Gene-editing startup Editas Medicine filed to go public this week, making it the first publicly traded company in the area of gene-corrective technology. Investors include Google Ventures, Bill Gates’s Bng0 and Khosla Ventures.
As part of our special series on Boston tech, we toured the lab of Editas co-founder George Church to discuss startups, genetics and the science behind resurrecting extinct species.
On March 15, 2013, genetic engineer George Church stood in the middle of a circular red rug onstage at the Gilbert H. Grosvenor Auditorium in Washington, D.C., describing a detailed plan for bringing a six-ton, 10-foot, fur-covered creature back from the dead.
By splicing genes responsible for traits like thicker hair, subcutaneous fat and curving tusks into the DNA of an Asian elephant, Church hopes to revive the long-extinct woolly mammoth, or at least create a version of the modern elephant that really likes the cold.
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“We’re trying to recreate species from information alone,” he said at the TEDx De-extinction event, looking every bit like the Harvard college professor he is, wearing a brown corduroy jacket and striped tie pulled just-too tight.
The thing is, if anyone can pull off this sort of sci-fi feat, it’s probably Church. Working in a pair of labs in the heart of Boston’s Longwood Medical Area, the 60-year-old scientist has done as much as anyone to improve our ability to read, write and edit the genome, the basic operating system of life. Along the way, he has mentored a generation of leading genetic researchers, co-founded 14 companies and counting, filed more than 60 patents and authored or co-authored hundreds of scientific papers.
I know what you’re thinking, though: We’ve seen this movie, and it didn’t end well. The very suggestion of tinkering with DNA to bring back prehistoric beasts inspires fear, queasiness and even contempt among many.
But if you get past the reflexive response (it helps knowing woolly mammoths were vegetarians) there are some surprisingly sound scientific, ecological and even ethical arguments for trying: The advances may also help preserve endangered species, protect fragile habitat and possibly even curtail global warming (more on that head-scratcher in a bit).
But while all those reasons are true, or at least plausible, the more you talk to Church, the more you suspect they’re partially rationalizations after the fact. Above all, he wants to push hard on the boundaries of the possible.
Church has been obsessed with the future since childhood and he is determined to get there as fast as he can, even if it means bringing back some pieces from the past.
“The best way to predict the future,” he said onstage that day, “is to change it.”
Transparency
Less than a mile from Fenway Park stands a set of connected glass towers known as the Center for Life Science.
Take the elevator up to the Wyss Institute for Biologically Inspired Design, badge through the doors, walk down the hall and you’ll arrive at Church’s lab, a small white square room.
Church fills the space. He’s 6-foot-5, 250 pounds, with a thick gray beard that calls to mind Santa Claus for some. When he went on the Colbert Report in October 2012, in what must have ranked among the few times a geneticist made it onto late-night TV, Stephen Colbert drew a different comparison: “Are you playing God, sir? ’Cause you certainly have the beard for it.”
On the day I visited the lab, Church was wearing khakis paired with a short-sleeved button-down shirt, square glasses and the same brand of black orthotic shoes he’s worn for a decade. He was carrying, as he always does, a tiny laptop with a piece of gray tape over the webcam.
“Is that for privacy?” I asked.
“I don’t know,” he said with a smile, “I don’t actually believe there’s any such thing as privacy.”
Certainly less for him than most. In fact, he goes to great lengths to be as transparent as possible, posting his genome, medical history, personal biography, daily schedule and much more online.
You can see that he had a heart attack, battled carcinoma and suffers from dyslexia. He also has an odd variety of narcolepsy that friends and colleagues say can be difficult to detect.
“He’ll fall asleep, but then ask incisive questions about what you’re talking about,” said Sriram Kosuri, a former student in the Church Lab who is now an assistant professor at UCLA.
Perhaps most surprising, given Church’s successes in academia and industry, you’ll find that he repeated the ninth grade and flunked out of Duke. He posts the official letter from the associate dean for anyone to see.
Church strives for radical transparency in part because he believes that sharing health data is crucial for untangling the links between the human genome and diseases. But he also believes it is the responsibility of scientists working in controversial areas to be open about their work.
It is part of the reason why he talks about unsettling stuff on conference stages, answers long lists of questions from journalists and encourages colleagues to participate in the public debate. He has also written about ethical issues in this field and called for implementing safety measures, including surveillance systems.
“We can’t just say that we intend to do good things,” Church said.
But he can be plenty provocative himself, most famously when he suggested in his 2012 book, “Regenesis,” that a Neanderthal could be delivered back into the world through “a surrogate mother chimp — or by an extremely adventurous female human.”
After a questionably transcribed interview in Der Spiegel hit the Internet, he stressed it was not a serious proposal.
