Broad-spectrum biotechnologies and their implications for synthetic biosecurity

We live in a rather pleasant time in history where biotechnology is blossoming, and people in general don’t appear to be using it for weapons. If the rest of human existence can carry on like this, that would be great. In case it doesn’t, we’re going to need back-up strategies.

Here, I investigate some up and coming biological innovations with a lot of potential to help us out here. I kept a guiding question in mind: will biosecurity ever be a solved problem?

If today’s meat humans are ever replaced entirely with uploads or cyborg bodies, biosecurity will be solved then. Up until then, it’s unclear. Parasites have existed since the dawn of life – we’re not aware of any organism that doesn’t have them. When considering engineered diseases and engineered defenses, we’ve left the billions-of-years-old arms race for a newer and faster paced one, and we don’t know where an equilibrium will fall yet. Still, since the arrival of germ theory, our species has found a couple broad-spectrum medicines that have significantly reduced threat from disease: antibiotics and vaccines.

What technologies are emerging now that might fill the same role in the future?

Phage therapy

What it is: Viruses that attack and kill bacteria.

What it works against: Bacteria.

How it works: Bacteriophage are bacteria-specific viruses that have been around since, as far as we can tell, the dawn of life. They occur frequently in nature in enormous variety – it’s estimated that for every bacteria on the planet, there are 10 phages. If you get a concentrated stock of bacteriophage specific to a given bacteria, they will precisely target and eliminate that strain, leaving any other bacteria intact. They’re used therapeutically in humans in several countries, and are extremely safe.

Biosecurity applications: It’s hard to imagine even a cleverly engineered bacteria that’s immune to all phage. Maybe if you engineered a bacteria with novel surface proteins, it wouldn’t have phage for a short window at first, but wait a while, and I’m sure they’ll come. No bacteria in nature, as far as we’re aware, is free of phage. Phage have been doing this for a very, very long time. Phage therapy is not approved for wide use in the US, but has been established as being safe and quite effective. A small dose of phage can have powerful impacts on infection.

Current constraints: Lack of research. Very little current precedent for using phage in the US, although this may change as researchers hunt for alternatives to increasingly obsolete antibiotics.

Choosing the correct phage for therapeutics is something of an art form, and phage therapy tends to work better against some kind of infection than others. Also, bacteria will evolve resistance to specific phages over time – but once that happens, you can just find new phages.

DRACO

What it is: Double RNA Activated Capsase Oligomerizer. An RNA-based drug technology recently invented at MIT.

What it works against: Viruses. (Specifically, double-stranded RNA, single-stranded RNA, and double-stranded DNA (dsRNA, ssRNA, and dsDNA), which is most human viruses.)

How it works: DsDNA, dsRNA, and ssRNA virus-infected cells each produce long sequences of double-stranded RNA at some point while the virus replicates. Human cells make dsRNA occasionally, but it’s quickly cleaved into little handy little chunks by the enzyme Dicer. These short dsRNAs then go about, influencing translation of DNA to RNA in the cell. (Dicer also cuts up incoming long dsRNA from viruses.)

DRACO is a fusion of several proteins that, in concert, goes a step further than Dicer. It has two crucial components:

  • P that recognizes/binds viral sequences on dsRNA
  • P that triggers apoptosis when fused

Biosecurity applications: The viral sequences it recognizes are pretty broad, and presumably, it wouldn’t be hard to generate addition recognition sequences for arbitrary sequences found in any target virus.

Current constraints: Delivering engineered proteins intracellularly is a very new technology. We don’t know how well it works in practice.

DRACO, specifically, is extremely new. It hasn’t actually been tested in humans yet, and may encounter major problems in being scaled up. It may be relatively trivial for viruses to evolve a means of evading DRACO. I’m not sure that it would be trivial for a virus to not use long stretches of dsRNA. It could, however, evolve not to use targeted sequences (less concerning, since new targeting sequences could be used), inactivate some part of the protein (more concerning), or modify its RNA in some way to evade the protein. Even if resistance is unlikely to evolve on its own, it’s possible to engineer resistant viruses.

