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I was deeply affected by this podcast, which outlines a number of specific scenarios that could lead to an engineered pandemic (as well as promising routes to prevention). 

I decided to invest in creating a transcript (thanks to Rev for the rough draft and Heidi Basarab for edits and subtitles many edits). 

If you prefer a summary, this one is solid, if a bit garbled. But I didn't regret a single minute of the ~2 hours I spent on this conversation (2x speed is available on YouTube and many podcast apps).

I'd be very interested to hear criticism of Reid's views, since this isn't a space I know well and the very compelling story being told makes me wonder what I'm not hearing.


Introduction: Imagining the outbreak of an engineered pandemic

Rob Reid: Imagine we're in another pandemic and the disease has been deliberately engineered to be more contagious and way more lethal than COVID-19. That's right: It's a man-made pandemic. And the virus is so deadly that it kills roughly half the people it infects. So, if you and your spouse catch it, at least one of you will probably die, and maybe you both will. Likewise for any other duo: you and your best friend, you and your kid, the president and vice-president. And an uncontrollable outbreak is underway.

Next, imagine this outbreak sweeping through a power plant. Did the lights stay on with half the staff dead or dying and the other half thinking they’re next? And if the power goes out, how do we reach the internet? And with no internet, how do we find out, well, practically anything that we need to know to navigate this unprecedented existential threat?

Now imagine you're a frontline worker at the power plant. You're caring for the sick or delivering food. People are getting wiped out at 50 to 100 times the rate of COVID. It's a coin toss as to whether you'll survive if you get sick. Do you report to work or do you hunker down with your loved ones at home until you all get really hungry? Supply chains disintegrate in situations like this. The grocery stores that actually opened sell out — and not just out of toilet paper — and they don't get restocked. Pretty much everything else disintegrates too. 

For all of its horror, COVID hasn't shut down the power, the water, law enforcement, or the flow of information. But something this lethal could just shut them all down. And while you may be more imaginative than I am, I just can't picture civilization surviving an encounter with something this deadly. And the problem is we're on a collision course with some version of this scenario.

Rob introduces himself

Rob: Hi, I'm Rob Reid. And I've been worried about artificially modified viruses for a few years now. My background is that I'm a longtime tech entrepreneur who went on to become a writer. I write science fiction for Random House, and I'm also a science writer and science podcaster. A while back, I wrote four articles for Medium about artificial pandemics and other subjects. That led to an episode on my own podcast, which is called the After On podcast and mostly considers fairly deep scientific issues in ways that non-experts can follow. That particular episode was a conversation with a thinker and entrepreneur, Naval Ravikant, and it led directly to a talk that I gave on the TED conference’s main stage about a year and a half ago. I'll be integrating some of that earlier work here, and then building on it in this short series.

In the course of it, I believe I'll persuade you that an engineered pandemic will almost inevitably happen eventually unless we take some very serious preventive steps. And I'll tell you exactly what those steps are. We'll also talk about the science and techniques that are at play here, and about the sorts of people who might actually want to inflict a pandemic on the world and what drives them. 

But first a big spoiler: It may not sound like it, but I'm an incurable optimist. I wouldn't be telling you all this if I wasn't convinced the story can have a happy ending. And more than anything, this series is about navigating our way toward one.

Did we get lucky with COVID, relatively speaking?

Rob: I'll start out with a strange claim, which is that we actually got rather lucky with COVID. I don’t mean this in an absolute sense, obviously — this is clearly the most horrifying year humanity has endured in quite some time — but we were lucky compared to what might've happened, in terms of sheer deadliness. I say this with the caveat that it's hard to know exactly how deadly COVID is in percentage terms. We can't just use simple ratios of deaths to officially reported cases, because huge numbers of cases never get diagnosed. Many people who catch COVID never get symptoms, for one thing. And for those who do get sick, testing capacity is notoriously inadequate, so countless cases go undetected.

But adjusting for all this murkiness, the World Health Organization estimates that between 0.5% and 1% of infected people died — and in many age groups, it's a tiny fraction of 1%. And I'm saying we got lucky, because there is no biological reason why the death rate had to be this low. 

Take SARS. It killed about 10% of the people it infected. That's an order of magnitude worse than COVID. And we were lucky with SARS, too; people got so obviously sick, and so fast, that patients were easy to identify and quarantine before the disease spread very far. So, fewer than a thousand people died of it. But if SARS had been like COVID and spread like mad when people were still asymptomatic or thought they just had a cold, we'd be living in a very different and badly diminished world right now.

SARS is a kitten compared to Middle East Respiratory Syndrome or MERS, which kills over a third of its victims. So we're incredibly lucky that it just happens that MERS isn’t very contagious. And then MERS is mild compared to H5N1 flu, which kills about 60% of the people who catch it, making it even deadlier than Ebola. Thankfully, it's insanely hard to catch. How insanely hard? Well, the World Health Organization tallied every instance of H5N1 over a decade and came up with just 630 cases and 375 deaths. To put that scale in perspective, lightning kills about 60,000 people in a typical decade. So H5N1 is barely contagious at all — in its natural form that is.

But unfortunately, there's an artificial form of H5N1 as well. It exists because several years ago, some scientists started poking at the virus in hopes of understanding just how dangerous it could be. Since it was plenty deadly but barely transmissible, they set out to create a contagious form of it. And you heard me right, they deliberately produced an artificial version of this ghastly virus with a terrifyingly high potential to spread easily between people. This incident is the basis of a grim pandemic scenario I opened with: a contagious, modified form of H5N1 killing half the people it infects.

Researchers have made this monster by manipulating its genes via passing the virus between several generations of ferrets (ferrets being common stand-ins for humans and virus research). Eventually they had a strain that could pass from ferret to ferret without any contact through the air. The head of the Dutch team, Ron Fouchier, candidly admitted that his creation was “probably one of the most dangerous viruses you can make.” Over in the U.S., the National Science Advisory Board for Biosecurity didn't disagree. In a press statement, it said that the modified viruses released could result in “an unimaginable catastrophe for which the world is inadequately prepared.” Coming from an organization that's not known for drama, the words “unimaginable catastrophe” are bone-chilling.

If that's not scary enough for you, I'll add that this work wasn't done in the world's most secure labs — literally. Both the Wisconsin and Holland facilities were certified Biosafety Level 3, which is a big notch below the top rating of Biosafety Level 4. This isn't very reassuring given the history of deadly substances erupting from profoundly secure labs. Think of the anthrax attacks of 2001, when the lethal spores found their way from a U.S. Army lab to the offices of the Senate majority leader. Or consider that the last person killed by smallpox caught it because the British lab let the bug escape after decades of globally coordinated efforts had eradicated it from the entire planet. Or consider Britain's 2007 foot and mouth disease outbreak, which began with a leak from a Biosafety Level 4 lab.

Incidents like these make it blindingly clear that any pathogen can potentially escape from any lab, because humans are fallible, and so are labs of any biosafety level.

Widening access to genocidal powers

Rob: Knowing these facts, what kind of person brings into existence a pandemic-ready bug that could be a hundred times deadlier than COVID, that could kill a majority of the people it infects, and perhaps be wildly contagious? 

In this case, not evil people. These were virologists who thought their research would help us face subsequent natural mutations in H5N1, but they were shooting dice with our future. And given their equipment and sophistication, they didn't need to ask any outsiders’ permission to do that. They may have run things by an internal review board of some kind, but they only needed outside permission to publish the results once they were done. And they did encounter some speed bumps on that front, but no regulator, no judge, no outside body of neutral citizens was in a position to say, “Don't you dare take that gamble, however small it may be, on humanity's future” — the gamble that your judgment alone gives you clearance to perhaps let millions of lives rest on an assistant never screwing up, or on your lab not being just a little bit imperfect.

I call this sort of thing privatizing the apocalypse. By this I mean that at the dawn of the cold war, playing chicken with doomsday went from being something no one could do, because it was impossible with pre-atomic weapons, to something that two people could do: Kennedy and Khrushchev, Nixon and Brezhnev, Reagan and Gorbachev, et cetera.

This transition traumatized generations, but the leaders represented giant countries with hundreds of millions of citizens, which made the act of risking annihilation a perverse form of public good. This approximate situation is still with us. And there's obviously plenty to dislike about that, but at least we've only needed to keep a fairly low number of decision makers in line: people who spend years looking after a nation's well-being, who have major international obligations that they hopefully take somewhat seriously, and who are subject to certain checks, balances and fail-safes. 

None of that's true for an autonomous researcher running a lab who decides to make an apocalyptic pathogen in the general name of science. Even if the odds of it escaping are small, the decision to play chicken with doomsday has effectively been privatized, which is plenty scary when the folks who get to toss the dice in these situations are very few and far between, and are generally good guys in white cowboy hats.

But as we'll soon discuss, the casino is about to throw the doors wide open, not because anyone thinks that's a good idea. Very few people have even considered this issue, which is a big part of the problem. Rather, it’s because relentless advances in technology are about to make these kinds of gambles and potentially genocidal powers very widely available to far more people than we can keep an eye on, and to people we can't keep in line by threatening with wrist slaps like delaying publication of their research papers.

The ‘disastrous’ handling of COVID

Rob: In the next section of this podcast, we'll talk about the terrifying proliferation of doomsday powers and who might abuse them and why. But for now, consider the landscape this is happening in. COVID is our dress rehearsal for handling something much worse. And in a lot of places, certainly including the United States, it has been one of the most disastrous dress rehearsals in the history of theater. It's like half the actors forgot all their lines and a quarter got bizarrely doctored scripts, which have them saying and doing the opposite of what they're supposed to do. The lights have caught fire. Half the costumes didn't show up and disease is spreading throughout the cast.

To step out of the dress rehearsal analogy, I'm referring to things like the ongoing disaster connected to adequate COVID testing and timely results, our early lack of PPE, our all-but-non-existent contact tracing, the lethal politicization of slowing infection via masks, et cetera. In an October editorial, the normally sober and understated New England Journal of Medicine frankly stated, “The magnitude of this failure is astonishing.” And remember, this is just a dress rehearsal. Opening night is coming, which means that as we do the post-mortem on this botched rehearsal, it's vital that we start planning maniacally for the next pandemic; that we start thinking obsessively about all the cannonballs we've had the great fortune to partially dodge lately; that we consider the next set of cannonballs, which are inevitably on their way; and that we humbly acknowledge that no one's luck lasts forever.

Why we must prepare ‘maniacally’ for the next pandemic 

Rob: For one thing, the rate at which disease is jumping over from animals to the human population is rising dramatically as we encroach evermore on natural habitats. So nature is taking pot shots at us with increasing frequency. As for artificial viruses, there's no reason they'll hit us at nature's relatively leisurely recent pace of one major scare every five to 10 years, because the cadence will be determined by the people behind them.

All this means that humanity's future depends on keeping our guard up if and when we put COVID-19 into the grave — and I mean way up, preparing for absolute worst case scenarios. Natural pandemics are random-case scenarios, because evolution is driven by blind chance, but nothing will be random about a virus designed by a malicious and murderous party. 

Unfortunately, we don't have a great track record for keeping our guard up after a major disease scare has passed. Despite all of the close calls of recent years, civilian biosecurity funding fell by 27% between 2015 and 2019 according to The Economist.

Meanwhile, governments haven't exactly inspired the private sector to carry the ball. The Economist also tells us that after the swine flu pandemic petered out, European and American governments reneged on contracts with vaccine makers, leaving them hundreds of millions of dollars in the hole. Speaking to the New York Times, virologist Peter Daszak summed up the situation, saying, “The problem isn't that prevention was impossible. It was very possible, but we didn't do it. Governments thought it was too expensive. Pharmaceutical companies operate for profit.”

In light of this, we should consider the finale one of the most popular TED Talks of all time, in which Bill Gates warns against the dangers of complacency. He wraps up by saying that if anything good can result from the current outbreak, “it's that it can serve as an early warning, a wake-up call to get ready. If we start now, we can be ready for the next epidemic.” Unfortunately, Gates didn't get his wish, because as many of you probably know, he wasn't talking about COVID but Ebola. That talk was recorded over five years ago. And of course, we were far, far from ready for the coronavirus outbreak that followed it.

Now, as I said up front, there are many steps we can take to dramatically increase our resilience against pandemics, both natural and unnatural. And although we have a history of hitting the snooze bar hard enough to scatter alarm clock fragments into the next county, the wake-up call we're getting from COVID is uniquely thunderous. In response to it, I say we take inspiration from the ways our own bodies fight off infections and build a global immune system to identify and destroy deadly new diseases on a planetary basis.

This system can be agile and adaptive, just like the ones in our bloodstreams. We'll talk about the components such a system might have, and the fascinating science and technologies underpinning each of them. And I think you'll agree that if we finally heed the warnings nature has been sending and resending and re-resending to us, we can navigate this danger. Bottom line: If you take only one thing away from this series, I want you to understand that a catastrophic pandemic is heading our way, but it's not too late to prevent its arrival if we can push our policymakers to rally to this challenge.

More on Rob’s background

Sam Harris: Okay, Rob, that was terrifying. Before we jump into the topic of pandemics, engineered and perhaps natural, let's just get a little bit of your background here. How did you come to be interested in this? And I know you have a generic interest in science as a science-fiction writer, but how did you come to be worried about this particular topic of the catastrophic risk posed by an intentionally engineered pandemic?

Rob: Well, I guess the earliest thread of that actually goes all the way back to when you and I overlapped briefly as Stanford undergrads. At the time, I was studying a ton of Arabic and Middle Eastern history. And after graduating, I went to Cairo on a Fulbright fellowship, where I spent a year doing research on the secular opposition — people who were pushing for a non-religious, non-dictatorial government, the faction whose political heirs ultimately, to a great extent, led Egypt's Arab Spring revolt, although they didn't actually gain any power from that. It’s a long story.

One person whom I spent a lot of time with back then was a guy named Farag Foda, who was Egypt's most prominent secularist at the time. And the fundamentalists hated him because he was vocal, he was for a non-religious government, and he was really brave. Tragically, not long after my year in Cairo wrapped up, Farag was assassinated. And that kicked off a ghastly wave of terrorism that Egypt endured throughout the '90s and beyond. And it was a really big shift because there'd been almost no terrorism in Egypt for years prior to that. And really as a direct result of that, I got very focused on terrorism as an issue. And that's a focus that persists to this day.

Fast forward significantly: I founded a company that created the Rhapsody music service, which some of your listeners might be familiar with. And although that's unrelated, for those who don't know about Rhapsody, it's pretty fair to say that it was the first Spotify. After I sold that, I really became a two-fisted person. I'm a tech investor some of the time, but I'm also a media/creative type of person. I’ve written a few books, a couple of which are science-fiction novels for Random House.

When I was writing my second science-fiction novel, After On, I delved into a whole bunch of the technologies that we'll be talking about today — particularly synthetic biology. There was a subplot in the story that was connected to a syn-bio terror attack. And when the book came out, I decided to do what I thought would be a very limited podcast series, just going deeper into the science of the various things that were in this science-fiction novel. And then that podcast ended up taking on a life of its own. I've now done over 50 episodes, quite a few with leading lights in synthetic biology. So that's really where the other thread came in.

The power of exponential technologies

Sam: Yeah. Well, one thing that one gets from your discussion thus far is that it really can't be a matter of relying on there being no one willing to do this sort of thing. There's a level of incredulity psychologically that one has to cut through here when you think, “Well, who is going to want to unleash a catastrophic pandemic upon the whole world?” For some reason, it takes some convincing for people to acknowledge that not only will there always be someone who will, there will always be many people who will aspire to do that sort of thing. Ten is many, but there are probably hundreds, if not thousands, in any generation who would be willing to do such a thing. 

And therefore, it can't be just a matter of messaging successfully to these people, changing their minds, preventing the wrong memes from lodging in their brains. The memes are already there. Therefore we have to fundamentally make acquiring the technology so difficult as to dial down the probability that this will ever happen. 

As things stand now, we're on a collision course with the democratizing of this kind of technology. Where should we start here to absorb this initial lesson?

Rob: The first thing to think about are the near-future tools that a less sophisticated person — somebody who's not a top mind in synthetic biology — might be able to turn to in 10, 15, 20 years. These are tools that will be able to do things that the entire project of synthetic biology can't possibly do today. And what we need to do is to really exercise our imaginations about what tools like that could possibly do in a short period of time, because I would argue that there is a very different level of moral responsibility on inventors, scientists, and regulators. When we're starting to develop and handle a potentially catastrophic exponential technology — exponential being that this is something that can go in radically unexpected places in a short number of years relative to when we're handling a normal dangerous technology.

To use a somewhat silly example, whoever the medieval Chinese blacksmith was who first invented a firearm, we don't blame that person for mass shootings. Mass shootings approached us at an incredibly slow speed over centuries, meaning it was on us to dodge those literal bullets or not. And we could have done things to make mass shootings difficult and rare, like keeping guns out of private hands. Now, I don't want to dive into a Second Amendment discussion because that could last for hours. I'll just say that whatever your position on gun rights, we can agree that society had ample time to decide whether or not mass shootings are a reasonable price to pay for today's policy. This situation did not sneak up on us at an exponential pace.

It's very different when something's improving a thousand fold in a few years. Because while it's impossible for anyone to definitively predict where that trajectory is going to lead, the people closest to the technology have a much better shot at it than the rest of us, which puts a particular moral weight on them to ask what rapid changes could end up ambushing a society that just doesn't see them coming.

Here’s one example of this: The U.S. Department of Health and Human Services includes in its huge grip the CDC, the FDA, and the National Institutes of Health, and clearly has all the intellectual and technical firepower it needs to be  profoundly informed about synthetic biology, but it was the HHS of all entities that posted the 1918 flu genome to the internet in 2005. They did it when smart people like Ray Kurzweil, who's basically the godfather of exponential thinking, came out stridently against doing that and could have easily told them that this information might be catastrophically weaponized within a couple of decades. And we can't keep having failures like that, which means private-sector leaders and academics need to use their imaginations a lot to envision worst-case scenarios. They need to be very transparent about them and self-regulate more than any industry in history.

Meanwhile, governments have to be unbelievably smart about synthetic biology, and they have to monitor the industry relentlessly, and they have to regulate dangerous practices on a coordinated international level. And I'm generally a very free market-oriented person. So I don't say any of this lightly. But this sort of thing is just necessary when we have a wildly promising exponential technology that we want to nurture and benefit from, but which also has a cataclysmic downside.

And the funny thing is that we don't really have a good precedent or analogy that we can turn to, to guide us. This wasn't the case with digital technology, another exponential technology. Whenever we think of super AI risk today, computing posed no innate existential risk for its first 50-plus years. It could surprise and delight us with astounding unforeseen developments for years in a row. There was no real downside. So we just don't have a good historic map to turn to for guidance here.

Contrasting the public- and private-sector response to COVID

Sam: You and I are recording this during hopefully the waning days of the COVID-19 pandemic.

Rob: Let's hope.

Sam: We're in this frustrating uncanny valley of knowing that vaccine doses are everywhere, sitting on shelves. It's being administered at a shockingly leisurely pace. California was just declared the worst state in the nation with respect to the velocity of its vaccination program.

Rob: Good grief.

Sam: How we achieve that is anybody's guess, but many of us have drawn the lesson here that we have experienced a comparatively benign pandemic. I mean, it almost couldn't be more benign. It's worse than flu — perhaps tenfold worse — but it is still killing at most 1% of people infected, and disproportionately elderly people. So the impact of something tenfold more lethal, or more, is really difficult to picture. Or rather it's easy to picture how catastrophic that would be, because I'm not alone in thinking that this is a dress rehearsal we've experienced for something quite a bit worse. And we have just manifestly failed this dress rehearsal.

Our response to COVID has been abysmal. And it's been abysmal even though the scientific response has been amazing. The public health response has been as inept as you could have ever feared, but the research response, the molecular biology response, the vaccine production response, has been amazing. I mean, the Moderna vaccine was created apparently before there was a single death in the U.S. from COVID. It's astounding that we have the juxtaposition of that kind of technical competence and the utter mismanagement of a public health response. And as we know, and need not get sidetracked by, there's been a layer of political controversy and chaos that in part explains how bad we are at this, but not entirely. 

