Immortality, Inc.

by Chip Walter

  Hariri had often wondered why a mother’s body didn’t suffer the same rejection issues when a sperm cell and an egg created a new baby in nine months’ time. After all, even a fetus was a foreign body. Yet there was never a problem. Why? Because the placenta actually suppresses several classes of molecules that mask the fetus, the way a chameleon masks itself from the colors around it. Immunologically speaking, the mother never even realizes the baby is there! This was one of the great advances in mammalian evolution: the ability to gestate offspring in a protective womb instead of a pouch like a kangaroo, or the egg of a chicken or salamander.

  In Hariri’s mind, this meant placental stem cells could deliver an extraordinary biological trifecta: They could be used in any part of the body; they seemed to possess astonishing regenerative powers; and recipients didn’t reject them. So wasn’t it just a little bit crazy that every year over 129 million human placentas were being tossed into the trash? Hariri wanted to change that. He estimated that for every placenta used, researchers could create some hundred thousand treatments. Maybe some of them could even turn back the biological clock.

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  —

  VENTER FOUND STEM CELLS fascinating too, but his real interest was in unmasking the mysteries of the human genome. In his mind, that would introduce an era of truly preventative medicine, rather than the current model, the one in which people lurched into their doctors’ offices or emergency rooms, in pain or already sick. Doc, my knees are killing me. I can’t seem to see (hear, walk, talk) as well as I used to. I’m exhausted.

  In 2012, what else could a doctor do? Run some tests, figure out what the symptoms meant, react and try to repair the damage already done. Maybe some drugs could slow the progression. But wouldn’t it make more sense to get ahead of the trouble before it ran you over?

  That was why Venter wanted to unlock the secrets of each patient’s genome. Since the days of the Human Genome Project, he had believed that your DNA revealed pretty much everything about you (not counting your personal experience). It wasn’t just the way you looked, but the way your body tended to develop and grow strong, and then later, break down. Genes revealed whether you were shy or anxious or aggressive, easygoing or driven, or all of those in some combination. Every bit of information was there, but for now, almost none of it was known. This was why Venter felt it was so important to sequence as many human genes as possible. Once that was accomplished, you could finally know your own personal biological future in advance, and repair your body and mind before aging wore them down.

  But to make that possible, the cost of sequencing human genes needed to drop, and speeds had to increase. And that was precisely what was happening. The first human genome had cost three billion dollars; in 2013, the price was approaching $2,000, and dropping fast, just as Kurzweil had foreseen.

  The three scientists would have a lot more to discuss over the coming months, but once they had met, it became perfectly clear that they should join forces. By fusing two powerful medical technologies—genomics and stem cells—maybe they could pull off a kind of biological hat trick: an enterprise that revolutionized the practice of medicine, seriously extended life, and simultaneously improved its quality. Think of the dividends this might pay to society—not to mention the financial rewards it could reap.

  To make money, however, you have to spend money—and that meant large investments would be required. Not millions of dollars, or tens of millions, but hundreds of millions. That was where Diamandis came in. He was the Olympic class fundraiser—or as Venter put it, “quite the man about town.” Hariri called him an intellectual cupid. In the course of his many undertakings, he had made friends with just about every big wallet in Silicon Valley. Thus, in mid-2013, Diamandis sat down to brainstorm a board and put together a list of billionaires he thought might invest. Included were Elon Musk, Eric Schmidt, and Larry Page, Peter Thiel of PayPal fame, Microsoft co-founder Paul Allen, and Richard Branson, founder of Virgin Atlantic. That was the short list.

  Nine months later, in March 2014, Venter, Hariri, and Diamandis formed their triumvirate and announced the creation of Human Longevity, Inc., tapping the Valley’s deep pockets to pool a first round investment of $70 million. It wasn’t the kind of money Google could toss at Calico—but it got things rolling, and more would be forthcoming. Almost immediately, HLI’s offices sprung to life in San Diego and then Palo Alto. Instantly, the company became a key player. And in typical fashion, Venter began mustering his troops to spawn another breakthrough in genomics.

  | PART FOUR |

  SUCCESS

  ———

  The long habit of living, indisposeth us for dying.