“The neuroses”
Church was born on MacDill Air Force Base in Florida on Aug. 28, 1954. His mother, Virginia Anne Strong, was an author, attorney, psychologist and architect. His father, Stewart McDonald, was an actor, barefoot water-skier, race-car driver and reputed raconteur.
They separated when he was a young child. His mother remarried twice, the second time to Dr. Gaylord Church, who adopted nine-year-old George.
He spent most of his first decade in the middle class neighborhoods of Tampa, Fla., inhabiting a sphere he describes as “very, very limited.”
He walked to the corner store for candy and soda. He searched for sand dollars, fiddler crabs and dolphins along the shoreline. He attended a Catholic school where, as a Lutheran with a mind that ticks faster than most, he occasionally found himself in theological wrangles with his instructors.
Church got his biggest kick from examining the exotic instruments in his father’s medical bag. Dr. Church sterilized his own needles, and occasionally allowed his son to give him injections. It wasn’t until years later that he realized his dad, like many physicians of the day, was addicted to painkillers.
Young George got his first glimpse of a world more in tune with his imagination when he attended the 1964 New York World’s Fair, a tidy alternate universe on display in the pavilions covering Flushing Meadows’ Corona Park.
Disney’s audio-animatronic Abraham Lincoln stood up and delivered a five-minute address, a supercut of the 16th president’s speech highlights. IBM showed off handwriting recognition on a mainframe. Test pilot Robert Courter blasted through the air on a jetpack.
“Why would you not have a robot that looks like Abraham Lincoln, why would it look like an erector set?” Church said in an interview in his even smaller office at the Harvard Medical School, just across the street from the Center for Life Science. “Why use a computer with a punchcard, when you could use one with a touch pen on the screen? Why a car, when you could use a jetpack?”
“Everything made much more sense in Queens, New York.”
This was when he first developed the itching feeling that he refers to as “the neuroses.”
“I felt like I’ve been to the future, part of me lives in the future, and I’m stuck here,” he said. “I’ve been trapped back in time, and I have to make the most of it.”
Bringing back the mammoth
Far deeper in the past, during the last Ice Age, woolly mammoths ranged across the northernmost tips of the northern continents, foraging the tundra for grasses, sedges and shrubs.
They were not, in fact, particularly mammoth, standing no taller than elephants of today. But they were ready-made for the cold, with coarse fur, small ears, layers of fat and long tusks that may have been well-suited to digging up food under snow and ice.
It is a matter of ongoing debate why their numbers began to plummet roughly 10,000 years ago. Recent research suggests that the warming climate limited their grazing habitat. But early humans hardly helped, as spear marks suggest the animals were hunted for food.
Thanks to the frosty terrain, scientists have been able to study unusually complete specimens for such a long-lost creature, skin and soft tissue preserved in the permafrost. And that may offer the key to bringing them back.
Other than viruses, the only species that scientists have “successfully” brought back from extinction is the Pyrenean ibex. It died minutes later due to a lung deformity.
The researchers used cloning techniques because they had the benefit of frozen cells, a simpler process than the extensive genome editing that may be required for the long-gone woolly mammoth.
That raises real questions about whether the mammoth resurrection will work, how many attempts it will take and what kind of animal suffering might occur along the way.
“I don’t think it’d be worth it to create 100 crippled mammals in order to get one successful one,” said Hank Greely, a Stanford law professor focused on the ethical issues raised by biomedical technology. “I think animal welfare is a real issue.”
The bigger question is: Why do it at all? It applies to Church’s research, as well as the work of other scientists attempting to revive the mammoth, the passenger pigeon and the gastric brooding frog, a biological wonder that gave birth through its mouth before vanishing from the Earth.
There’s a long and varied list of criticisms: It is akin to playing God. Meddling in the stuff of life carries risks we can hardly predict let alone control. We’d be bringing animals back into the same habitat that couldn’t support them the last time. And de-extinction could present a moral hazard, undermining the urgency to preserve endangered species.
“So what do you have?” said Elizabeth Kolbert, the science writer for the New Yorker magazine, who has reported extensively on climate change and extinction. “You have some curiosity that has to be kept in a zoo.”
“I’m pretty down on the idea,” she added. “I think it’s basically being done for people, not for other species or for the planet. It’s being done because we think it’s cool, or it assuages our guilt.”
Others argue these revived animals won’t actually be the extinct species, but the closest facsimile within our technical grasp, with an overweighted emphasis on the differences most recognizable to humans.
If so, will science have really brought anything back to life, or simply invented something new? And if that’s the case, is it really conservation at all?
“One-time loser”
Church left home at the age of 14 to attend the Phillips Academy, a prestigious private school in Andover, Mass., where his interests deepened in math, biology, photography and computers. He taught himself how to program in Basic on a little-used computer he discovered in the math building’s basement, indulging in some light hacking on the computers at nearby Dartmouth.