We're a society that can't figure out how to produce masks at scale, it seems, or Q-Tips. So we have supply chain problems. It has been a colossal embarrassment and an excruciatingly consequential one, given the body count. And again, this is about as easy-going a pandemic as we could have hoped for. So what lesson do you draw from this, given that what would be engineered would very likely be quite a bit worse? And as we know and, as you've discussed and will discuss further in this series, there are natural variants of diseases that we're already worried about, which are quite a bit worse than COVID. And it's just by sheer luck that they haven't spread more efficiently than they have. So we know that almost everything on the menu is worse than COVID. And yet, this has unmasked our near-total inability to respond quickly to a challenge like this.

Rob: To summarize all that, frankly, the private sector has covered itself in glory and in many countries, certainly including the United States, the public sector has covered itself in shame. And we need to do much, much better than that. 

Envisioning hypothetical future diseases based on two metrics: deadliness and transmissibility

Rob: You mentioned order of magnitude. I actually think that's exactly the right way to think about hypothetical future diseases, because movements of 25 or 50% of different metrics are kind of hard to muddle out, but let's think about order of magnitude along two metrics: deadliness and transmissibility (by transmissibility, I mean how contagious the disease is). Particularly if there's an artificial pandemic, we can rely on the malevolent designers of that to dial things up significantly beyond where COVID is. And we also can't rely on nature, as you rightly pointed out, to keep things dialed down to where they are with COVID. 

So let's start with deadliness. As I mentioned in the recording, the World Health Organization puts COVID's case fatality rate somewhere between a half a percent and 1%. That could be dialed up by up to two orders of magnitude. At one order of magnitude it's five to 10%; at two orders of magnitude, it's 50 to 100%. And as you noted, these are not unheard-of numbers. SARS kills about 10% of the people it infects. H5N1 flu kills over 50%. So there is no biological reason why the next pandemic, even if it's natural, necessarily has to top out at 1% fatality, and if it's artificial, we can rely on it topping out higher.

As for transmissibility, which of course is how many people the average sick person infects: Without public health measures, COVID is two-ish or three-ish people, something like that. Estimates vary. To get a sense of what it would be like if the R0 was much higher, think of the measles, whose R0 can hit, I think, the 15 to 20 range. As an example, if you get into an elevator a minute or two after someone with COVID leaves, almost all the aerosolized particles will fall to the floor and you'll be extremely unlikely to catch COVID. But if you're unvaccinated for measles and a sick person leaves an elevator two hours before you show up, you could very easily catch the measles.

So imagine a one-order-of-magnitude disease in transmissibility — something as deadly as COVID currently is, but as contagious as the measles. The result of that situation would be that virtually everyone would catch it in very short order, and we'd have an unbelievably hard landing into herd immunity. I think that would be absolutely ghastly. The death rate would go north of what COVID is because hospitals would be overwhelmed, but I'm pretty confident civilization would survive. 

As for the death rate going up by one order of magnitude or five to 10%, I'm still confident society would march on, but a bit less so, not because of what it would do to people who are lucky enough to seclude at home — they could probably still dodge the virus — but what it could do to supply chains. If there's a five to 10% chance of death, do meat packers or grocery store workers show up at work? And if you start having food supply outages, even small anecdotal ones, just imagine the pandemonium of hoarding that would ensue, and the Road Warrior-like scenes that would unfold in stores. And we could barely handle the toilet paper shortage, which itself was kind of like the GameStop run-up. I mean, it was a reflection of crowd psychology, not an actual supply chain breakdown. Still, I don't think that's a civilization-canceling scenario either, but it'd be way more dangerous than what we're facing now.

As for two orders of magnitude beyond COVID, all bets are off. I mean, I don't know if anyone shows up to work if there's a 50 to 100% fatality rate, or if there's an order-of-magnitude jump in fatality combined with one in transmissibility. And in that sort of scenario, I start worrying about staffing the electrical grid. Because if the power goes out for a sustained period over a national grid or, God forbid, a global footprint, civilization teeters very, very quickly. If there ever is a wide outbreak — and I'll come back to the words “wide outbreak” in a moment — of a two-orders-of-magnitude disease, the only way society could possibly survive would be with very meticulous contingency plans that are drilled at local and national levels and very, very careful to keep power, food, and law enforcement flowing. Those are plans which I'm sure we don't currently have. 

Sam: It was right behind the Q-Tip plan and the mask plan.

Rob: Exactly. Once the Q-Tip contingency plan was in place, the “survive a doomsday apocalyptic disease” plan followed. 

A much better alternative to facing a wide outbreak scenario would be to have an incredibly robust global immune system response to quash the disease the instant it shows up on a radically improved global surveillance network, which we're going to talk about a lot later in the series. In any event, with somewhere between one to two orders of magnitude, distributed between deadliness and transmissibility, I do think civilization teeters. And there's no way we could survive a wider outbreak much more than one order of magnitude without a radically improved public health game.

Sam: There are a couple of threads I want to pick up on here. One is this distinction between natural and synthetic pandemics. You focus on the synthetic possibility, but really everything you say is just as relevant to anything nature might cook up for us.

Rob: I absolutely agree.

Sam: Also that I think the boundary there is a little blurry, because even in the case of natural pandemics, you're still talking about human behavior. Anyone who's putting a bat on top of a pangolin and calling it lunch is teasing out xeno viruses from the womb of nature. That's one vector by which they get into our population. 

We have to figure out how to modify human behavior across the board so as to reduce the likelihood of this thing happening, and we already know that there are natural viruses and other pathogens that have very high lethality, and a single mutation could make them super transmissible in ways that they're not currently. We know that nature is running that experiment continuously. This is the Darwinian principle by which things change.

Should we conduct ‘gain-of-function’ research?

Sam: But there is one human behavior that I think we do want to shine a light on. It’s related to the experimentation on H5N1 that you discussed. This is what often goes by the name “gain-of-function research,” where biologists, in studying how a pathogen might behave, can actually modify a genome such that it acquires a different rate of transmissibility. Let’s say something that was not yet transmissible to humans becomes so. It's easy to see how well-intentioned people might think it wise to do such research, assuming they have extraordinary confidence that they're not going to accidentally leak one of these pathogens out of their labs. We know so much about how difficult it is to be perfectly careful in an ongoing way that after a few minutes of reflection, some of this research seems patently insane.

What's your current view on the H5N1 research that you began speaking about?

Rob: Well, you made an important point, which is that gain-of-function research is done by well-meaning people. It's done with the public health agenda in mind. These aren't mad scientists; they're trying to probe the worst things that could conceivably happen, so we can better prepare for them. The whole debate that the scientific community, and to a lesser degree society at large, has had is actually tied to this H5N1 research that we've been discussing.

There was, and to some degree remains, some confusion about the virulence and transmissibility of the H5N1 modified viruses that were created. Some have questioned the consistency of the statements at least one of the researchers made. Also, the transmissibility that the research achieved was in ferrets. We really have no idea how these viruses would behave in humans. Of course, they didn't infect humans. It could be way worse than the ferret results. It could be a dud. We don't know. 

For this reason, I use the H5N1incident both as a scary and thought-provoking historic fact. This happened, and holy shit. But I also use it as a bit of a metaphor and a touchstone for conversation. What we can say is that a virus of unknown but potentially catastrophic power resulted from gain-of-function work in 2011, using the technology that time.

To assess what that means for our security, now we need to consider the speed with which the tools and techniques of synthetic biology have been improving since 2011, and the degree to which they've been spreading. And we'll get into much more detail on that later. But the short answer is these tools are improving with unbelievable speed and, just as rapidly, they're spreading to very large and broad levels in academic biology and beyond. The original H5N1 in gain-of-function research was the roughest of prototypes for what's possible now, for a much, much larger group of people. This makes any clouded understanding of the human transmissibility of those original viruses immaterial. 

Getting back to what happened: In 2014, there was a series of blunders that the U.S. government committed in relation to some scary pathogens. In one incident some live anthrax spores were mailed from one lab to another. In another really crazy one, live smallpox virus was discovered in a forgotten FDA storage facility. 

As a result of these (and some other things), concern ramped up about deadly pathogens. One result of this was a pause on government funding of gain-of-function research — and I want to emphasize that it was a pause in government funding. Gain-of-function research wasn't in any way banned. This just meant the U.S. government wouldn't fund any of it. (Both of those projects received some U.S. government funding.) 

As for private research, there was what I think was called a “request for a voluntary moratorium” on gain-of-function research. It was nothing like a ban and certainly nothing like enforcement. 

Then, after three years of careful thought, I'm sure the government put together some ethical frameworks and other things. Government funding for gain-of-function research resumed. I think that was in 2017. Then, in 2019, funding for the exact two H5N1 research projects that we've been discussing resumed. Now it’s all systems go for gain-of-function, as far as the U.S. government's concerned. 

As for whether it should actually be practiced, given this a huge amount of thought — and I fully appreciate the conceptual value of anticipating the worst bugs that might arise naturally by developing them artificially first — I still do not believe gain-of-function research should be carried out at all. 

The first reason is that it is enormously possible that nature will never get around to creating the ghastly things that we invent with our gain-of-function research. No highly contagious form of H5N1 has ever managed to evolve across many centuries. Widespread gain-of-function research will inevitably bring God-awful pathogens into existence that would never have existed otherwise. Why do that? 

An even better reason to never do any gain-of-function research is, as you pointed out, no laboratory of any level of security can be wholly immune from leakages and accidents. History shows us this very, very clearly. If you'd like I could run through a few quick and unfortunately chilling examples that illustrate that.

Sam: Sure.

Rob: The first one that I often draw attention to was a smallpox leak that occurred back in 1978. The timing is relevant because just one year before that, smallpox had been eradicated from the entire world after a heroic 10-year effort. Right before that eradication effort, two million people a year had been dying from smallpox. In the late sixties, after hundreds of millions had been killed in the first half of the century—

Sam: Something like 500 million people died in the 20th century from smallpox.

Rob: Crazy, crazy numbers. And so we can imagine the level of care and attention that must've been lavished on every remaining sample of smallpox one year after the eradication. But nonetheless smallpox managed to escape from a British lab that infected two people and killed one of them. The last person in history to die of smallpox died as a result of a lab leakage. 

As for Biosafety Level 4 labs, which is the very highest level of biosafety by an international set of standards, it’s extremely rare. There aren't a lot of them in the world.

We can look at a foot and mouth disease leakage in Britain — once again, back in 2007. Again, this timing is relevant because just a few years before that Britain's cattle industry had suffered a crippling foot and mouth outbreak. People were on high alert for foot and mouth disease in the U.K.. Despite that, the virus literally leaked out of this BSL-4 lab into the surrounding groundwater. Then, two weeks after that lab resumed work, it happened again. We're at the pinnacle of biosafety in a country that's been blighted by this disease recently and we have this leak. [Facetiously] I'm glad that we really want to do gain-of-function research into pathogens that might imperil civilization itself.

By the way, many very level-headed people believe that COVID itself might've leaked out of a Biosafety Level 4 lab, the Wuhan Institute of Virology. I haven't dug deeply enough into that to fully form my own point of view on whether that could have been a leak or not, but it's definitely not just the opinion of the tinfoil hat crowd. 

The last example, which is relevant for an additional set of reasons (and as if all of that isn’t grim enough), is the anthrax attack of 2001, which killed five people. This was a week after 9/11. Envelopes containing anthrax spores showed up at some media outlets, as well as the offices of a couple senators, including the Senate majority leader, Tom Daschle. As it happens, I was in Daschle's office that week, so this one's seared into my memory. It turns out that those spores came out of a high-security U.S. Army biodefense lab — probably at Fort Detrick in Maryland, although some people think it might've been another Army lab.

There's always going to be a swirl of mystery and conspiracy theory around this one because the FBI's main suspect actually killed himself before the indictments or trials. Regardless of who took the spores out of the lab, it's hard to imagine a country at a higher level of alert than the U.S., one week after 9/11. It's hard to imagine a significantly more security-minded and security-capable organization than the U.S. military. Yet, even in those circumstances, anthrax made its way from the heart of the military industrial complex into the office of the Senate majority leader, again proving two things. 

First, any facility can leak. But it also showed us that safety measures, which are meant to prevent accidents, are all but helpless against a malicious insider, because that's not the disaster scenario they're designed around. The odds of there being an unhinged insider go up as you increase the number of places working with disastrous pathogens. The consequences go up as the pathogens become exponentially more terrifying than anthrax or even COVID, which again, leads us to question why in the world we would ever do gain-of-function research.

Sam: Yeah, well there's another variable here, which you discussed throughout the series: the prospect that this technology will become increasingly democratized. You'll have high school students performing experiments that now the most sophisticated laboratories would struggle to perform, because there's some desktop piece of technology five, 10, or 15 years from now embedded with so much knowledge that you don't even have to be a person in the field (in this case, biology), to do experiments that no teams, or only a few teams, are currently capable of. It's very easy to see how the consequences of this meddling will get away from you. The idea that we are poised to spread the tech around to the level of high school students is fairly terrifying.

Rob: But at the same time, there is something that's undeniably cool about high school students discovering things like synthetic biology and doing really cool things with it. A little bit of a sidetrack: to me, the most vivid evidence of SynBio technology in high schools is something called the iGEM (International Genetically Engineered Machine) competition. iGEM is an annual SynBio jamboree for students which spun out of MIT a while back.

Each year thousands of students grouped into several hundred teams compete in creating little SynBio marvels. Those teams come out of grad schools, they come out of colleges, and they do come out of high schools. I recently eyeballed the list of last year's teams. I'd say about a quarter of them came out of high schools. The high school projects I read about included a virus testing system that delivers PCR [polymerase chain reaction] technology at home, which is not easy to do. Another was a field kit you could take out of the woods to test wild mushrooms for toxicology. There is pretty sophisticated stuff coming out of today's high schools. I do think iGEM is a great thing, as I mentioned. I don't think that we have to worry at this instant about a rogue high school kid doing something catastrophic with SynBio today. But we do have to appreciate that this is the end point of the academic transmission channel, and it's wide open.

Things that are only possible for today's top SynBio professors will rapidly diffuse to smart grad students, and then to smart undergrads, and then to smart high school kids, and eventually to dumb eighth graders. We obviously can't put a Biosafety Level 4 protection protocol in every high school. We either have to stop the diffusion of this technology, which I think would be tragic and also completely impossible, or we have to start building safeguards that selectively prevent dangerous practices down the line, which is tricky because our intuitions reliably defeat us when exponential change is involved.

There's a famous question of whether it's better to have a million dollars or a penny that doubles every day for a month. Our intuition screams, “Take the million bucks!” but it turns out the penny is a much better deal. I believe we have this miswiring because our ancestors simply never encountered exponential processes when they were living and evolving on the savannah. They had to solve defacto Newtonian physics problems when they went hunting, when they fled predators, when they were cracking things open. That mathematical intuition is very hard-wired into us, but exponential processes aren’t. 

Therefore, we have things like HHS [the U.S. Department of Health and Human Services] naively posting the Spanish flu genome to the world. Rather than laugh at that, we need to be unbelievably concerned about what information and methodologies we're putting out in the world today. To me, the awesomeness of the speed of this advance in SynBio is best captured by looking back at the Human Genome Project, which lasted 13 years, cost about $3 billion, and ended in 2003 — so, not in ancient history. At that point the team had basically read out a single human genome. Today you can have your genome read not for $3 billion, but for $300. 2003 wasn't that long ago. It's a 10-million-to-one price drop.

Sam: Yeah, that's flabbergasting.

Rob: That is the pace of change that we are simply unaccustomed to dealing with, that our ancestors were utterly unaccustomed to dealing with, and that defeats our  intuition. I go back to the point I made earlier: that there’s a much, much higher moral weight on those who are deep in the process of creating this technology to try to forecast the things that might otherwise blindside a society that doesn't see them coming. There really needs to be a symphony of coordination between academia, a self-regulating private industry, and really smart public health people to prevent catastrophic unforeseen circumstances.

Sam: Okay, well, are you not surprised to know that you have not yet made me an optimist, Rob? But happily you've got further installments in this series to try.

Rob: Absolutely. There's more to come, and much more that is optimistic.

Would someone really unleash a doomsday virus?

Rob: We've talked about the apocalyptic nature of artificial pandemics. Now let's consider the reason someone could possibly have for unleashing one. Doing this would almost certainly doom the unleasher. If he doesn't die of his own awful disease, he ends up in a post-apocalyptic hellscape. That doesn't sound like a great incentive structure. It's fair to question whether anyone would ever actually do such a thing. A doctrine called “mutual assured destruction” comes to mind. It got us through the Cold War; the basic idea was that if a nuclear slugfest would annihilate everyone, neither side would start one.

The policy had some terrifying holes in it, but you just admit, here we still are. Meanwhile, a vial filled with an obliterating contagion has its own mad deterrence built into it. If we could trust the Soviets with thousands of nukes — and it turns out we could — who couldn't we trust with that vial? I have explored this issue in writing, in talks, and in interviews. I've come to gravitate toward a handful of examples that really help frame it. 

On the question of whether anyone would ever unleash a doomsday virus, I often think of the Las Vegas shooter who murdered 58 concert goers in 2017. For starters, unlike the Soviet Union, he was committed to self-annihilation, making him undeterrable by nature. Given that, would he have preferred to unleash something a hundred times worse than COVID, if he somehow had that capability? Obviously, we don't know if he would have done that. But we sure can't say he wouldn't have. After all, this guy, like countless other mass shooters, had no proven boundaries when it came to inflicting death and untold suffering on as many strangers as possible. There's really no reason to think he even grazed the outer limits of the horror he would have liked to inflict. We can't say he didn't want to topple civilization. We can only say he didn't get to. 

Now, this guy was no rocket scientist, nor was he a world-class biologist. In 2017, that meant he didn't get to have a vial full of deadly man-made viruses. We don't know what he would've done with one, but here's the thing: I bet he didn't know squat about ballistics, either, and that he couldn't have designed a semi-automatic weapon any more than he could have hoisted himself to Mars. But he did get to have a private arsenal, which illuminates a critical point: Even if it takes geniuses to create a technology, and more geniuses to translate it into something functional, it may only take a sick lunkhead to operate those tools. 

Technology as ‘a force multiplier’ for mass murderers

Rob: Now, the frontiers of biology are generating extraordinary tools. For now, they're both created and operated by brilliant people, but there's no reason why this has to be the case forever. In fact, the tools and techniques in question are set to spread far and wide, which we'll discuss in a bit. But for now, the key point I always make when discussing this topic is that when suicidal mass murderers really go all in, technology is the force multiplier. 

For a low-tech example of this, I often cite a series of school attacks that occurred in China several years ago. There was a rush of 10 of them. Just like in the U.S., they were carried out with the deadliest things you could find in the local stores, but since this was China, that wasn't semi-automatic rifles, but things like knives and hammers and cleavers. Just like the Vegas shooter, the 10 attackers in China pushed their technology to its murderous limits. All of them combined killed less than half as many victims as the Vegas shooter alone. 

To slide to the other end of the tech spectrum, consider the Germanwings pilot who decided to end it all in 2015. He wasn't armed with a knife or a machine gun, but with an Airbus 320, which he drove into a mountain side, killing everyone on board. Well over twice as many people died as they did at the hands of the Vegas shooter, who killed more than any other mass shooter in history. Again, in the hands of suicidal mass murderers, technology is the force multiplier. 

With this in mind, let's return to the problem of artificial superbugs. Here the question isn't whether someone can make a bug that could potentially kill at the scale of a world war. That one was already answered twice when those two teams made H5N1 flu contagious almost a decade ago. The real question now is: How many people can create something diabolical? I ask because as the group of people who can do this grows, our ability to monitor and deter them vanishes. 

To frame this, let's reconsider that situation in the Cold War, when just two heads of state held annihilating powers. The world ultimately spent trillions of dollars to monitor them and to deter them from hitting the red button. Early warning systems, diplomacy, fast militaries, maintaining the balance of power, missile stockpiles so huge they could destroy the enemy even if they struck first, et cetera — all of this to deter just two people from doing the unthinkable. What if we had to keep the chieftains of 30 nuclear arsenals in line? Or a thousand? There wouldn't be enough money or resources in the world to fund all that deterrence.

