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Enemies of All Maladies

Andrew Leonard | December 22, 2016 | Story News and Features National

Joe DeRisi flashes a grin that suggests he knows exactly how ridiculous his next statement is going to sound. “We want to build the Tesla Factory of cell biology,” he says.

It’s a typical Silicon Valley elevator pitch, DeRisi knows, but as with all good VC hype jobs, there’s truth beneath the shtick. The UCSF biochemist was recently tapped by Facebook CEO Mark Zuckerberg and his physician wife, Priscilla Chan, to colead the Biohub, the first stage in the couple’s 10-year, $3 billion philanthropic effort “to cure, prevent, or manage all diseases”—yes, all of them—“by the end of the century.” On the one hand, DeRisi’s over-the-top rhetoric is an ironic hedge against some impossibly outlandish goals. (A disease-free 22nd century? Sure. Why not.) But on the other hand, the scientist is dead serious. DeRisi does want to build an Elon Musk–style gigafactory of medical research. And he truly does believe that amazing breakthroughs in treating disease are inevitable.

Of course, ending not just one disease but all of them in the span of 83 years is “an audacious goal,” acknowledges the puckish, twinkling-eyed biochemist. “But if you don’t set high goals for yourself, then you automatically have lower goals.” He laughs, as if to underline the point: What kind of fool wants to shoot for lower goals?

DeRisi and his fellow Biohub codirector, Stanford bioengineer Steve Quake, have been pledged $600 million from the Chan Zuckerberg Initiative (CZI)—the 13-month-old limited liability company that Chan and Zuckerberg set up shortly after the birth of their daughter, Max, as a vehicle for giving away a vast majority of their wealth—to tackle the core mysteries of human molecular biology. With the help of a swarm of new technological tools and supersmart software (not to mention the kind of financial backing that scientists can only fantasize about), DeRisi and Quake plan to make giant strides in figuring out how the human body works—and how, all too often, it doesn’t.

Now, DeRisi and his Biohub colleagues know what you’re thinking. A medical moon shot that mashes up the Valley’s favorite buzzwords with the eternal verities of sickness and death? We might need to borrow a new word from ancient Greek to describe what’s going on here, because our old standby, hubris, suddenly seems insufficient. But these cutting-edge researchers also know something that you likely don’t: that recent advances in genomic sequencing, gene editing, and imaging technologies are bringing us closer to decoding, treating, and possibly even eliminating killer diseases than ever before. “In just the last five to six years, we’ve seen amazing quantum leaps in technology,” DeRisi says. “We now have an arsenal of tools that allow investigations of cellular biology and systems and disease at a scale and pace that dwarfs anything that came before it.”

This is, in part, why DeRisi is unfazed by the knee-jerk skepticism that follows any expert discussion of the Biohub. Dressed in shorts and a T-shirt and looking for all the world like he just cut classes at his alma mater, UC Santa Cruz, DeRisi is known among his colleagues as “the Energizer Bunny on crack.” At 46, he is the chair of UCSF’s highly regarded Biochemistry and Biophysics Department and one of the top scientists in the country in his specialty, the use of genomic sequencing technology to identify infectious diseases. His lab in UCSF’s Byers Hall is maintained by 29 technicians, postdocs, PhDs, and physicians, all trying to crack the code of infectious killers.

As an example of what’s already possible, DeRisi tells the story of a patient who came to S.F. General in 2014 complaining of headaches and double vision. Over the course of a year, doctors made a diagnosis of tuberculosis and prescribed a treatment plan, but the patient’s ailment continued to worsen. He was hospitalized, and finally DeRisi was called in to see if his lab’s experimental techniques could save the day. The lab sequenced cerebrospinal fluid extracted from the patient, matched it with its database of infectious diseases, and discovered that the patient’s brain was filled with tapeworms—a treatable problem.

A few years ago, attempting to do what DeRisi’s team accomplished for this patient would have been hugely expensive and time-consuming. A few years before that, it wouldn’t have been possible at all. But with the cost of sequencing technology plummeting (DeRisi estimates that the price for sequencing a given amount of genetic information has “dropped by something approximating 50,000-fold” over the last decade), a future in which every tricky infection can be tested and diagnosed with exquisite precision is at hand.

