The J Curve

Tuesday, August 03, 2004

Genetically Modified Pathogen (GMP) Policy

In repose to my first post requesting topics of interest, “anonymous” noted that this blog is the top result on a Google search for “IL-4 Smallpox”... a dubious and disturbing honor for what I was hoping to be a content-free blog.

Anon also asked “what do you think of DHS efforts for a realtime bio-sensor network?”

It is possible that with the mobilization of massive logistical resources around the planet, we will prevail over genetically modified and engineered pathogens (GMPs). But I would not bet on it. It would be great to have a sensor network, but with most Health and Human Services offices lacking a basic Internet connection, we have a way to go.

From what I can tell, a crash-program in antiviral development may provide a ray of hope (e.g., HDP-cidofovir and some more evolutionarily robust and broad-spectrum host-based strategies).

Most importantly, from my random walk through government labs, talks with policy planners, CDC folk and DOD Red Team members, I haven’t seen any policy bifurcation for GMPs (for detection and response). I think there should be distinct policy consideration given to GMPs vs. natural pathogens.

The threat from GMPs is much greater, and the strategic response would need special planning. For example, the vaccinations that eradicated smallpox last time around may not be effective for IL-4 modified smallpox, and in-situ quarantine may be needed. “Telecommuting” for many forms of work will need to be pre-enabled, especially remote operation of the public utilities and MAE-East &West and other critical NAP nodes of the Internet.

The delicate "virus-host balance" observed in nature (whereby viruses tend not to be overly lethal to their hosts) is a byproduct of biological co-evolution on a geographically segregated planet. And now, both of those limitations have changed. Organisms can be re-engineered in ways that biological evolution would not have explored, nor allowed to spread widely, and modern transportation undermines natural quarantine formation.

In evolution, pathogens do not become overly lethal to their host, for that limits their own propagation to a geographically-bound quarantine zone. Evolution may have created 100% lethal pathogens in the past, but those pathogens are now extinct because they killed all of their locally available hosts.

A custom-engineered or modified pathogen may not observe that delicate virus-host balance, nor the slow pace of evolutionary time scales, and could engender extinction level events with a rapidity never before seen on Earth. Given early truncation of the lethality branch (truncating a local maximum), evolution has not experimented with a multivariate global maximum of lethality. The pattern of evolution is small and slow incremental changes where each intermediate genetic state needs to survive for the next improvement to accumulate. Engineered and modified pathogens do not need to follow that pattern.


  • Hi Steve,

    Thanks! Your blog looks great. I did some polishing of now that you've announced it more widely. Still needs work but getting better.

    The GMP regulation issue is actually something I discussed with the Army War College earlier this month. The Australian IL-4 smallpox event was truly chilling.

    I don't know yet to what extent it would have played out the same way in a real world dispersement situation. I don't know if those experiements have been done. My intuition is we would have seen a lot less population virulence, self-quarantining among the rabbits (sick rabbits don't spread pathogen except in enclosed artificial spaces), etc.

    In other words, I suspect that human engineering of GMPs for increased real world virulence in complex species is going to be a lot less disruptive than we think. But on the face, this study suggests otherwise. I'd love to know if DHS plans to study this GMP contained but more real-world similar dispersion environments. I would hope that experiment is under way, and even if it turns out to support my intuition above I'd expect the results to remain classified.

    Bottom line, I think lot more (and more selective) biotech security would be helpful. In my opinion biotech, while it will provide benefits that restore us to the mean, is not central to our planetary acceleration the way infotech is. They are two very different research and development agendas and should be regulated as such.

    Perhaps ISAC can get some funding to study this in the next few years. Few really understand the issues at present.


    John Smart
    President, Institute for the Study of Accelerating Change
    johnsmart(at) |
    2227 Amirante, San Pedro, CA 90732

    By Blogger John Smart, at 5:16 PM  

  • JS,
    I hope you are right. It is the same sentiment I heard from the government labs people. But I wonder what assumptions go into their model for the rate of spread and the human dynamic among care givers and quarantine enforcers. Using Ro from past pandemics might not be accurate.

    Self-quarantine would certainly occur, and economic collapse is probably a given. People would not go to work. I guess that’s the best scenario.

    Let's assume IL-4 mousepox and smallpox have similar effects on their hosts (this is an unknown). The IL-4 splice into mousepox made the virus 100% lethal to its host, and 60% lethal to mice who had been vaccinated (more than 2 weeks prior). Even with a vaccine, the IL-4 mousepox is twice as lethal as natural smallpox (which killed ~30% of unvaccinated people).

