by Chip Walter
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…
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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?
17 | HUMAN LONGEVITY, INC.
During all of those heady years following the completion of the Human Genome Project, during his globe-circling explorations of microorganisms and the creation of the world’s first artificial life-form, Craig Venter hadn’t really given the problem of aging and death much specific attention outside his brief adventure with Aubrey de Grey. All of that changed, though, the day he got on the phone with Bob Hariri and Peter Diamandis in the fall of 2012, not long after Art Levinson, Bill Maris, and Larry Page had their dinner in Palo Alto. Diamandis and Hariri had a business venture in mind, and they thought Venter might find it intriguing.
Diamandis was one of Silicon Valley’s most visible personalities: a dark-haired 51-year-old entrepreneur with backgrounds in molecular biology, medicine, and aeronautics that he had gathered while studying at MIT and Harvard. His father had been one of the most celebrated magazine editors in New York, and at one point owned more than 22 specialty magazines including Mademoiselle and New York.
Despite earning an M.D., Diamandis turned away from medicine. Space exploration was his personal fascination going back to his childhood, and in the 1990s, after a series of grand entrepreneurial efforts, he finally landed a fitting project when he created his first XPRIZE. It offered $10 million to any company that could privately build and fly a ship carrying three people into space twice within two weeks. It took eight years, but finally, in 2004, SpaceShipOne took the prize. More importantly, it launched a whole series of XPRIZEs that soon came to influence people up and down the Peninsula, from Larry Page to Elon Musk.
These days Diamandis’s XPRIZE projects are designed to drive the invention of just about everything from lunar landings to the elimination of poverty. Create “radical breakthroughs for the benefit of humanity” is the phrase Diamandis likes to use. These successes, together with the inception of Singularity University (created with Ray Kurzweil) in 2008, cemented Diamandis’s reputation as a mover and shaker in Silicon Valley.
Unlike Diamandis, Bob Hariri was a newcomer to Silicon Valley, although he had known the XPRIZE founder for a decade. Hariri was also a great lover of aviation and an interesting character: big and burly, yet in no way gruff. There could be a boisterous side to him, but when he was talking business, he grew focused and quiet. He had grown up in Queens, raised with his older brother by a single mother, not far from where Ray Kurzweil had lived and wandered during his youth in Jackson Heights. The family wallet had been pretty thin at times, but his mother had always felt that education was a top priority, so he joined the Navy Reserve and got his engineering degree, figuring to become a Navy pilot. He had wanted to fly for as long as he could remember, but his graduation came right at the end of the Vietnam War, and that left very few opportunities to become a career pilot. So, being good at math, and a self-confessed control freak, he switched to med school and took a commission in the National Guard. What better way, he figured, to keep control over his body and his health than to become an M.D.? Hariri eventually did do some flying in the military, but it wasn’t until after he became a neurosurgeon and began building his career that he actually went out and bought his own jet.
Given their common passions for medicine and flying, who cou
ld be surprised when Hariri first met Diamandis at an XPRIZE event for doctors fascinated with space and aviation? The two men hit it off right away.
The idea that led to the phone call with Venter originated when Hariri suggested to Diamandis they create a company based on a big breakthrough Hariri had made in the early 2000s: his discovery of placental stem cells. When they first discussed the idea, aging wasn’t even on the agenda. Hariri simply felt that placental stem cells held enormous healing and regenerative promise on a whole range of levels. But then one day he and Diamandis found themselves talking with Ray Kurzweil and Bill Maris at GV. That was when the idea of tackling aging came up. This was very near the time when Maris was rolling out his own thoughts on longevity with John Doerr and others at Google. Thus, by the time Diamandis and Hariri got on the phone with Venter, they decided to pitch their new company as a play dedicated to a long and healthy life.
Venter’s enthusiasm for the business was good news all around. Hariri saw Venter as a true pioneer, a renegade, and visionary—someone who knew how to get it done, whatever “it” was. Hariri had watched Venter manage these sorts of endeavors more than once over the past three decades, not just with the Human Genome Project, but with many of his other undertakings. He knew Venter had hired hundreds of researchers and scientists over the years, and built teams that moved the dial. Nor was it lost on Diamandis and Hariri that Venter’s involvement would attract tons of media and venture capital. He was, after all, generally considered the world’s foremost genomics expert, and one of the world’s highest profile scientists. There could be no doubt, Venter was the Big Dog, and thus his co-founders were perfectly happy to spend whatever time with him he was willing to give.
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HARIRI’S VIEWS ON HUMAN HEALTH and aging were different from Venter’s, but by no means contrary. Venter believed fervently that all of human health and behavior could be known, if only the mysteries of DNA were unmasked, and that included aging. Hariri saw placental stem cells as “regenerative engines” that could be tapped and then “turned into medicine.”
These explorations had begun 25 years earlier, when Hariri was working as a neurosurgeon and trauma doctor at the New York Hospital-Cornell Medical Center. Day after day, he watched patients come into the emergency room with severe brain injuries, and it was a painful thing to witness. He never forgot the case of a woman who had arrived after a senseless automobile accident. She was young, and the injury was bad. Every time he spoke with the family, the big questions they always asked were: “How will she be? Will she come back? Could she be a mother to her children again?” It broke his heart. Just as the family was asking Hariri these very questions, he was paged for another reason: His wife was being prepped for the first ultrasound of their daughter-to-be. He answered the agonized family as best he could (the prognosis was not promising) and headed to the obstetrics department. But he couldn’t stop thinking about that woman. Doctors, it seemed to him, were getting pretty good at saving people from traumatic injuries, but not doing nearly so well at repairing the resulting damage. There had to be a better way.
As he was thinking about this, Hariri walked into his wife’s room and saw the ultrasound image of his daughter-to-be. Right above the image he could also see the sonogram of her placenta. Compared to the fetus, it was immense, and that made Hariri think.