With the Biohub, Zuckerberg and Chan are sprinting headlong into this future. They aim to put an arsenal of new tools in the hands of the best scientists and software engineers that mountains of Facebook money can buy, and then wait and watch, hoping that over the next few decades, their Murderers’ Row of researchers will make breakthroughs in treating everything from heart disease to cancer to neurodegenerative terrors like Alzheimer’s and Parkinson’s.

The opportunity is a dream come true for scientists like DeRisi. “The way the technology is moving today and our fundamental knowledge of biochemistry and microbiology and genomics and computational sciences is advancing,” he says, “we are incapable of predicting where we are going to be even five years from now. With a 100-year time span, it’s really sky’s the limit.”

Surveying his current lab, itself an enormously impressive assembly of people and technology, DeRisi promises that the Biohub version will be “bigger, faster, better.” But still, every disease vanquished? Within the next 83 years? DeRisi shrugs. “It’s easy to be a cynic,” he says, “but, given the rate of rapid technological change, it’s also easy to be an optimist.”

So this is what
three billion bucks buys you. Among the standing-room-only audience gathered in UCSF’s William J. Rutter Center in late September to hear Zuckerberg and Chan reveal the details of the Biohub were Mayor Ed Lee and Lieutenant Governor Gavin Newsom, the leaders of UC Berkeley, Stanford, and UCSF, and a slew of nationally renowned scientists and doctors. Bill Gates even dropped by to offer some closing remarks. (He called Chan and Zuckerberg’s agenda “bold.”)

The 82-minute dog and pony show looked, on the surface, very much like the annual product rollouts of Apple, Google, and Facebook. There were PowerPoints, a Facebook Live feed, fanboy applause, and rhetoric about changing the world. When Zuckerberg told the audience that “you can take any system and make it much, much better than it is today, whether it is code, hardware, biology, a company, an education system, a government,” he might as well have been declaring Silicon Valley’s particular strain of manifest destiny.

But there were also some significant differences. When Cori Bargmann, the head of science at the Chan Zuckerberg Initiative, talked about investing in research projects that might not pay off for “20 or 50 years,” she was describing a longterm approach quite at odds with that of the typical Silicon Valley startup CEO or venture capitalist (or even NIH grant giver). When Chan—who, in addition to cofounding the CZI and acting as CEO of an education startup called the Primary School, is a working pediatrician at UCSF—talked about the pain of telling parents that a child can’t be resuscitated, her emotions were palpable. “In those moments and at many others, we are at the limit of what we understand about the human body, the limit of our ability to alleviate suffering,” she said, trying—unsuccessfully—to stifle tears. “We want to push back that boundary.” Then she left the stage to find a tissue.

So what’s not to like? Well, if you tuned in to social media in the hours and days after the announcement, just about everything. The backlash came immediately, and it came hard. “Can $3 Billion Cure Zuckerberg’s Ego?” read one USA Today headline. “Zuckerberg typifies millennial naivety,” declared a representative tweet. “$3 billion to cure ALL disease! The US gov spends $27b a year on HIV & can’t even make a dent.” Some credible medical experts attacked Zuckerberg and Chan’s understanding of how medical research works, their overweening confidence, and even their basic math. After all, as the above tweet suggests, the combined annual medical research budgets of the federal government, academic institutions, pharmaceutical companies, and dozens of philanthropy-funded research institutes add up to over $100 billion. Another measly $3 billion over 10 years? That’s a rounding error.

Some critics claimed that it was inherently undemocratic for a handful of billionaires to determine society’s spending priorities. Others looked askance at the details of the Biohub’s legal contract with its participating institutions, which give them potential ownership rights to new inventions and intellectual property. But at the basic gut level, it all kept coming back to hubris.

Alex Berezow, a senior fellow of biomedical science at the American Council on Science and Health, articulates a common response. “The main objection is that it’s simply not possible to think that the goal of curing all disease is a reasonable goal,” he says. “It’s kind of like saying, ‘Why don’t we just fly to Alpha Centauri?’ Well, you know, people have thought about this, and really smart people say it’s really hard to do. It is such a broad goal that it is absurd. We’ve had thousands of scientists working on these diseases for decades and spending billions of dollars, and then we have the guy who founded Facebook, and he says, ‘I’m going to cure everything.’ What are we, chopped liver? What do you think all the rest of us scientists are trying to do?”