    The last wave of “natural” human smallpox killed over one billion people. Even if we vaccinated everyone, the next wave could be twice as lethal. And, of course, we won’t have time to vaccinate everyone nor can we contain outbreaks with vaccinations.

    Imagine the human dynamic and policy implications if we have a purposeful IL-4 outbreak before we are better prepared…. Since vaccinations are ineffective, there are several serious implications:
    1) Health care workers cannot come near these people.
    2) Ring vaccinations and mass vaccinations would not work; it breaks through.
    3) Victims could not be relocated (with current people and infrastructure) without spreading the virus to the people involved.
    4) Quarantine would be essential, but it would be in-situ. Wherever there is an outbreak, there would need to be a hairtrigger quarantine.
    5) Unlike prior quarantines, where people could hope for the best, and most would survive, this is very different: everyone in the quarantine area dies.
    6) Where do you draw the boundary? Neighborhood? The entire city? With 100% lethality, the risk-reward ratio on conservatism shifts.
    7) How do you enforce the quarantine? Everyone who thinks they are not yet infected will try to escape with all of the fear and cunning of someone facing certain death if they stay. It would require an armed military response with immediate deployment capabilities.
    8) The ratio of those available to enforce quarantine to those contained makes this seem completely infeasible. With unplanned quarantine locations, there is no physical infrastructure to assist in the containment.
    9) Once word about a lost city spreads, how long would it take for ad-hoc or planned “accelerated quarantine” to emerge? Once word of the quarantine policy spreads, doctors would have a strong perverse incentive to not report cases until they made it out of town…

    I hope there is some error in this logical flow.

    With some planning, we could think about containment suits (expensive) and accelerating trials of antivirals like HDP cidofovir.

    Unfortunately, this is just one example, and not a particularly difficult genetic modification. According to Preston in The Demon in the Freezer, a single person in a typical university biolab can splice the IL-4 gene from the host into the corresponding pox virus. The techniques and effects are public information. The gene is available mail order.

    By Blogger Steve Jurvetson, at 9:16 PM  

  • LOWER BARRIERS TO ENTRY: Every year technology trends are lowering the “barriers to entry” to the world of mass destruction.

    It used to take a coordinated effort of many people to kill a million people. And a billion people, well, leave that to smallpox.

    Compare nuclear weapons to bio weapons. Information access, raw material access and popular experience with the techniques differ widely. Biotech knowledge is tightly coupled to economic progress. Commercial interests ensure the availability of materials, know how and trained people.

    We are entering an era where a single person can design, build and release a weapon of mass destruction. And it does not require a "rocket scientist" any more or an expensive lab.

    Dealing with the motivation to attack may be more effective than containing all possible attackers, especially since the trend toward interdependence and globalization means that the would-be attackers are among us. And our social constructs in the West don't seem well suited to implement a societal immune system.

    And then there are the crazy people. This might be a separate category of problem for which reasonable motivational approaches may fail.

    Writing in the Seattle Times, William Calvin, a Neurobiologist at the University of Washington, wrote: "There is a class of people with ‘delusional disorders’ who can remain employed and pretty functional for decades. Even if they are only one percent of the population, that’s 20,000 mostly untreated delusional people in the Puget Sound area. Even if only one percent of these has the intelligence or education to intentionally create sustained or widespread harm, it’s still a pool of 200 high-performing sociopathic or delusional techies just in the Puget sound area alone."

    By Blogger Steve Jurvetson, at 9:50 AM  

  • A BIGGER THREAT THAN NUCLEAR WAR:For a Republican point of view, I have been discussing these topics with Newt Gingrich. The opening line of his forthcoming book: ”Biological warfare is the largest threat to the human race, a substantially bigger threat than nuclear war.” The reasons pivot on relative ease of access, difficulty in monitoring (vs. radioactive materials), and distributed effects from deployment.

    Recent bioweapons, such as anthrax, were trivial to manufacture and distribute, but they were the “BB guns” of bioweapons (treatable with antibiotics and non-contagious). Contagious pathogens engender an entirely unique set of social phenomena. A planned release of a contagious pathogen would trigger a massive wave of social isolation and economic collapse. Simply, people would not go to work.

