by Chip Walter
Of course, it was true that some people lived longer than others. And there was the vague and accepted understanding that genes and personal habits—either good (exercise and proper diet), or bad (overeating, too much alcohol)—had an effect on how quickly one’s biology would bite the dust. But there was never any doubt that bite it would. Aging was simply what happened to anyone who survived long enough to have it happen. The best you could hope to do was treat the inevitable symptoms. If you were really fortunate, your obituary might read: “Died from natural causes.” Which was to say, you wore out. But the idea of slowing aging, or reversing it? That was the stuff of science fiction, not serious research.
Nevertheless, the trends set in motion in the postwar medical world continued. Life was lengthening. Life expectancy in the 1960s now began to approach 70. But again, of those who lived longer, cancer took increasingly more lives, and heart disease was skyrocketing. By 1968, death from damaged hearts peaked at more than 350 per 100,000 people. Because so many had for so long died of infectious diseases, the connection between heart attacks, smoking (everybody smoked), high cholesterol, or high blood pressure had gone right over the heads of the medical experts—they had never been major killers.
Now they were, and researchers in the life sciences began to glimpse the ways high blood pressure and atherosclerosis damaged the vascular system and heart. Not that they had it all figured out. In the 1950s and ’60s, doctors still used a term called “essential hypertension” to explain that people actually needed higher blood pressure to get blood to patients’ brains. That was what made it “essential.” But when researchers began to develop beta-blockers and other drugs that reduced blood pressure, they realized “essential hypertension” wasn’t essential at all. It was just hypertension, and it was blowing people’s vascular systems apart like bad tires. Men (more than women) dropped over in their 60s, or even 50s, from acute coronary thrombosis or myocardial infarction with the random, but inevitable, destruction of a sudden thunderstorm. President Eisenhower had had two heart attacks while in office and finally passed through the veil in 1969. Louis Armstrong died in 1971. J. Edgar Hoover in 1972. President Lyndon Johnson in 1973. All from heart attacks.
Now, suddenly, saving hearts became imperative. On December 15, 1967, Time hailed Dr. Christiaan Neethling Barnard on its cover as the man who performed the first successful heart transplant. The surgery, the magazine said, was “epochal.” The feat seemed both the most outrageous and, at the same time, perfectly sensible way to defeat the new scourge. Nevertheless, it wasn’t a panacea. For most, heart disease, stroke, diabetes, and cancer simply became the new ways to die. It was sad, but what else could one do?
Researchers did have some ideas. Building on the breakthroughs in antibiotics and postwar molecular drug development, they began to connect new dots and develop pharmaceuticals that, if they couldn’t cure the emerging diseases with the same lethal efficiency vaccines and antibiotics had, could perhaps treat the symptoms and slow the damage. The first beta-blockers became available in 1958. They included diuretics designed to slow damage from congestive heart failure and hypertension. Then came calcium channel blockers, and ACE (angiotensin-converting enzyme) inhibitors: more medications for treating high blood pressure, heart failure, and diabetic neuropathy. A long, long list of other “vasoconstriction” drugs flowed as the pipelines of the pharmaceutical industry continued to widen.
Yet, despite these incremental advances, none represented the sorts of breakthroughs that had been made with infectious disease, nothing like a single vaccine or drug, some silver bullet that could wipe out whole classes of killers. That was because these disorders were far more complex. By definition, infectious diseases came in the form of viral or bacterial attacks from outside the body. If you killed the bug, you killed the disease. But the newest top killers were different. They were the result of the body’s own complex and inscrutable biology. Yes, smoking and poor diet and other outside factors could be, and often were, contributing factors. But diabetes, cancer, heart, and vascular disease were largely killing people because they were simply getting older, and the sources of the deterioration were tough to unmask.
Medicine had hit a new kind of wall. There were no knockout punches for these diseases. When it came to aging, the best that Medicine—the kind with a capital M—could manage was to nibble at the edges.