  —THOMAS BROWNE

  18 | CHEATING DEATH

  In the 21st-century world of Silicon Valley, not many people had heard of Benjamin Gompertz, and there was a good reason for it. Born in the 17th century, he was a little known, self-taught mathematician. Because he was a British Jew, he had been barred from a university education, so he took up work at the London Stock Exchange. In his spare time, though, he absorbed all the writings of Isaac Newton and mastered every kind of advanced mathematics. When a couple of his close relatives founded the Alliance Assurance Company in 1824, Gompertz became its head actuary.

  Insurance companies like to know when, as a group, people die, and the central duty of an actuary is to figure that out. And that was how the young math whiz came up with an equation known as Gompertz’s Law of Mortality. It provided a mathematical indication of when people are most likely to depart the planet.

  Art Levinson found this equation fascinating. When he talked about it at Calico, he would leap to the whiteboard to write it out and then rapidly plot its graph, also known as the Gompertz curve. When expressed, it looked a little like the bottom end of a steep ski slope.

  To most people, the equation didn’t make a lot of sense. It read: H(t)=αeßt+λ.12 But to Levinson it was a beautiful thing. He admired its clarity and logic. To take something as powerful and emotionally complex as living and dying and express it in a simple scientific formula—well, that was perfection!

  The H(t) in the formula stood for the many deadly hazards humans face over time (t). The variables on the other side of the equal sign together explained how, exactly, all of that dying happens. The really important variables in the equation were alpha, beta, and gamma—the α, ß, and λ in the equation.13

  Levinson had entirely forgotten about Gompertz, until he, Botstein, Kenyon, and the rest got to talking about the mathematics of growing old. Without realizing it, Levinson had seen this same Gompertzian insight back when his uncle Howard had sent him The World Almanac. As with those statistics, the Gompertz equation revealed that during the early years of life, the beginning of the curve was pretty flat; death and danger were remote, and health was abundant. Then as the curve began to rise, it showed that each year death marched exponentially closer. The steepness of that curve said something chilling about human life span: The likelihood of dying doubled every eight and a half years! Which meant that by the time you got to 70 or 80, you were not going to last much longer.

  Levinson explained the workings of the equation like this:

  Alpha represented the personal, genetic hand nature dealt you—bad cards or good—together with your own experience: stress, diet, medical treatments, exercise, and economic/social status. Alpha could change from person to person depending on all of those variables. Gamma was a random, but lethal, event: a car accident, drowning, murder—the sorts of tragic occurrences that were completely random. But the third variable, beta, was universal, a force that affects all human beings regardless of their personal experience. No matter how terrific someone’s genes and upbringing are, no matter how well one handles stress or how rigorously one might work out and faithfully consume a Mediterranean diet, he or she was not going to live 200 or 300 years. No human lived that long.

  Why? Because for one reason or another, evolution long ago set a universal life limit for
every animal, including humans. The maximum for Homo sapiens appeared to be between 110 and 120 years. No one lived 150 or 200 years. Therefore, if you were really going to radically extend human life, it was clear someone was somehow going to have to change beta. It was the only way you could really solve the Ultimate Problem.

  Levinson had come across the equation when he met Larry Norton about 25 years earlier. A physician and cancer biologist at Sloan Kettering, Norton had used the formula to describe how cancer tumors grew. Slow at first with the initial tumor, and then rapidly as tumors spread to other parts of the body. Norton’s insight forever changed the way cancer was treated with radiation and drugs. One scientist called the Gompertz curve “one of the greatest quantitative laws of biology.”

  Among the traits that Levinson found particularly appealing about the equation was that it split the problem of dying into three neat pieces.

