by Chip Walter
In the grand scheme of things, though, incremental progress didn’t really eliminate aging. Levinson had explained precisely this insight a few years back, when he was attending a scientific soiree in New York with a tableful of scientists and doctors, including two Nobel laureates. What effect, he asked, did they feel eliminating all cancer would have on the average human life span? Immediately, two of the cancer experts answered they thought 10 years was about right. All at the table nodded. But one of the Nobel Prize winners thought a little longer, and then said, “You know, I don’t think it would change things much. Maybe a year or so.”
Well, said Levinson, this might amaze you, but if we wiped cancer clean off the map today, we would only increase average life span by 2.8 years. That was it.
The table was stunned.
On the one hand, the improvement seemed almost trifling: a mere 2.8 years. Still, if you cured it, think how many tormented people would be saved. Or think of how much pain and suffering the elimination of Alzheimer’s would mean. Alzheimer’s was now the fastest growing disease on Earth, and no one had a clue about how it happened, why it happened, or where it came from. Levinson wasn’t entirely sure if eliminating all aging would eliminate Alzheimer’s, or other forms of dementia. The point was, even if you arrested aging, some diseases might still continue. So why not hedge your bets by developing ways to skin the Calico cat one disease at a time. That was hemisphere number one.
Levinson’s second hemisphere took the opposite approach. That division within the company would focus exclusively on the roots of aging itself. This was entirely virgin territory, and who knew if it could be solved—and even if it could, how long it would take? It might happen in small increments, or with one mighty breakthrough. But it wasn’t going to happen fast. The time lines and money required were staggering. That was a big reason so few tackled aging—that, and the fact that aging still wasn’t considered a disease.
Luckily, Google didn’t think along the lines of your average venture fund. The brain trust there had decided to step away from old-fashioned notions of capital investment and instead create a few selected moonshots to see what sort of magic they might turn up. That was a big part of Larry Page’s view of the Google way, and a big reason Levinson agreed to come on board. If even one or two of Google’s moonshots spun into orbit, there would be more than enough return on investment to cover the losses for those that failed.
Levinson’s final variation on Maris’s original deck came from his belief that Calico needed to bring in a serious pharmaceutical partner. Levinson suspected this idea might not go over well at the Googleplex, and indeed eyebrows did rise. It could dilute the venture’s holdings; such partnerships could be messy and lessen Calico’s control. Why not keep everything within the family? But Levinson held to the belief that a Big Pharma player could haul some heavy water when it came to the brutal bench work involved in medicinal chemistry, toxicology, drug development, and testing. The advantages would make the partnership stronger faster, and would outweigh the loss of any downstream dilution of corporate stock. Levinson wanted Calico to focus on solving the biological roots of disease. Let the pharmaceutical partner execute the solutions. The board decided they would have to mull over that idea.
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IT WAS A SHORT MEETING, maybe 30 or 40 minutes, including the questions asked by all involved. In due course, it was time to let the board think through the whole presentation, especially Levinson’s newest ideas. And so Maris and Levinson departed to await their decision.
As they did, both men felt the meeting had gone pretty well. After enough board meetings, one got a feel for these sorts of things. Yet, decisions could go sideways, and not every question had been buttoned up. They hadn’t even agreed on the total investment yet! Amazing when you thought about it. And yet the feeling was that those details would be worked out soon enough.
Fifteen minutes or so later, Eric Schmidt walked out of the boardroom, looking very serious. He ambled down the hall where Levinson was standing and grabbed his hand.
“Well,” he said, “you got it.” Pregnant pause. “Now don’t fuck up!” And then they all laughed—the chairman of Apple, the executive chairman of Google, and the CEO of Google Ventures. Such are the little pivots that arise when decisions to change the course of history are made.
15 | CAGE MATCH
On September 8, 2013—a little less than nine months after the January board meeting—Larry Page posted a statement on his blog: “I’m excited to announce Calico, a new company that will focus on health and well-being, in particular the challenge of aging and associated diseases. Art Levinson, Chairman and former CEO of Genentech and Chairman of Apple, will be Chief Executive Officer.”