None of this, of course, was immediately obvious. When President Richard Nixon launched the war on cancer in 1971 with the passage of the National Cancer Act, it had the scent of John Kennedy’s race to the moon. Throw enough money, brainpower, and technology at a problem and the next thing you know, you’re bounding around the lunar surface hitting golf balls.
The problem was, going to the moon was largely about engineering and physics. Diseases were about biology, and biology was a far more unpredictable demon than engineering. In those days, the scientists spearheading the research thought cancer was a single disease. Forty years later, they had learned the hard way that it was 100 different diseases, at least, and each one required different treatments.
Not that progress wasn’t made. By 2008, heart disease had been halved, strokes decreased by two-thirds, and new drugs joined with increasingly ingenious treatments and early cancer detection to reduce the disease 21 percent over the previous 13 years.4 At Genentech, in the 1980s and ’90s, Herb Boyer, Art Levinson, and the rest of their teams were snipping DNA with recombinant technology to create pharmaceuticals that attacked diabetes, heart failure, and colon, ovarian, and rectal cancers at the virological/molecular level. Under Levinson’s leadership, Genentech developed some of the first monoclonal drugs, like trastuzumab (trade name Herceptin), which could seek out and destroy specific cancer cells—in this case, an ugly and lethal form of breast cancer. That, in turn, reduced the debilitating damage that radiation and chemotherapy did to the whole body. All of these were postponing death for millions of people. But there was still the dark side: People were living longer, yes, but too often they weren’t living better.
4 | DROOL CUPS AND NAME TAGS
In 1900, the number of Americans who lived past the age of 65 amounted to a mere 3.1 million people. By 2010, more than 40 million graced the nation. Baby boomers were watching more and more of their parents being kept alive by statins, beta-blockers, blood thinners, and diabetes medications, but still they watched them slowly deteriorate, shuttling in and out of hospitals, joining the ever expanding ranks of assisted living facilities. If living longer only meant passing your last years doddering around nursing homes with a drool cup awaiting the arrival of the Great Beyond, who wanted that?
Meanwhile, the cost of keeping the elderly alive was rising by the day. A generation earlier, these souls would have long ago passed away. Yet here they were, collecting Social Security and Medicare, enriching the pharmaceutical industry, and creating more patients for the world’s hospitals than ever. In 2010 the National Institutes of Health (NIH) projected that by 2020, the cost of cancer care in the United States would top $157 billion a year—and the disease struck down the elderly far more than anyone else. The same went for treatments of old standbys like heart disease and arthritis, plus the latest new killer: dementia. Bodies were lasting longer, but brains were blinking out. Thirty-five million people had been diagnosed with some form of dementia around the world, and if the situation didn’t change, the experts at the World Health Organization projected the caseload would triple to 115 million by 2050. The bill? Six hundred four billion dollars a year: one percent of the entire world’s GDP.5
Not that anyone for a moment preferred a quick death over these treatments. But how long could this go on? Many experts simply assumed this was the tattered world in which most of the aged would live. Gerontologists meditated on how the thinning ranks of the young could possibly handle the economic sinkholes boomers would create as they became the next generation to fall to pieces—not just in the United States, but also throughout western Europe and Japan, and the other so-
called advanced nations. In Japan, businesses were now delivering more diapers to the elderly than to infants and toddlers!
Policymakers perceived a supreme irony: Long life was creating an epidemic of new diseases. And baby boomers were not pleased with the results. They knew all too well how the body breaks down, and gerontologists could run the numbers for them in excruciating detail. Maximum lung capacity drops 40 percent between the ages of 20 and 80. At age 40, the eyes have difficulty seeing up close; heart rate drops 25 percent by age 75; half of a 30-year-old man’s muscle mass disappears by the time he is 60; spinal disks are habitually crunched, bulged, or ruptured; bones weaken and veins twist. Arthritis and osteoporosis set in like some biological cat burglar. At 70, memory and reaction time begin to sputter. And this happens in people who are in reasonably good shape!
