Monday, December 28, 2015

Thoughts on the Synthetic Biology of Seveneves

Neal Stephenson's Seveneves is a sprawling space novel of truly epic ambition and scope, which I enjoyed thoroughly.  I'm not going to review it or give a detailed plot summary, but there are aspects related to the biology angles which interest me enough to scribble -- which means I must reveal some key plot points.  I've grown increasingly sensitive to spoilers and (yo Charles Schulz's ghost: thanks for wrecking Citizen Kane for me at a young age!) for myself prefer to go into a major book or movie as cold as possible.  So, if you haven't read the book and were planning to do so, please don't jump beyond the jump break.  If you do, don't blame me for any reveals!

Okay, the minimal plot summary up to the landing in the cleft.  Sometime in the very near future, the moon breaks up, catalyzed by some mysterious early event.  Humanity tries to save some thread of itself by boosting people, supplies and a genetic repository of human zygotes and gametes.  Due to a series of human mistakes and unpreventable natural disasters, humanity is finally whittled away to eight women (one of whom has gone through menopause) and a small fraction of the stores  In particular, the human genetic repository is destroyed when its sunshade is ripped away in a collision (ala Skylab).  But, the precious biotechnology machines have survived, so the one of survivor who is a biologist (Moira) is able to generate new humans via parthenogenesis (with males being edited back in at some point in the future), racing the biological clocks of each of the "Seven Eves" to generate a new set of seven human races.

Now, I get this is science fiction and one must suspend a bit of disbelief.  But given the great pains Stephenson went to getting the orbital mechanics right (or at least seemingly right to this non-expert), some further analysis of the biotech isn't utterly unfair. Also, since he posits this in essentially the immediate future, technology available during the first two sections of the book is pretty much going to look like technology today.  Not that everyone agrees on this: in a Reddit thread someone complains that the Project Orion technology could save the moon fragments from raining down on Earth, ignoring the fact that moving masses by exploding nuclear weapons never got off some crazy drawing boards (my father worked on aircraft nuclear propulsion early in his GE career, so I know a few things about crazy nuclear transportation schemes).  The big challenge for the early biotech, as I see it, is replacing the supply chain.

In the book, the biotech machines aren't discussed much, but there is at least a suggestion that they run autonomously.  Indeed, I suspect most laypersons have no clue what is involved in biotech supply; our reagents tend to be relatively compact and we don't have huge smokestacks. but supplies and waste we certainly do have -- which is going to be tricky in the tightly closed (or nearly so) ecosystem of the human settlement in The Cleft.

For starters, biotech uses a lot of disposable plasticware.  Well, it is supposed to be disposed; my undergraduate lab had nearly no funding, so we washed micropipette tips.  But normally, and if you really are worried about reproducibility and precision, everything is used once.  If you have a huge supply of hydrocarbons courtesy of long-ago plant life, as we do, that works well -- but the moon's crust (as evidenced by the Apollo and Luna samples) is exquisitely poor in carbon.

The surface does have plenty of silicon, so one could switch back to glass, but that's going to be shift.  Not only does everything need to be re-engineered to work with rigid glass rather than flexible (as in for forming seals) glass, but glass has very different surface properties.  Those surface properties are going to change what sticks and what doesn't, which will change everything.

Okay, once the labware is straightened out, there's the challenge of biosupplies, ranging from agar to culture medium for mammalian cells.  That's going to be very tricky.  Perhaps some of this can be finessed; perhaps cultures can be run in microfluidic systems which use only the minimum amount of medium needed and substitute micelles for spatial separation on agar.  But that again means rejiggering all the procedures and processes, at a time when time is short, and there will still be a need for medium components.

Then there are the all the oligonucleotides; Moira has offered to allow the Seven Eves edits to their offspring to add limited enhancement and remove deleterious alleles.  The general workflow for this would be to assemble appropriate CRISPR vectors in E.coli and then transfect these into human cells.  Synthetic biology might solve some of the other issues, but again that's going to require more oligos.  I'm not even clear on where the nucleotide inputs come in (biological to be sure), but some synthetic chemical magic transforms them into phosphoramidites, and actually making oligos also requires sizable amounts of nasty solvents such as acetonitrile.  Plus you need to make the resins for support.  None of these should be utter show-stoppers, but they will all be miserable constraints on tightly managed carbon and nitrogen budgets -- plus initially Moira has only seven helpers (assuming she trusts the nefarious Aïda). 

Okay, now lets zoom ahead to final phase of the book, 5000 years later. Humanity has thrived in orbit and the Earth has been terraformed.  Water and carbon have been obtained in quantity by steering and mining appropriate comets and asteroids.  Five millennia is a long time for tech development, but there is an interesting implication as the humans in orbit repopulate the Earth with a wide range of plant and animal life, including birds and mammals.

Now, of-and-on I've mentally dabbled with the idea of engineering lifeforms, and clearly there are a lot of systems, particularly around membranes and organelles, that would be really hard to build from abiotic scratch.  Indeed, when Venter and company built an organism they effectively built it within an existing organism.  

Image the time in orbit: in addition to the eight humans, what remains of Earth's biodiversity?  Not much.  No megafauna.  No vascular plants; the Swarm's agriculture relies on algae.  That sounds like it for deliberate savings.  Of course, then there will be all the stowaways: various bacteria and yeasts as part of our normal microbiome and probably a collection of mites.  Endurance will certainly have some additional microbes, perhaps even retaining some Streptomycete glory.  Thankfully, most extant pathogens will have been left behind, which is more than offset by the various hazards of living in space.

So, if we don't assume that in those 5K years the space-bound humans have cracked the problem of building a cell completely from scratch, that means all those plants are probably engineered from the algae brought aboard.  That's not very surprising or unsettling; since Endurance and the Swarm carried all known genetic sequence data (and the book does stress that the available sequencers are run flat out until the Hard Rain begins).

So, where did all those animals come from?  Are they modified algae, modified fungi -- or modified mites?  Or, given the ethical flexibility (to be extremely generous) shown by Julia and Aïda,  are creatures that roam this future Earth sporting edited human genomes?  That's one unsettling but plausible scenario.

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