But when I ask his opinion on the scientists hired by the CZI to do the work, Berezow’s tune changes: “The people they selected were fantastic,” he acknowledges. “Absolutely.”

In the weeks after
I talk with DeRisi at his lab in UCSF, interviews with a half dozen scientists directly or peripherally involved with the Biohub reiterate his core theme: The sky really is the limit. Bob Tjian, a 67-year-old Berkeley biochemist and molecular biologist who recently stepped down as director of the Howard Hughes Medical Institute, in Chevy Chase, Maryland—which disburses nearly $800 million a year to elite researchers and science education programs—tells me that new developments in microscope technology have given him the ability to watch how proteins function in real time, something he never thought would have been “possible in my scientific lifetime.” Quake talks about recent innovations in the field of single-cell genomics that allow the manipulation of individual cells. CZI science chief Bargmann observes that the unexpectedly rapid advancement of immuno-oncology drugs means that people who would have received a death sentence from certain types of cancer 5 or 10 years ago now have a decent chance of a cure.

There’s a widespread, almost giddy, sense among the CZI scientists that crucial new insights into how human molecular biology works, into how genes function, are at hand. Translating that basic knowledge into an understanding of how diseases wreak their havoc is, in a nutshell, what the Biohub is trying to do. And at the heart of this merger of new tech and biology is data, more data than any single puny human mind can begin to comprehend. Data of such complexity and volume that simply storing it is a major logistical concern. Here is where Zuckerberg’s rhetoric about “engineering” social change starts to make sense. The guy who invented a social network in his Harvard dorm room may not know a lot about medical research, but he is obviously an expert at assembling engineering teams, then scaling them to infinity.

The engineering room and the server farm, even more than the laboratory and the clinic, are where modern science now lives: “Biology is rapidly becoming an information science,” DeRisi says. Given that fact, software engineers are now an essential commodity for scientific research. However, this reality doesn’t match the way science is currently funded. The National Institutes of Health does give away $30 billion or so to researchers every year, dwarfing what the CZI has to offer. But it’s not clear that our taxpayer dollars are being spent with optimum efficiency. “On a typical NIH grant,” says DeRisi, “you can’t put, ‘Oh, we’re going to have a six-person software engineering team.’” Most researchers, he says, are fortunate just to rope in a “computer-science-undergrad part-time intern to write you a script or two.”

That no longer cuts it. To make sense of the vast amount of data being thrown off by all the sequencing and high-tech imaging and real-time capture of gene expression that scientists are immersing themselves in right now, you need the kind of machine-learning and big-data capabilities that are currently being deployed by the likes of Amazon and, yes, Facebook. Those engineers aren’t easy or cheap to get, but early proof of Zuckerberg’s inexhaustible wealth of tech connections came a few weeks after the Biohub unveiling, when the CZI announced that it had plucked Brian Pinkerton, Amazon’s search VP, to be its CTO. Pinkerton, incidentally, started his career more than 30 years ago as a graduate student in a computer science lab at the University of Washington (where, even more incidentally, he happened to invent one of the web’s very first search engines, WebCrawler, in his spare time).

When I catch up with Pinkerton a few weeks after the announcement, he talks about how he’s looking forward to helping the Biohub scientists with straightforward tasks like moving and storing the huge amounts of data they’ll be generating. But later, he says, the tasks will get much more complex: To ferret meaning out of terabytes of gene-sequencing data will likely require a level of machine learning that makes Amazon’s purchase predictions and Facebook’s facial recognition tools look quaint. But that’s the kind of problem that software talents are eager to tackle. Before he’d even left his desk at Amazon, Pinkerton says, he was already receiving emails from engineers keen to join him.

Once you stop thinking about the Biohub as a Valley pipe dream and start thinking about it as a simple talent- and technology-leveraging mechanism, it starts to make more sense. The biochemistry and molecular biology departments of UCSF, Stanford, and Berkeley are among the top in the country, and per capita there is no place in the world that has more top programmers than the Bay Area. Chan and Zuckerberg are organizing that talent into a single entity for the first time, creating a kind of scientific Avengers for medical progress. Will they cure all disease? Who knows? Will it be fun to watch them try? How could it not be?