We're lucky that two is such a low number. We're also lucky that the heads of state of the superpowers were mostly serious, stable people who spent decades making their way to the top. 

We could probably say similar things about a very different duo: the two head researchers who created the contagious form of H5N1. They were brilliant biologists, the heads of labs. They had decent budgets and excellent equipment, and spent years cultivating their minds until they could do things that no scientists had done before. A decade ago when they did their thing, the cadre of people who could create genocidal pathogens was a pretty elite club with really high admission standards that would tend to weed out loopy, erratic people. What if that club grows, and the hurdles to joining it plummet? Again, try to imagine an analogous world with thousands of sovereign nuclear powers. It's a very unstable picture. 

The emergence of a new exponential technology: SynBio

Rob: On the biology front, we're way past the point when just two-ish people in the world could groom a bug as deadly as the contagious form of H5N1. The reason is a new branch of science called synthetic biology. I'll call it SynBio from now on for short. It is what's known as an exponential technology. That means it gets more powerful and less expensive in rapidly compounding ways. The output that cost a thousand bucks last year might cost $500 today, $250 next year, and before we know it just pennies. 

When this occurs, things don't just get cheaper. Capabilities spread from nobody, to a handful of people, to masses of people. We've all personally lived through this with computing — another exponential technology. Fifteen years ago, not even Bill Gates could casually place video calls from his cell phone. But today, billions of people can, and I'm one of them.That sure doesn't mean I know more about computing than Bill Gates knew 15 years ago. 

This happens all of the time with exponential technologies. Over just a few years, complete non-experts pick up capabilities that were initially beyond the top people in the field. That's pretty cool when it's video calls — and not so much when it's unleashing an artificial disease. 

To give you a sense of how steep the exponential curve is in biology, I always cite the Human Genome Project. It lasted 13 years and cost about $3 billion. When it ended in 2003, the team had read and documented a single human genome. Today, you can have your genome read for $300. That's a 10-million-to-one price drop in less than 20 years. The impossible is now affordable, and soon it will be practically free. 

Of course, lots of things are still extremely hard in SynBio. For now, only a tiny handful of truly elite scientists can generate viable replicating viruses from scratch just from genetic code. It's a good thing that capability is so rare because the genomes of eradicated monsters like smallpox and the flu that killed 50 million people right after the First World War are up on the internet for anyone to download.

Yes, that means smallpox can now be created from scratch by anyone with the skills and motivation. Two researchers recently proved this point by synthesizing the closely related horsepox virus, which is extinct and harmless with a $100,000 budget and some mail order DNA. This definitively showed that highly specialized scientists can now cook up some smallpox, but that elite monopoly won't last, because rare capabilities routinely become widespread when exponential technologies are in play. Again, think of video calls. 

The trailblazers on the edge of SynBio tend to be brilliant, career-minded and highly non-murderous. But as the trail gets worn down and the tools get simpler, lower and lower levels of skill expertise and long-term dedication will be needed. At some point probably fairly soon, freshmen pre-med students will have homework assignments that the entire field of SynBio couldn't complete today.

How rare are suicidal mass murderers?

Rob: With this in mind, let's go back to that grim subject of suicidal mass murderers. The ones who hit those Chinese schools had simple tools and killed a few dozen people between them. The guy who killed a lot more people than that in Vegas had guns, which much smarter people than him designed to slaughter humans. The Germanwings pilot had a plane designed by people much smarter than him, and so on. Each killer hit the limits of his technology, but there's no reason to think they hit the limits of their ambitions. None of them was in a position to die while launching a pandemic, but once again, that doesn't mean none of them would have given up the chance. It just means none of them got to.

So how rare are these people? These days, the U.S. alone averages over one mass shooting per day. According to the gun violence archive, a big proportion of the perpetrators are suicidal, and a big fraction of that sub group, like the Vegas shooter, take every random stranger they can with them. We need to worry about this group as massively deadly technologies become widespread, because again, their death tolls reveal the limits of their technology, not the limits of their bloodlust.

No doubt, some people in this category have no upper limits. Each year, this group is replenished as hundreds of people throughout the world go on a final deadly spree. Think of those killers as being in a circle on a Venn diagram. It's very small and stable in size but it's extremely significant.

In a neighboring circle are those who could trigger the deaths of millions of us if they really wanted to. That circle is even smaller, it's barely a speck, but it's growing. It used to include just a few heads of state, as we discussed. Then in 2011, assuming their creation was in fact contagious between humans, those H5N1 biologists ended it. 

These days, quite a few more scientists are surely in that circle, because in biology, the heroically difficult feats of 10 years ago are just a hell of a lot easier now. The enabling technology is simply moving so fast. For instance, the world's most celebrated and prominent gene editing tool, which is called CRISPR, didn't even exist when the H5N1 flu was modified. Today CRISPR is taught in high schools. Post-CRISPR tools, which are even more powerful, are now cropping up and proliferating.

Again, we have two circles in our Venn diagram. One contains the people who are going to snap this year and kill as many people as they can. The other contains those who could kill millions of us or more if they really wanted to. That second circle is set to grow with insane speed due to the proliferation of evermore powerful SynBio tools and techniques. This means that unless something changes, those circles are going to collide and intersect, and the world will be home to someone who wants to kill us all and is capable of producing or obtaining an annihilating pathogen.

Why engineered pathogens — even those designed by ‘white-hat’ researchers — could be significantly deadlier than natural ones 

Rob: The deadliness of that pathogen could have absolutely no precedent, because for all its faults, a bug like the coronavirus has nothing against us. Technically, viruses aren't even alive, and many deadly ones actually become less deadly over time because killing off all your hosts is no way to win the game of evolution. Natural viruses will never go out of their way to maximally harm us. They just don't have ways to do it. 

That wouldn't be true of someone who sits down to design a deadly virus. For instance, one thing that makes COVID dangerous is that some people are contagious without any symptoms. That period's thought to last a few days. Why not extend it to a month? The coronavirus won't take that on as a personal goal, but a designer might. A designer might also make something a hundred times deadlier than COVID, like a contagious form of H5N1 flu.

This wouldn't be easy, but used as a function of tools and skill. We know the raw tools of DNA synthesis and editing are improving at breakneck speeds. As this continues, some profoundly skilled people with perfectly benign motives will probably design some profoundly deadly things. They might be virologists pushing biology to its limits, graduate students doing thesis projects, or militaries or counter-terrorism units exploring what their enemies might cook up. I expect that almost all of the people playing this game will be white hat operators, precisely because of the brilliance and resources that it'll require at first.

But that doesn't mean their work can't be dangerous. For starters, we've already talked about how many deadly bugs have found their way out of secure labs, and they could also escape in non-physical ways because although good guy scientists may make critters in Petri dishes, they'll really be creating tiny data files. 

The H5N1 genome is just that — a packet of information with just 10,000 letters in it. That's nothing. A transcript of this recording would have way more letters than that. And data networks get hacked constantly. When they do, the significant files go missing, then get copied and copied and copied. Just ask any music label, movie studio, or Fortune 500 company that let hackers get the intimate details of millions of customers. Ask Equifax.

Now, when the first deadly genome gets swiped and spread all over the dark web, technology may not be advanced enough for bad guys who are not elite scientists to do much with it. But the internet never forgets, and a decade or two later, the technology to synthesize genomes could be a million times more powerful and in a million labs.

You see, injecting the time variable between the brilliant good guy who does the hard work and a later bad guy who abuses that work is really destabilizing, because while the bad guy may not be brilliant at all, a couple of decades could give them access to vastly more powerful tools that make up for that. Again, think of the Vegas shooter, who was no ballistics expert, but who stood on the shoulders of generations of them. Or think of whoever posted the genetic recipes of smallpox and the 1918 flu to the internet. They couldn't possibly have been thinking exponentially, which means they either couldn't imagine a near future in which platoons of people could resurrect those diseases, or they didn't bother trying.

A world in which every high school bio lab has a benchtop DNA synthesizer

Rob: With this in mind, please dial up your inner science-fiction writer for a moment. Let's imagine it's the intermediate future, a few decades out, and every high school bio lab has a benchtop DNA synthesizer. These already exist, as we'll soon discuss, but definitely not in high schools yet, because they're way too expensive. However, like the personal computers of the 1970s, they'll get much cheaper and better, and it's hard to imagine their descendants won't end up in high schools. 

Now let's imagine this high school printer can crank out a complete error-corrected virus genome if you input its genetic code. You can't do this with today's DNA printers. They can only produce batches of about 2,000 error-corrected letters of DNA, whereas viruses typically run in the low tens of thousands to hundreds of thousands of letters. But history has shown that 10 to 100X improvements are fairly short walks in exponentially compounding technologies like SynBio. Recall the 10 million X improvement in reading DNA in the 18 years since the Human Genome Project.

Next, let's imagine that modern tools make the complex process of translating a genome into a viable replicating virus easy enough for smart high school kids to master. Now, everything I've described so far is so plausible that it verges on inevitable given enough time. If it doesn’t happen in this decade, then a bit further out. And yet I've described an all-but-impossible world, because remember, those genetic blueprints of smallpox and 1918 flu are already floating around the internet, and God only knows what other blueprints will eventually join them. In our scenario, any smart but disturbed high school through post-doc student, along with millions of people working in life sciences could start an outbreak. That world just can't exist, or at least not for long.

So we need to do whatever it takes to avoid ending up on a glide path that leads to it. When I think of this kind of intermediate future, suicidally murderous individuals worry me because the world produces so many of them. Groups with those motives are much rarer, but they're inherently scary too, because groups can be way more capable and formidable than individuals. And some groups do have bizarre urges to sweep the Earth of humanity. There are plenty of doomsday cults out there, and at some point, one of them will get bored and decide to speed things along.

Japan's Aum Shinrikyo cult did this. It gathered over a thousand members, including several biologists, and it meant to bring about the end of the world, but the tools to do that just weren't around in 1995. So it made its big move with the sarin gas attack in the Tokyo subway. When the next Aum Shinrikyo comes along, I doubt they'll limit their arsenals to deadly gases. 

Meanwhile, environmental or maybe animal rights extremists could decide that humanity doesn't deserve a future. Or consider the strange philosophy of antinatalism, which argues that human lives are so unpleasant that the ethical thing is to minimize the number of humans living them. For now, the people who think this way just try to avoid having children, but who knows where that could lead.

The crazy motives we can imagine driving someone to launch a doomsday pandemic are terrifyingly broad, and that's not counting the ones we can't imagine. Meanwhile, the ways for dangerous, well-intentioned work to leak out are boundless.

SynBio’s extraordinary upside 

Rob: That's the bad news, but luckily, there is a way out of this. That's the whole premise of this series. But before we get to the right way out, let's briefly discuss the wrong way out, which would be a technology ban, because we can't stop SynBio from advancing, and we'd be fools to try. If a worldwide ban is enacted, could we really trust China and Russia to respect it? Would they trust us? Could anyone trust North Korea? Unlike nuclear programs, which require vast industrial complexes and therefore can be monitored, biology can be practiced almost invisibly. So swear off SynBio, and you're giving some rival a SynBio monopoly. Again, think of North Korea. This is a really bad idea. 

Much more importantly, we shouldn't want to stop SynBio in its tracks because its promise is almost boundless. It's already starting to revolutionize medicine, and it's set to save untold millions of lives. It holds extraordinary promise for the environment in the form of crops that need fewer pesticides, biodegradable plastics, and perhaps even biofuels secreted by engineered microbes. And it has some sci-fi wonders up its sleeve, like clean meat that's molecularly identical to the real stuff, but it's produced without animals, so there's no suffering in factory farms and greenhouse gases are sharply cut. 

Yet another giant reason not to end SynBio tech is that our greatest allies will be people trained in this field. And while a tiny handful of such people will almost inevitably go rogue as training proliferates ever more broadly, the ratio of allies to enemies will be staggeringly high in our favor. I mean, think about it. The bar to being a good guy is that you're opposed to wiping out humanity. That's about as low as a bar gets. So the more SynBio experts the world creates, the safer we'll be on a certain level. 

So how do we put the good guys to work protecting us? In the next part of this series, we'll talk about the right way out of this predicament.

The ability to resurrect smallpox

Sam: I'm back with Rob Reid. Rob, you have raised this terrifying memory of what smallpox did to the world and the prospect that it could be resurrected. What's your thinking there?

Rob: Well, I'd say the thing that unfortunately gives us confidence that some people out there could resurrect smallpox today if they put their minds to it is that someone recently created the harmless but closely related horsepox virus from scratch, and they're very closely related. So if you can create one, you can absolutely create the other. In fact, the researcher behind that indicated in one of his interviews that part of the reason why he did this horsepox work was to force the world to confront the possibility that smallpox could be resurrected. 

How many people could create these viruses today (in addition to this researcher, whose name is David Evans)? In asking that, I think there are two things to note. The first is that the horsepox work was done in 2016, so this was almost five years ago, using the tools of its day. All kinds of SynBio tools have improved dramatically since then. And secondly, it was done by a very talented team, which kind of constricts the group of people who could do this, because at the time it was actually the largest virus that had ever been assembled from scratch. So that was not a small thing to do. 

So who did this? Like I said, his name is David Evans, and he's a virologist at the University of Alberta. When he has described his work publicly, both in a paper that he put out there and in interviews, he has basically said two things that I'm paraphrasing here. One is that for good or for ill, the world's full of talented scientists who, like him, can stitch together disparate bits of widely published knowledge to create ready-made recipes on the internet. So that's the bad news. 

But he also said that doing what he did would require advanced scientific training, a very specialized lab, and a fair amount of inside knowledge — all of which I'm sure was entirely true in 2016, and all of which I'm equally sure is less true today.

I can't reliably place David Evans in the global constellation of virologists, but for what it's worth (and take this with a grain of salt), I found what looks like a bottomless list of the world's most influential virologists online based on AI rankings. It presumably includes things like academic citations and whatnot. He wasn't listed in the top 500. So take that with a big grain of salt, but it doesn't seem like he's the top virologist in the world. 

If we triangulate from that, I would say that conjuring up the horsepox virus, and therefore smallpox, would probably be hard but doable for a high-powered academic virologist who's really determined to do it. And my gut sense tells me there are probably hundreds of people in that category — not thousands but not mere dozens. That's a really high number when you think of the terrifying power each of those people could potentially wield if they went off the rails. I mean, we are, in a very real sense, counting on all of those people to never “go Columbine.”

Sam: The analogy to guns is not reassuring, because guns do not have this exponential quality to them. You only kill as many people as you shoot. It's not like you unleash rounds of ammunition onto the world and they keep spreading and killing people. And we know where the trendlines for all of this technology, and really any technology, tend to go, which is to embed the highly specialized knowledge that was required to create the tech in the tech itself, such that a person without any real knowledge can use it and leverage all of that power to whatever end. 

And so, as you pointed out, you don't have to be a master of engineering or ballistics to own the most powerful firearm available and use it, and someday, you won't have to be a virologist to engineer a virus if we don't manage to contain this technology.

The open-endedness of a SynBio attack

Rob: Yeah. And a really scary thing you kind of touched on is just the open-endedness of a SynBio attack. I mean, every terrorist attack we've experienced so far has had inherent limits to it. There are only so many people on an airplane. There are only so many people in a building that's being attacked, or there are only so many victims one person can shoot before the cops show up. But COVID makes it abundantly clear how open-ended the disease's damage can be. We still have no idea what the final bill is going to come to.

And what's also scary is to think about what a dud of a SynBio attack would look like. Let's take someone who's really smart and really determined, who has completely mastered the best biological tools that'll be available 20 years from now. What if that person sets out to cancel humanity and falls 99.9% short of that goal? That's eight million dead. And just imagine how the U.S. would react to an attack that kills on that scale. 

I mean, just think of how we reacted to 9/11, which killed fewer people than COVID currently kills on a bad day. We reacted with two wars costing trillions of dollars and civil liberty ramifications. The scary thing is that not only can we not afford to suffer a successful SynBio attack, but we probably can't afford to experience a failed one.

Sam: Yeah. Well, again, the analogy from COVID is depressing because this is just about as benign as you can imagine while being worse than the ambient level of contagion that's already there. I mean, if this were any more benign, we would barely notice it. And it has brought global civilization to something like a standstill. We don't know what the ultimate bill will be from it, but we know it is certainly more than a million dead globally and trillions of dollars. And again, if it were any more like flu, it would be the flu. And so you have to imagine that this is the dud scenario, and it's still scarcely tolerable. 

The potential for SynBio attacks perpetrated by ‘lone-wolf’ operators versus organized groups

Sam: We're talking about, by definition, people who would intend to harm vast numbers of people by doing something in this space. The prospect that this can happen by accident is something we've touched on, and that's also terrifying, but here we're talking about the most malicious case. Who are we imagining would do such a thing?

Rob: Well, it's an interesting question, and it's obviously a really important one. And what I personally go back and forth about is whether the risk is greater from lone-wolf individuals or from groups of organized individuals. 

On the one hand, groups are obviously way more dangerous on a one-to-one basis if we compare a single group to a single individual with an identical goal. Obviously, unlike the individual, the group of five people, let's say, can be five places at once. It can pool expertise that might be hard to find in a single person. It can pool resources. There are just countless advantages.

But the thing is, it's not really a one-to-one comparison, because lone-wolf operators are way more common when it comes to suicide attacks. Even if we include suicide bombings, which are the works of groups, in those statistics, lone-wolf suicide attacks are way more common. I mean, we had more than one mass shooting per day in the U.S. last year. Many were suicide attacks and almost all of them were lone-wolf operations. Things like Columbine, where you have multiple shooters coordinating, are incredibly rare. So I worry about groups because of their capabilities, but I worry about lone wolves because of sheer numbers. 

It's also hard to find groups in history that have been committed to total annihilation. The only one I can think of is Aum Shinrikyo. I'll bet even ISIS’s leaders would have been horrified on their worst day by a plan to exterminate humanity. That kind of nihilism is just much easier to imagine in an unhinged individual than an organized group. 

But that said, groups aren't really historically known for focusing on trying to do things that are utterly impossible on a technological basis, which has been the case with total annihilation up until now. Thank God. And there are schools of thought that might just be a few deranged steps away from considering that. For example, should we be worried about what the outer fringes of the environmental movement, or maybe the animal rights movement, might do 10 years from now, if they think they can create an off switch for humanity? Or maybe a particularly unhinged group of antinatalists?

Sam: Yeah. I mean I would divide this more or less, as you have, into two possibilities. One is ideological and would, more or less, require a group to do anything like this. There has to be a belief system, some kind of doctrine that makes sense of this kind of apocalyptic genocidal behavior and suicidal behavior (unless you've also vaccinated yourself against this pathogen, which is, I suppose, also a possibility, although then we're imagining very competent people doing this). 

But in the case of a lone wolf, I guess it could be ideological. One person can have a rationale for what they're doing that may seem consistent to them, and they may be alone in doing it, but there are so many more ways for people to just snap, and it doesn't even have to make sense, right? And they're equipped with this technology. They are far more dangerous than a school shooter. He may have some internal story as to why he's doing what he's doing, but it doesn't need to be of the sort that we saw with someone like the Unabomber, who published a disconcertingly coherent manifesto, and he was a group of one, essentially. 

They really are very different problems, even though they're terminating in the same way. I mean, I know this from the space of just having to deal with crazy ideologues and crazy people more than I would want. You can have people who bend their attention toward you based on an ideology they hold that disagrees with you, and they criticize you and attack you, and in the worst case, pose a security problem. But then there are just crazy people who think you're sending the messages. And that's a completely different problem to think about and to try to mitigate. And when you're talking about truly democratizing this tech and putting it in the hands of people who could be starkly delusional, we clearly have to find some way of closing the door to this.

Rob: Yeah. And it's interesting to think of that starkly delusional side of it. I mean, one chilling example is the guy who shot up the movie theater in Colorado at a Batman premier, dressed as the Joker. He was a PhD candidate, I want to say, in some biological science with an NIH [National Institutes of Health] grant. So that level of delusion can actually penetrate into fairly high academic circles. And then, as the technology proliferates into ever lower circles, that high bar matters less and less. And we’ve never really thought of this before, but I guess an interesting question to ask ourselves (and I just have no idea of the answer) is: What percentage of the daily mass shooter population in the U.S. is actually schizophrenic, or in some way deeply delusional? I mean, we should know that as a society.