    And yes, “weaponizing” pathogens for survival in a container (in a rocket for example) and efficiently releasing it at the right altitude with just the right droplet size is difficult. But that’s overkill, so to speak, and reflects a cold war era mentality.

    Since the terrorists can be among us, they have much easier options. They can let nature run its course by self-infecting and then riding the subways and circulating in airports for days. If they figure out the perfume bottles, they can work on aerosol release on the last day of a pediatrics conference (before everyone flies home). The have many simple options that don’t need a lab.

    Here is some more detail from Richard Preston on the relative ease of working with bioweapons, in this case IL-4 smallpox: “It was a formula for a superweapon… It's so simple that a grad student could do it… The standard cookbook for engineering a virus is a four-volume series of bright red ring binders entitled Current Protocols in Molecular Biology… it's sold on Amazon... Designing a hotter strain of smallpox is as simple as following a recipe-style protocol outlined in binder four, section 16.15. So long as you have a stock of smallpox, the genes that you'd want to insert can be ordered through the mail. If people are evil enough to use smallpox as a weapon, Mr. Jahrling reasons, surely they would be willing to tweak it to make it more deadly.”

    Of course, smallpox is just one example, and access to the pathogen is difficult today: “Many experts believe, however, that the smallpox virus is not confined to these 2 official repositories and may be in the possession of states or subnational groups pursuing active biological weapons programs. Of particular importance and concern is the legacy of the former Soviet Union's biological weapons program. It is widely known that the former Soviet Union maintained a stockpile of 20 tons of smallpox virus in its biological weapons arsenal throughout the 1970s, and that, by 1990, they had a plant capable of producing 80 - 100 tons of smallpox per year.” Many of those scientists have since scattered around the globe.

    The quote comes from the Dark Winter simulation, which predicted millions of infections and the collapse of the U.S. economy within two months, all from 30g of smallpox released in three cities.

    Bill Joy summarizes that “The risk of our extinction as we pass through this time of danger has been estimated to be anywhere from 30% to 50%.”

    If we can properly model the costs of inaction, we may be able to justify a bit more preparation. If the former USSR devoted more scientists to their bioweapons program than their nuclear weapons program (Preston), and if they produced 20 tons of weaponized smallpox, then we may want to rethink the relative priorities of our defensive spending. Especially in this historical window of maximal vulnerability – where we have only a partial understanding of the genetic bases of disease; where it is easier to destroy than to heal, and entropy may run wild though the information systems of our biology.

    By Blogger Steve Jurvetson, at 11:00 AM  

  • The discussion here focused essentially on "official" development of highly potent bioweapons.

    Governmental projects for GMPs production aimed to be used as weapons do have a major advantage. Co-evolution of defensive systems is included in the program, to help prevent dissemination within "friendly" populations, including ones own army and population. A "good" bioweapon is one for which the second level of dissemination may be strictly controlled, hoping that natural evolutionary events will not lead to the emergence of new, not expected and thus uncontrollable variants.
    The latest is particularly truth for viral GMP, able to evolve rapidly. The IHV paradigm of fast evolution should be kept in mind from everyone developing viral weapons.

    Steve mention the "single person" initiative. I believe this is the major danger to take care about. There are at least two points to consider:
    a) The home-made, unpublished techniques, may prove particularly ingenious and difficult to manage as most of the scientific staff will not be informed/trained to address them.
    b) It is very difficult to include the co-development of protective measures. That would imply the availability of coworkers, and thus some organizational schema, incompatible with a personal initiative.

    I don't intend to scare you, but the scenario is one of the possible ones. I have work on it, the five last years, observing the opportunities offered in a French provincial university. More then 70% of the molecular biology labs could be used for it! In three of them, it would be easy to do this kind of jobs without any possibility that someone ever be aware, as no controls exist. I suppose that the same apply to a large number of other universities around the country. Now, that's truth for viral GMP's.

    Considering bacterial GMPs, which are somehow easier to handle and produce (at least for a bacteriologist), there are more then 20 labs where the above described situation would be truth. With a slight variant; protective measures could be planned as an antibiotics cocktail, to preserve self, family and friends.

    Why this doesn't happened yet?
    The only rational explanation I see, up to now, is that there is no real profit.
    It would be a desperate action, and such aren't usually planned over the next few weeks needed to create and produce the "freak".
    If you are angry, you go out and shout or find some friends and have a beer, or something stronger, and then you calm down.
    Or even if you plan the destruction of the world you sleep on it, then the next morning you think about it a second time and see that there is no good. And drop the idea, or keep it just to write a science fiction/thriller book about.

