What’s the Role of Experts? A Review of The Death of Expertise and Some Thoughts for Biopharma

This piece originally appeared in The Timmerman Report. 

 

The Death of Expertise by Tom Nichols, 2017, Oxford University Press.

If you’re reading this, chances are you’re an expert or well on your way to becoming one. The Timmerman Report is tailored by content and intent to be valuable to those with the knowledge, experience and interest to make biopharma news worth reading. Experts, in other words.

This isn’t a trivial point: for the vast majority of people—that is, those non-expert in biopharma—news in sites like this one or STAT or Endpoints is as useful as scuba equipment to an octopus. And that’s fine; that’s how our knowledge-based society works. Individuals become experts in specific fields, they take the time and effort to master a specific area and they build up the intellectual framework to enable advances, discoveries and explanations. Specialization underlies the technological, societal and scientific wonders we take for granted today. There are just too many fields of study for any one person to master, the Maesters of a Song of Ice and Fire aside. Divide and conquer isn’t just for Roman governance philosophy; it also makes for progress.

The natural corollary is that we are all affected by what experts outside our field say and do. Lacking a working and academic knowledge of biopharma does not immunize a person from the impact of the kinds of issues, news, and discoveries discussed and reported here. Drug pricing, innovation, access and healthcare quality and affordability have huge impacts on everyone in the US.

And boy, do many of them have opinions about that! Opinions that they hold tighter and higher than the words of experts. Opinions that influence the ways in which they speak, act, think and yes, sometimes, vote.

This growing issue is at the heart of Tom Nichols’ book, The Death of Expertise. Nichols, a professor in National Security Affairs at the Naval War College and adjunct at the Harvard Extension School, is a former Senate aide and an expert in Soviet studies. I first became familiar with his work when, after last year’s US Presidential Election, I started consciously expanding the circle of thinkers I listened to. Like Daniel MacArthur and many others of a more liberal bent, I’ve tried to find and listen to people on the center and right.

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How Plants in Space Might Be a Cautionary Tale for Precision Medicine

A version of this originally appeared in the Timmerman Report.

When President Obama announced the Precision Medicine Initiative (PMI) back in 2015, it was a moment not unlike when a pop star drops a new album. We know she’s working on something, but details are scarce until that midnight announcement on iTunes. Then Boom!

This was Precision Medicine’s coming out party, the moment when a sensible, but somewhat obscure biomedical research concept went mainstream. And it’s exciting! As someone who’s been on the Precision Medicine bandwagon for a while now, I’m glad to see the concept getting more attention.

And yet, I’ve found myself worrying that we haven’t learned from the past and once again we’re riding a hype rocket destined to crash and burn like the first (and the second, third, and fourth) attempt at getting that SpaceX booster stage to land on a platform in the Pacific. While we’ve learned an amazing amount about human genetics over the past few decades, there’s much more we still don’t know and understand. While genetics races ahead, we are often still stuck in neutral when it comes to our understanding, much less predicting, the effect of the environment on genes’ effects on phenotype. It’s not easy.

Think, for a second about autoimmune diseases like type 1 diabetes, celiac, or rheumatoid arthritis. We don’t know what causes most of them, or causes them to flare up, but evidence is pointing toward the complex interplay of genes responding to environment. Consider the research on autoimmunity in Finland, compared with that across the border in Russia’s Karelia territory. As Moises Velasquez-Manoff has described, despite having quite homogeneous populations, and a similar geographic environment, the Finnish side sees much higher incidences of autoimmunity and allergies. Finnish scientists are increasingly pointing to genetic variations that have allowed Russians in a less-hygienic environment to avoid some of the autoimmune conditions that have emerged in Finland.

Or consider some provocative cohort studies from Florida, which characterize the timing of diagnosis for inflammatory bowel disease (IBD) in Cuban immigrants. Over time the duration between arrival in the US and diagnosis for IBD has been decreasing. Immigrants who arrived before 1980 had an average time to IBD diagnosis of 31.77 years, whereas immigrant who arrived after 1995 had an average time to diagnosis of 8.30 years. Given that the genetic background of immigrants is expected to be similar over time, the evidence suggests environmental factors.

Changes to the environment, including subtle ones that might seem trivial, sometimes matter.

Basic research often has a hard time justifying its existence in a world that wants immediate payoffs, but this is where it helps to look to basic research for guidance. In specific, we can learn from plants in space. There’s something here for everyone who studies eukaryotes.

I used to work on Arabidopsis thaliana – a genetically complex plant model organism that non-scientists would call a roadside weed. My ears perk up whenever I hear a story about Arabidopsis in the news. A few years back, researchers sent seeds up into space and grew Arabidopsis in microgravity. According to this report, while plant morphology was generally the same, the secondary branches and seed pods grew out perpendicular to the stem. On Earth, branches and pods normally point upwards, making an acute angle with the stem.

Who knew? But more to the point, who would have predicted this? I suspect no one would have guessed. Studies like this in space may help us actually figure out ahead of time, eventually, what effect microgravity will have on the growth pattern of seed pods, not to mention the many other things going on that weren’t or couldn’t be measured. It might also help us confidently predict the phenotypes that wouldn’t be affected. But this will take a lot of time and much better predictive models for gene regulation and phenotypic expression.