At the time, the general view of the placenta was that it was nothing more than a system for shuttling blood from the mother to the growing embryo and fetus: a simple vascular interface. But the engineering side of Hariri told him that didn’t make sense. If the placenta was just a vascular interface, it would be small during the early stages of an embryo’s development and then grow pretty much at the same rate the fetus did. But this giant organ was way bigger than the fetus, which meant it had to be supplying a lot more than blood. And that was when the lightbulb lit up.
The placenta was—how could Hariri put it—an unappealing structure, big and meaty, shaped like a bloody pizza with something resembling a coaxial cable attached: the umbilical cord. It wasn’t something that many researchers were eager to scrutinize. Every obstetrician knew that once a baby was born, the placenta was immediately disposed of. Doctors called it the “afterbirth.” But Hariri admitted that in the course of his life, he had been willing more than once to explore a dumpster or two—so why be queasy about probing the placenta for its secrets?
Eventually Hariri’s explorations revealed that the organ was a very long way from useless. In fact, it provided everything an embryo needed to develop into a healthy, living, breathing child: It brimmed with pluripotent stem cells, life’s purest form of cell, capable of morphing into whatever the body required—liver, muscle, even neurons. This was how living things were made as they developed. Some pluripotent stem cells transformed into skin. Others became bones or hearts or kidneys—all the cellular matter that made a human possible. This also made placentas magnificent stem cell factories. Yet every day nearly all of them were tossed in the rubbish!
A discovery like this might have prompted a lot of scientists to write a paper extolling their findings in a peer-reviewed journal; Hariri had done it himself plenty of times. But this time he didn’t write a paper. He wrote a patent. Patent Number 7045148, to be exact, filed in December 2001 and granted the following September.11 The application explained, in detail, how to collect “embryonic-like stem cells from a placenta” to recharge the stem cells of other humans. The way Hariri saw it, the placenta was a machine, an organic factory designed to create any sort of cell the human body could possibly need, including those that were damaged or dying.
Soon after the patent was created, Hariri founded the Anthrogenesis Corporation and LifeBank, Inc. Later Celgene, a multibillion-dollar pharmaceutical company, bought both companies in 2002, to form Celgene Cellular Therapeutics. Hariri was named chairman, founder, and chief scientific officer.
All that work had gone swimmingly, but by 2012, Hariri felt it was time to more directly explore using placental stem cells to regenerate muscle, bone, and organs. Most of Celgene’s work at that time was focused on cancer. As important as that was, Hariri felt broader possibilities lay ahead. That was when he passed his thinking on to Diamandis.
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THERE WERE REASONS THE THREE MEN decided to create a company that attacked aging. Like Kurzweil and Levinson, Venter had lost his father early in life, and this affected his belief that it was crucial to get ahead of diseases that kill before, not after, they did their damage. His dad, John Venter, had been one of those men who believed you kept your personal opinions and conditions to yourself. Unfortunately, that hadn’t worked out so well. One night, he died of a massive heart attack in his sleep, only a couple of weeks after he had passed a cardiac stress test. Or at least said he had. The autopsy showed his blood vessels were a clogged mess.
Now, Venter was watching his mother grow increasingly frail, and that was also not fun. So at least maybe he could learn from the experience of his parents, and reduce the pain and disease that obliterated the quality of life for millions of people.
When Hariri made his breakthrough placental cell discovery, he saw it as a powerful agent for maintaining health. The cells not only supercharged the fetus during pregnancy, but the mother’s body as well. He had seen women horribly sick with autoimmune diseases like multiple sclerosis or Crohn’s disease who would often go into complete remission when they became pregnant. The pregnancy seemed to somehow unleash the immune system in miraculous ways to protect both mother and child.
The abiding hope of early researchers had always been that stem cells could somehow be used to repair broken spines, wounded bodies, and ailing organs. As early as the 1960s, stem cells extracted from bone marrow had been successfully used to treat and eliminate certain cancers. But those cells had to be taken from the patients themselves or a genetic match—otherwise they were rejected. That’s because they were multipotent, not pluripotent, mea
ning they could only morph into a relatively small subset of other cells closely related to their origin: blood or bone or kidneys, for example. This made them less flexible than pluripotent cells, which are capable of becoming any cell in the body. But in the early 2000s, pluripotent cells were rare—and, at the time, only available from embryos whose harvest (especially during the Bush administration) raised all sorts of ethical issues.
That was why Hariri found placental stem cells so exciting. They were always pluripotent, but did not come from a human embryo, which made harvesting them less problematic. At Cornell, Hariri had witnessed the power of placental cells during fetal surgery. These were cases in which a fetus might be suffering from a heart or lung problem that could kill or severely injure an infant after it was born. To repair the damage before birth, teams made incisions not only into the mothers, but also into the fetuses themselves. Throughout the procedure, the fetuses would always remain connected to the mothers through the placentas and umbilical cords.
After these procedures, Hariri watched two remarkable things happen. First, the babies that were born almost always fared far better than they would have if the surgeons had waited to operate after they were born. And second, the new infants showed no scarring or incisions from the prenatal surgery. The placenta had pumped so many fresh stem cells into the fetus before birth that the body had entirely regenerated!
Another advantage of placental cells was their unusual immunological capabilities. It was well known that when any foreign object entered the body—a cold virus, a bacterial infection, or a simple splinter—the immune system instantly recognized the offending agent and went to work destroying it. This was why rejection was such a struggle after organ transplants, and why stem cells used by other donors had to match. The host body wanted them out, even if the donor wanted the new cells or organs in. But placental cells acted as if they were your very own, preserved at birth and ready to take over for the tired and sick cells that needed replacement.