    By Blogger OldCola, at 1:35 AM  

  • I would like to propose a reality check here.

    Future-thinkers like Bill Joy and Martin Rees who suggest that human beings have the capacity of extincting ourselves with GMP technologies, or even causing tens of millions of human casualties, are not, in my opinion, looking carefully enough at the immune systems (biological, cultural, and technological) that are today deeply protecting us from that possibility.

    The reason the genetically engineered IL-4 mousepox event would be far less lethal in the wild vs. artificial enclosed spaces with small populations has to do with how rapidly viruses mutate, and how the less lethal and commensal variants always get preferential transmission and also immunize against the more lethal variants. (See Paul Ewald, _Evolution of Infectious Disease_, for more on this poorly understood story).

    Rapid mutation is a major way all genetically simple pathogens (and all viruses and bacteria are incredibly simple by comparison to us) avoid complex immune systems, so this defense also limits their total lethality in a fundamental way that I think we don't yet fully appreciate.

    You need to cite lots of cases to see the self-limiting nature of these infections, and deal with lentivirus (subclinical infections with later expression) and other objections to make the case well.

    Suffice it to say that there has never been any plague that has extincted any species, in any environment, in known history. If anyone can supply me (johnsmart(at)accelerating(dot)org) with purported evidence to the contrary, please do so.

    Historically, plagues have emerged through Differential Immunity, by jumping from one highly immunized group of humans to another poorly immunized group of humans through new contact, as occurred in the Black Plague (from China), the colonization of the New World, and (in the last major example), the post WWI Spanish Flu Pandemic. But Differential Immunity (both human to human and human to other animals) is rapidly disappearing in our global, instantly communicating culture, eliminating the last great source of devastating plagues.

    Matt Ridley has also noted that these threats aren't synergistic, either, as far as we have seen from the data. That means we can't splice something together that might kill, in a worst case open dispersement scenario, 3% of the human population with something that might kill 2% of the population and get something that could kill 10% of the populace. Each pathogen uses a very simple attack strategy, by comparison to our complex immunity, and each simple strategy rapidly loses lethality in the open population.

    It is a poorly reported fact, for example, that there is a large and growing fraction of the population of Africa that is HIV+ but will never get AIDS (this was reported first in prostitutes in the early 1990's, if I recall corrrectly). Immune systems and the intelligence they protect always win in the network as a whole, even as individual catastrophes educate and accelerate the development of the network.

    As a disclaimer, I need to restate that this is still poorly understood material. We need much better study and data. It is certainly true that a GMP attack that killed a thousand people in any country, or tens of thousands, would be a terrible catastrophe, and I think we need better global controls of this information to minimize that possibility. But we should keep the debate centered on the realistic problems, and the many small things we can do on a daily basis that might save thousands (not millions) of human lives tomorrow.

    Let's start by improving our understanding and use of the biological, cultural, and technological planetary immune systems that protect our accelerating intelligence better each day.


    John Smart
    President, Institute for the Study of Accelerating Change

    By Blogger John Smart, at 10:13 AM  

  • John: Thanks for a great contribution. And I agree with the conclusion that systemic safety nets and a societal immune system may be essential.

    But I’m not sure about the argument that rapid mutation will mitigate the problem. If true, your argument would pull the concern away from a lifeboat strategy, but I don’t see the logic leading to the other extreme - that only thousands of people might be at risk. The propagation of mutant strands wouldn’t play out that fast. My intuition here is guided by the disturbing detail that natural smallpox killed a billion people last time around.

    And each species that crosses a population concentration threshold has its own pox virus (insect, mouse, cow, human, etc.), so I’m not sure how your differential immunity argument would apply to re-released smallpox as it is specialized for humans.

    I have received some interesting emails in response to your comment by people who did not want to publicly post on the blog.

    One person wrote: “Manipulating diversity generators (pathogens against immunity systems) is a relatively easy problem to solve if you wish to imbalance natural systems.” BUT “I wouldn't like to publish on the Net a winning strategy for use of bio-weapons, not just GMPs.”

    I would second that. The point is not to push the ball forward on these topics; this discussion is an aggregation of widely available public information. I just hope that those with a role to play in homeland security become aware of the magnitude of the threat. This tread started with a concern over complacency in the ranks of those who should care.