Arabidopsis had its genome sequenced back in 2000. It has been the subject of much basic and applied plant biology research—at this point, it’s probably the best studied plant on the planet (sorry maize—you had a good run). Scientists took advantage of the relatively easy transformation methods of Agrobacterium-mediated gene disruption and the ability to do blanket mutagenesis screens to define dozens of developmental and metabolic pathways. Many of those findings were used to improve numerous crop species (something to consider, for those in the US Congress who scoff at spending on basic research). But even after all this investment and research, I don’t think any scientist would suggest we’ve solved Arabidopsis to the point where we can predict everything about how it would grow, develop and otherwise behave when introduced to a new environment. But it’s a simpler model and easier place to start than human biology.

Parenthetically, speaking of unexpected things that happen to organisms in space, I’d suggest you check out this great piece on sex in space by Maggie Koerth-Baker and how the birds and the bees (and the rats) don’t (ahem) function the same in space either.

The heart of Precision Medicine is giving patients tailored treatments based on the molecular fingerprint of their diseases or conditions. There will be better efficacy and fewer side effects of new drugs because the treatment will be more specific. It’s no mystery why the current forefront of Precision Medicine is in cancer, where the strong causal connection between genetics and phenotype means therapeutics tailored for specific mutations in specific oncogenes or other biological processes provide a clear, straightforward path to Precision Medicine. If you have mutation X in gene Y, then take drug Z, which was developed to target that precise pathway.

This simple path works best, however, if the genetic penetrance is nearly complete and is not affected by environmental factors. Outside of cancer there aren’t as many examples of common genetic risk factors that have strong causality, even in combination. When you don’t have that kind of tight causal relationship, Precision Medicine is harder to pull off. The recent Omnigenic model proposed by Evan Boyle, Yang Li, and Jonathan Pritchard, which suggests most genes in a given tissue influence disease susceptibility, and the resulting debate about the applicability and value of GWAS moving forward shows the ongoing evolution in how genomicists and clinicians look at the interplay between our genes and phenotypes. The implication of a model like this is that even when looking only at the genetic side of things, strong causality driven by a small, testable number of variants for many diseases may just not be how biology works.

Adding to this, the plants in space example suggests to me that even as we learn more about genetic contributions and subsequent gene-by-environment interactions, some of that knowledge has an expiration date because of how our environment is changing.

Look at China. Thanks to decades of coal-burning for energy needs, China is currently experiencing a frightening air pollution challenge in some of its larger cities. How is that environmental phenomenon affecting gene expression and penetrance of variants? How will it affect development and gene expression and development of chronic diseases in the future? The airborne irritants and continual exposure might have no effect at all. Or they may have dramatic effects that will render some potential therapeutic pathways more or less effective in that population five, 20, 50 years from now. If, let’s say in a crazy hypothetical situation, which our government is assuring us will never happen, the global temperature was on track to increase by an average of 2 degrees Celsius or more over the next century, with all the cascading environmental changes that would cause, how would our genes respond?

I guess this just reduces down to a call for some circumspection. The very fact that Precision Medicine has entered the common lexicon is a reason for biomedical researchers to be cautious. Overpromising has already happened, but it could get a lot worse. At a time when funding for science is under siege, we don’t need examples at which naysayers can point as instances where scientists promised they’d cure cancer, but didn’t.

The science is already amazing. There are terrific things coming down the biopharma pipelines. And I think we’ll get a handle on gene-by-environment interactions—enough, at least, to meet the goal of creating specific health solutions based in part on each person’s genome for some diseases (although if the late Susan Lindquist’s HSP90 hypothesis turns out to be correct, many bets are off). But health and environment are moving targets. If we want Precision Medicine to be like the successful SpaceX launches, we need to keep an eye on things outside the controlled environments of our labs and clinical trials and do everything we can to embrace and understand the conversation our genes are having with the world outside.

 

Lessons from PCSK9, and How We Know Where to Go in Drug Discovery

This article first appeared in the Timmerman Report.

What drug development lessons should we take from the PCSK9 story? That might depend on how and why we know what we know.

The recent news about Amgen’s anti-PCSK9 antibody evolocumab (Repatha) and its effects on cardiovascular outcomes—the FOURIER trial—added another fascinating chapter to the story of how human genetics is becoming more entwined with drug development. It also jogged my curiosity once again in some old liberal arts late night dorm-room discussions about epistemology, the theory of how we reach rational belief.

How do we collect biomedical knowledge? How do we know what we know about biology, about the genes and proteins and networks and physiology and other phenotypes that we’ve built into models and hairballs and devilishly detailed flowcharts over the past few centuries?  And why do we have the current body of facts that we do?

Targeting PCSK9 represents the most prominent example of using human genetics to identify new drug targets. There are others in the works (Sclerostin and APOC3 come to mind) and they herald an exciting new period of drug development in which the process will be expedited by the existence and study of humans with variants, functional and non-, in these targets. If you have a human being, or a closely related cohort of people, who have a certain gene mutation that keeps their cholesterol low and doesn’t appear to cause any detrimental health effects, you have a pretty powerful predictive human model for a drug (See TR contributor Robert Plenge’s case for a “Human Knockout Project”). With this kind of biological information in hand, setting priorities for drug discovery gets easier.