Yet—and this was the strange thing—this only seemed to add to the boomer mentality. All things were possible, right? So maybe there was some way to stop aging and maintain youth. Hadn’t all the medical advances of the past century proved just that again and again? In the baby boomer’s mind, if you were sick, you simply went to the doctor and were taken care of. It had always been that way. A shot, an antibiotic, a pill, a knee replacement, an MRI—some drug or treatment; there was always a solution, or at least that was the expectation. For boomers, invincibility was a birthright, and under no circumstances was the status quo acceptable.
Nevertheless, aging itself—the true molecular underpinnings of it—refused to knuckle under. Only now were some mainstream researchers beginning to grapple with its complexities. Truthfully, no one really knew what aging was. A disease? A series of diseases? Just the natural order of things, impossible to change, like it was impossible to travel faster than the speed of light?
Back in 1961, American anatomist Leonard Hayflick had found that if you put fresh human fetal cells into a petri dish and let them divide, they would hit their limit at 40 to 60 divisions, then give up the ghost. It was called the Hayflick limit, and it reinforced the idea that dying was a natural—and unstoppable—process.
In 2013, scientists from 10 top universities and institutes around the world published a paper entitled “The Hallmarks of Aging” in the scientific journal Cell. It outlined in yet more detail the many captivating ways the body deteriorates: genomic instability and mitochondrial dysfunction, stem cell exhaustion, and cellular aging. The free radical theory of aging explained how rogue oxygen cells insistently damage DNA like little bombs; the telomere theory held that each time a cell divides, its life span grows shorter until it can no longer be replicated; and the DNA repair theory said we simply lose our ability to effectively restore our cells as we age. Some scientists thought maybe marauding retrotransposons—scoundrel snippets of replicating genes—bogged down our DNA, or the cross talk between each of our own cells and the mitochondria within them became increasingly garbled. Any, or all, of these could be the source of our collective and inevitable doom.
Nor did researchers think aging was simply a matter of a body’s cells breaking down like an old machine. Yes, the brutal hammering that life inflicts on DNA in every body every second—upwards of 10,000 insults a day, per cell (that’s ten thousand hundred trillion hits a day)—takes its toll at the hands of common culprits like radiation from sunlight, chemicals in food and water, mental and emotional stress, and the work of dealing with rogue oxygen molecules (those itinerant free radicals). But that was only the half of it. Usually evolution’s marvelously maximized molecular systems repaired this damage, and the human body continued to function just fine. But with age, the repair mechanisms themselves start to break down—and that accelerates the sabotage.
You could think of the whole arrangement as a recipe. Researchers had known for a long time that DNA doesn’t simply hold the instructions for replicating a cell; it also acts as the operating manual for the cell itself, in the way a recipe tells a chef how to combine all the right ingredients at just the right time and in just the right way to make a fabulous soufflé. When we’re young, the recipe works fine. But imagine a recipe whose key instructions slowly become blotted out with dabs of butter, or some misplaced relish. Or imagine the words disappearing to the point where the cook starts guessing at, or eliminating, the recipe’s instructions. Then the soufflé might not work so well.
Thus it is with living and dying—or at least, that’s what many researchers think. The more smudged and ragged the DNA, the more proteins and ribosomes and enzymes cease to do what they once did so well in their youth—the more death stalks us. The instructions DNA sends—for building muscle and collagen, or white blood cells, heart cells, or sheathing for nerves—begin to unravel; as a result, proteins stop folding the way they should. After a while, individual cells become so compromised that they no longer function properly, at which point still more unraveling occurs.
In some cases, the cell concludes that it’s doing more damage than good and commits hara-kiri—something biologists call apoptosis. One theory is that a cell’s decision to kill itself is evolution’s way of reducing cancer, which happens when cells go sideways and begin dividing uncontrollably. Apoptosis is a fine evolutionary fix that removes damaged cells in the short term, like the weekly trash pickup when you are young. But in the course of life, even the trash system starts to break down and fails to show up, leaving even more dead and damaged cells behind.