On a meta level, DRACO’s inventor made headlines when his NIH research grant ran out, and he used a kickstarter to fund his research. Lack of funding could end this research in the cradle. On a more meta level, if other institutions aren’t leaping to fund DRACO research, experts in the field may not see much potential in it.

Programmable RNA vaccines

What it is: RNA-based vaccines that are theoretically creatable from just having the genetic code of a pathogen.

What it works against: Just about anything with protein on its outside (virus, bacteria, parasite, potentially tumors.)

How it works: An RNA sequence is made that codes for some viral, bacterial, or other protein. Once the RNA is inside a cell, the cell translates it and expresses the protein. Since it’s not a standard host protein, the immune system recognizes and attacks it, effectively creating a vaccine for that molecule.

The idea for this technology has been around for 30-odd years, but the MIT team that discovered this were the first to package the RNA in a branched, virus-shaped structure called a dendrimer (which can actually enter and function in the cell.)

Biosecurity applications: Sequencing a pathogen’s genome should be quite cheap and quick once you get a sample of it. An associate professor claims that vaccines could be produced “in only seven days.”

Current constraints: Very new technology. May not actually work in practice like it claims to. Might be expensive to produce a lot of it at once, like you would need for a major outbreak.

Chemical antivirals

What it is: Compounds that are especially effective at destroying viruses at some point in their replication process, and can be taken like other drugs.

What it works against: Viruses

How it works: Conventional antivirals are generally tested and targeted against specific viruses.

The class of drugs called thiazolides, particularly nitazoxanide, is effective against not only a variety of viruses, but a variety of parasites, both helminthic (worms) and protozoan (protists like Cryptosporidum and Giardia.) Thiazolides are effective against bacteria, both gram positive and negative (including tuberculosis and Clostridium difficile). And it’s incredibly safe. This apparent wonderdrug appears to disrupt creation of new viral particles within the infected cell.

There are others, too. For instance, beta-defensin P9 is a promising peptide that appears to be active against a variety of respiratory viruses.

Biosecurity applications: Something that could treat a wide variety of viruses is a powerful tool against possible threats. It doesn’t have to be tailored for a particular virus- you can try it out and go.

Current constraints: Discovery of new antibiotics has slowed down. Antivirals are a newer field, but the same trend may hold true.

Also, using a single compound drastically increases the odds that a virus will evolve resistance. In current antiviral treatments, patients are usually hit with a cocktail of antivirals with different mechanisms of action, to reduce the chance of a virus finding resistance of them.

Space for finding new antivirals seems promising, but they won’t solve viruses any more than antibiotics have solved bacterial infections – which is to say, they might help a lot, but will need careful shepherding and combinations with other tactics to avoid a crisis of resistance. Viruses tend to evolve more quickly than bacteria, so resistance will happen much faster.

Gene drives

What it is: Genetically altering organisms to spread a certain gene ridiculously fast – such as a gene that drives the species to extinction, or renders them unable to carry a certain pathogen.

What it works against: Sexually reproducing organisms, vector-borne diseases (with sexually reproducing vectors.)

How it works: See this video.

Biosecurity applications: Gene drives have been in the news lately, and they’re a very exciting technology – not just for treating some of the most deadly diseases in the world. To see their applications for biosecurity, we have to look beyond standard images of viruses and bacteria. One possible class of bioweapon is a fast-reproducing animal – an insect or even a mouse, possibly genetically altered, which is released into agricultural land as a pest, then decimates food resources and causes famine.

Another is release of pre-infected vectors. This has already been used as a biological weapon, including Japan’s infamous Unit 731, which used hollow shells to disperse fleas carrying the bubonic plague into Chinese villages. Once you have an instance of the pest or vector, you can sequence its genome, create a genetic modification, and insert the modification along with the gene drive sequences. This can either wipe the pest out, or make it unable to carry the disease.

Current constraints: A gene drive hasn’t actually been released into the wild yet. It may be relatively easy for organisms to evolve strategies around the gene drive, or for the gene drive genes to spread somehow. Even once a single gene drive, say, for malaria, has been released, it will probably have been under deep study for safety (both directly on humans, and for not catastrophically altering the environment) in that particular case – the idea of a gene drive released on short notice is, well, a little scary. We’ve never done this before.