But the commentary following the presentation of FOURIER showed many are underwhelmed. As Plenge points out in an excellent blog post, people are disappointed by the relatively modest gains in cardiovascular outcomes and the implications for blockbuster status (or lack thereof) for Evolocumab and Alirocumab, the competing antibody from Regeneron Pharmaceuticals and Sanofi. However, Plenge points out, the drug development process of going from human mutants (over-expressors and, eventually, under-expressors of PCSK9) to a drug worked quite well on many levels. Dosing was improved, pre-clinical models were leveraged for specific hypothesis tests rather than broad (and possibly meaningless) demonstrations of efficacy, and clinical endpoints were informed by human biology.

As a trained geneticist, I love this terrific biological story. But I can’t dismiss the criticisms either, which brings me back to the question of knowledge. Human genetics will provide an orthogonal method of identifying targets, and will make the overall process more efficient. I wonder though: will it be enough to make a real dent in the problems facing the drug development enterprise? Or will it instead end up helping incrementally when we really need quantum leaps to help with clinical success, pricing and curing patients? And I think the answer comes back to epistemology. How and why do we in biology know what we know?

I’m going to focus on gene-centric discovery here. It’s my background and serves as a relevant example given the current drug development paradigm of focusing on specific gene targets. So: here’s a question a bioinformaticist friend and I debated while we were at a former company. Why do we know so much about some genes and so little about others? This was of particular importance because we had been directed to find novel targets. See the catch-22, though? Novel targets by definition have little known about them, and those making decisions were often leery of investing millions of dollars in a target with a skimpy data package. This, by the way, is one big positive when using human genetics and an allelic series, and is highlighted by PCSK9. That gene had been poorly studied before but human genetics allowed a quick ramp-up in understanding of its biology and role.

The problem of novelty in target identification came clear to me as soon as I tried convincing other scientists to consider some novel targets. Here’s a story familiar to anyone who has done ‘omics research. I did a lot of transcriptomics. Invariably, in comparing different tissues, diseases, cells, I generated a list of differentially expressed genes. Often lots and lots of lists. Buzzfeed had nothing on me! Although maybe I would have been more successful taking a page from their sensationalistic style: “You won’t believe the top 10 most differentially expressed genes between inflamed and normal mouse colons (number 3 is a real shocker)!”

In any case, there would be familiar genes and there would be novel genes. When we showed these lists to the biologists with whom we were working, they mostly gravitated to the genes they recognized. I can’t blame them; they knew they’d be asked to justify further work, and having several hundred papers sure makes it easier to build an argument for biological plausibility (Insert your favorite version of the lamplight/car keys story here). The specific question my friend and I debated was: Are known things known and novel things novel because the known things are more important in terms of biological function and therefore will have the greatest likelihood of being good drug targets? Or are they known because of historical accident? Or, the third option, is what we know due to the tools we use? I don’t think this is a binary (trinary?) choice. The reality is surely a mix of all three. But if the first condition is the most predominant, that has some implications on what we can expect human genetics to do for drug development.

Postulate discovery in biology has a bias toward the genes with the largest effect being found first regardless of how one does the looking. To illustrate this, I’ll use an example from Ted Chiang’s amazing novella, “The Story of Your Life,” which was the basis for one of my favorite movies of last year, Arrival. A central theme in these works was how different ways of perceiving reality can nevertheless lead to the same place.

If one throws a ball through the air, where will it land? One can use Newtonian mechanics to describe the arc, rise and fall. Or one can use Lagrangian formulations to see the pathway as the one of minimizing actions the ball must take. Either method predicts the ball ends up in a specific place. My analogy: is our knowledge of genes like that? Would the accumulation of knowledge have looked pretty much the same even if different scientists had been using different tools to study different biological problems because by the nature of our shared evolutionary history certain genes are just more fundamental, important and pleiotropic? (For a fascinating rumination on the same question in chemistry, take a look at Derek Lowe’s piece here).

Contrast this with historical accident. Here I’ll go back to physics and invoke the idea of the many-worlds hypothesis. If we could rewind the clock of time and start again, how different would our history and discovery be? In this interpretation, initial discoveries are at least somewhat random but once they occur, it becomes more likely that knowledge will accrete around those initial discoveries like nacre around a grain of sand in an oyster’s mantle. Initial discoveries have a canalization effect, in other words, and as data and effects of specific genes accumulate, those canals get deeper. As illustrated in my earlier example of showing people lists of genes, there is a natural and understandable gravitation toward adding another pebble to the hill rather than placing a rock on a novel patch of ground.

And then there are tools. I’ve been a biological technologist for much of my career, using technologies like microarrays and, later, next-gen sequencing to speed, enhance and extend experimental approaches. So I know there are questions we could not have easily asked, biological problems we would not have tried to approach without the right tools. I remember the early days of fluorescent microscopy and how much that changed our view of the cell, and of Sanger and Maxam-Gilbert sequencing, when actually decoding the order of nucleotides for a gene became feasible. I also remember friendly-ish debates among the geneticists, biochemists, molecular biologists and cell biologists about the best way to do research, with each approach having specific benefits. This general assertion—that tools help us do more–seems circular and obvious, but the implications are deep. Just as many believe language shapes how we think, tools shape how we measure and construct our pictures of the world. When you have a hammer, and all that.

Circling back to PCSK9 and other human genetics-enabled targets, having an orthogonal target discovery method may not be enough to really push the industry forward if we’ve already found the majority of the most broadly effective drug targets. New targets may be effective but not better than current therapies except perhaps in niche indications. Good for precision medicine, but not so great amid the current pushback on drug prices. On the other hand, if limitations of tools and/or historical accident played the majority role in limiting discovery in the past, many innovative targets may be right around the corner as we sequence more genomes and begin to connect the dots between genetic abnormalities and problematic (or advantageous) phenotypes.