He found a way to combine his interests at Duke University when he discovered the crystallography lab, which harnessed all these tools to study the structure of molecules and atoms.
In the mid-1970s, Church won a National Science Foundation grant and immersed himself in studying transfer RNA, which serves a critical role helping DNA produce the proteins that make up organs, tissues and bones. He cranked out five notable papers, but failed two classes.
“I would work like 100 to 105 hours a week on research, and that’s all I did,” he said. “I was the typical obsessive scientist. Maybe a little atypical.”
After flunking out, Church applied to Harvard and only Harvard. He got in, despite being what he describes as “a one-time loser,” likely due to an especially kind letter from his adviser, an unusually weak pool of candidates that year, or both.
Church was anxious about this early failure as he got started on his doctoral program, but uncoiled a bit when he walked into a class and realized that the professor was presenting one of his papers.
In the early 1980s, as part of his PhD thesis work, Church developed methods for what are known as direct genome sequencing and molecular multiplexing, essentially methods for speeding up the reading of DNA by sequencing multiple strands at once in a mixture.
The ideas didn’t catch on right away, as the field’s attention would soon focus on the Human Genome Project, the $3 billion and more than decade-long effort to sequence the first full human genome.
Much to the frustration of Church, the project relied on slower technology, locking in what he saw as incremental improvements. But genomics went into hyperdrive once the project was complete, as multiplexing and other advances dramatically cut the cost and improved the accuracy of sequencing.
Church became a professor at Harvard, set up his own lab and sought other scientists in his own mold: People who didn’t necessarily look perfect on paper, but were single-mindedly focused on ambitious research.
Jay Shendure, a graduate student there during the early 2000s and now a professor at the University of Washington, recalls Church handing him a half-sheet of paper one day.
“It was a list of six ideas and, if you’re a graduate student trying to come up with a project, they were just nuts,” he said. “They were basically ideas that might result from an acid trip, but you’re faced with this question: Do I want to gamble on what would be a very hard, long-odds thing? Because if you could do it, it would be a very big deal.”
Biotech 2.0
The Church Lab was a blur of scientific creativity by the mid 2000s. He and his researchers cranked out a series of breakthrough papers that helped create the modern toolbox of genomics.
A 2004 Nature article described a method of DNA synthesis, essentially printing out strands onto specially-designed microchips, that reduced the costs by a thousandfold.
A 2005 Science paper, on which Shendure was the lead author, unveiled a refined multiplexing process that allowed them to analyze millions of genomic sequences all at once.
A 2009 Nature article introduced multiplex automated genome engineering, or MAGE, a method for making dozens of changes to a bacterial genome simultaneously.
And a 2013 Science paper demonstrated the first use of CRISPR, a precise editing technique widely considered a game-changer for the field, to engineer human cells.
The lab’s innovations helped form some of the technical underpinning of what is known as “next-generation sequencing,” a critical advance relied upon at companies like Illumina, Complete Genomics and Oxford Nanopore.
Meanwhile, Church co-founded a series of businesses himself that have taken advantage of the improvements in reading the genome for medical diagnostics (Knome, Alacris), writing DNA for research purposes (Gen9) and editing the genome to develop medical treatments or biofuels (Editas, Joule, Egenesis).
Many of his 14 businesses are located throughout the Greater Boston area, several just a short stroll from one another within Cambridge’s Kendall Square.
It is hard to overstate how much these and other advances in the field have pushed forward genetic engineering from the early days of Genentech, when researchers used enzymes to painstakingly cut and insert bits of genetic code in what is known as recombinant DNA technology.
“It was like building a house out of Legos with boxing gloves,” said Steve Jurvestson, a partner at venture capital firm DFJ, which invested in Gen9. “Now we can literally just print out life. That, to me, is mind-bending.”
Scientific credit is a tricky thing. Teams of researchers work on projects together, advances tend to happen in several places at once, and pieces from here and there add up to bigger strides together.
But Church’s peers say that science is years ahead because of his lab’s work. That’s no small thing in the genetics field: In a little more than a decade, the price of full genome sequencing has plummeted from about $3 billion to around $1,000, utterly flattening the curve of Moore’s Law by comparison.
“He rightfully gets a lot of credit for that,” Kosuri said.
Planting a stake
Interviewing George Church is daunting, because you don’t know where to start. Look at his lab’s website and you’ll see work ranging from aging therapies to microbiome research to genome engineering to cancer-killing nanorobots.
In 2005, Church spearheaded the Personal Genome Project, an effort to build an open database of health information from thousands of willing participants. These days, he’s most focused on the BRAIN initiative, a joint effort with DARPA, the National Science Foundation and other organizations to improve our rudimentary understanding of the brain and its myriad disorders.
