Astrogator's Logs

New Words, New Worlds
Artist, Heather Oliver             

Genome Editing: Slippery Slope or Humane Choice?


Science fiction is awash with engineered humans, from the now-classic GATTACA to the demi-gods of Banks’ Culture; the concept is linked to that of cloning and carries similar strains of hubris and double-edged consequences. As with cloning, gene engineering is no longer science fiction. Protein and Cell just published the results of a Chinese research team that used a DNA editing technique called CRISPR/Cas9 to alter early trinuclear (triploid) IVF embryos.  This technique has been used in many organisms, including mice, to successfully change specific genes. It’s a variation of gene therapy; the major difference is that in this study the repair was done at the low-number cell stage instead of postnatally.

[Parenthesis for the detail-oriented: CRISPR stands for clustered regularly interspaced short palindromic repeat, a common configuration in gene editing methods derived from bacterial defense systems. Cas stands for CRISPR-associated system – a CRISPR and its associated nuclease, which recognizes and clips the palindrome. The technique puts a target sequence with a desired nucleotide change in the CRISPR construct and introduces it plus a modified Cas enzyme into a cell or organism; the introduced system replaces the endogenous target sequence with the engineered one].

Triploid embryos, ova fertilized by two sperm, are mostly miscarried during the first trimester. The extremely few fully triploid infants that survive till birth have severe defects and without exception die a few days after delivery. The experimental triploid embryos additionally carried a thalassemia mutation in the HBB (beta-hemoglobin) gene. Thalassemic heterozygotes can lead a quasi-normal life with occasional blood transfusions, provided they are monitored. Homozygotes live a life of gruesome suffering and die before age 20 unless they undergo bone marrow transplantation.

The study documented several serious stumbling blocks, though none were unexpected: primarily low efficiency and low fidelity. Dependable introduction into cells is not trivial and the difficulty increases the more specialized the cells are, which is one reason why germline or embyronic editing is easier than its adult counterpart. Also, techniques of this type, which include RNAi, are prone to off-target effects (changes of quasi-homologous non-target sequences) and mosaicism due to expression variation – particularly with gene families, of which hemoglobins are one. As the study’s authors explicitly state, the technical issues must be competely resolved before such methods can go into clinical mode. Which leaves us with the other part: the eternal battleground between “can” and “should”.

Given the embryos’ triploidy and homozygous thalassemia, the primary ethical dilemma of tinkering with potentially viable entities did not arise in this study. Even so, Science and Nature rejected the paper summarily citing ethics concerns, and the usual people were interviewed saying the same things they said about IVF and cloning (briefly: unnatural hence unethical, slippery slopes, designer babies). Beyond the original furor over IVF babies, recall that a few months ago the UK allowed the generation of triparental embryos for people who carry mitochondrial mutations that would result in disease. And although many diseases are multigenic, others, equally devastating, would yield to such therapy.

Not surprisingly, many scientists and ethicists have called for a temporary moratorium on such experiments until consensus guidelines are developed. This happened at least once before, with recombinant DNA (the famous Asilomar conference of 1975). The original fears around gene splicing proved baseless, the grandstanding of Cambridge mayor Alfred Vellucci notwithstanding. The same is true of IVF, which has resulted in millions of perfectly normal humans, though the wars around gene therapy and GMOs are still raging, partly driven by issues other than feasibility or outcomes.

In my opinion, the meaninful dividing line is not between humans and all other animals. The real dividing line is between repair and enhancement (and what the latter really means). It’s almost certain that such methods will be tried on the less privileged first and, once perfected, will be preferentially accessible to the well-off – possibly indefinitely, if the current re-stratification of humanity by wealth persists. At the same time, it’s equally clear that the CRISPR technique has passed the proof of concept test and will eventually be used. I, for one, cannot imagine many future parents who will opt for no intervention if they are told that their child will develop Tay-Sachs, sickle-cell anemia or Huntington’s disease.

The burning question, of course, is if attributes deemed socially desirable will also be on the table with CRISPR. Thankfully, almost all suchlike attributes are polygenic and/or strongly susceptible to environmental input. Closer to the bone, a condition like monogenic deafness carries the dilemmas now associated with cochlear implants (I will not discuss “IQ” or autism, since these are not defined by single genes or, in some aspects, at the gene level and therefore don’t fall into this conversation). There is also the issue of consent, which means that adults are likelier to be eventually allowed to try exotic changes – with far greater risks attached, because of the intrinsic difficulties I discussed earlier.

At one end of this lurk the specters of eugenics and coercion – and, if financial and power stratifications escalate, the fear that humans may eventually split into Eloi and Morlocks. However, speciation requires total isolation of founder populations… and masters rarely withstand the temptation to mate with their slaves and servants, whether it’s an act of love or lust. Another fear is that the editing of an “undesirable” gene variant into extinction will have unforeseen consequences, since germline or embryonic editing is heritable. Many disease alleles have persisted because they confer advantages to heterozygotes: sickle cell to malaria, cystic fibrosis to cholera. As I never tire of repeating, “optimal” status is context-dependent. But if we fine-tune the editing techniques to the point that they become safe for routine use, re-introducing known alleles will be equally easy (creating new ones is definitely terra incognita, though these could, and should, be pre-tested in non-human systems).

On this, as with recombinant DNA, I’m a cautious optimist and venture to hope that the perfected CRISPR technique will be used with awareness and care for good – to ensure that monogenic diseases don’t lead to shortened or stunted lives. We may end up with a mosaic of guidelines, but eventually familiarity will dispel our wired fear of the new. We’ll still have to struggle with diseases that are less tractable, like dementia. And if CRISPR gives rise to a few more blue-eyed babies, I think we can live with that.

