The day Larry Page posted his famous blog announcing Calico’s arrival, Art Levinson was well into ruminating on who might make up the company’s leadership. Hal Barron was one of the candidates. He was a Yale Med School cardiologist who had been Genentech’s chief medical officer for 12 years before serving the same role at Roche when the Swiss company bought the remainder of Genentech in 2009. Levinson already considered Barron the best drug developer in the world—so when Barron reached out, Levinson immediately asked him to become Calico’s president of research and development.
Another key executive was David Botstein, the selfsame firebrand who 30 years earlier had risen up at the meeting in Cold Spring and harangued the assembled scientists on the injustice of spending billions to sequence the human genome. A “program for unemployed bombmakers” were his exact words. Since then, Botstein had become a believer. The years had transformed him into one of those statesman-scientists whose intellectual capital and political mileage were honored and valued more than his fulminations. He could still be gruff and cantankerous, though, and rarely withheld his opinion if one came to mind, which was often. Like Barron and Levinson, Botstein was also new to the field of aging. Genetics was his wheelhouse, and he was considered one of the world’s experts. He had even written a book on the subject, Decoding the Language of Genetics, which combined his insights into the history of genetics with efforts to make the arcane language in the field easier to comprehend. Everyone was grateful for that.
Cynthia Kenyon contacted Levinson the minute the news of Calico hit the wires. She was one of the true leading lights in the longevity field, the Herbert Boyer Distinguished Professor of Biochemistry and Biophysics at the University of California at San Francisco. She would head up all of the company’s research on aging.
Bob Cohen, an M.D. and oncology specialist, joined the brain trust too. Cohen and Levinson went way back to the early 1990s, where he had helped Genentech and Levinson develop some of their most successful breakthrough cancer drugs. Cohen had a knack for connecting scientific advances that related to human disease. And Levinson knew his opinions and insights would be absolutely honest: something Levinson greatly valued.
Three years later, in 2016, Calico would also bring in Daphne Koller as chief computing officer. Koller’s pedigree in AI was undisputed. She had landed her first university degree when she was 17, and then a master’s a year later, both at the Hebrew University of Jerusalem. That was 1986. By 1995, she had won her Ph.D. in computer science at Berkeley and was teaching at Stanford’s computer science department. In 2004, the MacArthur Foundation awarded her a $500,000 “genius” grant. She used some of the time and money to do research with biologists at UCSF, Levinson and Kenyon’s old stomping grounds. While there, she developed a new type of cancer gene map that used Bayesian techniques to help explain why breast tumors in some cancers spread to bone.
For the first several months of the company’s existence, the Calico Five—Levinson, Botstein, Barron, Cohen, and Kenyon—wandered between the Googleplex in Mountain View and YouTube’s offices in San Bruno, corporately homeless. They were sitting on $1.5 billion of high-grade, high-tech, Big Pharma money, and the company didn’t even have a place to hang a shingle! This might seem odd, but for Levinson it was typical. Better to avoid discussions about such things as office space, as well as staff and equipment and all the financial nightmares that go with it, until everyone could bring a little more clarity to the table.
During their itinerant wanderings, the group read and reread paper after scientific paper on aging, peer-reviewed documents in scientific journals like Nature, Cell, and The Proceedings of the National Academy of Sciences. There were no shortages of hypotheses. The team brought in experts to ask every question they could imagine about longevity and aging and disease. In between, they divvied up the science and made presentations to one another, debated and plotted approaches. They visited research centers throughout the country—all the usual suspects (and a few elsewhere, including Aubrey de Grey, who very much wanted to work with Calico). Then they came back and tore the prevailing wisdom apart some more. Aging was not only poorly understood, they concluded; it was horribly understood. It reminded one of Craig Venter’s oft quoted insight almost 20 years earlier that “We don’t know shit about biology.”