Of course, the Chan Zuckerberg Initiative
is far from the first foray into philanthropy for “Mark and Priscilla,” as everyone involved with the Biohub likes to refer to them. Six years ago, the couple notoriously jumped into efforts to reform the Newark, New Jersey, school system with a $100 million donation aimed at creating a model for fixing public education across the entire nation. It was bold, it was audacious, and by many accounts it was mostly a failure. (Chan and Zuckerberg declined requests to be interviewed for this story.) But in the definitive account of the reform effort, Dale Russakoff’s The Prize, Chan and Zuckerberg end up coming off a lot better than most of the other participants in the saga, including New Jersey governor Chris Christie and Newark mayor (now U.S. senator) Cory Booker. Zuckerberg, writes Russakoff, “had vowed at the outset to learn from his experience….Based on his subsequent initiatives, he seems to have learned a lot.”

Try. Fail. Iterate. Try again. Fail again. Iterate again. It’s another Silicon Valley shtick. But one of the key things Zuckerberg and Chan learned from their Newark misadventure was to do more homework next time. According to Russakoff, such research is visible in a slew of educational programs targeting underprivileged children that the CZI has funded since then.

Before launching the CZI, in fact, the couple spent two years interviewing scientists, doctors, philanthropists, and medical research administrators as part of their strategy to figure out where their billions would make the most impact. Their basic goal, as stated by Chan during the September unveiling, was “to dramatically improve every life in Max’s generation and make sure we don’t miss a single soul.”

Crucial to this are Chan’s and Zuckerberg’s ages: Both are still only in their early 30s, a fact that makes veterans of the medical research funding world swoon. There’s a big difference between a thirtysomething embracing a long-term research project and an octogenarian signing on to do the same. “They are talking very long timelines,” says Berkeley’s Tjian. “That’s the one thing the NIH isn’t doing so well. They want to know an answer in four years. They want to know that you have ticked off all the specific aims that you said you were going to do [in your grant proposal]. And if you didn’t, well, that’s it.”

By multiple accounts, Tjian played a critical role in encouraging Chan and Zuckerberg to focus their dollars on building tools that would push basic science forward. It’s a goal that Tjian is familiar with, having pursued it successfully during his tenure at the Howard Hughes Medical Institute. (It is no coincidence that Bargmann, DeRisi, and Quake were all HHMI investigators—a badge of honor in the medical research establishment.)

Tjian tells me the story of how, while at HHMI, he funded the work of physicist Eric Betzig, whose dream was to build an optical microscope that would break through physical limitations previously thought to be hardwired into the nature of light. In 2014, Betzig won the Nobel Prize for his work. Tjian now has one of the microscopes Betzig built in his own lab at Berkeley. “These microscopes are unbelievable,” Tjian says. “They allow me to track proteins flittering around in the nucleus of a live cell. It’s a game changer. Now I can watch proteins that are getting stuck, or at least being waylaid, by Huntington’s aggregates. I can actually show you why certain proteins are malfunctioning in the cells of the striatum, which is the target of Huntington’s disease.”

Neurodegenerative diseases like Alzheimer’s and Huntington’s, Tjian says, “will really whack us this century, the longer we live.” But the more we understand the “fundamentals of disease mechanisms,” the better chance we’ll have of limiting the threats’ impacts. It’s not a short-term project, Tjian stresses. But again, that’s why he’s enthusiastic about the potential of a decades-spanning commitment from a 32-year-old billionaire. Zuckerberg “got it,” Tjian says. He knows it’s going to take a long time.

But even in light of all the recent technological progress, I have to ask Tjian what he thinks of the claim that the CZI could “cure, prevent, or manage all diseases.” Shouldn’t they have anticipated the negative response? “When Mark first presented this statement to me, I said, ‘Well, you know, that’s reaching really, really high,’” Tjian recalls. “But I didn’t dissuade him from it, because what do you want him to do, reach middle? This is not somebody who ever reaches for middle.”

Cori Bargmann is
sitting on a park bench in Menlo Park, a block away from temporary offices too cramped to squeeze both of us into. She’s talking about a specific type of neuron that produces a small, protein-like molecule called a neuropeptide that is critical for wakefulness. If these neurons are destroyed or damaged, she tells me, some people can develop a disorder called narcolepsy-cataplexy, a condition that can cause one to suddenly fall asleep, collapse while active, or even fall into a waking dream state. “So that’s an example of a cell type with a function that helps you understand a brain disorder that teaches you something about normal sleep and waking states,” she says.