I think if we kind of follow the logic of all this, we start realizing that suicidal mass murder could absolutely begin to pose a national security risk. And if we look at it through that lens, we should probably be treating every mass shooting kind of the way we treat the crash of an airliner — with an incredibly serious effort to figure out exactly what went wrong and what aspects of the case might've provided warning signs, and develop a real epidemiology of this phenomenon. I don't know that we're not doing that, but I don't believe that we are, and it's something that we really ought to understand a lot better.

Sam: Yeah. That airline crash you referenced, the Germanwings flight, where it’s all but certain that a pilot intentionally crashed the plane — that's one of those cases where this is a murder suicide that most people have never even thought about. I mean, it was just one of the most horrific things you can imagine, but you can see how it's a very odd case. You could see someone being, I would imagine in this case, suicidally depressed enough to be capable of doing something like that. And you have to think it presents psychologically as different from arming yourself and showing up at a school and shooting people. It's a different act. It is, in fact, the more murderous one, but it is a more abstract one in some ways, you would imagine, from the point of view of the pilot.

The pilot's experience is he's just committing suicide, right? And obviously he knows he has a few hundred people on the plane with him whom he's going to kill, but you could imagine that there's some state of the human mind where all of those deaths are really an afterthought, and there's no kind of murderous rage needed to motivate the instantaneous murder of hundreds of people. Whereas there would be, if you're going to start killing people with a club out in the world or shooting them one by one. At least it does strike me that the method of creating harm really does select for a different population of people who would be capable of causing that harm.

Rob: Yeah. There'd be a squeamishness that the pilot wouldn't have to overcome that somebody who's actually getting into the gritty business of killing people would have to overcome.

Sam: Yeah. I mean, the moment you've bought into ths idea, you want to commit suicide anyway, right? And for whatever reason, you're happy to kill a lot of people in the process. But after that, it's all hypothetical. There are no up-close and personal encounters. There's no conflict. There's just a plunge out of the sky with you and with the controls. And this is analogous to different actions in times of war, right? It takes a different kind of person to just drop a bomb from 30,000 feet, knowing all the while that beneath that bomb there are hundreds or even thousands of people who are dying. That's different than trench warfare or any other sort of conflict that produces death. 

This is the example I give somewhere, I think in my first book, The End of Faith. When you find out that your grandfather flew bombing missions over Dresden in World War II, that's one thing. If you hear that he killed a woman and her kids with a shovel, that's another thing. The visceral reaction to that difference is an appraisal of just how different a person you would need to be to do those two things. And yet we know the person would have killed many more people flying a bombing run over Dresden than he would've killed with a shovel. 

These differences matter when they interact with technological innovations, because we are now in a world where you could kill a lot of people with what never seems like anything more than an idea. It is a kind of an abstraction, even when you're going through the steps required to weaponize a virus, because on some level, you're not sure what's going to happen. You're just going to release this thing into the wild and see what happens. It's all hypothetical until it isn't, right? I don't know. I can see this kind of possibility interacting with mentally unwell people of various sorts, where the bar to initiating this kind of thing is quite a bit lower than other acts of violence that would not be nearly as harmful.

Rob: Yeah. Because most of that process of engineering this thing and even unleashing it would involve gazing at a computer screen, and dabbling with lab equipment. And the level or bar to being able to brutalize somebody with a shovel is one thing. It's lower, I'm sure, when it comes to killing somebody as a sniper in war from 500 yards. It's yet another thing dropping a bomb, and designing and releasing a pathogen might even be more abstracted than that.

Sam: You can imagine people just deciding to do things that pose incredible downside risk, but [the outcome is] still never quite sure. So you could just say, “Well, I want to get a lot of people sick to make a point. There is a possibility that this could get completely out of hand and kill millions, but that's not my intent. But what the hell.” Right? It's the exponential part here that just makes this so scary because you keep rolling the dice. And again, what we have with COVID seems like a best-case scenario.

Rob: Yeah. And I just thought of a grim scenario I hadn't thought of before. You could even get somebody with a messianic complex who decides, “I'm going to release a minor pathogen to warn the world about this stuff,” and sends off a warning shot that could get out of control. There are all kinds of motivations that people could have.

Sam: Well, whenever you have a destructive technology of this sort that can be unleashed by a single person, that variable alone is enormous. I mean, just the fact that it takes perhaps a dozen fairly technical people to produce anything like a crude nuclear bomb means that the difficulty factor for one person, even a super-competent person, is just too high. There's just too much engineering to do. There are just too many parts to put together. Moving the thing requires collaboration. You need some people. And when you take that away and you deliver into the hands of any single person technology that is potentially even more destructive, that seems like it does change the game significantly.

Rob: And groups get busted. Groups get busted because they have to communicate with each other. They get busted because somebody defects. They get busted because they have a lot of surface area with the rest of the world, and somebody's going to try to impress his girlfriend by blabbing about something. When you look at the statistics — I don't remember the exact numbers — the number of terrorist plots that have been reported as foiled since 9/11 is a pretty impressive number. A very small number of plots actually went forward. 

But if you look at somebody like the Vegas shooter or Omar Mateen, who shot up the nightclub in Orlando, there was no coordination. There was no signal leakage. All the actions that those people took, and that most mass shooters take in preparing for their crimes, are perfectly legal. And so if it's one person, it's almost undetectable. So I guess as we talk about this, I'm swinging toward being more concerned about lone wolves than groups.

Sam: Okay. Well, let's get back into it and listen to section three.

Building a global immune system to fight off worldwide threats

Rob: A while back I said the way out of this is to build a global immune system to identify and destroy deadly new diseases, and there's plenty of inspiration to take from our own bodies. Our immune systems are simply amazing. They fight off countless attackers each year without us even noticing and countless attackers or bugs the immune system has never encountered before. Yet it fends off these completely unknown enemies because it's agile, adaptive, and multilayered. 

We need to build something like this for humanity as a whole to fight off new worldwide threats early, whether it's an artificial disease or a natural one. The great news is we can do this if, after putting COVID behind us to whatever extent we're able, we maintain our focus on the threat of new diseases, and do so much, much, much more — and more intensely than we did after SARS, MERS, Zika, et cetera. As we'll see, doing this properly will take big investments, which can be very tricky to fund, but let's compare that to the cost of doing nothing.

The Congressional Budget Office estimates that COVID will cost the U.S. alone $7.9 trillion in economic activity, while former Harvard President Lawrence Summers pegs the domestic cost at $16 trillion. Whichever estimate you use, it maps out to tens of trillions of dollars worldwide from COVID.

An artificial bug could be vastly more deadly and destructive. Indeed, as I said earlier, I'm not confident that civilization could even survive something like a highly contagious version of H5N1 flu. Meanwhile, I can't imagine everything I'm about to discuss combined costing even 1-2% of the bill that COVID alone is sticking us with. And these measures would come with a massive side benefit in that they’d defend us from natural diseases as well as artificial ones. That would include previously unknown enemies like COVID, and dreadful annual reruns like the flu. 

Let's talk about the flu for a second. The White House Council of Economic Advisers estimates that it costs the U.S. alone $361 billion a year in medical spending and lost productivity. This maps to over a trillion dollars worldwide. And as we'll discuss in a bit, we might all but eradicate the flu if we get just one thing off of my wishlist. We wouldn’t definitely eradicate it, but we'd have a great shot at it for less than 1% of the flu's annual costs. 

Modern life sciences, absolutely including SynBio, are magical arts, and we can ensure to enlist them against ancient enemies along with emerging ones. Now, as I said, this immune system should be a global thing, but global initiatives can take years to generate. So we can, and should, get started everywhere at national levels, although it would be best if we eventually do things collaboratively and cover the globe.

Summary of what a global immune system could look like: 5 key components

Rob: I've divided the immune system into five components. The first is about making it much trickier for bad actors to hijack our SynBio infrastructure and use it to churn out awful things. The second component is outbreak surveillance. The earliest days of an outbreak can make all the difference between derailing a disease and letting it go global. So we should monitor the biosphere for new outbreaks as carefully as we watch the skies for enemy nukes. As we'll see, some really interesting science could help a lot with this if it gets the right funding and prioritization.

The third component is about hardening society against a SynBio attack or a natural pandemic. In military terminology a hard target has some protection and it's tougher to destroy than a defenseless soft target. For example, you could say the U.S. hardened its airports back in the seventies when it first equipped them with metal detectors, then hardened them again after the 9/11 attacks by creating the TSA (Transportation Security Administration). 

Component number four is about conquering viruses. This is all about getting ahead of the next viral outbreak with vaccines and medications that could just stop it in its tracks. There's a huge amount that could be done here, but again, it's all about getting the right funding from a society that tends to under-invest badly in these things.

I call the last component “battle infrastructure.” What do we need in place to fight the next novel disease after it has broken out, to either stop it from becoming a pandemic or to dampen a pandemic that takes off despite all of our other measures? At least one thing we'll discuss may sound like science fiction. 

The immune system I'll describe will be a dual-purpose framework. While some parts of it are specifically targeted at artificial diseases, some of it would also pay huge dividends in our never ending battle against natural ones. So even if no one ever attempts to create an artificial bug, which I find almost impossible to imagine, it would still pay for itself probably hundreds of times over by saving lives, suffering, and economic damage.

Before we start I should say this isn't meant to be the last word on anything. Instead, it’s a framework for thinking about how to respond to an existential threat humanity faces, one that the COVID crisis has brought into much sharper focus in the year and a half since I gave my TED Talk about these things. It's not meant to be comprehensive; it can't be. For one thing, this podcast is meant to have a manageable duration. Also, so much is changing in SynBio and infectious disease research due to COVID that one writer can't hope to have it all on his radar. There might be dozens of measures and promising technologies we're slotting into each of my notional components, and if some form of this immune system does arise, I certainly hope it will be that deep and rich. So my hope in this is to start a conversation, not to complete one — a conversation that could lead to a blueprint for an immune system more agile, multilayered, and adaptive than anyone can currently imagine.

Component No. 1 of the global immune system: Hardening the SynBio infrastructure

Rob: So onto component one: hardening the SynBio infrastructure. A few minutes back I mentioned the TSA. Most of us have a friend who likes to say that if they wanted to hijack a plane, it would be so easy because the TSA sucks. Next time that happens, ask your friend how many U.S. hijackings there have been since the TSA got started and cockpit doors were hardened. The answer is zero, not because it has become impossible to hijack planes, but it's tricky enough that hardly anyone bothers. So while we haven't made aviation invulnerable, because that is impossible, we've made it much, much harder to disrupt. This is what we need to do with the act of creating deadly artificial bugs. We can't make that completely impossible, but we can push it past the reach of most people, including people acting on urges that will eventually pass. This matters a lot with someone bent on suicidal mass destruction, because most suicide attempts, and many mass shootings, are driven by transient phases of extreme rage or despair.

An analysis of over 175 academic papers showed that less than 4% of those who tried and failed to kill themselves successfully did so later. That's obviously 4% too many, but it shows that most suicidal phases are impermanent. Hijacking, of all things, is an interesting parallel. Believe it or not, it was once possible to hijack a plane almost on a passing whim. Between 1968 and 1972 there were 130 U.S. hijackings, almost all of them by domestic perpetrators. Many of them were radicals who just wanted to go to Cuba. It got so bad that Cuba created a special dormitory for wayward American hijackers. Alarmed citizens, meanwhile, swamped the FAA (Federal Aviation Administration) with anti-hijacking suggestions, like building trap doors outside of cockpits. Eventually metal detectors and so forth dropped the ambient level of hijackings from about 40 a year to almost zero.

Now we clearly can't live with dozens of biological attacks per year, so we need to think carefully about hardening the products and services that create synthetic DNA. Luckily this process is already well underway. 

Formation of the International Gene Synthesis Consortium (IGSC)

Back in 2010 the U.S. Department of Health and Human Services issued guidance to secure SynBio practices, and by then the industry had already founded the International Gene Synthesis Consortium, or IGSC, which is all about biosecurity. Its member companies represent about 80% of the world's gene synthesis capacity, although nobody's quite sure how accurate that estimate is. The government's guidance asked the industry to screen its customers for bad actors, and to look out for orders of dangerous DNA sequences.

The IGSC created a regulated pathogen database. Its members now follow special review processes for potentially dangerous requests, and contact the FBI when appropriate. They also follow government watch lists of terrorists, people subject to export controls, and more. I discussed these issues with science policy expert Sarah Carter. She has estimated that IGSC members spend an average of almost $15 for each synthetic DNA order that they receive on biosecurity compliance, which is a very serious investment. So there's lots of great news here. 

The bad news is that the government hasn't once updated its guidance. That's a 10-year lapse in guiding one of the fastest moving industries in history. Plus, that ancient government guidance is just that: guidance. In other words, it's voluntary. And while it's impressive that the IGSC’s members produce maybe 80% of the world's synthetic DNA, is that really enough?

I'll use an analogy that many current and former American high school students will identify with. When I was growing up, my five-town area, of a few hundred thousand people total, had exactly one liquor store that reliably sold beer to teens. Every young beer enthusiast knew all about that store, and for a while, there may as well have been no drinking age whatsoever. There had to be 99% compliance with the liquor laws amongst liquor stores in our area, but that hardly mattered. So I'd say when the fate of the world might literally hinge on controlling deadly DNA, 80% self-directed compliance to voluntary guidance is nowhere near enough. That other 20% in the hands of companies that are doing their own thing is a gaping hole. And even for its members, the IGSC is no real arbiter because it thoroughly lacks independence. Its chair works for an IGSC member called Thermo Fisher Scientific, and the other folks who give it bits of their time also work for one member company or another. So if you're wondering why the IGSC website has no phone number, it's because they have no phone.

Luckily, I wouldn't call this a pure “fox watching the henhouse” scenario because SynBio executives have huge incentives to prevent SynBio attacks. As humans, they'd suffer as much as the rest of us, and even a botched attack that hurts no one could lead to calls to shut down their industry. That said, any company's prime directive is to make money, and every IGCS representative has a day job in a company that has to make quarterly goals. So it's not surprising that in a recent SynBio industry survey, Sarah Carter wrote that the people she interviewed “repeatedly emphasized that biosecurity considerations were not a priority for the industry overall, with very little attention paid to the topic by investors and in industry venues.”

This isn't true everywhere. A thought leader in this field is Twist Bioscience, a relatively large and publicly traded SynBio company and an IGSC member. A company representative told me that Twist treats the consortium standards as a baseline starting point for their own biosecurity measures. They have a small full-time staff of PhDs who drilled further into every DNA order that could possibly be misused. And the list of sequences that trigger reviews goes far beyond the IGSC's regulated pathogen database. 

That said, not everyone has Twist's resources, and the cost of synthetic DNA is dropping, while the cost of screening is increasing, as databases of concerning sequences grow larger and more complete. This means screening is eating up a growing share of companies’ margins, which increases the incentives to cut corners. And my contact at Twist said that some companies are, in fact, opting out of the IGSC for profitability reasons — particularly internationally. This worries him, and he's not alone. The World Economic Forum and a nonprofit called The Nuclear Threat Initiative have teamed up to address it. They've proposed a common screening platform that's robust, open source, and given to all industry players for free (or at a very low cost). In a 2020 white paper, they wrote, “Development of a common mechanism for screening pathogen and toxic DNA would reduce the time and expertise required to adopt and implement synthetic DNA screening practices, and thereby expand those practices to a wider range of DNA providers.” They hope to have this available this year.

Should governments regulate DNA screening?

Rob: In their white paper, they called for governments to require DNA screening practices through legislation or regulation. And although I'm generally a very free-market-oriented person, I fully agree. Governments worldwide should collaborate on tough regulations to forbid the distribution of any synthetic DNA to anonymous parties or known bad actors. As for dangerous DNA, it has its uses in research and other settings, and there are gradations of danger which should be treated differently, but in general it should only be provided to highly trusted customers with excellent reasons for needing it. 

And as for pandemic-grade DNA, it should never be synthesized or distributed, period. I'll add that there's no reason to ever mutate living organisms in ways that could let them cause devastating pandemics (I'm looking at you, H5N1 flu, and those who modified you in 2011) — not even if the head researcher has the most angelic history and motives, because no lab is 100% secure, as we've discussed. Plus, lab security is about preventing accidental leaks, not deliberate ones, and it's always possible that some lab worker will pass through an incredibly dark year and decide to cause the world enormous harm. 

This is evident in the mass shootings that happen on a roughly daily basis in the U.S. alone. No social class or level of education makes people immune to this. The regulators should be as brilliant as the people in the industry they oversee, and they should coordinate globally. Yes, the U.S., China, Russia, and others disagree on plenty, but they each have everything to lose from SynBio run amuck.

‘Center-to-the-edge’ transitions from specialists to users

Rob: Finally, regulators need to move as fast as the industry. That means no more 10-year lapses. For one example of what happens when regulators fall asleep, that ancient U.S. government guidance didn't foresee the rise of benchtop DNA printers, which could be the future of the industry. These generate DNA in users’ labs so they don't have to order it from companies like Twist. 

This is significant because history is full of transitions from the center to the edge. By this I mean capabilities that used to be provided by specialists migrate into the hands of users themselves. For example, getting photographed used to require a technician with pricey gear. To send text messages, people used to go to telegraph offices. Printing anything on paper required professionals with special equipment. All these things can be done by users themselves now. The list is endless.

The move from the center of the edge is generally a wonderful and empowering trend, but there have been regulatory tragedies. For instance, the explosion in child pornography has been partly attributed to the fact that pictures are no longer printed in photo laps where developers could spot something evil. At some point, benchtop DNA printers will be powerful enough to aid and abet an apocalypse. Long before that they all need to report any dangerous sequences that they're asked to create, triggering level-headed review processes.

Luckily, this is already happening. The most advanced product on the market is called the BioXp. I spoke extensively with its creator, Dan Gibson. The way it currently ingests and processes raw materials requires close communication between its user and its manufacturer, a company called Codex DNA, which Dan co-founded. Codex is an IGSC member, and it doesn't let its printer synthesize any DNA without a review. Over time BioXps will become more autonomous in terms of the raw materials they process, but Dan says, they'll continue to report all print runs back to Codex so they can be reviewed, like any order, by an IGSC member. So far so good, but this won't be the status quo for long. For one thing, the current version of the BioXp is analogous to the Apple II computer in 1977, which is to say that as revolutionary as it is, its capabilities are minuscule compared to what's coming. And with the passage of time, the limitations of the BioXp and its errors will melt away — limitations like its current inability to crank out a virus-length genome.

Another factor is that someday there'll be cheap knockoffs of the BioXp's distant descendants, and they'll be capable of things we can scarcely imagine, because remember, a lone lab tech can now sequence a human genome in a few hours — something that recently took the entire field of biology 13 years. So we can count on the fact that someday undergrads will be doing things the entire field of SynBio can't possibly accomplish right now, and many of them could be using knockoff DNA printers made by amoral companies that cut corners and ignore safety measures, unless they're sternly required to follow them. By then hundreds of thousands of people could have access to gear that could cause a terrifying outbreak, and we cannot count on all of those people never having a catastrophically dark day.

So there needs to be an iron set of rules, and an iron culture about keeping dangerous DNA out of the wrong hands, and the most deadly DNA out of all hands. The time to create these universal rules is now, not a few months before distributed printers attain apocalyptic powers. 

This may sound like a terrifyingly tall order, and I'm sure government skeptics are particularly aghast at the need for brilliant and fast-moving regulators, but remember: In less than a century we humans banished diseases that had plagued us for millennia, made 200-ton chunks of metal fly, and transitioned from slide rules to the internet, and I'm just talking about shaping an industry that's still in its infancy and is leaning in the right direction. We can put a very serious lid on this.

That alone won’t make it completely impossible for some disturbed person or group to make a profoundly lethal pathogen — as with eradicating all hijackings, that is impossible — which is why our immune system has four more components.

Component No. 2 of the global immune system: Early detection 

Rob: So let's talk about the second component, early detection. Early detection is everything in epidemics, especially when a new disease is stalking the earth, like COVID or any artificial pathogen that could be unleashed in the future. That's because in the first days of an outbreak, cases tend to grow exponentially, and we saw how profound exponential growth is when we discussed SynBio speed of improvement. 