If that was true of biology then, it was even truer of aging. The way Levinson and the rest of the Calico Five saw it, this was partly because the field was still so new, and partly because it had a way of attracting quirky, even sloppy, scientific work: the kind that tilted, ever so slightly, toward the less than rigorous side of the equation. As a result, little truly serious research had been devoted to it. People spent billions on vitamins and supplements to avoid aging, yet not a single pharmaceutical company had spent a nickel on developing any antiaging drugs.
Given the garbled state of the research, Levinson decided that Calico should put aside the then accepted lists of “what kills us” for the time being. Maybe those theories were correct. Maybe death was all about telomeres and free radicals and transposons. If so, good luck to those researchers; his hat was off to them. But from where he sat in 2013, it was best that Calico go back to the drawing board. Get it right on your own. Be rigorous. That was the only way to really bring the beast to ground.
SOME OF THE RIGOROUS WAYS to bring the beast to ground had roots in Cynthia Kenyon’s work. She was a star in the longevity field largely because of a strange and pioneering discovery she had made long before Google and Calico existed—even before Art Levinson rose to become Genentech’s CEO and Craig Venter crashed his way through the HGP. It had to do with, of all things, worms—a particular kind of roundworm properly called Caenorhabditis elegans, C. elegans for short.
It was 1993, and one of Kenyon’s doctoral students was looking at whole bunches of the tiny creatures in petri dishes at her UCSF lab. Kenyon later remembered that her student called what she was witnessing “magical”—not a term you would normally apply to worms. What made them magical was that they kept refusing to die at a time when they should have been long gone. When Kenyon herself peered into the microscope, she remembered thinking. “This can’t be possible!”
But it was, and Kenyon felt she knew why: She and her team had modified a key gene in this batch of worms called Daf-2, a protein related to sensing insulin glucose. The little creatures consisted of 21,000 genes, a total of 100 million base pairs of DNA. That was a lot of information. And yet when Kenyon and her team changed just those two tiny nucleotides, the worms lived to twice their normal age!
Most C. elegans survived about 21 days, and remained youthful until around day 12. That was normal. But after that, they began to slow down. By day 17, they looked like the worm version of folks in the nursing home, and three days later, they were gone. But not these; they were whooping it up like teens on a beach long after day 17, or even day 30. They even stayed sexually active longer. If this were to happen to your average septuagenarians, they would look and act like 35-year-olds, and be living the good life right up to 150.
Kenyon was so surprised by the finding that she went back and double-checked the work. She even repeated the experiment to be sure. It all checked out. And that was good news—because thanks to those magic genes, her career took a 180-degree turn.
NOT LONG BEFORE, Kenyon had found herself in something of a dead end. During her days studying biochemistry at Georgia Tech, she was invariably polite and soft-spoken—and even now, in her 60s, sometimes spoke like a midwestern teen from the 1950s, using words like “Gee!” and “Cool!” She could even come across as a little ditzy, but that was far from accurate. Kenyon was smart and thoroughly driven. She was valedictorian of her graduating class at Georgia Tech, earned her doctorate at MIT, and did postdoctoral work at University of Cambridge before landing at UCSF.
But Kenyon did have a stubborn streak—or maybe tenacious was a better word. She didn’t care if other people said she was wrong, as long as she felt she was right. Her father liked to say, “There’s a right way to do things and a wrong way. And then there’s Cynthia’s way.”
Maybe that was why Kenyon decided to explore aging research, even though it did not go over at all well with her colleagues. One told her the field was a backwater for crackpots who couldn’t do really important science. It was for losers, because nothing could be done about aging, certainly nothing genetic, because genes didn’t affect the length of any creature’s life span; that was set. Didn’t she realize that small creatures lived short lives and large ones lived longer ones, and that when it came to life span, genes were not a factor?
Kenyon begged to differ. Because of her background in genetic development, she believed it was clear that genes were the master switches that flipped just about every imaginable biological behavior. So why not aging?