  There was little anyone could do about gamma. It was impossible to change or eliminate it. As horrible as it is, people sometimes die for no good reason.

  Alpha could be improved, but only up to a point; after all, science had already nearly doubled human life span over the past 115 years, at least in the world’s wealthiest nations. Continuing advancements in cancer, and a cure for Alzheimer’s, would improve alpha even more, and that would be wonderful—but it would not fundamentally change the human ability to pass beyond that maximum limit. That was why alpha was getting tougher and tougher to improve. If nothing else killed you, your chances of dying, on average, still doubled every eight and a half years. Evolution had created an upper limit, and no amount of luck or abundant alphas were ever going to improve beta.

  But what if you could change beta—actually amend the inborn life span of the human species? That was a different story. Hadn’t Cynthia Kenyon found something like this with her Daf-2 discoveries? Was a solution to beta lurking there, hidden among our three billion genes, that could help the human race make the leap from 80 years past 115 to 200 or even 300, maybe more?

  To explore that idea, Levinson asked one of Calico’s computational biologists, a researcher named Eugene Melamud, to run some numbers and see exactly what happened if beta could be beat.

  Melamud started by reviewing a sample of 100,000 Americans. The statistics showed that by age 50, fewer than 5,000 of those people die: almost 50 percent from poisoning, 18 percent from accidents and other killers. Heart disease dispatched hardly more than 6 percent!

  But remember, the average human’s chance of dying doubles every eight and a half years, and so after age 50 the decline gathers speed, despite all the beta-blockers and cancer drugs we have thus far applied to our afflictions. By age 60, the number of the deceased reaches 11,000, and by age 72, 25,000 have passed through the veil. At age 100, fewer than 3 percent of those 100,000 will still be living. Melamud’s graphs showed that the longer people lived, the longer the list of diseases became: malfunctioning hearts, cancer, and Alzheimer’s being the three biggest killers. Whatever slowed those diseases and increased life span occurred thanks only to alpha’s whack-a-mole–style medicine.

  For fun, Melamud changed the statistical model for beta—the constant 8.5-year number that set the evolutionary life limit for humans at no more than 120 years. When that number was zeroed out, the calculations didn’t merely show an improvement; they blew everybody away. If the increase in beta was halted at age 30—a huge if to be sure—the median life span of that person would leap to 695 years! That was just the median. Some people might live nearly 1,400 years. If you stopped the clock at age 50, the number dropped to 181 years, still more than twice the average.

  Levinson even asked Melamud to run the formula if beta were frozen at age 10, the safest of all ages. The math stunned him: The expected life span for 10-year-olds sans beta was 7,987 years, with 90 percent of them living almost 30,000 years! With beta at zero from age 10, a child’s genes were so squeaky clean that almost nothing could kill them. The aging clock would stop, and they would simply continue to repair themselves, pretty much indefinitely.

  Of course, this would require accomplishing something that, up until now, only the great gears and wheels of evolution itself had accomplished: resetting life span at the most profound genetic and molecular level. But Levinson’s point was, beta was powerful! If you wanted to get a really big bang for your time and energy, that was where the magic would be. And if it were accomplished, it would represent the greatest scientific and historic leap in all of human experience. Was it possible?

  19 | METHUSELAHS

  By mid-2016, Calico was bustling along. It had 98 employees, with more in the pipeline. The research labs inside of its growing South San Francisco office were strewn with names like the Lily Pond, Northwest Territory, and Middle Earth. Walls of glass were covered with handwritten graphs and computations: the aggregated thoughts and insights of Calico’s growing roster of lab cats. And everywhere, researchers were hunkered down, working out the ways to bring death to a halt: some in the microscopy section and others in cell biology or computational science.

  Soon Calico was developing arrangements with Ancestry.com to investigate centenarians who seemed, inexplicably, to live so long; the oddities of yeast and the ways they might explain long life; and, perhaps most interesting of all, animals in the biological hinterlands that lived extremely long. The Calico team had found some pretty fascinating examples.