COVID illustrates the cost of ignoring a novel disease's outbreak. A study published in Nature estimates that if China had implemented lockdowns and other measures three weeks sooner, the number of Chinese COVID cases could have been reduced by 95%. Had that happened, who knows if the disease would have reached the rest of the world. And the tragic fact is, China squandered much more early lead time than that, according to an investigation by the Wall Street Journal. The head of the country's own Center for Disease Control and Prevention learned about the outbreak not from some advanced disease monitoring system, but from reading the news online, and by then there were dozens of suspected cases. 

Why? Among other things, the Journal reports that local hospitals didn't log cases in the Chinese CDC’s real-time tracking system, plus local authorities wanted to hide bad news from Beijing. National leaders later followed suit by hiding information from the rest of the world. This is not meant as national finger-pointing, because my own country's CDC has a dismal COVID history. I instead want to show how vital early detection will be if a deadly artificial pathogen is ever unleashed.

So how do you find the first signs of a pandemic? It's not like you can just Google it. Or can you? One of the most fascinating COVID-related articles I've read was written by a data scientist named Seth Stephens Davidowitz for the New York Times in April of 2020. In it, he showed that Google searches for the phrase “I can't smell” almost perfectly track the prevalence of COVID across the 50 U.S. states. Loss of smell had only just been recognized as a COVID symptom at that point, so the article’s charts seemed almost magical to me. 

In a conversation, Seth told me that Google is remarkably generous with their search data, and he didn't need any special access to write his piece. In it he boldly predicted that eye pain would emerge as a COVID symptom. This was not recognized as a symptom at the time, but he'd seen searches for it spike by as much as 500% in countries like Italy, Spain, and Iran, when they were in the throes of their COVID outbreaks. Sure enough, within a few months news articles were identifying eye pain as a COVID symptom.

If you'd like to hear a lot more about this than I can squeeze in here, and many other topics Seth has explored using data science, I interviewed him for my own podcast, which is called the After On podcast. I'm posting that interview simultaneously with Sam's posting of this episode, meaning that it should be available now. 

So could searches be used to predict outbreaks? Work by Bill Lampos of the Computer Science Department at University College London says yes. He and a team of researchers dug deep into search traffic across several countries and compared it to reported COVID cases and deaths. They found that search traffic pointed to national outbreaks an average of 16 days before case counts started to spike. This could be an amazing tool for countries trying to get early warnings of outbreaks before local doctors have even seen many patients. And in fact, Bill told me that Public Health England is now using this tool for its COVID models, as well as a search-powered flu detector that his team has built.

I'd like to see this kind of work grow exponentially for our global immune system. Since we don't know what symptoms an artificial pathogen, or any new disease, would trigger, we should continuously scan the search sphere for every known symptom of every known disease. And yes, I know that sounds like an insanely tall order, but big data is called big for a reason. Any symptom spike outside of a seasonal norm, like the huge spike Seth saw in loss-of-smell searches in Italy, could be a signal. And if it's a cluster of symptoms, it could be a strong signal, especially if that cluster shows up in more than one place at once. 

Building this would present all kinds of interesting data science challenges. As Seth and I discussed in our interview, the biggest one would probably be dealing with false positives. But Bill Lampos believes that such a system is buildable. Better yet, he wrote to me, “A moderate scientific research budget can support the development of a system like that.” This translates to the very low millions of dollars to potentially get way ahead of something that could cost us trillions, or even cost us everything.

Of course, there are many offline places to search for emerging pandemics. One of the best, and certainly most obvious, is in the bodies of sick people who turn up at doctors’ offices. One day artificial pathogens could strike anywhere, but meanwhile, we can greatly expand our virus-hunting expertise by relentlessly identifying and neutralizing new natural diseases and hotspots where viruses commonly jump from animal hosts to humans. Southern China is one such place, and parts of Africa are others. SARS, MERS, Ebola, and perhaps COVID all jumped from animals, and are known as zoonotic viruses. Zoonotics are especially dangerous because until the moment they jump, no human body has any immunity or experience in fighting them.

An amazing program that's just rolling out in West Africa called Sentinel could be a role model for the developed world as well, as we gear up for a time in which new diseases could strike anywhere. One of its co-leaders is Pardis Sabeti, who has appointments at both Harvard and the Broad Institute. The Broad is basically a joint venture between Harvard and MIT, and it's worth knowing about because a huge proportion of the world's best genetic science is coming out of there. Sentinel is called “a pandemic preemption system for the real-time detection of viral threats,” and it's launching first in Nigeria. It will be a multi-tiered system. Its creators believed that we are “on the cusp of a new era.” 

They go on to say, “Ultra-sensitive genomic technologies have the unprecedented ability to detect virtually any pathogen, including those circulating under the radar, and can be leveraged to create simple point-of-care diagnostics to be deployed anywhere. In parallel, powerful new information systems allow us to continuously collect, integrate, and share viral surveillance data by unifying these tools into a coherent system. For the first time ever we can detect and prevent pandemics on the ground before they start.”

So basically it's sci-fi grade genomics meets cloud computing, and it sounds pretty good. Sentinel will be built around a three-tier system with simpler tools out in the field and more powerful ones in regional and national centers, and data about every single infection flowing back to a central system for tracking and analysis. If a patient has one of the area's top priority diseases, Pardis expects that they'll be able to identify it within an hour, and to identify any other known human virus within a day. When I asked her how long it would take to create a test for a previously unknown disease that they discover in the field, she said, “A day to build it and a week to know that it works.”

Pardis absolutely believes we need something like Sentinel in the U.S. and throughout the rest of the world, although her own focus is currently on West and Central Africa, and she shares my concerns about biosecurity. So could we afford a worldwide Sentinel system? I've seen the program's budget, and while it's confidential, I can say that it's absolutely within the reach of any developed country, and any less developed country with just a little bit of outside financial help. In the U.S., adjusting for cost-of-living factors and population size, I estimate it would cost in the low billions per year. This is a trifling sum compared to what we lose to the flu alone every year, let alone a pandemic like COVID, and it's negligible compared to what a truly nasty artificial pathogen could cost us if it goes undetected for a few critical weeks.

How else might we detect a new pathogen? Well, how about plucking it right out of the air? A handful of researchers are now pioneering bioaerosol science, including Mark Hernandez at the University of Colorado. One technology he's excited about is called “condensation particle capture” or CPC. This uses humidity to condense incredibly tiny particles out of the air. It then concentrates them into a little vial from which DNA and RNA can be sequenced. Next-generation CPC systems are small, roughly shoebox-sized. They're also networkable and cheap — about a thousand dollars each. Someone needs to collect those little vials, so CPC doesn't provide instant results, but if the samples arrive at a robust enough lab, there's no limit to the number of pathogens you could test for. 

Mark and I talked about a plausible future CPC system which could do analysis right inside the box with a miniature robotic lab. He believes that if the right R&D resources are applied, this could be achieved in about five years, and the system might be about the size of a ticket kiosk. These could be deployed to transit hubs and other places you'd want to monitor particularly closely.

There was actually an early U.S. government effort to do something like this called BioWatch. It arose in the wake of the anthrax attacks of 2001, and was deployed in dozens of cities, targeting six pathogens. Although it got some terrible press, Mark says BioWatch wasn't bad for its day, that it did pull genetic information out of the air and achieved its goals to some degree. Another technology Mark is excited about has the fabulous name “spectrophotometric comb.” This is more physics than biology, and uses lasers to characterize gases and the particles in them. The proportions of gases we exhale change when we get sick, and tracking changes could be a fantastic early warning tool. A group Mark works with has proposed an experiment looking at the breadth of mice infected with COVID to see how their exhalations changed as they got ill.

Unlike CPC, Mark could see this technology one day plugging into a phone. Breathe into it daily, and it will produce a baseline understanding of what you exhale when you're healthy. Diverge from the norm and it could mean something's wrong. As the science gets smarter about what different shifts mean, better early warnings could be delivered, and if millions or billions of people start to do this regularly to monitor their personal health, the aggregate data could amount to an amazing early warning system.

Mark is one of over 100 contributors to a global microorganisms survey called MetaSUB run by geneticist Chris Mason, a professor at the Weill Cornell Medical College. Each year researchers in 114 global cities, plus an outpost in Antarctica, spend a day sampling an average of 50 local sites. Some sample the air, like Mark Hernandez. Others sample wastewater. But most of them swab surfaces in places including public transit systems, shopping malls, hospitals, and homes. You could think of this as a microorganism census, but it could be converted into a massive disease surveillance network by doing swabbing and analysis on a daily, rather than yearly, basis. Chris Mason ballparks that a budget of about $3 billion would enable this with extremely deep genetic sequencing, which would uncover even highly rare bugs in each environment.

Like everything discussed in this series, that's nothing compared to the annual cost of the flu, let alone a devastating pandemic, and about half of that cost is for reading genes — costs which are continuing to drop dramatically. Over time this could let hundreds of additional cities join the survey for the same budget, or the budget could be increased to expand coverage. After all, this cost is peanuts compared to the stakes. Over time, investments in R&D could result in robotic systems to do the swabbing automatically, and do the genetic analysis right on the machine, potentially enabling far more sampling, or allowing more to be accomplished on the same budget. The bottom line is disease surveillance is an incredibly promising frontier for improvement, if we prioritize the right investments today.

Funding pandemic preparedness in the U.S. — a matter of national defense?

Sam: Okay. Well, Rob, in thinking about how to solve this problem, we have to think about how to pay for the solution. What is the role of money in this equation?

Rob: Well, I think there are two things to think about: How much is it going to take, and is society actually going to be willing to make those investments given that society basically hit the snooze bar after SARS, after Zika, and after a bunch of other things? This time around there are definitely some promising signs. I do think that COVID's wake-up call is uniquely noisy, and the Biden Administration has, of course, drawn up a mega-billion dollar pandemic budget. But with almost all the conversation (understandably enough) focused on the immediate project of fighting COVID, it's a little hard to tease out what permanent changes will be made to our pandemic readiness. But there are some really good ideas starting to circulate. And also the real tests won't be what we're doing against pandemics in 2022, but what we're doing in 2032, if we've been lucky enough to have a quiet decade. Do we lose focus and let our capabilities atrophy after COVID's a distant memory?

And for this reason, the right way to look at this — and I think the only way to look at this — is through a national security lens. We spend massive amounts on defense every year, even though the huge majority of our military capacity isn't being used at any given moment, because we want to be prepared for an extreme military emergency that has never happened before. And since pandemics are huge national security risks, that's definitely how we need to budget for them. And viewing through this lens, I'd say, for example, the odds of another pandemic happening vastly outweigh those of an all-out nuclear war happening. And the U.S. currently spends about $35 billion a year, according to at least one report that I saw, maintaining its nuclear arsenal, while the world as a whole spends about $70 billion a year. Now that kind of annual budget would fund every pandemic preparedness measure I'm going to mention in this series many times over.

So there’s a significant precedent for this level of investment to avoid a major national security risk, and an investment that I think would do the trick of defending against future pandemics if it's spent wisely — which, of course, governments don't always do, but they can in a pinch, and this is in a pinch. But it needs to be a relentless investment year in, year out, across even pandemic-free decades. So again, the analogy has to be defense spending, which like an even bigger example is counter-terrorism, which the U.S. has spent trillions on since 9/11, including two world wars. That shows we absolutely have the resources to fund almost any imaginable pandemic immune system on a national or global level. It's just a matter of political will.

Sam: Yeah, and the point I would make here, which I think we've made at least a couple of times already, is that everything we're saying about defending against a SynBio attack applies to natural pandemics.

Rob: Absolutely.

Sam: Even if we manage to completely solve the problem we're mostly focused on here, and we keep the tools of SynBio out of the hands of all the bad or crazy people that could ever want to wield them, we still have this massive risk, which we know is never going away: that nature will produce the next pandemic. And if it doesn't wipe us out, it still could be much worse than COVID — unimaginably worse than COVID — in its effects on civilization if we can't immediately deal with it. So every step we would take here to prevent bioterrorism, we should be taking anyway to prevent the bioterrorism of Mother Nature.

Rob: Yeah. That's absolutely the right lens to look at it through. And every countermeasure we're going to talk about, or pretty much every one of them, is equally applicable to natural pandemics. On top of that, just look at the flu. Even if we never face another pandemic again, which is awfully unlikely, the White House Council on Economic Advisers put the annual cost of the flu in the U.S. alone at $361 billion a year in lost productivity as well as medical spending. That maps out to a trillion dollars a year, and hundreds of thousands of lives worldwide. And there are plenty of ways to recoup any investment that we make against these things.

Monitoring requests for dangerous DNA

Sam: Yeah. So how do members of the IGSC screen for dangerous DNA? How is any of this being monitored?

Rob: Well, the good news is it's actually a really interesting and ambitious precedent, and it's a great place to start when we think about hardening our SynBio infrastructure against being hijacked. 

I'll start with a quick overview of the market for long error-corrected strands of DNA and RNA. Those strands are mostly assembled by specialized companies for customers who don't want to create their own advanced DNA synthesis capability, which is almost everybody, because that's very expensive to build. It's like how people used to get their photos developed at drugstores rather than building darkrooms at home.

Now, decentralized DNA creators are almost shockingly unregulated. There's just this voluntary guidance, which the government issued over 10 years ago to keep dangerous DNA away from bad guys, and which has never been updated. But luckily, the industry itself doesn't want a Hindenburg moment (in this case, a catastrophic biosecurity lapse), because that could lead to massive regulation, or even the industry getting shut down. That’s why we have this self-regulating body called the IGSC, which doesn't really have its own staff or resources, but its members jointly maintain a comprehensive database of pathogen genomes. That's the main function of the IGSC as far as I can tell.

The members screen all of their orders against that list. It's pretty impressive. And every order is tagged red, yellow, or green. So if there's no meaningful overlap between the order and the genetic code of any known pathogen, the order is marked green and it sails right through. That's about 95% of orders. But about 5% of orders are yellow, and that means there is significant overlap with some stretch of DNA in a pathogen. Those orders are very carefully reviewed for maybe an hour or two, and it usually turns out that the overlap is with a benign stretch of DNA — maybe it's a housekeeping gene, or something like that.

But every so often, a yellow order becomes a red order, because the genetic code that someone's requesting is directly connected to some kind of dangerous machinery in a pathogen. And those orders take several hours to review. Sometimes they’re approved, sometimes they're amended, and in some cases, I understand, they're actually reported to the FBI.

Now, the thing that's interesting is this review work is done by bioinformaticians, who are very often PhDs. So it's a very thorough apparatus and it's also very expensive, and the industry is doing this on its own already. It's a hell of a start, but it's expensive, which is why some companies are just opting out of the whole thing, and don't join the IGSC at all. And none of this is required by law. The IGSC claims that it represents 80% of total industry capacity, but that is really just an educated guess that someone (and nobody can seem to remember who) made many years ago. And I'm totally confident in saying that it's very outdated, because the IGSC has exactly one Chinese member, and China's SynBio capacity is growing like mad, because it's a huge government priority.

What needs to change in the current IGSC monitoring system

Rob: So what should change? Well, the guidance on SynBio safety, first of all, has to stop being voluntary. It has to stop being 10 years out of date. It definitely has to apply to 100% of the industry, and it must be internationalized through careful cooperation with China and everyone else. And that's a very tall order. But the great news is that the starting point that the IGSC has coordinated can absolutely form the core of the first layer of our global immune system to harden up our SynBio architecture, because if it's universalized, it would, without question, hugely reduce the number of people who could do something awful with synthetic DNA. Working around universal restrictions would require so much more planning, and so much more stealth and skill, than simply ordering something from a rogue supplier that doesn't implement any protections. 

So we have a great start. But it does need to be universal. And, again, it has to be up-to-date. Ten-year lags won’t cut it.

Sam: But what is the mechanism that would enforce compliance internationally? Certainly if we're talking about a rogue state, it's in the very nature of being a rogue state that it is not compliant with international demands. North Korea is a perfect example. But even state-level misbehavior aside, even within labs or among individuals within other countries, what leverage do we, or any collective, have to make sure that this compliance is truly international?

Rob: Yeah. There are two dimensions to that. One, how do you get IGSC-like regulations enforced by all countries that have private SynBio industries? That is challenge number one, and it's an ample challenge. But I'm sure there are many industries that have relatively universalized regulations throughout the world, in part because it’s in the interest of the industry to not have to comply with rules associated with countless jurisdictions that might be different and so forth. Still, that’s hard to do, and I don't want to minimize that.

But state actors are a whole other wrinkle, because if you look to the Montreal Protocol for reassurance, the hole in that analogy is that state actors themselves didn't have big chlorofluorocarbon projects of their own. Those were industrial ingredients. They were coolants for air conditioners, for making foam packaging for McDonald's, and for that sort of thing. So in that case, governments were regulating society, which they're perfectly happy to do, but sovereign governments could get really grumpy about restrictions on their own actions. Therefore, it's not hard to imagine the Chinese state, or the U.S. for that matter, secretly developing government SynBio capabilities to stay ahead of the rest of the world. 

So, in addition to an internationally coordinated IGSC-like system for keeping private industry safe, we definitely need something like the Nuclear Non-Proliferation Treaty for SynBio amongst nations. That is a really tall order, and it's not something that I have a ready-made playbook for, but I will say that as we scale up all of our national protective layers, it's really important not to neglect the international side of things. And this will require a feat of very significant and determined international diplomacy, without any question.

Lessons on international cooperation from COVID

Sam: So, in relation to this point of cooperation and its enforcement internationally, are there any lessons to draw from our experience with China and COVID? There are so many ways in which cooperation almost happened and then failed. And we're still trying to figure out to what degree you think that rank deception is just the story of what China has done here. But what lessons do we draw from COVID?

Rob: Well, it's obviously not an encouraging example on many levels: the denialism, the suppression of people spreading the word about the outbreak, the fact that people in regions like Wuhan are often afraid to report bad news up to Beijing. So there was stonewalling internally, according to that very extensive research that I cited in the recorded material. According to the Wall Street Journal, there was awful stonewalling on an international level.

But what we can hope for — and I don't think this is a naive hope — is that a lot of people in a lot of countries are looking at all the botched responses to COVID and saying, “Never again.” And I hope they're saying it with the kind of determination that carries over across years, and across decades.

And in a weird way, the encouraging thing is that I think China's disease detection system might've actually been up to the challenge of containing COVID, but for some tragically delayed responses. And Beijing would presumably do everything possible to avoid those in the future. Based on that, my optimistic side says the world already may be closer than we think to adequate warning and detection systems. 

I’m getting this idea from a fascinating paper in the journal Nature. The lead author is Shengjie Lai at the University of Southampton. The paper analyzes China's so-called non-pharmaceutical interventions against COVID, which is a fancy term for quarantines and lockdowns.

Sam: It's a fancy term for welding people into their apartments.

Rob: Exactly — and masking and that kind of thing are also “non-pharmaceutical interventions” or NPIs. The paper's analysis goes into a lot of depth and says that if these interventions had been implemented a week earlier, China's COVID cases could have been cut by about two thirds, by something like 85% if they had been implemented two weeks earlier, and by 95% if the lockdowns and so forth had happened three weeks earlier. 

So, did China have three weeks? And the answer is these interventions started on the 23rd of January (or I think it was that date). As early as late December, a heroic doctor that some people have probably heard of named Li Wenliang first sent a message to some fellow doctors warning of a SARS outbreak in Wuhan. 

So that's over three weeks of lead time. And since this was a lone doctor successfully tuning into the pandemic just from his narrow personal experience, I think we can safely assume that the local health authorities, who would have had much broader access to data, had to be aware of something.

This is just terrible to even think about, because the 95% drop in China's cases may well have prevented the global outbreak. But it also feels really unlikely that a delay like that will happen again in a post-COVID world. There's just going to be so much more urgency about any warning signs. And meanwhile, there are a ton of things we can do to dial up the sensitivity of early warning systems throughout the world, which we'll talk about. And all of that together gives me real optimism about our ability to detect — and hopefully also snuff out — potential pandemics, whether they're natural or artificial.

