by Chip Walter
Before joining Calico, Koller knew she could write her own ticket at any of Silicon Valley’s great Cloud makers: Google, Facebook, Apple. But did she really want to create software that made better Twitter feeds, or cool faces on Snapchat, or yet another product that piled up more of the planet’s digital ad revenues? In the sprawling world of Google, she would be a blip: one more very smart human in a sea of geeks. But Calico was different. She had never forgotten Steve Jobs’s grand goal: “Make a dent in the universe.” At Calico, maybe she could make a dent—save lives, perhaps millions—even her own.
Thomas Bayes would have appreciated Koller’s interest in saving lives, being both a Presbyterian minister and a devoted supporter of the humanist philosophies that called for the rational improvement of the human race—also the foundation of transhumanism. The mathematician’s work had been largely forgotten when Koller first began exploring it. But she liked the way he thought. It delivered a human flexibility unusual in mathematics. Instead of using set rules and cold logic, it was designed to adapt.
A simple example was the big urn problem. Imagine a large urn filled with balls. Half are black, the other half white. What was the likelihood that when one of the balls was pulled from the urn, it would be black? Well, obviously, 50-50. But what were the odds of pulling the very next black ball from the urn? Now the situation had changed; every time a ball was retrieved it would change again, and again, depending on the situation. Bayesian probability took these differing possibilities into account, or tried to. In the jargon of computer scientists, it both explored information and then exploited it—not unlike a human mind.
Good news, too, when it came to computer science, because Koller knew the world was becoming an increasingly noisy and confusing place. The rigid rules created by most computer code simply would not get the job done. Not where biology was concerned, and especially not molecular biology, which was about as messy as it got. No algorithm written by the human mind—no matter how fast or logical—could resolve the complex and rapid molecular pathways at work in a genome or a biome or any “ome.” Not that humans were completely useless; the initial coding had to be set up correctly. But after that, the algorithms were cut loose do their stuff, independently, like a living thing solving each problem it faced as it faced it without constantly coming back for human instruction. This was the only way that the billions of genetic communications could be unsnarled.
When Koller developed her cancer gene-mapping techniques at UCSF after receiving her MacArthur grant, the program blasted through data on thousands of genes, and then tested the likelihood that changes created by one gene could be teased out by locating changes in the others. She also developed code that examined the rates at which specific genes within a cell created its corresponding protein, and how that creation depended on signals from proteins encoded by still more genes.
All of this sounded a lot like Kurzweil’s pattern-recognition nodes. Both needed to understand context and then react on their own in real time. Kurzweil’s AI nodes were meant to solve a broad range of problems that could eventually lead to immortality. Koller’s algorithms were more specific, delving way, way down into the noisy, and entirely invisible world of organic chemistry by letting the algorithms come up with their own solutions. But in this way, they too were thinking, artificially.
David Botstein, Calico’s chief scientific officer, was of the opinion that understanding these pathways was central to Calico’s hopes for success. He and Levinson agreed that crunching lots of numbers to figure out what the human genome was trying to say was crucial—but Botstein wanted to know more. What the hell were all of those molecules inside the genes actually doing? How did a gene turn some proteins on and some off? How did one gene affect others? If only you could rummage among them all, look them in the eye, and say, “Ah-hah! Now I understand what you’re up to.” That was the only real way anyone could hope to begin undoing all the damage that took the human body apart.
To achieve this, Botstein was having custom-made sequencers developed for Calico, and Calico alone, by two companies collaborating in California: Pacific Biosciences and Bionano Genomics.21 These hand-built sequencers, and these only, he felt, would provide the kind of resolution that revealed the invisible machinations of proteins and molecules.
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ONE OF THE PROJECTS Calico began exploring when Koller arrived in 2016 illustrated just how numbingly complex the problems were that the company faced. Between 2006 and 2010, an organization called the UK BioBank recruited 500,000 subjects between the ages of 40 and 69 years old and tested the living daylights out of them. BioBank’s researchers could tell you just about everything about the project’s recruits: their inflammatory markers, cholesterol and hormone levels, saliva samples, urine and blood results. They could tally up grip strength, the volume of the recruits’ brains—even how quickly they could walk 100 meters. The genes of 100,000 participants had already been sequenced, and then those people were asked to wear 24-hour activity monitors for a week. Recently, fMRI machines had begun scanning a fresh batch of 100,000 people. All of this in addition to the vast database BioBank was already developing about recruits’ diet, cognitive function, work history, and digestive health.
Venter and the researchers at Human Longevity, Inc., had been gathering information at a blistering clip too, but it was hard to imagine a more robust aggregation of human biology than the findings the UK Biobank was compiling. In addition, the bank had also begun following up with those in the studies, plotting their progress as they marched forward. Already they had tabulated 9,000 phenotypes correlated with their unique DNA.
The numbers were mind paralyzing: trillions of cells, each interacting with billions of genes performing untold numbers of biological interactions. All of them unveiling the two faces of humanity. One that could reveal you and you alone; the other that represented the great biological database that made all humans possible. The questions were endless—and who could say which genetic alterations provided the final answers? Koller felt pretty sure Calico would find more than one, but less than 5,000. She wondered if maybe five major genetic pathways could eliminate aging. If so, perhaps Calico could then come up with five drug regimens that would intervene and repair the killing. That would solve beta outright.
