that they were stirring up no end of controversies. The reason Church was seeing the organoids for the first time that evening was that he’d aroused another controversy, tangentially related to the science that would soon give them their first Woolly Mammoth.

  Not long ago, the New York Times had published an article revealing that a private meeting involving 130 of the world’s top biologists, ethicists, and chemists had taken place at Harvard Medical School, in order to study the possibility of creating human cells from scratch. That is, they would create the human cells without a donor, completely synthesized from the ground up.

  Initially, the project was called HGP2: The Human Genome Synthesis Project, and was meant to be an extension of the original Human Genome Project and Church’s Personal Genome Project, except this time, rather than read the DNA code that was the basis for human life, or publicize individual genomes beginning with George Church’s, now the goal was to write that sequence, to create it, in a lab, using chemicals. Essentially, HGP2 could, according to some of the press coverage, lay the groundwork for making a person without the need for biological parents.