This is all a way of explaining the significance of another major project to be tackled by the Biohub: a cell atlas. The project aims to create a comprehensive map that will document the characteristics of every type of cell in the human body. “I see the cell atlas as an enabling tool,” says Bargmann, “that can be used to understand every aspect of biology in more detail and every function in health and disease.”

A tool that can be used to understand every aspect of biology in more detail: It takes a few moments for Bargmann’s words to sink in. She’s talking about a manual that would identify not just every type of cell in the body, but also how those cells change over time, how the genes in those cells express themselves to perform different functions. The goal is almost unimaginably complex: A cell atlas is kind of a map of life itself, one in which the closer you look, the more detail you find. Bargmann, who will continue to run her neuroscience lab at New York City’s Rockefeller University while presiding over science at CZI, says that one of the first things her team needed while she was a leader of the NIH planning committee for President Barack Obama’s Brain Initiative was “a parts list” for the brain. The cell atlas, an idea that has been championed for several years by computational biologist Aviv Regev, is a more comprehensive version of the same basic idea: You can’t figure out how the machine works if you don’t understand its constituent parts.

But building the cell atlas is a big job, bigger than any single entity, even with access to Zuckerbergian billions, can tackle on its own. Collaboration across institutional boundaries hasn’t always been easy in the scientific world, even when everyone is ostensibly working toward the same greater goal. When Bargmann addressed the assembled bright lights of the Bay Area at the unveiling of the Chan Zuckerberg Initiative, she drew a big chortle when she noted that the Biohub represented the collaboration of “three great universities”—UC Berkeley, UCSF, and Stanford—“that have not cooperated formally this way in the past, ever.”

The laughter reflected some painful history. An attempt to merge the Stanford and UCSF hospitals 20 years ago was an unmitigated disaster—“a case study in failure,” according to DeRisi. The two faculties failed to merge culturally or logistically, annual operating losses ballooned, and less than three years after it began, the venture was dissolved to the tune of $176 million in red ink. Now faculty at the three universities compete for the same grants, and the institutions themselves compete for the same faculty. Even as each university has successfully established a leading national position in the interrelated disciplines of biochemistry, biophysics, bioinformatics, and molecular biology, they have sometimes done so at the expense of one another.

You could argue that Bargmann’s mandate, at least so far as the Biohub is concerned, is to change all that. To get scientists and software engineers and funders throughout the region working together for a common purpose, she has been entrusted with forging a new template for cross-disciplinary research. “You have to build up a certain critical mass of different kinds of people to make this very complicated ecosystem work,” Tjian says. “And biological research is about as complicated as it comes, because the problems we are trying to confront are immensely complex.”

Indeed, it’s all extraordinarily ambitious and complicated, but as Bargmann and I reach the end of our conversation in Menlo Park, she starts listing, off the top of her head, medical innovations of the previous 80 years that would have seemed like science fiction to anyone who came of age a century ago. The first antibiotics. Drugs to lower blood pressure. Statins that reduce the chance of heart disease. Stents. Valve replacements. Chemotherapy. Immuno-oncology drugs. “In the 1980s,” Bargmann says, “HIV was a death sentence, and now if you are diagnosed with HIV at age 20, your life expectancy is 73. It’s a manageable disease.”

With that perspective, is it really crazy to say that 83 years from now, we will have rendered Alzheimer’s or Huntington’s “manageable,” if not curable? Or that pancreatic cancer will no longer be a death sentence? Would it actually be a surprise to anyone that a medical research institute designed to take advantage of the Bay Area’s unique conglomeration of scientific and technological talent led us into a dazzling future? No, it wouldn’t.

But what really is crazy is the weird alchemical magic at work here. A social media network that barely existed 10 years ago, that almost all of us use, none of us (except for advertisers) pay for, and most of us complain about, has generated an astonishing mother lode of cash that is now being diverted to supporting the efforts of some of the most accomplished scientists of our time in their quest to solve the most basic mysteries of life. That’s kind of nuts. It’s also pretty cool.

Originally published in the January issue of
San Francisco

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