And that was why Kenyon’s life-doubling discovery became giant news. When she (and her students) published the first paper in Nature, December 1993, researchers suddenly found themselves wondering if maybe there was some real science to this aging/longevity thing after all. Maybe there were genes that fundamentally affected how long an organism lived. And maybe those genes could be changed. And if they could…
SOME 20 YEARS LATER, when Art Levinson first came across Cynthia Kenyon’s idea that it might be possible to genetically toggle the age of a living creature, he too was stunned. Could there really be molecular gears so fundamental that they could double a life span, even a worm’s? Then, when he read that another genetic pathway dubbed TOR (target of rapamycin, also related to insulin resistance) doubled the lives of the worms yet again, he was even more amazed. These experiments had now quadrupled the critters’ lives, which made them the equivalent of a high-spirited 320-year-old human being. In time, researchers found ways to increase the animals’ life spans by a factor of 10! Still later, similar gene manipulation radically increased the life spans of fruit flies.
Now everyone knows that humans aren’t worms or fruit flies. But we do share many genetic pathways with seemingly remote creatures, including mice. So researchers tried rearranging the Daf-2 genes in some mice, and, remarkably, they lived twice as long too. Genetically speaking at least, mice were a lot closer to humans than worms; the two shared 99 percent of their genetic makeup, which suggested results in mice might have serious implications for humans.
Not that Kenyon or Levinson were planning just then to arrange a trial that altered Daf-2 genes in a lot of human infants to see if they lived for the next 300 years. That would require some sort of longevity pill of its own, and it was why researchers used mice and fruit flies and worms in research trials in the first place: to get quick results. Besides, it was way too early, and because the FDA still didn’t consider aging a disease, any such trial would be impossible.
But there might be other ways to go at the problem.
One of the several benefits researchers had found in Daf-2 mice mutants was a reduction in cancer. The mutated gene seemed to diminish oxidative stress in the animals, which in turn reduced cancer rates. What if Calico were to consider an FDA trial that reduced cancer using insights from the Daf-2 experiments? That would look like nothing more than an intriguing cancer trial, and if it worked, great. And if an additional side effect was that the same people in the trial slowed their aging as well, even better.
This wasn’t an entirely new idea. Others had already attempted similar research. In one trial, scientists attempted to reduce arthritis by using a cancer drug to destroy senescent cells that formed in the joints of aging mice. The idea was that these cells—the kind Aubrey de Grey finds so captivating—increase inflammation in the body. If the drugs reduced senescent cells in painful joints, was it possible your average human would also become generally healthier and younger? It turns out the lab rat trial was right on the money. Human trials were scheduled for 2018, with results expected in 2019.
In the Bronx, at the Institute for Aging Research at Albert Einstein College of Medicine, director Nir Barzilai was working to raise $50 million for an FDA trial he felt could slow aging in one fell swoop, using a drug called metformin. It had been around since the 1950s, and was used to lower insulin resistance in people with diabetes. It turns out that the drug has effects similar to Kenyon’s mutated Daf-2 gene. It reduces insulin resistance, and also lowers cancer rates, oxidative stress, and maybe even Alzheimer’s in animals and patients treated for type 2 diabetes.
In general, tweaking genes that lower insulin resistance seems to fake the body into believing it is living in a world where food is scarce. From an evolutionary viewpoint, the genetic processes within the species say, “Okay, listen up! We need to focus on finding food and staying alive, so let’s slow the aging process until the situation improves. Later, once we have more food and are sure we can live well enough again to create new offspring, we can do our job, have some babies, and get on with dying.” Or put another way, starvation had the effect of slowing aging.
Neither animals nor DNA actually “think” this way, but that was more or less what seemed to happen on a molecular level, and precisely what Daf-2 seemed to do. These master switches shifted the creatures’ evolutionary clocks to ensure the species survived long enough to improve their chances of making more offspring later. The question was: Could scientists perform the same wonders for Homo sapiens?