One fact was clear: The ultimate answers weren’t going to come from a “who.” They would come from a “what.” Maybe not from Kurzweil’s neurobots, or human-machine hybrids. Not yet. But from increasingly intelligent machines that were thinking up new ways to think. Their very own ways. That made them the new oracles: software reading the burnt offerings of all that massive data accumulating at exponential speed as the contraptions taught themselves to mend humanity, rather than terminate it. Imagine: Machines solving the ultimate human problem.
The irony was almost cosmic.
28 | WOULD IT ALL WORK?
Mortality stalks us all. In the fall of 2016, Craig Venter got word that he was diagnosed with prostate cancer. Stage III. I saw him the day he sent the email out to HLI’s staff. He had made a routine visit to the Health Nucleus, and there his biology found him out. No one ever wanted to get news like that—especially a man who intended to live out the full allotment of his 120 years. It was ironic. Here was all of that information in the genome that he himself had worked so hard to uncover, and now it had come home to roost.
But for him, that was a good thing. A glorious thing! He still had vivid memories of that rat-shack-Quonset-hut excuse for a hospital in Da Nang where he laced up those shredded and blasted 18-year-olds while the life poured out of them. But now HLI could help millions dodge the bullets of their own death. He himself was the proof. The Health Nucleus had found the cancer, the surgeons quickly plucked out the offending prostate, and now he was free of the disease. The 10-year survival rate was 99 percent. He’d be 80 by then. But the technology would be 10 years better too.
To keep pushing that technology, Venter announced in 2017 that
HLI would meet his threshold of a million genomes by 2020. The company was already rolling out its latest, top-of-the-line Illumina sequencers to accelerate the work.
In the meantime HLI’s machine-learning algorithms kept chewing up the data to make more sense out of the massive, genetic dictionary it was trying to decode. Researchers there had developed a new algorithm to sequence one of the most important regions on the human chromosome: chromosome 6, responsible for the regulation of the immune system, central to understanding autoimmune diseases, cancer, organ transplant compatibility, and allergies. That discovery could speed the creation of new drugs that touched on all of those diseases.
By early 2018, Human Longevity, Inc., also revamped its Health Nucleus services to create two basic memberships: HNX and HNX Platinum. Platinum was still priced at the full $25,000, plus $6,000 a year after two years if you wanted continuing access to the higher-end package. That included updated tests that might reveal bladder cancer or congestive heart problems or atrial fibrillation. Also included were total-body MRIs, comprehensive lab work, full screening of your body’s chemical composition and health, neurocognitive testing—even a gait and balance tracker, among several other medical analyses. These were clearly for the very wealthy.
Plain old HNX was considerably less expensive at $4,950 for a onetime membership. It delivered whole genome sequencing, complete MRI, and about half of the other platinum-level services. After that initial cost, patients would continue to pay $2,950 annually for four ongoing services designed to reveal trouble before it could do too much damage.
The really big plan, though, was for HLI to launch 50 Health Nucleus sites around the world. Venter saw these at last bringing his medical revolution into the mainstream. The new centers would roll out within the next year in places like Asia, Europe, and the United States. If Venter had his way, the prices would continue to drop.
Would it all work? Venter looked around his office and smiled. “It has to,” he said. How else could HLI hope to acquire one million integrated genomes, and how else would the world’s medical practitioners come to understand that the time to prevent disease was now, rather than by playing catch-up with the Dreaded Symptoms after the fact?
From the outside, everything at HLI seemed to be humming along. But on the inside, it wasn’t. Venter’s goals were ambitious, and costly. Multiple executives had departed, and the company was burning cash at a furious rate. Finally one day in May 2018, a majority of the investors and board at Human Longevity, Inc., made it clear in a conference call that it had to stop. Venter didn’t agree, and when others on the board held fast, it was a Mexican stand-off. Venter decided he had no other choice but to walk out of HLI’s sunny San Diego headquarters. It was over that fast.
The departure had the eerie echo of Venter’s removal from Celera, the company he ran that had accelerated the sequencing of the Human Genome Project. He had departed there a mere 18 months after standing before all the world to announce the great endeavor’s completion in the summer of 2000. Back then, he said he faced severe pressure “from the people who put up the money…so I was walking a tightrope, though at times it felt like sliding along a razor blade.”22
The end of that relationship had been bitter enough, but this time HLI also sued the J. Craig Venter Institute (JCVI) for stealing HLI’s trade secrets. Venter denied the charges. JCVI attorney Steven Strauss said the claims were “baseless, without merit, and contain numerous factual errors,” adding that JCVI planned to “vigorously defend against these allegations as the legal process advances.” One way or another, though, Venter was off the board and no longer HLI’s CEO. The triumvirate—Venter, Hariri, and Diamandis—was dissolved.
In July 2018, HLI promoted Dr. David Karow as its interim CEO, Scott Sorensen as interim chief operating officer, and Noah Nasser as chief financial officer. Both Karow and Sorensen had been hired as executives under Venter’s watch. Nasser arrived shortly afterward.