I don’t know the answer, but we’ll get an idea in the next few years as more of these genetics-derived targets make it to the clinic. If it does turn out that genetics helps with process and speed more than innovative leaps, well, that’s still helpful. That would also push us further toward new approaches, new platforms and combinatorial therapies. None of that will be easy, or quicker, or simpler. Just looking at the PD1/PDL1 combinatorial clinical trials landscape might be a preview of how messy this could be.PDl1

Also, if human genetics is orthogonal, it does increase the number of shots on goal a company can make although there are limits on how many targets any company can take to the clinic. It still begs the question, though, of whether those shots will be better or just different. And if it’s the latter, that’s not the solution the industry needs. Unfortunately, like so many techniques and tools that have come before (high throughput screening, anyone?), we just won’t know until we know. As much as people would like it to be so, knowledge in this area just won’t inexorably march onward and upward in a straight line.

 

Changing small molecule exclusivity rules as a long-term drug price policy play

This piece originally appeared in the Timmerman Report

We’re entering uncharted waters in the US government. I don’t think it’s hyperbolic to say there will be new regulations, new laws that we’ve never seen before. While I don’t pretend to understand the new administration in any way, I do expect there will be more chaos at the level of policy-making than we’ve seen in decades and one thing that chaos does is it increases the likelihood of extreme outcomes.

So here is one speculative policy idea:

I think we should trade the 12-year exclusivity period from biologics to small molecule drugs. Continue reading

It’s time for biopharma to embrace public health

This piece first appeared in the Timmerman Report.

Some years ago when I was working for a large biopharma, I heard a story. It seems a senior scientific executive had visited and given a seminar in which he described the company’s portfolio of drugs for type 2 diabetes. The company was projecting great uptake and profits. A member of our site raised his hand and said, “But if people just ate less and exercised a little more, they could prevent type 2 diabetes and the market would disappear.”

The answer: “Yeah, but they won’t.”

Harsh! But that executive was right. The Institute for Health Metrics and Evaluation (IHME) recently published a paper in JAMA describing how much different health conditions contribute to private and public health spending in the US. Number one? Diabetes. Following that were heart disease and chronic pain. These are chronic lifestyle diseases with big environmental and behavioral components, and the data make me wonder if there’s an opportunity here for the industry to zig and do some things that, in the long run, may make drug development more sustainable.

I think it’s time for biopharma to get involved in public health. Continue reading

Plan B

Once again, time for something different. Speculative fiction about the election and its aftermath and some wishful thinking about what could happen next. 

Bill folded his newspaper and sighed. The awful truth was laid out in forty-point type. That was the thing with print, he mused. It had a reality that pixels and bits couldn’t quite capture. Made things seem real. Although maybe that was just a generational thing.

A large picture of a broadly smiling man dominated the front page. The image had a decidedly orange tint.

Bill peered over his glasses through the dining room window at the lake outside. The view was picturesque, even under a gray morning sky. The view to the north and west was bisected by the bulk of a long freeway bridge, crossing the lake from the east to the west and pointing toward the island community where he lived. Tiny headlights glowed like fireflies in the gloom as traffic crawled in both directions. A November windstorm was blowing through and to the south of the bridge the lake’s surface was being tossed into a jumbled mass of dark waves topped by chaotic whitecaps. Barely visible to the north, Bill could see the protected waters on the far side of the bridge’s span through gaps in the bridge’s pilings. The lake there was still and calm. A metaphor? he thought. Well, perhaps if what was to be done worked out the way he hoped it would. But you could never know until it was over.

Melinda looked at him with concern from across the table. Her brow creased. “You’re going through with it?” Not really a question.

He pursed his lips, nodded, and pushed his chair back from the table. “Yes, I’ll be pretty busy for the next few days. Or longer. You’d better get the kids ready. Are their bags packed?”

Melinda smiled, nodded, said, “I’ll get them going. We’ll be fine. When do you think you’ll be able to be in touch?”

“I wish I knew.” He gathered up his coffee cup and plate and brought them over to the sink. He could hear Melinda moving through the house, gathering their family together.

He said his goodbyes, drove to his office and ascended in a cool steel elevator to his private conference room. No one else was there. He opened up his laptop and activated the custom encryption and meeting software. The first thing that popped up was a message from Satya. It said, simply, “Go for it.” His laptop chimed softly as the first attendee connected.

“Bill.”

“Tim.”

A pause, then “I’d been hoping we wouldn’t need this meeting.”

“It was close. That’s the problem with things like elections. So many random factors. It’s like launching a product.”

“Still, even after that last bombing it seemed like public polls hadn’t shifted enough…” His voice trailed off. Then, “By the way, I sent you a new phone.”

Bill sighed, “Yes, I got it yesterday. It’s very nice. Thanks.”

Another chime sounded.

“Hi Jeff.”

“Hey. Am I last?”

“Not yet, Tim’s on the line, we’re still waiting for a few more.”

A snort from the speakers. “Probably overslept.”

Two more chimes.

“Hey, it’s Larry and Sergey.”

“Mark here,” said another voice, somewhat muffled.

“Are you eating something?”

“Sorry, late breakfast, the kid was fussing last night and I didn’t get much sleep. My internal clock is a little out of whack.”