Potential approaches and challenges to building monitoring systems that detect viral threats

Sam: Is there any more that you've uncovered on the monitoring front, or just how we can pay attention to what's happening in the world? Because again, this is the kind thing that by its very nature will emerge by stealth. You know what I mean? I guess some maniac could decide to take the Bond villain approach to this and say, “Even if my demands are not met I will be releasing the doomsday virus on New Year's Eve.” But generally speaking, we're just going to hear about people getting sick somewhere, and we're not going to know what's going on, or for how long it's been going on, unless we build some system by which we detect these things earlier and earlier.

Rob: Yeah. I would definitely like to draw attention back to that Nigerian system called Sentinel Alerts. It's being rolled out in Nigeria. I talked about it [earlier]. Just to quickly review: I think they call it “a pandemic prevention system using real-time detection of viral threats,” or something like that. The expectation with Sentinel is that they'll be able to empower community health workers to diagnose any of a region's most common and highest priority viral infections (the highest priority ones being rare, scary viruses like Ebola) within an hour. They’ll be able to basically diagnose any known human virus within a day, by pushing things up the chain to a central organization. And my back-of-the-envelope math on that, as I mention in the recording, is that it would cost in the low billions to try out something like that in the U.S.

And you've got to ask yourself: Why in the hell haven't we done that? And part of the answer is that some of Sentinel's technology is very new, and also the amount of genetic sequencing that it involves would have been impossibly unaffordable just six or seven years ago. 

But the bigger reason is the American healthcare system is just this baffling thicket of overlapping jurisdictions. Some things are managed by 50 different states. Other things are managed by 3,000 different counties. And at least for now a nationally coordinated system like Sentinel seems to be completely beyond us.

Just one example of this is from [a 2021 editorial] in the New York Times. It said that 20 million COVID vaccines have essentially gone missing in the U.S., which is a huge number given that 40 million vaccines have actually been injected so far. And I think the intent of the editorial was that these vaccines had gone missing from the standpoint of the federal government, which basically means the federal government is pumping out the nation's scarcest and most precious resource into 3,000 counties in 50 states and losing track of it. And we obviously need to do better than that. 

When it comes to disease surveillance, we need to implement what Sentinel is bringing to Nigeria: a real-time radar of viral infections. And obviously counties can't build that. It needs to be a national system. I think it would have to hinge on radically expanding the testing and diagnosis of all respiratory infections, flu, rhinoviruses, minor brushes with the common cold, the whole shebang. Currently, we don't even attempt that. Have you ever in your life had a flu diagnosis? Has a doctor ever said, “Hey, you don't have the flu, you have a rhinovirus,” or “You have influenza A, not influenza B”?

Basically, no one has ever experienced that, because people usually recover from these things, and collecting the data didn't seem important. But this must change, because the only way we're going to know if something new and dangerous is emerging is if we track the full national inventory of viral infections as closely as we can. In my mind, that means we need a “project warp speed” for diagnostics and for testing — not just COVID testing, but every respiratory infection we know of. And I understand the Biden Administration plans to invest a lot of money in tests. 

I don't know how much of that is for the current crisis and how much of that is ongoing, but we basically need a whole new category of diagnostics that can test for multiple diseases and that are reliable, that are cheap as hell, and above all, that can be taken at home, because we want to track these things much more closely, but we don't want to trigger an avalanche of new doctor visits. We don't have the capacity for that. And most people wouldn't bother with a doctor visit for a mild infection anyway.

So these tests should be in every home, they should be free, and somehow the results should be automatically logged in the national cloud. Maybe you need to scan some coded display on the test with your phone to get the results. And all of this disease information needs to go into a real-time integrated system that's inhaling a lot of other data as well — something like NORAD, the super high-tech military command that scans the skies for nukes and enemy planes. We need a disease-tracking center that's staffed 24/7 by data scientists looking at data from all kinds of sources, such as all of those diagnostic tests, online search engine queries, and so forth. 

Hopefully, we're also smart enough to invest in a bioaerosol grid and the technologies I talked about for pulling viruses out of the air in public spaces. That data should also feed in continuously to a national tracking system. And hopefully we're also smart enough to build a hugely expanded version of that academic project which tests surfaces, wastewater, and air samples for viruses in over a hundred cities. That data would feed into the tracking system, too.

The system obviously should also be dialed into the local public health systems, so if there's an alarm signal somewhere, you can get boots on the ground and see what's happening. 

That's quite a wishlist, but we could build something like that, and it would be an amazing layer in our global immune system.

Sam: Yeah. At least two parts to this are distinct. There's the actual diagnostic end of it, where you have to swab the door handle on a bank, or the keypad on an ATM, or somebody's nose to get a saliva sample. And then you need to take all the friction out of the system that allows those samples to be processed and analyzed.

But then there's just this massive information integration problem, and prospective and retrospective search of the data, looking for patterns. And I have to think that when it comes to that second piece, companies like Google and Palantir and other major tech corporations that have so much engineering talent could profitably spend 20% of their time there. It has to be shouldered as a responsibility by every smart person who has something to contribute [to solving this problem].

My fear is that we will solve COVID; the vaccines will ultimately get distributed and they will work, if not in the first volley, maybe in the second. We still have variants now that could be outrunning some of the vaccines, but you can imagine us putting this behind us fairly conclusively, and then ushering in a roaring twenties spirit of “We've reset everything, hallelujah.” We could lose the lesson that we really must draw from this, which is we can't let this happen again. 

Again, this is a dress rehearsal that we have manifestly botched in almost every way, apart from the speed with which we produced vaccines. So I do worry that once we get out from under this, we will lose the sense of urgency and just assume that this thing only happens once a century anyway, so we can go back to sleep.

Rob: Yeah, and I'll come back to the idea that this absolutely needs to be viewed through a national security lens. And maybe, just because the Department of Defense is so damn good at lobbying for hundreds of billions of dollars every year, we hold our nose and put [the responsibility for preparing for the next pandemic] under them. They sure know how to lobby for dollars. It has to be something that is done relentlessly, year in and year out, like we do with funding military capacities that at almost any given moment are 99% unutilized. And we've become okay with that as a society, because we know that we someday might need to draw on emergency capacity. 

But the other thing is how the IT will work. I'm just glibly describing something like NORAD, which I assume works really well. I don't know, I've never been there. But what we do know is that the IT contracting that the government has done for all kinds of things has, at times, been completely catastrophically inept.

Sam: Yeah.

Rob: And just look at the debacle of the vaccine rollout. The New York Times had an article that I just mentioned about the 20 million vaccines that have gone missing. The article also mentions that the federal government gave Deloitte a $44 million no-bid contract to develop software for states and others to use during their vaccine rollouts. The product is simply catastrophic, and a lot of health departments have completely ceased to use it. 

We can't have that level of incompetence, and that lack of seriousness, invade or infest something like this if we're really going to build a radar screen for emerging pandemics. We can absolutely do it, but I'll take much more heart from the kinds of things that companies like Palantir can allegedly do than from the kinds of projects the federal government has overseen. It's hard to imagine a more urgent task than getting vaccines distributed, but even that IT project was colossally botched.

So there needs to be a completely different level of governance with much, much higher standards and again, just a radically higher level of seriousness as we tackle this thing. Maybe this gets back to that notion of [capable people in SynBio giving 20% of their time to work on the problem] — not that you would want a national detection grid to be staffed by part-timers. But maybe people who are intent on careers in SynBio view things from a linear standpoint. Maybe they could say, “I'll give 20% of my career to doing work in the public interest.” And maybe we could have some really top-flight people from academia and private industry see to it that these systems are outstanding and work incredibly well.

Sam: Yeah. And I'm sure there's a role for philanthropic organizations here to point resources in the right direction and lobby for this being a priority. Some of the most important work that can be done here, I think, is just to make the case that we need to allocate resources at the governmental level. [That way, we’d avoid] the problem that we've run into all these long years with climate change. We're still barely at the starting line because the war of words has been so difficult to win. And we really need to figure this one out. 

Somehow I think this is less abstract to most people than the risk of climate change is, but we're also living in a country where it seems that at the time of this recording, something like half the country is fairly carefree about the prospects of catching COVID and quite worried about getting vaccinated for it. It's the absolute inverse of what you would think would be psychologically possible.

So we obviously do have a major messaging problem here, which also requires a commitment of resources. And that is, in large part, the purpose of this podcast. So Rob, let's listen to the fourth and final section of your by turns fascinating and harrowing meditation on the future of SynBio and global pandemic.

Component No. 3 of the global immune system: Hardening society against future pandemics

Rob: This brings us to the third component of a [national] immune system, which is hardening society against future pandemics. What can we do to toughen things up? 

Well, probably dozens of things. And as I said earlier, this podcast can't be a comprehensive list of everything we could do, but I'd like to lay out a couple of intriguing possibilities that might just be game-changing. For now, they're both unproven. But they're examples of the types of investments — in some cases, tiny ones — we should be making to bulk up our arsenals. 

UVC light

Rob: The first is a very particular ray of light: ultraviolet light, or UV. As you may know, UV is invisible to human eyes. It's carved up into various bands and sub bands, just like radio. UVA and UVB light from the sun shine through our atmospheres and cause sunburns and skin cancer. A higher frequency band called UVC light doesn't get through, but we can make it ourselves with lamps.

UVC has a lot of energy, so much so that it kills microorganisms by frying their DNA. You may have seen it sterilizing things in hair salons. It's also used to sterilize operating rooms, hospitals, and buses in some countries, but only when those places are empty, because again, UV light is bad for us (or at least most of it is). 

The UVC spectrum has its own little neighborhoods. One of them is called far-UVC, and fascinating research shows that it may not damage human tissue at all. David Brenner, a radiation physicist at Columbia University, has done most of the groundbreaking work here. In a July 2020 interview with TED's David Biello, he explained that light around the 222 nanometer wavelength just can't penetrate the dead cells that form the surface of our skin and our eyes.

He has exposed the skin and eyes of mice, as well as human skin, to it. And there's no sign that it gets through that outer layer to do any damage. But viruses and other bugs are much tinier than we are. And this light zaps them. David Brenner's experiments have shown that it kills off airborne thugs like influenza and coronaviruses. He'd like for far-UVC lights to be in indoor spaces everywhere, and to be switched on safely in the presence of humans whenever outbreaks occur. He has calculated that 99.99% of the pathogens in an enclosed room could be knocked out by these lights in just a few minutes. 

Now, this wouldn't sterilize diseases out of existence. After all, it takes seconds, not minutes, for a sick person to sneeze on you in the subway. But it could bring the ambient level of pathogens way down and completely sterilize surfaces. In other words, while it wouldn't make the built environment virus-proof, it could harden it quite a bit.

But there's a puzzle here. Dangerous UV wavelengths aren't all that much longer than far-UVC. It's all measured in nanometers. So why can the bad UV penetrate our skin when far-UVC can't? I talked to a Scottish physicist based in Australia named Charlie Ironside. He explained that different materials absorb and reflect different frequencies of light. And the proteins in our cells happen to be highly absorbent right around that magic 222 nanometer wavelength. When light is absorbed, it decays away exponentially as it enters the material. So, boom, our outer layers of dead cells are bulletproof, or at least very opaque at 222. 

To make far-UVC today, you need clunky tubes, which are big, ugly, inefficient, and generate way too much heat. Charlie has spent decades working with LEDs and has issued a call to arms to the industry to make far-UVC LED products. If things work out, he thinks they could even be integrated into smartphones, letting them act as germicidal wands. There would be no more need for hand sanitizer. But a lot of research and development would need to be done. And as Physics World recently pointed out, nothing's going to happen until safety is proven beyond a doubt. 

David Brenner's intriguing experiments notwithstanding, this has yet to be done. If you're like me, you're wondering why in the world not. Safety studies would cost in the millions in a world that's losing trillions to a pandemic, a world which will, without question, face future pandemics. And this could be a game changer. Alternatively, it could be a dud, but we'll only find out if we put it to the test. Our global immune system has to fund research that could strengthen our pandemic readiness, especially when next steps cost so little, and excellent research shows that the results could be transformative.

The BCG vaccine

Rob: This brings us to the BCG vaccine. BCG prevents early childhood tuberculosis. The vaccine has been given over 4 billion times since the 1920s, more than any other vaccine. It's so safe it's given to over 120 million infants each year. And there have been signs, over almost the past century, that it fights many diseases beyond tuberculosis. Way back in 1927, a Swedish study found that BCG-vaccinated children turned out to be three times less likely to die from any cause. More recently, a 25-year study of over a 150,000 kids in 33 countries showed the vaccine reduced lower respiratory tract infections by 40%, and a very recent study in Greece showed an 80% drop in respiratory infections amongst older adults who were given the vaccine, as well as a 50% drop in all other forms of infection. 

BCG superpowers go far beyond this. It's now a frontline treatment for bladder cancer, and there are promising signs that it might even help to prevent cancer from arising in the first place, and possibly even prevent Alzheimer's.

BCG seems to work its magic by strengthening the innate immune system over the long term. Think of this as being your body's first responders. It's the innate immune system that instantly kicks in when something punctures your skin, or when you first get an infection. It's ready to fight anything, unlike the adaptive immune system, which creates highly effective specialized responses to specific enemies, but needs time to get started. 

So could widespread BCG use help foil a pandemic? Well, as early as March, people started noticing the countries with long-running BCG programs, such as Japan, generally had much lower COVID infection and death rates than countries with no BCG programs, such as the U.S. A rigorous study of this effect appeared in the July 28th edition of the Proceedings of the National Academies of Sciences. To control for things like socioeconomics, population structure, and urbanization, the researchers looked at a set of what they called “socially similar European countries.” They found that for every 10% increase in a BCG coverage index, COVID death rates dropped by 10.4%. 

An intriguingly stark example was found in Germany. Back when the country was divided, East Germany pursued a policy which has yielded far more BCG coverage in today's elderly adults who are, of course, the most vulnerable group to COVID. And today the death rate from COVID is 290% higher in Western Germany, the opposite of what we'd expect to see given that Western Germany is the far more prosperous region. 

Is all of this just a coincidence? Of course, it could be, which means this screams for multiple clinical trials. They should be run in places like the U.S. where almost no one has ever had the vaccine. Researchers would then give one group of people BCG, and another group a placebo, and then compare COVID infection rates between the groups over time. 

Although some BCG COVID trials are in fact underway, I'm still stunned by how hard it is to raise tiny tiny research funds for such obviously important work. As I was researching this, I got to know two scientists who are proposing some exceptionally well-designed research into BCG's benefits for an extremely vulnerable population to COVID. They're from one of the world's top and best known universities. But instead of running their trial they were hunting for a few million dollars in funding during a pandemic that's costing the U.S. alone $7 trillion, at least. Again, this is insane. Even though BCG, like far-UVC light, could admittedly turn out to be a flop, we won't know until we fund the inexpensive research that tells us. 

You might question why this research is still important with so many COVID-specific vaccines entering the market. The answer is that we have an entire planet to vaccinate, almost 8 billion people. Some of the new vaccines are expensive, with limited production capacity, whereas BCG costs as little as 7 cents a dose and is made by 22 different manufacturers throughout the world.

COVID aside, this could be a game changer for future pandemics. BCG's greatest superpower seems to be fighting respiratory infections of all types, and a huge percentage of pandemics, as well as novel diseases with the potential to become pandemics, are respiratory in nature: SARS, MERS, COVID, flu, tuberculosis itself, you get the picture. And God forbid we ever have an artificially modified H5N1 outbreak. But if we do, that will be a respiratory nightmare. If a future pandemic could be greatly softened by a precautionary BCG vaccination program, we'd be fools not to do the inexpensive research to either prove or debunk BCG's efficacy. And again, if we do decide to vaccinate people, BCG costs as little as 7 cents a dose, so giving the largest, totally unvaccinated country, the U.S., full coverage would cost peanuts.

If you'd like to learn a lot more about the BCG vaccine, tuberculosis and more, I interviewed a brilliant Harvard epidemiologist named Megan Murray for my own podcast, which again, is called the After On podcast. Her academic focus is tuberculosis and she knows a ton about BCG and its potential. Our interview runs for well over an hour and goes into much more depth than I can cover here. 

Strengthening the social safety net to address mental illness

Rob: The last method for hardening society that I'd like to highlight doesn't hinge on cutting-edge science, but on plain old public policy. It is to greatly increase the social safety net that keeps people from sliding into states of extreme despair. Though it may be hard to feel empathy for suicidal mass murderers, we have to accept that all of them arrive at profoundly dark places that few of us can even imagine. These are not swift journeys and all involve some form of mental illness, be it extreme depression, uncontrolled rage, pathological narcissism, schizophrenia, or something else.

We need to study the case histories of everyone who snaps in this way and greatly increase our vigilance and generosity in detecting and treating the relevant conditions. Here in the U.S., a de facto policy emptying asylums for the mentally ill back in the '80s has done us no favors. More broadly speaking, every single one of us can be a white blood cell in this global immune system by each doing what we can to ensure that no one goes unloved.

Component No. 4 of the global immune system: Conquering viruses

Rob: This brings us to the fourth component in our immune system, which is conquering viruses. But before we talk about viruses, let's briefly discuss bacteria, which can be extremely dangerous. They cause things like cholera and bubonic plague, which still bubble up in places with overwhelmed healthcare systems. Plus there are so-called “superbugs” which resist all antibiotics. These killed about 700,000 people in 2016 and could be over 10 times as lethal by 2050, which means they could significantly exceed the death toll of even COVID. We're desperately under-investing in new antibiotics and this urgently needs to change.

That said, almost every major epidemic since antibiotics were discovered has been viral: influenza, polio, mumps, yellow fever, measles, dengue, AIDS, SARS, MERS, COVID. And as for true pandemics, only viruses cause them in the modern era. So why are viruses such tough customers? Ironically it's because there's not much to them. They lack the basic machinery of life and don't have any cells, so they infiltrate our cells. That doesn't leave as many targets when we go after them because we don't want to wipe ourselves out along with the virus.

Bacteria, on the other hand, are cells — ones which are very different from ours. That gives us loads of targets when we fight them, and many of our antibiotics are broad-spectrum, which means they can wipe out all kinds of bacteria (sometimes too many). This makes it almost certain that the first deadly artificial pathogens will be viruses. 

So does the second factor, which is that bacteria are radically more complex than viruses, and are therefore much harder to engineer. Other deadly critters like the parasites that cause malaria are more complicated still. Complexity also makes it almost certain that early man-made bugs will be modifications of existing viruses, not completely artificial ones, because it's currently beyond anyone's capacity to make complex functioning viruses from scratch.

So how should we face the threat of artificially-modified viruses — terrors like the contagious version of H5N1 flu which has already been created? Well, I'd say we should face them exactly how we should have been facing natural viruses for decades. We should take steps that probably could have stopped COVID in its tracks. 

There are two main sets of tools to consider. The first is vaccines to prevent viruses from infecting us in the first place. The second is therapeutics, a fancy word for medicines to help us fight viruses if we do get infected. The trick is that so far both sets of the antiviral tools have been very narrowly targeted at very specific diseases, rather than having the broad-spectrum disease-fighting power of many antibiotics.

Therapeutics to fight viruses post-infection

Rob: Let's start by talking about therapeutics. John Hopkins Center for Health Security Senior Scholar Amesh Adalja sums things up, writing, “The existing armamentarium” — by the way, I love that word — “of antiviral drugs is rapidly expanding and now covers several viral families. However, very few existing antiviral agents have spectrums of activity that even slightly measure up to the spectrum of penicillin or sulfa, the first antibacterial agents discovered.”

But it's not hopeless. In a conversation with me, Amesh pointed to several viral therapeutics that hit multiple targets. One influenza treatment has proven effective against Ebola. Another medicine fights members of four virus families: herpes, pox, adeno, and polyoma. And something called ribavirin, which was name-checked in the movie Contagion, can help treat hepatitis C and E, influenza A and B, parainfluenza viruses, Crimean-Congo hemorrhagic fever, metapneumovirus, New and Old World hemorrhagic arenavirus, and SARS, although unfortunately, ribavirin has what Amesh calls “serious toxicity issues”.