The moment the blog hit the wires, press, pundits, geeks, researchers, venture capitalists—everyone in Silicon Valley—jumped as if they had been shocked with a cattle prod. Phones and emails started lunging around the Valley like great, arcing live wires ripped from the moorings of the main line. Here was one of Silicon Valley’s grand pillars of entrepreneurial achievement, and Arthur Levinson, a bona fide Silicon Valley heavyweight, joining forces to run this crazy new operation funded with bushels of Googlebucks. The combination of the two immediately and fundamentally changed the entire landscape of longevity research.
The word on the grapevine was that Page and his colleagues would be writing many checks—upwards of one billion dollars—focused exclusively on annihilating aging. One rumor had it that when Levinson asked Larry Page how much money Google could ante up, Page simply said, “I’ll let you know when we run out.”
Though no one outside the inner circle knew it at the time, the initial, ground-floor investment from Google was $250 million. That was the money provided to get the operation on its feet; another $500 million was in the hopper when needed. That was half the money. The other half was coming from the pharmaceutical partner that Levinson had argued at the January board meeting would be so important to the Calico fold: AbbVie, a huge firm that already employed 28,000 people and delivered drugs to 170 different countries. That deal wouldn’t be consummated until the fall of 2014, but when it was, AbbVie would kick in up to $250 million more, with another $500 million to come. If Calico could prove its solutions looked reasonably safe and workable, AbbVie would have the option to take the drugs into late-stage FDA trials, and then all the way to market. Still more money for that would come later. So for now, a cool $1.5 billion was guaranteed to be in the bank.
The other big shock, once the press got hold of Page’s blog, was the news that Google was getting directly into the health care business. At the time, this surprised those who populated the Valley. After all, wasn’t Google a software company that made search engines and such? The very name was synonymous with computing. But Page wanted to assure everyone that computing was beginning to touch all sectors of life, and that included ending aging and death—even if, in Page’s words, it appeared “strange or speculative compared with our existing internet businesses.”
Barely a few heartbeats after Page’s blog posted, Time magazine dispatched journalists Harry McCracken and Lev Grossman to get on the job. “Google vs. Death”—what a story! Except there wasn’t much about Google or death in the article. Instead, the piece mostly focused on explaining Google’s moonshots. There was something to be said for moonshots—not so much because Calico, itself, could somehow guarantee longer life, but because Google had decided to back the company in the first place. And who could deny that it was a big deal? That was the underlying, vibrating, unconscious appeal of Calico—Google, Page, Levinson, a billion and a half dollars, life and death.
It was now clear, the best and brightest in the Valley were coming, armed with trainloads of cash tackling the one thing no one in the Valley had yet figured out how to manufacture: time. Hadn’t they all recently seen Steve Jobs, supreme scion of the Valley, brought low, just like every other mortal? The man who appeared indomitable, who had said our goal
should be to “put a dent in the universe,” who had famously written, “Here’s to the crazy ones”—hadn’t even he succumbed, relegated in his last moments to a single, all-encompassing, but inscrutable word, “Wow!”10
Yes, death was the great equalizer, but who wanted to be equal? Who wanted to simply pass away, be left behind? Dying was more than sad; it was an unequivocal cosmic slap-down! A booming message that said who was really in charge, and what really mattered. And it was not the human race—not even Silicon Valley’s anointed, wealthy, driven, and brilliant specimens. It was Death.
But, now, maybe there was hope: for baby boomers, Silicon Valley’s denizens, and all those afterward who didn’t want to die. Maybe, at last, the human race was rising up. A cage match! The brightest, smartest, and richest facing off with the ultimate serial killer. No more tricks or miracle cures, or declamations and ruminations full of sound and fury signifying, in the end…nothing. No, now the human race had its A-Team on the case and woe betide the avenging angel, death’s nemesis. In effect, Google and Larry Page were out–Silicon Valleying Silicon Valley. Others along the Peninsula might say, “Hey we unveiled a new phone or iPad or car last week. What are you up to?”
“Us? Oh, we killed death.”
16 | FIRST PRINCIPLES
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.
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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.
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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?