Scientists had also learned that not all damaged cells repair themselves or commit suicide. Some simply become “senescent”—useless, but alive enough that they aren’t scooped up and removed as dead. They serve no other purpose except to cause trouble, a little like the zombies of The Walking Dead. And over time, they accumulate. Unlike cells that kill themselves, senescent cells can lead to cancer, which is one theory that explains why cancer increases with age. And if they don’t cause cancer, then their misfiring DNA can produce proteins and enzymes the body doesn’t need or want: loose cannons that begin ransacking the body’s good cells, burdening an already battered body as it ages. In the end, hearing and eyes falter, major organs—including the brain—fail, strength diminishes, the heart stops, and we die.
Clearly, where aging was concerned, there was no shortage of Need. The market and the desire for a long and healthy life were immense. But was there anybody out there with the Will to actually do something about our inevitable and universal demise?
As it turned out, there was.
| PART TWO |
WILL
———
I sing the body electric.
—WALT WHITMAN,
Leaves of Grass
5 | CALICO
The evening of October 18, 2012, was warm and cloudless the way Silicon Valley evenings often are. Art Levinson had just departed Laurene Jobs’s home and was motoring along in his aging Lexus to see Larry Page, and a few others, for dinner at his house in Palo Alto. Laurene was Steve Jobs’s widow, and as Apple’s chairman Levinson had driven down earlier from San Francisco to review a few matters with her.
On and off, Levinson had been thinking about the get-together with Page. He was skeptical, but that wasn’t unusual for him. He was always skeptical. But this particular idea…well, it was intriguing. Very intriguing.
A few weeks earlier, Bill Maris had contacted him, and that had led to the dinner. Along with Sergey Brin, Page was the co-founder of Google. A little more than a year earlier, he had taken over from Eric Schmidt as the company’s CEO, reins he and Brin had voluntarily handed Schmidt in 2001, when the company was still in its infancy. Maris was the head of Google Ventures (also known as GV), a fund that since 2008 had thrown hundreds of millions of dollars at cutting-edge start-ups like Uber, Nest, 23andMe, and a long catalog of others. Together, those businesses had made Maris one of the most successful venture capitalists in Silicon Valley.
Maris reached out to Levinson and told him about his idea. Maris knew it might seem a little out of the ordinary—well, maybe way out of the ordinary—but he hoped to get Levi
nson’s feedback. He wanted to create a start-up designed to cure aging—even death itself.
Levinson had been aware, vaguely, of various efforts to extend life. He had heard of Ray Kurzweil’s prescriptions for radical life extension, had come across Aubrey de Grey’s work on abolishing aging here and there, and suspected the National Institute on Aging (NIA), Harvard, MIT, and other organizations of that ilk had likewise dabbled in the question. But this was a different beast entirely. Google was involved, and Google had a way of bending the fabric of culture and economics the way black holes bend light and gravity.
Levinson knew this because not long ago, he had been a member of Google’s board himself. This was not likely to be some small-time, lab coat, federal grant effort where a few mice were run around the maze and written up in another peer-reviewed science paper. Google had cash, lots of it, and serious intellectual firepower. And that meant any endeavor it brought to the table would also bring serious muscle.
So, Maris asked, was Art willing to talk?
Yes. He was.
* * *
—
THIS THRILLED BILL MARIS to no end. He had been pondering his Big Idea for a while now, and having a heavyweight like Levinson interested vastly improved the chances of the whole endeavor advancing from concept to reality.
Maris had begun to cook up his concept after noticing in the late 2000s that just about every health care company in the world seemed to be either building a computerized diagnostic company of some sort, or a high-tech hardware device designed to improve health. Clearly, biology and computer science were melding. He had also seen this with J. Craig Venter’s work during the Human Genome Project in 2000. Venter had accelerated the use of computers to translate DNA’s molecular messages into digits. That meant researchers could, at least theoretically, reorganize them in all sorts of absorbing ways to unlock the mysteries of the human genome—as well as the drugs that might improve their shortcomings.