So what do we do with all this? Amesh told me he'd like to see a serious multi-year program to test every antiviral medicine that's ever been developed against every dangerous virus family. They're reluctant to put a firm budget on this. He said it could cost several billion dollars and take several years, which is chump change in light of what we're up against. And this would give us something crucial that we lack: a complete understanding of what our existing weapons can already clobber. For now, we make these discoveries haphazardly or reactively — as we did when the Ebola medication remdesivir proved to have some effectiveness against COVID. There may be some truly broad-spectrum wonders in our viral toolkit already that we just don't know about, so let's figure this out.

Amesh also calls for us to proactively develop new antivirals to cover full viral families, such as all coronaviruses. Pull that off and you've tackled SARS and MERS, as well as four causes of the common cold and, above all, COVID. Just imagine where we'd be now if we'd launched a successful campaign against the full coronavirus family right after the SARS crisis in 2003. With a powerful anti-coronavirus treatment in our arsenal, COVID fatalities could have been a tiny fraction of today's death tolls, and society and the economy could have been far less disrupted.

Amesh notes that it usually takes about a billion dollars to get a drug to market. That’s big bucks, but small change compared to what's at stake — even if you do this for every viral family that sickens humans, of which there are just a few dozen. (However, there are a few viruses that don't currently infect us that we should probably sharpen some weapons for. Remember those zoonotic viruses? An organization called the Global Virome Project keeps a wary eye on bugs that haven't yet jumped to humans but may one day do so.

Like so much of what we're discussing, all of these antiviral measures would bring massive benefits against natural pathogens as well as artificial ones, and strictly in light of the endless costs that natural diseases inflict on us, we'd be crazy to skimp here. Also, there are things that could help bring the costs down, such as software-based modeling and screening of drugs against specific diseases — a new field that's showing a lot of promise and appears to be very cost-effective.

Vaccines to protect against viral infections

Rob: Of course, the other side of the viral defense equation is vaccines. Let’s start by talking about the flu again, because a lot of smart people have been calling for a universal flu vaccine for years. By this, they mean a vaccine that works against all strains of the influenza virus. If you stamp out the seasonal flu, you've protected people from rogue versions of H5N1 flu for free, along with countless other variations. A universal flu vaccine would also hopefully be good for multiple years, unlike the annual vaccines we currently get.

There are a lot of good reasons to get blanket protection from influenza. As we've already seen with H5N1 flu, it can be hacked in terrifying ways. It also kills three to 500,000 people worldwide each year and costs over a trillion dollars in global economic activity. Plus, it mutates constantly, reinfecting people who recovered from earlier strains. Those mutations can also trigger deadly pandemics, as happened in 1918 and three times since. Finally, the current vaccine is just so inadequate. It's only 10 to 60% effective, depending on the year, and its manufacturing is largely based on 1940s technology.

One of the top people who has long called for a universal flu vaccine is Harvey Fineberg, a former dean of the Harvard School of Public Health and a former president of the National Academy of Medicine. He told me that he thinks it would cost just $100-200 million to fund a fully dedicated effort that would have “a very good chance” of developing a universal flu vaccine over about 10 years. You heard that right, just $100-200 million a year. And he points out that even if he's off by an order of magnitude, and it costs $1-2 billion total, it's a staggeringly good deal.

Now, you could spend this money only to find out that a universal flu vaccine is impossible with today's science. Harvey puts those odds at at least 25%, and maybe as high as 50%. But if we take the worst possible numbers from all of his ranges and figure it's $2 billion to get just a 50-50 shot at saving the world a trillion dollars and hundreds of thousands of lives each year, it's still the deal of the century. 

Of course, there's no reason to stop with the flu. Harvey thinks similar programs against other viral families would cost similar amounts and face similar odds. If given the budget, he'd start with universal influenza and coronavirus vaccines. He thinks we've learned enough from this to make later efforts targeting other viral families faster and cheaper. So again, let's say we take the worst possible number from Harvey's ranges and launch universal vaccine programs against the few dozen virus families that sicken humans. This one-time moonshot program would cost less than 5% of what the flu alone costs the world every year, and less than 1% of COVID's bill. Even if artificial bugs are forever pure science-fiction, this is an investment humanity cannot afford not to make. 

No, you wouldn't have to get all those shots (although you'd be wise to get the influenza and corona ones). Instead, we'd stockpile these vaccines and have them ready in case something as bad or worse than COVID emerges from one of those many viral families. And as with viral therapeutics, just imagine if we had the foresight to launch a family-wide coronavirus vaccine program in response to the SARS outbreak in 2003. Society literally could have been inoculated against COVID before it even raised its head.

Component No. 5 of the global immune system: Battle infrastructure

Rob: Let’s turn to our global immune system’s final component: battle infrastructure. Let's say the worst happens and an evil artificial bug or something nasty and natural is on the loose. What do we need in our arsenal that we'll wish we had invested in today? 

Rob: As a first step, Harvey Fineberg thinks we should adopt a national security mindset toward pandemics. And I fully agree. These can be threats on the scale of a world war after all, which calls for a unified command. And Harvey believes the head of it should carry “the full power and authority of the American president to mobilize every civilian and asset needed to win the war.”

That's the approximate opposite of how the U.S. met COVID. To cite one small example of dozens, the federal government here triggered a bidding war between the 50 states for critical equipment and supplies by refusing to coordinate purchasing and distribution. This turned the states into rivals rather than allies, while prompting hoarding and backstabbing. In the words of the Wall Street Journal, “Some states turned against each other. One refused to give another contact information for lab supplies, fearful of being outbid. Governors kept shipment details secret. Other governors dispatched state police to airports to guard their cargo.”

A bigger example is how the federal government left it to each state to concoct its own defense and public health strategy against COVID. Of course, by definition, states don't have national institutes of health or national centers for disease control. Thus, states were badly underpowered, and made their best guesses as to what might work, resulting in a stew of conflicting policies and even quasi-border controls against citizens of other states. Could you imagine approaching something 10 to 100 times deadlier than COVID with this sort of flailing? The virus would finish us.

Temporary accommodations to help exposed people quarantine

Rob: Harvey also thinks voluntary quarantine should be more widely practiced and available on demand. By this he means offering temporary accommodations to people who have been exposed to protect the people they live with. This is important because close, extended indoor contact is the surest way to catch someone's infectious disease. Just consider how badly COVID spread in nursing homes. 

Now, it may seem heartless to suggest that someone consider separating from their housemates or family, but saying you should quarantine at home is an invitation to infect everyone there, while only getting ad hoc homespun medical care (unless you happen to live with a doctor or a nurse). Is that less heartless or more?

Imagine someone's instead offered a free stay at a hotel that has been shuttered by a pandemic. Harvey outlined a compelling pitch to me. You could stay somewhere that other people would pay hundreds of dollars a day to live in. You'd have room service because that enables social distancing. You'd have 24/7 Zoom access to everyone you love via in-house broadband. Okay, you won't get spa services, but you will protect your family for the next 10 to 15 days. Quarantine locations could have trained personnel ready to manage mild infections much better than most people's housemates. And if things turn ugly, someone under quarantine could be transferred smoothly and directly to a hospital.

We haven't seen much of this sort of thing outside of a few places like New York City, perhaps partly because China adopted a very coercive approach to this with what they called “fever clinics,” which gave the practice a bad name. It also takes forethought and perhaps some earmarked funding to set up a more comfortable voluntary program. And COVID caught the world unawares. But we have no excuse for letting the next pandemic sneak up on us. If it's something much deadlier and more contagious than COVID, a complete lack of quarantine could really sink us.

Stockpiling defensive tools like PPE

Rob: To all this I'll add the dead-obvious suggestion that personal protective equipment, ventilators, and other defensive tools should be stockpiled to a degree that verges on absurdity, and that all nations should try to establish highly local supply chains for this critical gear. Also, the stockpiling should not be limited to governments. Just as all homes are mandated to have smoke detectors, home stock piles of N95 masks, hand sanitizer, and other essentials should be mandated by law and perhaps paid for with government funds to ensure high compliance. I say this as someone who tends to be highly anti-regulatory by nature. But if we get whacked by something much worse than COVID, we cannot afford months of supply outages, hoarding, price gouging, and counterfeit products on the personal protection market like we saw at the start of this pandemic.

If you think all of this sounds like a totalitarian imposition, recall that personal hygiene and PPE use don't just affect the person practicing or not practicing them; they affect everyone, because scofflaws and free riders infect the rest of us. So this isn't a matter of personal freedom, like choosing junk food. It's a matter of civic obligation, like refraining from drunk driving. In this spirit, universal PPE stockpiles should be accompanied by a predefined set of rules and levels. For instance, if a region goes to a certain infection level during an outbreak, universal mask-wearing in public becomes mandatory. Everyone knows the levels and the rules. Everyone has the gear at home. There are no excuses.

Challenge trials

Rob: Another relative novelty we should consider seeing more of is challenge trials. These involve testing a vaccine by deliberately infecting healthy volunteers with the disease it targets. Now, I know that sounds insane, so let me explain the rationale, using COVID as an example. Big COVID trials inject tens of thousands of people. Half of them get the vaccine, half get completely inactive placebos. Then everyone waits until a few hundred people come down with the disease while going about their ordinary lives. If most or all of the sick people turn out to have gotten the placebo — in other words, if the people who got the vaccine don't get sick — then the vaccine is a winner.

There are two issues with this approach. First, it takes a long time to recruit tens of thousands of people to take an experimental injection. Second, it can take months for enough people to get sick on their own to generate statistically significant data, which is normally fine. But what happens if thousands of people are dying each week? If your vaccine works and you could have saved several months by running a challenge trial, tens of thousands will die waiting for the results.

Compare that to the number of test subjects who might die from deliberate infection. In the case of a COVID challenge trial, that number may actually be zero. The reason is you'd probably mostly allow young volunteers to enlist — people who are quite unlikely to die from the disease. And instead of signing up tens of thousands of participants, you'd have just a few hundred. Why? Because you don't have to wait for a small percentage of a huge group to catch the disease to get the few hundred infectees it takes to determine efficacy. In challenge trials, everyone's infected, and at least with COVID, if they're all healthy and mostly in their twenties or thirties, the odds are decent that literally no one out of a few hundred participants will die.

But what if one or two volunteers do die? Isn't that unconscionable? Well, compare that to the tens of thousands of people who could end up not dying if your vaccine works. When are one or two lives worth more than tens of thousands of lives? Well, when lawyers are involved, for one thing. And that's one reason why we don't see challenge trials: because the loved ones of someone who dies participating in one might sue the trial manager, whereas the anonymous masses who die waiting for a vaccine trial to run its course have no one to sue but Mother Nature, and she doesn't pay up.

Another reason is that doctors are deeply squeamish about imperiling anyone in their care, as they should be. Not only do our moral instincts scream this, but the Hippocratic Oath famously says, “First, do no harm.” The culturel of medicine is built on that foundation, which of course is hugely admirable, but it makes it hard to put the good of the many ahead of the good of the few, if the few happen to be under your care, and the many are countless strangers.

Now, an important moral dimension to consider about challenge trials is the mindset of the volunteers. If they're fully informed of the dangers, as they absolutely must be, what are their motivations? Well, if they're not being paid, they're probably signing up because they're willing to take a risk to help fight something awful that threatens society. People joined the U.S. military after the 9/11 attacks for somewhat similar reasons. Those volunteers put their lives on the line too. Many of them died and society didn't reject their offers of service, so should it reject people who volunteer for challenge trials?

These aren't hypothetical beings, by the way; tens of thousands of people have volunteered to participate in COVID challenge trials via an organization called 1Day Sooner. No one has taken them up on that offer. I could fill a podcast twice as long as this one exploring the nuances of challenge trials and their morality, but I'll leave it to you to decide where you stand on this complex issue. And if you really want to dive into a rabbit hole, google the term “trolley problem” while you're thinking it through. 

The one good thing about any future pandemic is that it'll happen in the future, of course, giving SynBio’s exponential momentum some growing room. This is great, because as I said early on, SynBio itself and the countless people who will one day practice it at doctoral levels, high school levels, and everything in between are our best defense against evil uses of biology.

Reasons for optimism

Rob: I'll close on an appropriately optimistic note, by describing one of the coolest things I see in SynBio’s mid-term pipeline: teleporting vaccines. And, yes, I mean that metaphorically, but only just. To appreciate how valuable this could be, let's imagine that an artificial pathogen or something natural and much more lethal than COVID is on the loose. Having taken the various precautions I discussed earlier, we have an effective vaccine that targets its viral family, but it's incredibly deadly out there, and all supply chains are fragile or breaking. It also takes months to manufacture hundreds of millions of vaccine doses using standard methods, let alone billions of doses for the entire world. In this situation, you'd want the vaccine available everywhere now, not in a few lucky places a few months from now.

You'd also want as few miles between you and your personal dose of that vaccine as possible, so wouldn't it be great if vaccines could be printed right at the local pharmacy — or better yet in your living room? Enter the BioXP, the DNA printer I talked about earlier. It will soon be able to directly convert the four basic genetic letters — A, G, C and T — into DNA or RNA strands, giving it unlimited flexibility in what it can write, just as four-color inkjets can produce any imaginable image. Its creator, Dan Gibson, actually invented it with vaccine production in mind — particularly RNA vaccines, a new technology which is behind the wildly exciting vaccines from Pfizer and Moderna.

And here's where his teleporting term comes in. Imagine you have the genetic code of a working vaccine at the center of your system, for example at the Centers for Disease Control in Atlanta. If you now print that genetic strand in thousands of pharmacies and doctors’ offices, you've basically teleported it throughout your network. Now, simply printing a strand of RNA doesn't give you an RNA vaccine. There are several additional steps, often referred to as “fill and finish.” Dan says the BioXP team is building these steps right into the machine. He believes fully integrated systems should be operational at pharmacies and doctors’ offices within three to five years.

As for consumer-friendly home systems, he puts those in the 10-plus-year time range, which I'm sure sounds like science fiction. But most of what's happening in SynBio today would have sounded like science fiction to the top people in the field when the Human Genome Project was wrapping up just 17 years ago — as would most of what everyday folks do with computing today compared to the minimal things that were possible on the world's most powerful computers just a few decades ago. That's the thing about exponential technologies: They can deliver science fiction in short timeframes. Of course, they can also enable evil or disturbed people to wreak terrible devastation, but they can enable the rest of us to prevent that devastation if we have the foresight to do it.

As we come to the end of this survey of what could go wrong with engineered pandemics, which is practically everything, and what we can do to protect ourselves, there are a lot of reasons for optimism. There are many steps we can take to nip tomorrow's problems in the bud. Most of them have huge dual-use benefits in fighting the natural diseases that clobber us constantly, and their costs are tiny compared to their benefits. To finish making this case for optimism, let's dial up your inner science-fiction writer one more time.

Imagine it's 10 to 15 years from now. A smart person with a biology background and a crippling emotional disease has decided to inflict a devastating pandemic on the world. He has access to a DNA printer with the raw horsepower to crank out any viral genome and tools we can scarcely imagine today, which easily translate printed genomes into replicating viruses. Worst of all, the dark web has given him the genetic code of that contagious H5N1 flu, which researchers created all those years ago, only it's an upgraded version that some darkly-motivated biohackers have made wildly more contagious than COVID.

But luckily, our deeply-disturbed protagonist lives in a world in which we had the foresight to defend ourselves from his attack years before he even thought of launching it. Strong laws require all DNA printers, not just 80% of them, to scan for deadly sequences before printing anything. So the only way to make his virus is from scratch, using methods that only a few elite scientists ever bothered to learn many years ago, before it became automated. That's a huge win right there, because with that one step we've radically constrained the number of people who could do something awful. In other words, the population of one circle in our Venn diagram —  those who could kill millions — has plummeted, greatly reducing the chances that it ever intersects with the other circle, which contains the people who'd like to kill millions.

But let's say this person actually is an aging elite scientist who still knows the obsolete methods of making viruses from scratch, and that he somehow infects a few people with his creation. At that point, our early detection system kicks in. We're monitoring the air, wastewater, and surfaces in hundreds of cities daily with tools that are several generations beyond what we have today, and everyone with a viral infection is diagnosed and logged the moment they show up at a clinic, and many more are feeding in data from simple rapid tests they take at home.

So unlike with COVID, the very first victims light up the global public health radar. If we're lucky and smart, by then virtually all humans have had a universal flu vaccine anyway, which would stop an H5N1 outbreak in its tracks, since it's in the influenza family. We've also made huge investments in therapeutics for influenza along with dozens of other viral families which can help cure the unvaccinated people who get sick. And if somewhere in the world there's a large unvaccinated geography, and the epidemic gets momentum there, we can fall back on our unified command for fighting disease. There are plenty of masks and ventilators, and no one's in a bidding war to access them, and within hours of that local outbreak vaccines are teleporting into pharmacies and even some living rooms, killing the outbreak in its crib.

That's my case for optimism. We do have time to create our global immune system before this happens. It can be multilayered, and like our own immune systems, agile and adaptive with a diversity of tools to tackle whatever threat emerges. 

The case for pessimism is that this immune system will not build itself. We've botched so much in the face of COVID, and if we respond to COVID's hope for defeat in the same way we responded to the end of SARS, the snooze bar could be the end of us. So for all my optimism there's absolutely no room for complacency. The new era in biology could put us in the best position we've ever occupied in relation to disease, but only if we make the right investments and take the right precautions today.

How optimistic is Rob?

Sam: Okay. Well, I'm back with Rob Reid. Rob, you finally brought us to something like a glimmer of daylight here at the end. Let's talk about how we might yet survive. How would you characterize your own outlook here at the moment? How optimistic are you?

Rob: I would say that I'm extremely optimistic for somebody who has marinated as much as I have in the twin dangers of suicidal mass murder and the relentless exponential advances in SynBio. They are not happy topics, and I've been marinating in them for much longer than I'd like to — since even before the pandemic. But for somebody who has really grappled with those issues, I must say I'm wildly optimistic. The science and technology in the pipeline are just so promising, and the dead-obvious things that we stumbled into during COVID should be extremely fixable, especially with a post-COVID mindset, which should give us all the political will we need to invest in fixing them. So, I’m definitely optimistic.

I think it's important to highlight that, because the last thing you want to do in talking about this stuff is to bring people directly from a state of denial to a state of despair. They don't do anything in either of those states. If you’re in denial, you don't see a problem. And if you’re in a state of despair, you think it's hopeless. In either case, you're emotionless. I think this is actually a problem that the environmental movement has had. I mean, I'll just pick on An Inconvenient Truth, which I thought was absolutely brilliant, but I do think it had the tendency to put people on an express train from denial to despair.

There's definitely no need to despair here. We can absolutely harness SynBio infrastructure to make it really, really hard for any but the most brilliant and determined people to do something awful. That is doable. We can definitely invest in pan viral vaccines and therapeutics. The cost of investment is trivial compared to the likely returns for all of us, and in doing that, we would really make ourselves a hard target for future pandemics (whether they’re artificial or natural). So, on balance, I think there's just so much we can do that can be so helpful.

Progress on UVC light technology

Sam: Okay. So, let's talk about some of the topics you raise in this final chapter. Where are we with far-UVC light technology?

Rob: Far-UVC has had unbelievably promising signs in the lab, but so far those have been relatively small academic studies. We need to do more research. The next step is to do rigorous FDA quality tests that fully establish whether these wavelengths annihilate pathogens without damaging human health, which is obviously unbelievably vital if we're going to contemplate exposing people to these lights for long periods of time during flu season or in the case of a pandemic. The signs are really promising but, we do need to do more. 

If things work out, unlike almost any of the other measures I'm talking about, this one could be really expensive in order for us to go all in on it. But we'd only do so in an incremental manner, starting with that relatively cheap step of [testing far-UVC light’s potential]. And it could easily turn out to be a complete flop.

But, like I said in the recording, that's completely fine, because while we're testing this, hopefully we will also be testing things like the BCG vaccine and dozens of other things. There are some incredible superweapons against pandemics, almost inevitably, in the tech and scientific pipelines. We just need to turn over the rocks. 

Anyway, if far-UVC light is everything we hope, the next thing we'll need to do is figure out how to make LED lights that emit it, because the current bulbs are huge, clunky, and unbelievably expensive. They create way too much heat for use in public spaces and require way too much maintenance. 