  It was obvious that if you compared, say, an elephant and a dung beetle, their life spans would differ. But what if you looked at two very similar animals and found that one survived much longer than its cousins? That was the case of a fish named Hoplostethus atlanticus, the orange roughy, which, not long ago, was a popular entrée on menus worldwide.

  Orange roughy is very similar to the common pirate perch, which lives in freshwater streams and lakes. Like most fish, they swim around for a few years and then move on to that great pond in the sky. Orange roughy, meanwhile, swim the world’s oceans, in cold water, hauling around pretty much the same genes as their perch colleagues. But how long do they live? The record is 149 years.

  When Levinson, who was an avid consumer of seafood, got that news, he stopped ordering orange roughy on the spot. It made him wonder how many times he had gulped down some poor Hoplostethus atlanticus in its youth, robbing it of a century of good times trolling the reefs off the Kamchatka Peninsula or Scotland’s North Sea.

  But the larger point was that one fish, the perch, was dead and gone in four years; the other stuck around for a century and a half. How did you explain that? This was another example of evolution finding a way to bend beta. And Art Levinson was bound and determined to get to the bottom of it.

  It turns out that nature has created all kinds of intriguing examples of this sort. Another was the naked mole rat, an underground-burrowing rodent also known as a hystricomorph that lives in East Africa. It’s just about the ugliest creature anyone ever laid eyes on: a mouse-size, pigeon-toed alien with beady, lifeless eyes, clawed feet, and yellow skin so pale and bloodless you’d think it had been sheared off a corpse and draped over its sepulchral body by some amateur taxidermist. At the end of its snout protrude two buck teeth that seem to have been randomly hammered in by some sadistic scientist.

  Yet some researchers adore the little beasts, partly because no other rodent lives as long as it does. The hystricomorph record was a male that a physiologist named Shelley Buffenstein brought to the United States from Africa back in 1980, when the little animal was only two years old. After a while, Buffenstein started calling the critter Old Man because he just went on and on. He finally died in 2010, but was still an alpha male in the nest, having a grand old time mating with the queen mole rat right to the end.

  Mole rats routinely lived 25 years. Your average mouse might manage to exist three, and your everyday lab rat’s life rarely ran to four. And yet those shorter-lived rodents shared a lot of the same genes as the mole rat. So why the big difference in life span?

  If anyone knew
the answer, it would be Buffenstein. She had been running the largest mole rat colony in the scientific world for years: 2,000 of the brutes at the Barshop Institute for Longevity and Aging Studies in San Antonio. In 2015, she brought her brood to Calico.

  Once settled, Buffenstein continued to compare her tribe with a whole herd of other rodents of the lab rat variety: hamsters, the Cactus mouse, the white-footed mouse, gerbils—even other types of blind mole rats. Some of the other mole rats lived up to 20 years, but none lived 30 like the Old Man.

  Buffenstein’s comparisons, once she had delved into the genetic noise, revealed that mole rats like Old Man enjoyed the benefits of a powerful protein known as Nrf2, which balances the damage oxidation does to cells, including free radicals. It exists in lots of mammals, including humans. Nrf2 in mole rat cells seemed to help improve the way they handled all sorts of perfidious assaults: oxidation, various poisons, inflammation, heat, deteriorating brain cells—pretty much anything that broke the body down.

  Nrf2’s molecular interactions were incredibly complex: thousands and thousands of bubbling, bouncing, invisible discombobulations across billions of molecules. But in a nutshell, the naked mole rat seemed particularly good at sensing and regulating oxidation in general, and free radicals in particular. If this oxidative stress isn’t cleaned up in any living thing, it accumulates a lot of damage. Thus, not unlike Kenyon’s mutated Daf-2 genes, Nrf2 sets in motion a whole domino effect of benefits with nothing more than a single protein that shields the little beasts so well that they live five to six times longer than nearly every other known rodent. One more example of evolution flipping a master switch and stopping the clock!