Meanwhile, his lab has been working on encoding books and videos in DNA, creating mosquitos resistant to malaria and “recoding” organisms to nudge them into producing entirely new proteins. The day I visited the lab, Church was ordering parts to build a dark-matter detector.
“He’s not an incremental thinker,” said investor Esther Dyson, an early participant in the Personal Genome Project. “He wants to put a stake out far and figure out how to get there.”
Church said that the focus in his lab is on treating and preventing disease, stressing that the woolly mammoth work is among the smallest and least-funded of his “side projects.” But the very nature of the end goal, with all its “Jurassic Park” connotations, means it is bound to draw more public attention than anything else he has done. (See: The story you’re reading.)
Printing out Elephas primigenius
Along the back wall of Church’s lab sits a blue metal box, basically a 3-D printer that works at the scale of molecules, spitting out custom-ordered strands of DNA.
In recent months, his team has used “oligo synthesizers” like this to produce sequences that haven’t existed inside living organisms for some 4,000 years, reconstructing lines of code extracted from the preserved bones, blood and flesh of Elephas primigenius. The woolly mammoth.
By sequencing those found fragments of DNA, scientists have been piecing together a full genome for the lost megafauna, which runs to nearly five billion base pairs — dwarfing that of humans.
Researchers can’t yet print out or stitch together a genome anywhere near that long, but Church and others exploring de-extinction are pursuing a different route, which draws on those improving editing tools.
They’re comparing the mammoth genomes to those of its closest living relative, the Asian elephant. The hope is they can print out the strands that differ, paste them into the right spots, insert that into an embryonic cell and implant it into the uterus of an elephant. If all goes well, 22 months later, voila: Woolly mammoth calf.
But genome editing is delicate work. The longer the strands and the more insertion points, the greater the chance that something will go wrong along the way.
Church has homed in on the woolly mammoth because he thinks it presents the best opportunity for success. There are relatively few differences, fewer in fact than between the Asian elephant and its present-day African cousin.
His team has already successfully inserted 15 changes into the elephant genome. They’re proceeding slowly and cautiously, he emphasized, ensuring the alterations aren’t damaging the cells.
“All this depends on very carefully evaluating every step, so that the elephants are happy and the public is happy,” he said. “But it could happen very quickly, if we’re lucky and clever.”
Pushing the boundaries of the possible
The best and most obvious response to why scientists should explore de-extinction is that we need new weapons in our arsenal, even if they are imperfect or make us uneasy. We have been fighting a losing war, and the stakes are about to get much bigger.
Stanford researchers, Kolbert and others argue that we’re in the midst of the Sixth Extinction, the latest in a series of mass species losses spanning the history of the planet, triggered in the past by meteors, climate shifts or reasons unknown. This time, humans seem to be the principal cause, as we encroach on habitat, alter the climate or kill for food, sport, fins and tusks.
The U.N. Intergovernmental Panel on Climate Change has said that temperature increases by the end of the century could wipe out as much as 70 percent of known species.
In other words: We’re already playing God, we’re just lousy at it. So shouldn’t we try to harness our technologies to address some of the problems we’ve caused as well?
When I asked Church why we should pursue de-extinction, several times in several ways, he moved across a number of themes.
He noted that the return of the passenger pigeon, which used to compete vigorously for food with tick-carrying rodents, could tamp down the surge of Lyme disease in this nation.
It is also believed that the woolly mammoth stomped down snow and ate away dark vegetation that absorbed heat in the Arctic tundra. He said that returning the creature in sufficient numbers may help protect the thawing permafrost, which sequesters more carbon dioxide than all of the rain forests combined.
Preventing disease, preserving habitats and slowing global warming are certainly answers a policymaker, environmentalist or Joe Public might want to hear. But no one can really say for sure how these complex systems will respond to the return of particular creatures, so it’s tricky terrain upon which to balance the whole argument.
Church doesn’t, however. The solid core of his answer comes later in our conversations. It’s a little messy and abstract, but basically amounts to the rationale for superconducting supercolliders and missions to Mars: Discovery for discovery’s sake.
Reaching beyond what seems possible is what springboards us into the future, spinning out all manner of practical if unpredictable advances along the way.
Bringing back a mammoth might refine gene-editing tools that help preserve endangered species, treat human diseases, or something else entirely. Nobody knows, and that’s the point.
Church draws an analogy to the moon landing, which directly or indirectly gave the world pacemakers, cordless drills, hazmat suits, solar panels, MRIs and on and on. It also inspired a generation of young minds to study science and engineering — or at least to respect its pursuit.
“Right now it’s a ratchet, things go extinct and that’s it,” Church said. “But if you can show an example, it becomes a field of progress, rather than steady decline.”
“I think you need both practical and awe-inspiring. And they’re all tied up together.”
This article originally appeared on Recode.net.
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