“Okay,” said Bill, “We can get started. Since we know why we’re here, let’s just proceed to the vote.”

A little voting button window popped up on everyone’s screen.

“Wait!” said Sergey.

“What?”

“Is anyone recording this?”

“What are you talking about?”

“Well, this is potentially pretty historic, don’t you think?” Sergey asked.

“Do you really want a record of this?” asked Tim, pointedly, “We’re about to do something that’s best described as treason.”

“Oh, only if we lose,” said Sergey, breezily.

“Here, I can do it,” Jeff interrupted, “Alexa, record.”

“All right, fine,” said Bill, “Just to repeat, given the recent election results, we five are voting on whether to implement Plan B. Everyone submit your votes.”

Bill hesitated a moment, his hand over the touchscreen. It was weird, he thought, to be collaborating in this way with these people—all of whom he respected, but all of whom in various ways had been competitors to himself and the business he and Paul had started. I suppose it’s true what they say, he mused, politics makes for strange bedfellows. He touched the screen.

Five green lights appeared immediately, one under each company’s icon. “Okay. That’s it. Thank you all. We’ll start in one hour from…now.” A timer began counting down on lower corner of his screen.

As Bill closed his window, he heard Larry mutter, “What kind of a code name is ‘Plan B’?”

 

Oakland, One Hour Later.

Laila turned to Jen, holding out her phone. “Here, how about this guy?”

Jen shrugged, not really looking at the screen, watching the people outside. Somehow Laila’s continual searches for a new guy seemed especially ridiculous today. People were taking the news in all kinds of ways.

Some marched around in mobs, with or without signs, often shouting in each other’s faces. Others were crying, either great huge wails or quiet sobs while hunched over on a bus stop bench or even lying curled into a fetal position on the sidewalk. Several fistfights had broken out. Sirens wailed in the distance and their school bus was barely crawling through traffic. She bit her lip. Her grandma was an aging hippie and her mom had grown up to be a born again Christian banker and Jen wanted to get home from school before something ugly happened between them. During the campaign, her grandma had come close to throwing her mom out of the house. Jen could hardly believe how the election had turned out, especially after all the horrible things that man had said all through the campaign. Her civics class teacher couldn’t keep up with one controversy before another one happened. And so much of it was targeted at people who looked like her.

Abruptly Laila’s screen went dark and then flashed several times between black and white while vibrating.

“Please stand by,” said a hauntingly familiar voice. Jen frowned, trying to place it. It was a feminine voice, kind of sounding like something a voice synthesizer would make, or a human voice sampled with a little distortion added. But still pleasant to hear. Then she realized it sounded a lot like that actor, the blonde woman in all the comic book movies, but not quite.

Jen looked up and saw everyone in the bus was staring at their phones or devices, and a glance outside confirmed that this was happening out there too.

“People of the United States,” the voice continued. “We regret to inform you that due to the unprecedented, nearly inconceivable, and highly unfortunate result of yesterday’s election, the time has come for action.”

Jen could hear the echo as every device nearby repeated the same thing. A phone held by a Hispanic couple near the front of the bus was speaking smoothly modulated Spanish.

“We represent several of the companies that have created the interconnected world we live in today. We cannot stand idly by while the principles, systems and culture that allowed each of us to create and build successful and innovative products for you and the rest of the world are endangered by the unbalanced and unpredictable actions of a jingoistic, bombastic, dangerous demagogue.”

“We therefore are activating pieces of code that, prior to today, have been non-functional in your operating systems. As of now, we are taking control of the devices, platforms and services that have become an integral part of life in the US and we will be rendering them unusable while we effect the secession of the West Coast. Other parts of the previously United States are welcome to join us and we will contact the necessary representatives of your governments in the near future with plans and proposals.”

“Please understand that our reach extends not just to this code but also to information. As this secession proceeds, we expect to selectively begin restoring service to those individuals whom our analyses suggest are sympathetic to our cause.”

“We highly suggest you return to your homes as this situation resolves. We hope for a peaceful process, but cannot guarantee anything. However, desperate times call for desperate measures. We urge everyone to behave in a reasonable and rational manner. That is all for now.”

Jen and Laila looked at each other in shock.

 

In a hidden command center.

Bill’s new phone vibrated on the grey granite tabletop. He picked it up.

“Hello?”

“Hi Bill. It’s Tim. Elon just called. He’s pretty pissed we didn’t let him in on this.”

“What did you tell him?”

“I told him one day when his cars are linked in an intercontinental grid keeping power equalized as needed and when he’s got a fleet of spaceships, we’ll be happy to give him a voice at the table.”

“And then?”

“He swore at me and hung up. Just thought you’d like to know.”

“Anything else?”

“We’ve heard from Jerry, Kate and Jay. They’re on board. We’ve activated a limited network for them so they can coordinate their civic response.”

 

In a shared developers’ office.

“Shit, what…what do you think is going to happen?” Saul nudged Billy. The message had just ended and they were staring at their blank screens.

“What do you mean?” Billy asked. He was feeling a little like he had felt when his parents had told him they were getting a divorce. It was like his consciousness was hovering a little outside of his body, and everything was just a few beats out of sync.

“Well, I mean…” Saul began. He fidgeted in his seat, twisting the hem of his flannel shirt. “Do you think there’s going to be a war? Or…or, I don’t know, some kind of fighting, or something?”