    One of the people mentioned above, sent this PDF update to Ewald’s analysis: “Previous results have suggested that in a homogeneous host population in the absence of super- or coinfection, within-host dynamics lead to selection of the parasite with an intermediate growth rate that is just being controlled by the immune system before it kills the host (Antia et al. 1994). In this paper, we examine how this result changes when heterogeneity is introduced to the host population... We find that the general conclusion of the previous model holds: parasites evolve some intermediate growth rate. However, in contrast with the generally accepted view, we find that virulence (measured by the case mortality or the rate of parasite-induced host mortality) increases with heterogeneity.”

    In short, mortality goes up with heterogeneity, and prior models assumed tradeoffs without testing those assumptions.

    By Blogger Steve Jurvetson, at 5:34 PM  

  • Hi Steve,

    You make important and sobering points. But I still think the biggest discovery we will make as we investigate these subjects better in coming years is a deeper appreciation why it is that immune systems statistically protect the average distributed complexity of all species so well. This in turn should lead to new opportunities to improve our species collective immunity.

    For my part, I read the increased virulence under increased heterogeneity cited in the article referenced above ("Within-Host Population Dynamics and the Evolution of Microparasites in a Heterogenous Host Population," Ganusov et. al, Evolution 56(2), 2002) as an empirical observation of the concept of differential immunity.

    As heterogeneity increases in the host population, due to arms races with the immune sytem, this would naturally select for increasing infectivity and lethality of the pathogen. But increased virulence will also be accompanied by reduced transmission of the more lethal variants (due to commensal outcompetition by the less lethal ones, and the immune systems education that occurs when you host nonlethal variants of the same bug). It may be primarily this dynamic (in my nonspecialist's opinion) that keeps sudden epidemics from breaking out in the original host (though a typical non-epidemic infection might kill almost the same number of humans in total, as it transitions from primarily an individual (humoral) to a species (genetic) immunity, the infection rate will remain low at any point in time, for the reasons proposed).

    Sudden and devastating epidemics seem to occur only in situations of differential immunity (e.g., using the power of one metazoan immune system against another). This occurs when a group or subgroup in any species or group of species that has slowly developed high immunity suddenly contacts virgins who haven't been involved in the same extended arms race.

    The plague of Justinian, the Bubonic Plague (from China) the decimation of the New World Indians by the Europeans, the Spanish Flu, all of these were due to differential immunity arms races followed by novel contact, as far as I can tell. I think that AIDS is very likely to also be in this category (I haven't reviewed the epi data but I would predict that we will discover it is, as so many Africans are now immune to AIDS).

    All of these plagues are sharply self limiting, as no one group of humans ever gets that far removed from another in space, time, or biological experience. And now that we are all one global intercommunicating immune system, differential immunity has much less ability to create plague than in prior decades. Statistically all these threats keep dropping over time, as global biological, cultural, and technological computation continue to accelerate. I expect one of our future information theorists will discover a law that predicts this decreasing probablity of lethal plague as computation of any sort (biological, cultural, technological) enters a niche.

    I think the history of "Plagues and Peoples" (see William McNiell's 1976 book by this title, for example) bears out the "unreasonably fortuitous" record of plague interaction with human beings, and I expect we will soon discover that not simply public health, but the complex dynamics of our increasingly globally networked immune systems have contributed to the decreasing lethality of plagues as a percentage of population infected over time.

    If I can do anything to help you to get appropriate attention and funding to these issues, please let me know how I can contribute.


    John Smart
    President, Institute for the Study of Accelerating Change |
    2227 Amirante, San Pedro, CA 90732

    By Blogger John Smart, at 1:22 PM  

  • hi thommmus

    lewellen said this would be an interesting sight to post my comments about nature on quack!!!!! i figures that once a stone is formed it shall be risen for all eternity to blossom into octopus welly's 8 times! fabulous! i once did a study on the white cliffs of dover and found it is actually made of cocaine and crisp packets. elephant sperm was once found in a baby sheep it gave birth to an ellysheep. 100 blue whales once sunk a ship the size of 4 titanics while swimming backwards in a whale race to the shore, maybe they should have swam forward instead because only 14 whales actually finished the race to the shore but they became beached whales anyway so all 100 whales died....shame! this is a cracking website and i shall be visiting it more regularly i look forward to reading your responses. all the best guys and galls

    By Anonymous james greenhalgh, at 12:03 PM  

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