Additionally, there’s currently a lot of objection and fears around gene drives in society, and the idea of modifying ecosystems and things that might come into contact with people isn’t popular. Due to the enormous potential good of gene drives, we need to be very careful about avoiding public backlash to them.

Finding the right modification to make an organism unable to carry a pathogen may be complicated and take quite a while.

Gene drives act on the pest’s time, not yours. Depending on the generation time of the organism, it may be quite a while before you can A) grow up enough of the modified organism to productively release, and B), wait while the organism replicates and spreads the modified gene to enough of the population to have an effect.

Therapeutic antibodies

What it is: Concentrated stocks of antibodies similar to the ones produced in your own body, specific to a given pathogen.

What it works against: Most pathogens, some toxins, cancers.

How it works: Antibodies are proteins produced by B-cells as part of the adaptive immune system. Part of the protein attaches to a specific molecule that identifies a virus, bacteria, toxin, etc.. The rest of the molecule acts as a ‘tag’ – showing other cells in the adaptive immune system that the tagged thing needs dealt with (lysed, phagocytosed, disposed of, etc.)

Biosecurity applications: Antibodies can be found and used therapeutically against a huge variety of things. The response is effectively the same as your body’s, reacting as though you’d been vaccinated against the toxin in question, but it can be successfully administered after exposure.

Current constraints: Currently, while therapeutic antibodies are used in a few cases like snake venom and tumors, they’re extremely expensive. Snake antivenom is taken from the blood serum of cows and horses, while more finicky monoclonal therapeutics are grown in tissue culture. Raising entire animals for small amounts of serum is pricey, as are the nutrients used for tissue culture.

One possible answer is engineering bacteria or yeast to produce antibodies. These could grow antibodies faster, cheaper, and more reliably than cell culture. This is under investigation – E. coli doesn’t have the ability to glycosylate proteins correctly, but that can be added in with genetic engineering, and anyways, yeasts can already do that. The promise of cheap antibody therapy is very exciting, and more basic research in cell biology will get us there faster.

Biotic replacement and evolutionary innovation as a global catastrophic risk

[Image: “Disckonsia Costata” by Verisimilius is licensed under CC BY-SA 3.0]

[This post has also been published on the Global Risk Research Network, a group blog for discussing risks to humanity. Take a look if you’d like more excellent articles on global catastrophic risk.]

Several times in evolutionary history, the arrival of an innovative new evolutionary strategy has lead to a mass extinction followed by a restructuring of biota and new dominant life forms. This may pose an unlikely but possible global catastrophic risk in the future, in which spontaneous evolutionary strategies (like new biochemical pathways or feeding strategies) become wildly successful, and lead to extreme climate change and die-offs. This is also known as a ‘biotic replacement’ hypothesis of extinction events.

  1. Biotic replacement in past extinctions
  2. Is this still a possible risk?
  3. Risk factors from climate change and synthetic biology
  4. The shape of the risk
  5. What next?

Identifying specific causes of mass extinction events may be difficult, especially since mass extinctions tend to be quickly followed by expansion of previously less successful species into new niches. A specific evolutionary advantage might be considered as the cause when either no other major physical disruptions (asteroids, volcanoes, etc) were occurring, or when our record of such events doesn’t totally explain the extinctions.

1. Biotic replacement in past extinctions

There are five canonical major extinction events that have occurred since the evolution of multicellular life. Biotic replacement has been hypothesized as either the major mechanism for two of them: the late Devonian extinction and the Permian-Triassic extinction. I outline these, as well as four other extinction events.

Great oxygenation event

2.3 billion years ago

Cyanobacteria became the first microbes to produce oxygen (O2) as a waste product, and began forming colonies 200 million years before the extinction event. O2 was absorbed into dissolved iron or organic matter, and the die-off began when these naturally occurring oxygen sinks became saturated, and toxic oxygen began to fill the atmosphere.

The event was followed by die-offs, massive climate change, and permanent alteration of the earth’s atmosphere, and eventually the rise of the aerobic organisms.

End-Ediacaran extinction

542 million years ago

The Ediacaran period was filled with a variety of large, autotrophic, sessile organisms of somewhat unknown heritage, known today mostly by fossil evidence. Recent evidence suggests that one explanation for this is the evolution of animals, able to move quickly and and re-shape ecosystems. This resulted in the extinction of Ediacaran biota, and was followed by the Cambrian explosion in which animal life spread and diversified rapidly.