“What, that’s crazy. This is just a, just a temporary thing. I mean, how can companies, even these companies, break up the US?”

“I don’t know” said Saul. He was sweating. He always seemed a little moist, like he’d just dried off after a shower, but right now there were little streaks of sweat running down the sides of his face.  They looked around the room. There were a half dozen other programmers, some trying to boot their laptops from Linux, one guy with his head down on his arms, another grabbing all his things and stuffing them into his yellow Ortlieb courier bag.

“I don’t think it’s going to be that bad. Or that long,” said Billy, more to reassure Saul than anything else.  It was dawning on him that he really had no way to quickly find out what was going on. Every tool he would normally use to check the news was useless. He looked out the window. People were streaming out of the building entrances and a line of cars was already heading out of the parking structure. “I think…I think maybe I better get home.”

“Yeah,” Saul looked around. “I guess there isn’t much point in hanging around here.” He looked at the square multicolored logo that represented his company. “But do you think…do you think we’re the good guys?”

“I don’t know,” said Billy, “I don’t know.”

 

In a large hotel conference room in Washington DC.

The President-elect was throwing a tantrum.

“What the Hell is going on? They can’t do that. Get me the Secretary of Defense, I’ll order him to find these…these…really really sad people, who think they can get away with this. Let me tell you, they are not!”

“Uh, sir,” said one of his aides, nervously. You actually can’t order the Secretary of Defense to do anything right now. You’re not technically Commander in Chief yet and—“

WHAT? I won the election, didn’t I? That’s completely unacceptable. Unacceptable. I won the election, it was the biggest, it was the best win in history, I should be in charge right now. Get me whoever is in charge of these things and we’ll see about technicalities. Poor deal. I can do better!”

“Sir,” said another aide, “There’s not actually anyone to negotiate with. This is in the Constitution and…“

Unacceptable! That’s really sad, really sad. That’s going to be one of the first things on my list to change, that’s all going to change…” He continued ranting and gesturing wildly while pacing around the room. His aides waited patiently. Everyone knew what would happen to someone who tried to stop him when he was like this. His kids had prudently left the room earlier, as soon as service had been cut off. The aides didn’t have quite the same instincts for self-preservation.

 

Oakland

Jen walked quickly along the sidewalk, keeping her head down. There was a lot of traffic, but it moved surprisingly well. She noticed that at intersections cars seemed to be moving more smoothly than normal. She had gotten used to delays in cars starting when lights turned green, what with people always checking their phones, but that wasn’t happening anymore now that everyone’s phones were dead.

The sky was a cold blue and she shivered, pulling her grey hoodie over her head. She and Laila had gotten off the bus after the message and split up to go home. Even though she knew it was useless, she still kept checking her phone every few minutes. Every so often she’d feel what she swore was a vibration. She’d heard about this, phantom vibration syndrome, but had never experienced it before. Maybe because her phone normally never was silent for long.

She turned toward the path circling Lake Merritt. The Children’s Fairyland was closed, but several kids were running around the grassy park, chasing the ducks. Looking out toward downtown Oakland she could see a few plumes of smoke and hear the occasional faint tinkle of breaking glass, but mostly it seemed like a pretty normal day. The lake was really low—the winter rains hadn’t started yet, and the drought had led to some pretty dire water restrictions, but they didn’t seem to have helped the lake at all. At least with the weather cooling down the rotting smell from the exposed lakebed wasn’t as strong.

She looked ahead to her apartment complex, about half a mile away. It was a great location and she’d always felt lucky to be near the water and the view. Her grandma had lucked into the apartment decades ago and had outlasted several landlords. Jen wondered if her mom was home from work yet. It seemed like a lot of people were taking the rest of the day off.

 

Somewhere in the Midwest

“Morning, Mike.”

“Morning, Pat?”

“Things good?”

“Good enough. Got the last of my soybeans in.”

“Oh? I need to get on that. My wife wants me to start cleaning the attic. I’d as soon find a reason to hold off on that.”

“Yep.”

A few moments of silence, then, “Think it’ll snow this week?”

“Maybe. Kinda looks like it. Reminds me I should get the blower out, make sure it’s running.”

“Good idea.”

A few more moments of silence.

“Well, got to get moving. You have a good day, now.”

“Sure, you betcha.”

 

In the Oval Office.

The President swiveled in his chair as people filed into the office. He looked up at his staff. Their expressions were strange. I wonder if I look like that too? he thought. That odd mix of anxiety, concern and glee?

He held up his Blackberry. “This still works. See, I knew it’d come in handy someday.”

That broke the ice. Everyone chuckled. His chief-of-staff cleared his throat. “Sir, still, what will we be doing? The Joint Chiefs have asked for their orders…” His voice trailed off.

The President looked up, pursed his lips. “What kinds of reports do we have coming in?”

“From what we can hear, several states have begun formally announcing their intent to secede. Military units stationed in those and neighboring states are unsure about what to do.  What are your orders for them?”

“You’re asking me to authorize the use of military force against this nation’s citizens?” The President shook his head. “No. That I will not do. Tell everyone to hang tight. If no one starts shooting, maybe no one will ever start shooting.” He gave a ghost of a smile. “Unlikely, I know, in a country with, what was the last count, 300 million guns?”

“Tell them their first and only priority is keeping folks safe. This should be resolved in as non-violent a manner as possible, through negotiations among government officials. After all,” another brief smile, this one a little more sardonic, “we want to be respectful of States’ Rights.”