Karow was a physician and researcher who had been working at the University of California at San Diego when he joined the company. His specialty was combining genomics and magnetic resonance imaging to find new ways to expose very early stage cancers throughout the body. Ironically, one of his pioneering finds was the early detection of prostate cancer.
Sorensen had joined HLI as chief technology officer after 16 years at Ancestry.com, a company that had worked with Calico. His focus was the integration of genomics and technology, as well as more effective and user-friendly ways to leverage HLI’s Health Nucleus software platform.
After Venter’s departure, it was unclear what, precisely, the next move would be. Outright dissolution of the company was one possibility. That, or come up with a less costly way to deliver on HLI’s big promise to revolutionize medicine. A 30-day deadline was set.
By midsummer 2018 the new team worked out a different approach: HLI would continue to focus on preventing disease early, a goal that Venter had all along considered a bedrock concept. The Health Nucleus approach would also remain central, integrating the use of MRI and other advanced scanning technologies while continuing to expand its database of omes: genome, metabolome, microbiome.
The major change came in shifting the scale and speed at which the company would now begin to move. The plan to open 50 Health Nucleus centers around the world was no more. Those centers were expensive and burdened by foreign regulatory issues. The way the board saw it, scaling them was not sustainable. Nor would Human Longevity seek any longer to aggressively gather a million integrated genomes—certainly not by 2020.
HLI’s new strategy was to disintermediate traditional medicine in the way that Airbnb and Uber had disrupted the hospitality and transportation industries. The current Health Nucleus center in San Diego would remain. But instead of the costly rollout of its own facilities worldwide, HLI began planning partnerships with a variety of institutions: physicians interested in longevity medicine, hospitals and clinics that wanted to prevent or slow the diseases of aging. HLI’s partners would gather participating patients’ blood tests, gather their omes, and provide imaging to HLI while the Health Nucleus service—now called Core Reports—would provide an online interface, as well as available experts to explain what all the data revealed. The key to the new approach was the software platform and database analyses that HLI proposed to deliver without the cost of brick-and-mortar HNX centers spread around the globe.
This model was similar to the back-end software platform and front-end interface that Airbnb uses to make it so easy for its partners to service millions of overnight guests around the world. Except in this case, the same sort of artificial intelligence that had the seer-like potential to reveal a customer’s future health would now power HLI’s platform.
Karow called this “democratizing precision health analytics,” which was another way of saying that HLI could still create a better medical mousetrap while simultaneously generating income and enlarging its all-important genomic database. After all, no one doubted that the Health Nucleus approach was working; by the end of 2016, after 500 clients had passed through the San Diego office, 30 percent discovered ailments they didn’t know they had, and another 14 percent learned of entirely new health issues that were potentially lethal. Now, almost two years later, 3,000 participants had used Health Nucleus, and the numbers had jumped to 40 and 14 percent, respectively. Obviously the preventative approach was getting results—and, again, these were people who thought they were in excellent health.
Given these successes, Karow wondered what HLI would find as prices dropped and partner organizations joined its more mainstream ranks. Theoretically, as prices decreased further, the database and analytics would grow richer; at least, that was the plan and hope. Today the cost of sequencing a human genome stands at roughly $1,000—$700 less than it was only three years earlier—and full-body MRIs are being completed in 45 minutes, rather than the one to two hours that most HNX scans initially took. By 2020, Karow predicts, services will drop from $5,000 an HNX
patient to $1,500 or less, and full-body MRIs will be completed in 30 minutes. The main thing was to build on past successes and focus on what Karow called a workable “commercial strategy.”
Still, by early 2019, the new HLI had yet to nail down even one Health Nucleus business partner. But Karow insisted the company’s finances were solid and partnerships would soon materialize. After all, who would have thought, when Airbnb was launched in 2008, it would be booking a million rooms a night within five years?
Given Venter’s past, you could almost have predicted the events that unfolded at Human Longevity, Inc. The man attracted drama like mass attracts gravity. He was the hare, not the tortoise. Do the experiment! But HLI’s pockets weren’t as deep as Calico’s, and even Silicon Valley investors have their limits. As one member of the genomic community put it, Venter was complicated. He lived by the idea that you stake out big goals and then try to live up to them. Sometimes it works; sometimes you crash.
Not that any of this was likely to stop Venter. He had been down roads like these before—in Vietnam, in Buffalo, at NIH, at Celera, and now at HLI. His passion for arresting aging remained strong. In the lawsuit that HLI filed, the company alleged that Venter, immediately after his departure, had begun planning to create a new company that would explore the “preventative medicine space.” Whether that was on the docket, or even true, remained to be seen, and Venter couldn’t say much while dealing with a lawsuit. As the summer of 2018 progressed, he and his wife, Heather Kowalski, said they had taken some time to “regroup, reassess, and de-stress.” By the fall, Venter had gotten back into the swing of things at JCVI and was continuing his ongoing organ transplant work with Martine Rothblatt at United Therapeutics. Was he giving up? It didn’t seem likely. It just wasn’t in his DNA.