Late Devonian extinction

375-360 million years ago

19% of families and 50% of genera became extinct.

Both modern plant seeds and modern plant vascular system developed in this period. Land plants grew significantly as a result, now able to more efficiently transport water and nutrients higher – with maximum heights changing from 30 cm to 30 m. Two things would have happened as a result:

  • The increase in soil content produced more weathering in rocks, which released ionic nutrients into rivers. The nutrient levels would have increased plant growth and then death in oceans, resulting mass anoxia.
  • Less atmospheric carbon dioxide would have cooled the planet.

Permian-Triassic extinction

252 million years ago

96% of marine species, and 70% of land vertebrate species went extinct. 57% of families and 83% of general became extinct.

One hypothesis explaining the Permian-Triassic extinction events posits that an anaerobic methanogenic archaea, Methanosarcina, developed a new metabolic pathway allowing them to metabolize acetate into methane, leading to exponential reproduction and consuming vast amounts of oceanic carbon. Volcanic activity around the same time would have released large amounts of nickel, a crucial but rare cofactor needed for Methanosarcina’s enzymatic pathway.

Azolla event

49 million years ago

Dead members of especially efficient fern genus built up in the ocean over 800,000 years and created a massive carbon sink, leading to a snowball earth scenario and mass global cooling.

Quaternary and Holocene extinction events

12,000 years ago –> ongoing.

The evolution of human intelligence and human civilization has lead to mass climate alteration by humans. Another set of adaptations among human society (IE agriculture, use of fossil fuels) could be considered here, but in terms of this hypothesis, the evolution of human intelligence and civilization could be considered to be the driving evolutionary innovation.

Minor extinction events

Any single species that goes extinct due to a new disease can be said to have become extinct due to another organism’s innovative adaptation. These are less well described as “biotic replacement”, because the new pathogen won’t be able to replace its extinct hosts, but it was still an evolutionary event that caused the disease. A new disease may also attack the sole or primary food source of an organism, leading to its extinction indirectly.

2. Is this still a possible risk?

It seems unlikely that all possible disruptive evolutionary strategies have already happened: Disruptive new strategies are rare – while billions of new mutations arise every day, any new gene must meet stringent criteria in order to spread: Is actually expressed, is passed on to progeny, immediately conveys a strong fitness benefit to its bearer, serves any vital function of the old version of the gene, is supported by the organism’s other genes and environment, and the organism isn’t killed by random chance before having the chance to reproduce. For instance, an unusually efficient new metabolic pathway isn’t going to succeed if it’s in a non-reproducing cell, if its byproducts are toxic to the host organism, if its host can’t access the food required for the process, or if its host happens to be born during a drought and starves to death anyways.

Environmental conditions that make a pathway more or less likely to be ridiculously successful, meanwhile, are constantly changing. Given the rareness of ridiculously successful genes, it seems foolhardy to believe that evolution up til now has already picked all low-hanging fruit.

How worried should we be? Probably, not very. The major extinction events listed above seem to be spaced by 100-200 million years, suggesting a 1-in-100,000,000 chance of occurring in any given year. For comparison, NASA estimates that asteroids causing major extinction events strike the earth every 50-100 million years. These threats are possibly on the same orders of magnitude.

(This number requires a few caveats: This is a high estimate, assuming that evolutionary advantages were a major factor in all cases. Also, an advantage that “starts” in one year may take millions of years to alter the biosphere or climate catastrophically. Once in 100 million years is also an average – there’s no reason to believe that disruptive evolutionary events, or asteroid strikes for that matter, occur on regular intervals.)

On a smaller scale, entire species are occasionally wiped out by a single disease. This is more likely to happen when species are already stressed or in decline. Data on how often this happens, or what fraction of extinctions are caused by a novel disease, is hard to find.

3. Risk factors from climate change and synthetic biology

Two risk factors are worth noting which may increase the odds of a biotic replacement event – climate change and synthetic biology.