Getting LEDs to emit far-UVC light will take significant R&D work. The whole history of LEDs is one of the industry turning its attention to new wavelengths of light and figuring out how to make them after some heroic R&D efforts. Figuring out how to make blue LED light was actually particularly difficult.

There's a really interesting story behind that, which we won't go into, but the LED industry is good at this. It’s basically about precisely tuning the alloys of the LEDs’ semiconductors. But far-UVC has already been demonstrated in a LED in the lab, I think in Japan. So, we know it's possible. It's a matter of bringing the science into technology. And once the technology is dialed in, we would need to build a fabrication plant to build the LED bulbs, which is probably a multi-billion dollar proposition. As I said, that would not be cheap, but it’s a step we would never take unless we had high confidence this was going to have a huge ROI for society. 

Once we're making the bulbs, the question becomes: How many bulbs, and who pays for them? If these things actually work, we'd clearly want them in public transit. I mean, just imagine how much safer a subway car would be if 99.99% of the pathogens in it are killed every few minutes, which is what the science out of MIT shows is possible.

We'd also probably want to put them in big public spaces. So, basically we'd have a lot of local governments buying bulbs, installing them, maintaining them, etc. As for where you go beyond that, it's probably several private decisions. Stores and restaurants might install them if customers call for them or want them, maybe more to keep safe from flu in flu season than pandemics in normal times. And maybe businesses will install them in offices (also with flu in mind, to cut down on sick days, which would pay for an awful lot of bulbs). 

So, the bottom line is this: If UVC becomes widespread, it'll cost a lot, but that cost will entail a lot of justified and incremental investments made by people who are thinking rationally. And the path to a wide deployment feels like it should be less than 10 years. It's not right around the corner. There's a lot of work to be done, and building a fabrication plant takes time, but if it makes sense to move forward, this is absolutely something in the intermediate future.

Why U.S. residents don’t have access to the BCG vaccine

Sam: Well, on the other end of the spectrum here, we have the BCG vaccine, which I only just heard about during COVID. Describe what this is and why we can't get access to it, even though it seems like an incredibly promising vaccine for a variety of reasons.

Rob: Well, what it is and why we can't get access to it here in the U.S. are kind of the same answer, which is that it's a frontline vaccine for infant tuberculosis. So, it's given shortly after birth to a high majority of the babies who are born on Earth in any given year. But, it has never been given in the United States. It was developed in the 1920s, and we definitely had a tuberculosis problem back then. So, I can't really say why we never had it. But I think by the time universal BCG programs started kicking in, it was much later than the 1920s. It was invented then, but I think it was more like in the 1950s, 1960s, and even 1970s before countries began implementing universal vaccine programs. And by the fifties, you had the first antibiotics, and antibiotics can be quite effective against adult as well as infant tuberculosis.

So, I think there just wasn't a huge TB problem in the U.S. by the time these vaccination programs really started coming online. And there is this unbelievably promising data going all the way back to the 1920s about BCG protecting against all kinds of things other than tuberculosis — above all, it provides broad-spectrum protection against respiratory infections. I think the most recent study was concluded just last year [2020] in Greece. In that study, they tracked older adults (I think it was people 55 and older) who were checking out of hospitals. I believe half of them got the BCG vaccine and half of them got a placebo. And the result was that those who received the vaccine had an 80% reduced incidence of any kind of respiratory infection and a 50% reduced incidence of infections of all kinds.

So, there's a lot of really intriguing data. And then, of course, there is the unbelievable data that appeared in the Proceedings of the National Academy of Science. It showed a huge inverse correlation between national BCG vaccination rates and COVID cases. 

Most of the state data — although not the Greek study — is what epidemiologists call “ecological data,” which means it is about groups of people rather than individual case studies. Also, it comes from observational studies rather than hands-on work with injections and patients. So, that inverse correlation amongst countries is classic ecological data. But obviously, to get a vaccine approved for a specific disease, you have to track cause and effect in individual subjects. In other words, you have to do a classic double-blind test with control groups, and a full phase-three trial for FDA approval is generally beyond the reach of academic budgets.

The people who have been poking at BCG are mostly academics, whereas pharma companies are just not going to spend their limited capital on testing a 7-cent vaccine that's in the public domain. There's no money in that. And I hope I'm not over-publicizing my podcast here, and if I am, just tell me, but I'll be posting a really detailed interview with a Harvard epidemiologist named Megan Murray. We discuss all of this. And Megan actually is hard at work on developing and trying to fund a phase-three trial, despite being an academic and this normally being an endeavor for pharmaceutical companies. We're counting on her to do this rather than Pfizer because it's a market failure. There are simply no deep-pocketed players who are incentivized to do this research. 

We really need to fix this, for two reasons. The most obvious one is that if BCG actually can protect against COVID, that would totally change the global vaccination timeline, because there are 22 BCG manufacturers throughout the world. And there are distribution channels for BCG into almost all of the developing world, with armies of people who know how to store and administer the vaccine. And it's obviously just morally urgent to speed up vaccinations in poor countries. 

It's also in the selfish interests of rich countries that are about to get all of the Pfizer and Moderna vaccines they need, because every person whom COVID infects is another opportunity for it to mutate. And COVID is incredibly prone to mutation, as we're seeing from these terrifying new strains. At least one of them, the South African strain, is partly resistant to vaccines. And so if we take our guard down after wealthy countries are vaccinated — if COVID keeps rampaging amongst billions of people — we can pretty much count on a new strain emerging, which may steamroll through all of our hardened defenses. Therefore, we need a great phase-three trial test of BCG against COVID, whether it's Megan's or someone else's.

And even if it's a long shot, I think it’s worth it. This test would cost tens of billions of dollars, not the billion-plus we spent on each candidate for Project Warp Speed, because there's no vaccine to be developed. It's just a test. And there are luckily some huge philanthropists, like Bill Gates, who have started investing in BCG with an eye toward COVID. But we shouldn't sit around and wait for somebody to gift this to the world. It should just be an immediate public investment. 

The other reason to study BCG much more deeply goes beyond COVID. It is that BCG seems to provide protection against respiratory diseases in general. If the pattern from the initial trial in Greece (which is very promising but just a first step) holds up, BCG could be a real game changer against the flu, as well as against future pandemics, which are almost sure to be respiratory in nature. It could solve all kinds of things.

But there's a lot to be studied. For example, how frequently does BCG need to be given to have this effect? Does it work in all age groups? Is it particularly effective against a certain class of respiratory infections? And again, we shouldn't be waiting for someone to gift this to the world, particularly because an initial set of academic studies would cost very, very little.

Sam: Yeah, we have to become increasingly sensitive to market failures in this domain (public health), and across all of the fronts in which we're seeing something like existential risk. I mean, we've been living with the problem of producing antibiotics in a market that can't effectively incentivize it.

Rob: Right.

Sam: So, we have antibiotics that are losing their power over every bug that concerns us. And we're meandering toward a time that will be indistinguishable from the 1920s and 1930s, when we simply didn't have the drugs that could solve our most basic infectious disease problems. And the reason is there's not enough money in it. A new antibiotic costs a billion dollars to produce, and you take it once for 10 days of your life. And then that's it — that is if you're unlucky, since most people wouldn’t have to take any specific new antibiotic, ever.

Rob: Right.

Sam: And yet if you need it, this is the one drug that's going to save your life. So, this is the role of government or major philanthropy. On some level, we just have to say, “Whether it makes any market sense in any rational time horizon for a business person or not, we have to spend money on these things.”

Rob: Yeah. And we've basically stood by as multiple antibiotic companies have gone out of business in the U.S., which has allowed this market failure to propagate to the point that I’m not sure who is even developing new antibiotics. I can only think of a few companies that are even in that business anymore. And we're talking more about viruses than bacteria, obviously, in this series, but, that is an equally glaring issue. In one estimate that I saw, within 10 years superbugs could easily be killing millions of people per year.

The prospects for developing vaccines for entire classes of viruses

Sam: Yeah. So, what are the prospects of developing vaccines for whole classes of viruses — a universal flu vaccine, a universal coronavirus vaccine? What have you uncovered on this front?

Rob: Well, this actually ties to what you were just saying about market failures, because in talking to some pretty informed people in this domain, it seems that a universal flu vaccine effort would probably have very good chances of succeeding at least 50%. That’s a shot worth taking. And the budget that I was quoted was probably in the range of $200 million over 10 years. For safety purposes, why not go up an order of magnitude to a budget of $2 billion over 10 years? Remember: The flu is costing the U.S. alone $361 billion a year in lost productivity and medical spending. And it's just flabbergasting. And I couldn't believe my ears when that budget estimate was quoted to me. And it couldn't have come from a more informed person: Harvey Fineberg. He's the former president of the National Academy Of Medicine and the former Dean of the Harvard School Of Public Health. More to the point, he has done a lot of work studying the potential for a universal flu vaccine, including at the Sabin Vaccine Institute

So, this is just another stunning market failure. Consider the worst-case scenario of spending $2 billion over 10 years if there’s only a 1% chance that it will work. Given that you could save $361 billion a year, you should do it. And according to Harvey, it's probably more like a 50% to 75% chance. And once again, to go back to what you were saying about antibiotics, this isn't happening because the pharmaceutical industry is not going to do it. It’s a lousy business proposition to make a cheap vaccine that people might only use just once.

I mean, one of the models for the universal flu vaccine is “one and done” in a lifetime; you'll hopefully never need a flue vaccine again. And even if it's annual or every five years, pharma companies just won't do this unless they're presented with non-market incentives. And obviously, this is also just a shocking failure of public policy, because the ROI on this would be profound. 

Now, the optimistic way of looking at this (which I prefer) is to say, “There's just so much low-hanging fruit here.” Harvey Fineberg believes that in addition to creating a universal vaccine effort for influenza, we could create one against any arbitrary number of viral families. And as I think I mentioned in the recording, he would suggest we start with influenza and coronavirus. We could get good at that and then start tackling more.

And there's only a few dozen viral families that actually infect humans. And there are probably also a few other zoonotic diseases out there from viral families that don't currently infect us, but that we want to be careful of. But even if you multiply this by every viral family you can think of, the cost of $2 billion over 10 years is just minuscule compared to what we spend maintaining our nuclear arsenal on an annual basis. It’s just minuscule compared to anything that seems comparable. This is especially true when we think of how quickly these COVID vaccines were created — in just days in the case of Moderna. So, we're obviously in a completely new age when it comes to vaccine science, which screams for ambitious new goals for vaccine science.

Sam: Yeah. And we've not only accelerated the time it takes to produce the vaccine itself, but we've accelerated the approval process. And it sounds like we could accelerate it even further if we changed our cost-benefit analysis of how we do research. Obviously, we're doing research now under duress with a global pandemic crushing economies and killing hundreds of thousands of people just in the United States. 

The ethics of challenge trials

Sam: But what role would challenge trials play here? This is something that many people first heard about in recent months under COVID, but they're controversial. What do you think about this?

Rob: Well, it's ultimately an ethical question. We can safely say that there's no “right answer” to this conundrum. But I do think that it helps a great deal to put concrete numbers on the assets and liabilities in terms of human lives. 

A quick review: A challenge trial would involve deliberately infecting a much smaller number of people than you would have in a normal trial with COVID. The numbers are really, really stark. For a normal COVID trial, you're talking about tens of thousands of volunteers. They get that huge number of people because they need to wait until there's maybe about 200 people who have come down with COVID from that vast base of 30,000-50,000 people. And once about 200 people have definitively tested for COVID, they can basically take off the blinders and figure out which of those people were in the control arm of the trial, and which of those people actually got the vaccine. Based on that, you can come up with exciting numbers like a vaccine that is 95% effective. 

Now, if you're just doing a challenge trial, instead of 50,000 people, you might just need 200 people, or maybe a little bit more in case some data points bounce out for some reason. That really collapses the timeframe relative to a normal trial. I mean, I don't know exactly how long a challenge trial would take, but recruiting 200 people would be harder on a per-person basis because you're asking them to submit to a hell of a lot more than just an experimental vaccine. You're asking them to contract COVID. But as I said in the recording, 20,000 people, I think it is, have already expressed a willingness to participate in challenge trials through a group called 1Day Sooner. So, there's already a body of recruits, and presumably it would not be anywhere near the challenge that it is with 50,000 volunteers. 

Then, in terms of the timeframe, you're infecting them on day one. You're not waiting months and months and months for people to contract the virus. It seems logical that this timeframe could collapse into a very, very low number of months. By comparison, I cobbled together a detailed timeline for the AstraZeneca vaccine. Its last phase of trials started in the U.K. on May 28th. They eventually recruited a smaller trial of 23,000 volunteers, mostly in the U.K., but also in Brazil. There was some weirdness with this trial that people might remember. There was a pause because of an adverse reaction in one of the volunteers, but that was only a six-day pause.

So, it generally proceeded along its timeline, and the results of this trial were reported out on November 23rd. In other words, it ran for just under six months. Most of that time was spent recruiting all of those volunteers and then waiting for enough of them to test positive for the trial to have a statistically significant result. 

During that six-month period — from May to November — over a million people died of COVID worldwide. That happened while what turned out to be an impressively effective vaccine was slowly and methodically tested. And we can probably assume that other vaccine trials had similar timelines. I just happen to know the dates with AstraZeneca. 

A challenge trial obviously wouldn't have been instantaneous, but it would shave months off that timeline — not weeks — during a time when thousands of people are dying every day. It would have involved deliberately infecting a few hundred people with COVID, and most of them would have presumably been younger volunteers. So, fatality rates probably would have been extremely low. It's all too likely that one or more of those people would have died. And it's also likely that very few of those 200 people would have caught COVID on their own. 

So, how do you balance the ethics of that? The numbers are enormous; hundreds of thousands, or a million people are dying during the running of this trial, versus perhaps a tiny handful, or even one or no, people are dying in a challenge trial. But it's very much like the trolley problem, isn't it?

Sam: Yeah, except there is the variable of consent, which I think is ethically decisive.

Rob: Good point.

Sam: There's no argument against someone deciding to consent to a challenge trial once they understand the risks they're running and the possible benefits. And as you say, it's surprising, but it is just a demonstrated fact that you can find people eager to serve on this front. You can find people eager to take all kinds of risks that any individual listening to this might never entertain themselves. Once there's a one-way ticket to Mars offered, you can be sure there are going to be thousands of volunteers willing to die on Mars. There's a spirit of wanting to advance the human project and be part of something great. 

And in this case, again, the relevant variables around just how widespread the illness is at each point when trials are being run affects how long you have to wait for people to catch the virus naturally.

Rob: Yeah. It totally affects it.

Sam: Also, it affects the perceived odds for anyone enrolling in a trial. How different is a challenge trial if a virus is burning so quickly through the population that you seem guaranteed to get it anyway? 

But I do think consent is the master variable here, ethically, and we certainly should be talking about running challenge trials under circumstances like this, where we're having to respond to a pandemic that is burning out of control. It would be different if we're preemptively trying to design a universal flu vaccine or a universal coronavirus vaccine under conditions where we don't feel like we're currently losing thousands of people a day to a pandemic. But it is very interesting. And it's amazing that so many people volunteered. It's great.

Rob: Yeah. I guess it's kind of like the people who volunteered for the U.S. military after 9/11.

Sam: Yeah.

Rob: There was a big surge of signups. People were certainly signing up to risk their lives, and the government didn't tell them, “No, we're not going to accept your service.” And I don't think there was any serious conversation about a challenge trial at all during this COVID period, was there? I don't think there was.

Sam: I remember it being spoken about, and obviously, people volunteered. But I think most of the conversation I heard about it was going on in the U.K. and not in the U.S.

Rob: I think you're right. There’s another thing to think about when it comes to regulators saying, “No, you can't do that type of thing.” It's interesting that certainly in the case of the Russian vaccine, and I believe the Chinese vaccine as well, some independent research has come out signifying that these are reasonably effective vaccines. In both cases, the countries started administering the vaccines without waiting for phase-three data, which at the time was generally viewed or discussed as being a particularly bad idea (at least, I'd say, in the Western media). 

As we find out that these vaccines actually work, maybe that's another policy that policymakers should consider, along with challenge trials, as future problems come up. While it's always easy to look back at something with the benefit of hindsight, imagine if the FDA had said, “Okay, Moderna has come up with this vaccine, and it’s going to go through rigorous trials. It hasn't yet, but we're facing an emergency. So, any U.S. citizen who is courageous enough to take the chance, and is willing to sign a thick legal document saying that they're not going to sue or anything, is welcome to take this vaccine. And it's an experimental vaccine, so there could be bad effects.” Those were probably unlikely, because I think they'd already done a safety trial before phase three but people would have been told that the vaccine may not work against COVID at all. 

We can imagine that perhaps millions of people would have certainly entertained that idea if there'd already been a safety trial on this thing. I mean, why not? And if millions or tens of millions of people had been vaccinated with Moderna, Pfizer, and Johnson and Johnson, and who knows what else during the six months of trial times, we might already be seeing the end of this thing.

Sam: Yeah. The safety stage is the most important part from my point of view. I mean, whether it's effective or not is obviously important, but it's the “first, do no harm” principle which I think everyone is rightly focused on, especially with a vaccine. As has been pointed out many times before, this is a medication you're giving to healthy people, by and large. This is not an intervention, a new form of chemotherapy when all other forms have failed you. What do you have to lose? In this case you have a lot to lose if the vaccine is basically unsafe. 

I guess the novelty of the current batch is relevant. The amount of work we do in this area, and the extent to which any new vaccine has already been pre-characterized by past vaccines that work by a similar mechanism, perhaps determine whether the safety concerns get dialed down more quickly.

Rob: Yeah. You're right with the mRNA vaccines. This was a completely new type of vaccine, and safety testing was especially important. But now that we have seen that these apparently are very safe vaccines, I do hope the policymakers take a different approach. For instance, I believe Moderna and Pfizer are already working on booster shots to take care of the South African and British variations. If we do need to go through a six-month trial process for those to get a perfect phase three, I would certainly hope that there would be an option given to adventurous people, which would certainly include myself, who are willing to take the chance that this is an efficacious way to get the vaccine before the phase-three trial is done, because we are in an emergency situation here.

Closing thoughts

Sam: Well, as should be obvious to everyone who has followed us this far, this is the beginning of the conversation, not the end. But, I know you and I, both together and independently, will keep our attention on this front. And we will certainly surface any good ideas we come across — any organizations that are moving the dial here (whether they’re in the philanthropic or for-profit space) — or rumors of government actions that seem auspicious. 

This really just needs to be kept front-of-mind: the pandemic response generally, and the SynBio privatization of the apocalypse problem, more narrowly. This is really something that our generation has been tasked to figure out. And I just want to thank you, Rob, for producing such a comprehensive and comprehensible document for us to all get started with.

Rob: Well, it was absolutely a thrill to be able to present it on your show, Sam. Thank you so much for that.





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Thanks for doing this, and I had a similar experience of being deeply affected by this story.

I'm by no means a biosecurity expert (I do have a bio background and forecasting experience related to COVID). Overall, I was also impressed and I have no especially strong criticisms of the content here except to say that his bullishness on UVC light and the BCG vaccine as important parts of "hardening society against future pandemics" seems unwarranted. 

UVC light: even if you could somehow get the technology to work and  get regulatory approval, this would almost only work against fomite transmission — and fomite transmission only constitutes a very small percentage of transmission events for SARS-CoV-2, which is also likely the case with other respiratory viruses we have reason to worry about

BCG vaccine: there was a lot of talk in early 2020 that it might confer some protection against SARS-CoV-2 by providing general non-specific protection against respiratory disease, and this was largely based on the observation that countries that mandate the BCG vaccine as part of their childhood immunization programs seemed to be far less hard-hit. But given epidemiological trajectories since then, e.g. India experiencing a huge COVID wave in spring 2021, this observation no longer seems to hold (or, at the very least, the correlation is far weaker). The jury is still out on whether the BCG vaccine provides at least some limited protection against COVID, but the evidence in favor of it almost certainly isn't strong enough to advise spending billions on vaccinating everyone with it as opposed to, say, investing more in universal flu vaccine programs and building additional vaccine manufacturing capabilities 

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