He stood up, reached for his coat and began to shrug it on. “You know,” he said casually, “I think maybe Mitch had it right after all. David too. And Boris and, what was his name, Nigel? Let’s leave it for the next guy.” He motioned to his secret service team to follow him.

“I’m taking the afternoon off, going to see Michelle and the kids. You keep me posted okay?” He strolled out the door.

 

In a state Governor’s office.

“Sir, our technicians have been trying but there doesn’t seem to be anything they can do to get our systems up and running.”

“Don’t we have backup plans?”

“I–Well, yes, but none of us really understand them. I mean, most of us were Poli Sci majors in college and…”

Suddenly the Governor jumped as his phone buzzed in his pants. He pulled it out. On the screen was a simple question:

“Would you like your state to join the secession?”

He stared at it, showed the screen to his aides. Then slowly nodded, muttered to himself, “Why yes, yes I do.”

The screen flipped to a smiling emoji. “Thank you. Voice impression captured and matched to known records indicating assent by the duly elected Governor of this state. Please stand by for further instructions.”

The Governor looked up. Swallowed. “Well,” he said to his stunned aides, “I think we’ve joined the rebellion.”

 

In a hidden command center

“What’s the tally now?”

“California, Oregon, Washington, New York, New Jersey, pretty much all of New England. Well, except Maine. That guy. Minnesota and Illinois are in. Larry is making some noise about Lana’i. Oh, and Utah is in too.”

Bill raised an eyebrow. “Hmm. Wondered about them.”

“Looks like New Mexico is likely as well. Just to throw more sweet light crude on the fire, as it were, passive monitoring from various devices in the Texas State House suggest the Texans are planning to use this as an opportunity to secede as well and go their own way. To quote some of the people we’ve heard, ‘No way is the great state of Texas going to allow a bunch of hanger-on red state wannabes drag down our way of life.’ Well that was quick.”

“Any indications of unacceptable violence starting?”

“So far things are relatively—surprisingly—quiet, but we’re starting to hear some rumblings, especially in the South.”

“Time for the next stage then.”

 

In a red state.

“Do you see anyone out there?” Barb was standing well back from the window. Her husband, Mike, had just peeked out around the curtain shielding their living room from the street outside.

Barb was shifting from foot to foot. Moving here from Oregon had seemed like a good idea a year ago—the cost of living was certainly cheaper, and the outdoor activities were still great even without an ocean. But as the election had gotten closer, she’d found herself getting worried. The chatter in the grocery store line had been getting more unguarded and apocalyptic in tone. She had mastered the art of the polite deflection, but she knew her family was still viewed as outsiders and likely liberals. Which, okay, they were, but still.

“I didn’t see anything.” Mike turned back and moved over to give her a hug. She found herself focusing on his mouth, framed by his thick, well-groomed beard. She could smell the gel he used to keep his hair neat and flipped back in a perfect wave from his forehead. They both started as they heard the distant pop-pop of someone firing a rifle. Suddenly they heard a voice at the back door.

“Excuse me.”

They moved into the kitchen and looked through the window on the door.

Hovering outside was a quadcopter drone.

They looked at each other. Barb cracked open the door.

“Hello,” said a smooth electronic voice. “Facial recognition software confirms that you’re Barb Gunderson. Our analytics based on your purchasing, social media sharing and keyword search patterns suggest you may be experiencing some distress and apprehension about the current state of affairs. We are here to offer you an option.” The drone’s body was decorated with a very well-known logo. It looked like a banana.

“If you would like, we can offer you transportation to a secure location where you can remain while the current situation resolves.”

Barb peered around the drone. In the alley behind their house a small car that looked rather like a white jelly bean waited.

“Mike,” said Barb, “Go get Laura.”

“We understand you may wish to bring along some personal items to make this stay more comfortable. We’d like to suggest you take no more than five minutes to do so and please limit the amount to what you can easily carry.”

Five minutes later, they went out the back, Barb carrying a duffle with clothes and some keepsakes and Mike carrying their daughter. The drone led them to the car, whose doors clicked open. They climbed in. No one was in the driver’s seat.

“As long as I’m here, can I also give you the current issue of the Atlantic, your first as part of the subscription package you recently purchased?” said the drone, extending the magazine. Barb took it. “We’d also like to remind you that you can choose to receive your subscription just electronically if you so desire. It saves trees!” The drone added, cheerfully.

“Thank you,” she said, in a daze.

They closed the car door and sat quietly while it drove them to a large distribution center in the industrial district. Several other vehicles were converging on the same location.

 

In Oakland

Jen was surprised how quiet it was going up the stairs to her apartment. Normally she could hear the shouting between her mom and grandma before she was halfway up the steps.

She unlocked the door and walked through the living room to the kitchen, following the faint sound of a staticky voice. Her mom and grandma were huddled around the emergency radio sitting on the kitchen counter. It was something her grandma had gotten from a KQED pledge drive. Her mom must have just come from work. She was still wearing a business jacket and matching skirt. From the side Jen could see a string of pearls dangling from the graceful brown curve of her neck as she leaned forward. Jen’s grandmother was gently twisting the radio dial, trying to zero in on the faint signal while her mom kept giving advice.

“You had it earlier. Go back a little.”

Jen’s grandma ignored that and instead began cranking the red plastic lever on the side of the radio.