Historically, a catastrophic evolutionary innovation seems to follow other massive climate disruption, as in the Permian-Triassic extinction explanation that followed volcanic eruptions. A change in conditions may select for innovative new strategies that quickly take over and produce much more disruption than the instigating geological event.

While the specific nature of the next disruptive evolutionary innovation may be nigh-impossible to predict, this suggests that we should give more credence to environment alteration as a threat – via climate change, volcanic eruptions, or asteroids – as changing environments will select for disruptive new alleles (or resurface preserved strategies.) This means that a minor catastrophic event could snowball into a globally catastrophic or existential threat.

The other emerging source of alleles as-of-yet unseen in the environment comes from synthetic biology, as scientists are increasingly capable of combining genes from distinct organisms and designing new molecular pathways. While genes crossing between wildly different organisms is not unheard of in nature, the increased rate at which this is being done in the laboratory, and the fact that an intentional hand is selecting for viability and novelty (rather than natural selection and random chance), both imply some cause for alarm.

A synthetic organism designed for a specific purpose, may disperse from its intended environment and spread widely. This is probably especially a risk for organisms using completely synthetic and novel pathways unlikely to have evolved in nature, rather than previously evolved genes – otherwise, the naturally occurring genes would have probably already seized low-hanging evolutionary fruit and expanded into possible niches.

4. The shape of the risk

How does this risk compare to other existential risks? It is not especially likely to occur, as described in Part 2. The precise shape or cause of the risk is harder to determine than, say, an asteroid strike. Also, as opposed to asteroid strikes or nuclear wars, which have immediate catastrophic effects, evolutionary innovations involve significant time delays.

Historically, two time delays appear to be relevant:

  • Time for the evolution to become widespread

Presumably, this is quicker in organisms that disperse/reproduce more quickly. EG, this could be fairly quickly for an oceanic bacteria with a quick generation cycle, but slowly for the 180,000 years it took between the first appearance of modern humans, and their eventual spread to the Americas.

  • Time between the organism’s dispersal and the induction of a catastrophe

EG, during the global oxygen crisis, it took 200 million years from the evolution of the species, to when the possible oxygen sinks filled up, for a crisis to occur. (At least some of this time included the period required for cyanobacteria to diversify and become commonplace.)

During the azolla event, azolla ferns accumulated for 800,000 years causing steady climate change. The modern threat from anthropogenic global warming is much steeper than that.

What are the actual threats to life?

  • Climate change
    • The great oxygenation event and the Permian-Triassic extinction hypothesis involve the dispersal of a microbe that induces rapid, extreme climate change.
    • Other events such as volcanoes erupting may change the environment such that a new strategy becomes especially successful, as in the Permian-Triassic extinction event.
  • Faster, stronger, cleverer predation
    • The Ediacaran extinction event and the Holocene extinction event involved the dispersal of an unprecedentedly capable predator – animals and humans, respectively.
    • This seems unlikely to be a current risk. The risk from runaway artificial intelligence somewhat resembles this concern.
  • Death from disease
    • Any event in which a novel disease causes a species to go extinct has a direct impact. Additionally, a disease might cause one or more major food sources to go extinct (for humans or animals.)
    • Globalization and global trade has increased the risk of a novel disease spreading worldwide. This also mirrors current concerns over engineered bioweapons.

5. What next?

Disruptive evolutionary innovation is problematic in that there don’t appear to be clear ways of preventing it – evolution has been indiscriminately optimizing away for billions of years, and we don’t appear to be especially able to stop it. Building civilization-sustaining infrastructure that is more robust to a variety of climate change scenarios may increase our odds of surviving such a catastrophe. Additionally, any such disruptive event is likely to happen over a long period of time, meaning that we could likely mitigate or prepare for the worst effects. However, evolutionary innovation hasn’t been explored or studied as an existential risk, and more research is needed to clarify the magnitude of the threat, or which – if any – interventions are possible or reasonable to study now.

Questions for further study:

  • How common are extinction events due to disruptive evolutionary innovation?
  • What factors make these evolution events more likely?
  • How often do species go extinct due to single disease outbreaks?
  • Can small-scale models help us improve our understanding of the likelihood of global warming inducing “runaway” scenarios involving microbial evolution?
  • What man-made environmental changes could potentially lead to runaway microbial evolution?