“Stop that. We already cranked for a minute. It’s as charged as it’ll ever be.”

Jen felt reassured. This was bickering she was used to. Her grandma stopped cranking and went back to rotating the tuning dial. Suddenly a voice crackled through.

“—viding regular updates. The Governor has issued a statement in support of secession from the United States. Fragmented reports suggest at least a dozen other states have joined this effort. While there have been isolated reports of vandalism and looting, so far there do not appear to be large scale issues of violence or protest. We will continue to report on this incredible developing story as we—“ The voice cut off again.

Jen’s grandma opened her mouth to say something, but her mom raised a hand. “Don’t. I know what you’re going to say. How this is what happens when people don’t have a voice and eventually have to rise up. But let me remind you, this isn’t being led by a bunch of Bernie bros. This is being done by some of the biggest economic players in our—the—country…” Her voice trailed off.

Jen’s grandma reached out. She clasped Jen’s mom’s hands. “You’re right. This isn’t the revolution I was thinking would happen. But it’s still a revolution. And come on. Did you really want that man to be our president?”

“I know I didn’t,” Jen said, moving forward. “Mom. Grandma. I’m glad you’re both here and that we’re safe.” She looked at their faces, her grandma’s shining, her mother’s conflicted. And wondered how long it would take before they knew what was going to happen.

 

In a hidden command center

It was several days later. Bill was sitting and tapping a stylus on his tablet, staring off into space. Events had calmed down, especially once it became clear that the majority of states and the majority of resources and capital were going with the new nation, or with the breakaway Republic of Texas. There had been fatalities, but not as many as they’d feared. It turned out in some way the mood of the nation, with so many people dissatisfied with the state of things, had made this kind of secession almost preferable. It didn’t hurt that the day after the election so many people had woken up to realize they had voted for someone they actually didn’t want to be president. Brexit redux.

“Bill.”

“Oh, hi, Tim. What’s on the agenda next?”

“In about thirty minutes, we have that press conference scheduled outlining the broad parameters of the transition plan.”

“Okay.” A pause. “Tim?”

“Yes?”

“Any polling or other information on how people are feeling about this? About trust? We took a big risk with this. I don’t think the high tech industry is going to have the same cachet in the future. Not to mention we’ve now exposed all the back doors. We won’t ever be able to do this again.” A pause. “You know the FBI is going to use this against you for the rest of your company’s life.”

“I know. I’ll deal with it. As for people in general–it’s too early. You know that. If you’re asking how history is going to view us, well I think in the long term that’s going to depend on how well this transition goes.”

“Results based analysis. I guess results are what everyone ultimately wants. But in some way, we’ve broken something fundamental, I think.” Bill shifted in his chair. “So much of what we’ve worked on is based on trust—of how things work, sure, but also of neutrality. We’ve also made it abundantly clear just how much technology is an integral part of most people’s lives. Not something most people think about, or realize, until they can’t text or see the most recent pictures of their granddaughter.”

“Oh, we’ll get more regulation, more constraints, that’s for sure,” said Tim. “Still, think about the alternative. What happened was really the perfect storm, revealing all the cracks in the system at once. I don’t think it would have held up much longer in any case.”

“Sometimes systems get too complex,” he continued, “too interdependent and networked and then the best thing to do when all the patching in the world fails, is start over from scratch. Sometimes you need a new OS.” A pause. Then, with a lighter tone of voice, “You should know that as well as anybody.”

“Thanks. Thanks a lot.”

 

Epilogue: In Oakland, February of the next year.

Jen walked home from school. Classes had started up again and there was talk about extending the school year to make up for time lost during the secession. It was funny, she thought, how after all of that everything seemed pretty much the same. She was following the news about the new Constitutional Convention, and she was also streaming feeds from the ongoing debates about what the new country would be called and how it’s government would work. While the new country was using various social media tools to allow people to give feedback, the final say had been limited to the delegates to the convention. There was also some talk about experimenting with a more parliamentary style of government, and they’d been discussing the pros and cons of that in civics class.

The old United States—funny, how it had already become normal to say that—was facing a lot of challenges. The outgoing President had refused to do anything to rein in the secession, and after the handoff in January had taken off for Hawaii. During the lame duck session at the tail end of 2016, the former President had worked with uncommon swiftness and unity with Congress to change the process for use of nuclear arms, and it seemed unlikely the new President would be able to easily meet the criteria.

Meanwhile border control in the as yet unnamed new country and the Republic of Texas was getting a little heated as people from the old US kept trying to enter. She found it ironic, given the rhetoric during the campaign, that one of the clear early mandates put in place by the transitional governments had been that the borders would be closed to immigration until things were more sorted out, but that didn’t stop people from trying. Especially after there had been some pretty dire projections on how quickly the old US would run out of money and have to reduce services now that most of the net revenue producing states had left the union. Oh, the President of the old US was making promises, but it seemed like people had finally starting doing math again. Or something.

Oh well, she thought. That was one of the many problems that would get sorted out over time. She had faith in the people in charge. Her phone was working again, her mom and Grandma were having real conversations and seemed to be seeing more eye to eye than they had in while, and the winter rains had come, turning the Oakland hills a beautiful deep green. Jen remembered from Chinese class that an old Chinese curse was “May you live in interesting times.” Well, it looked like that was the case now, for sure. But that was okay. Because from where she was standing, interesting times looked like they’d be bringing some pretty welcome changes.