Blue Eyes

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Ghost in the Shell: Why Our Brains Will Never Live in the Matrix

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22 Responses to “Genome Editing: Slippery Slope or Humane Choice?”

  1. Esebian says:

    “I’m a cautious optimist and venture to hope that the perfected CRISPR technique will be used with awareness and care for good”

    From your lips to God’s, or who/whatever’s, ears. But considering raging crackpots like Yudkowsky et al. celebrate victories in sanewashing their cultist ideologies by tricking ignorant 1%ers into funding their escapades, don’t you think a future like this is more likely than we’re willing to admit?

    Two persons apply for the same job. One carries genes that are supposed to “enhance” concentration, endurance, etc., yet are in doubt by consensus science, the other doesn’t. The first one gets the job because the corporation’s pet transhumanut says those genes are “superior to mehums.”

    It’s not only a question of the technicalities, but also of the further objectification of human life. We’re already treated like machines that happen to be made out of flesh and bone instead of steel and plastic, and as office drones and sweatshops show it’s inhumane. Germline manipulation techniques stand to just amplify the status quo.

  2. Athena says:

    No question that both crackpots and people who want quick-n-easy characterizations (and who will misrepresent science) will always be with us. The point about the CRISPR technique, however, is that it cannot be easily adjusted for “enhancements” — it’s fundamentally a repair technique.

  3. Zarpaulus says:

    I actually featured CRISPr techniques in a NaNoWriMo project I wrote. Using them as a form of adult gene therapy, specifically to remove a sterility gene in parahumans originally created as slaves.

    I\’m wary of the ethical implications of genetic enhancement as well. Letting the free market decide could easily result in a de facto caste system, but having the government make them mandatory or even simply subsidized would make humanity more homogenous. And of course, either way I expect autism would be up on the chopping block once the techniques become available.

    It is fortunate that CRISPr is so poorly suited to enhancement, and risky enough that it probably wouldn’t be worth using on benign heterozygous genotypes for a while.

  4. Athena says:

    Agreed on all your points. However, autism is not really amenable to gene therapy. Too complex for that. If it were, however, I think it would fall solidly into the “depends on degree” category, as would trisomy 21.

    Your NaNoWriMo project sounds interesting!

  5. Esebian says:

    Apparently there’s a monogenic, non-environmentally determinate mutation of the myostatin factor that vastly increases muscle mass.

    Would this be editable by CRISPR-derived techniques?

  6. Athena says:

    I don’t know the type of mutation so I can’t answer your question. However, myostatin is a member of a family (TGF-beta) so the off-target risks apply. What’s interesting is that its inactivation might help sufferers of muscular dystrophy.

  7. Christopher Phoenix says:

    If I understand what you saying here, CISPR will allow us to cure devastating congenital diseases that are “mono-genetic”, that is rooted in an error in a single gene. But, it is not readily adaptable to “enhancing” humans, because most traits are the result of the interplay of many genes and highly dependent on our environment- or not determined at the gene level at all.

    I’m all for this kind of repair! I find it rather ironic that people who profess to care so much about the rights embryos seem so unconcerned for the suffering of the people already born.

    The argument that “unnatural” technologies like CISPR should not be used to relieve human suffering seems particular disingenuous. What about all the unnatural technologies we use to enhance our well-being, from agriculture to sanitation to Iphones? Are they any more “natural” than gene editing?

    BTW- please delete my earlier comment, I hit the “submit” button by accident before I was done typing. :{

  8. Athena says:

    Precisely! Also, at this point the argument of “unintended consequences” doesn’t hold much water because we know what happens with the various naturally occurring alleles of genes that manifest as single-cause diseases.

  9. Christopher Phoenix says:

    I think part of the reason “unintended consequences” come up so often is the Dr. Frankenstein myth etc., which is well-known to the public in its various forms.

    On a different genetic strand… I know storycrafting takes a while (from experience), but since I’m biting my nails in anticipation I must ask. (-: How is the Wind Harp coming along? I hope everything is vacuum-tight and proceeding on the proper orbit!

  10. Athena says:

    Aww! *feels very flattered* You mean Spider Silk? The Wind Harp is already published and a sister story, The Stone Lyre, is out on submission. Both are part of the larger universe. I’ve been busy with editing other people’s stories for Shape the Dark, but I’ve also been working on and off on the story of the launch of the Reckless, which is is foundation stone of the Spider Silk universe.

  11. Christopher Phoenix says:

    Yes, I mean Spider Silk! I knew they were both in the same universe but I didn’t know what name to use for it. I read the Wind Harp and like it, so I am eager to find out more about the larger story arc. By the way, what is a plasma lance?

    The story of the Reckless? That’s exciting! What’s funny was that I was just thinking that it would be really fun to see the story behind the launch of the Reckless as I was typing my earlier message. Perhaps it is evidence of subliminal psi links between kindred minds?

  12. Athena says:

    A plasma javelin is a Gan-Tem weapon! *laughs* I envision it as an evolved, elongated version of a cutting torch (flame is plasma, after all) but this would be cooler and more focused.

    The story of the Reckless landing is told in Planetfall, where we catch a glimpse of Captain Semíra Ouranákis, at the helm during the landing. The person who launches the Reckless, also an Ouranákis, is a scientist working under duress who ends up doing something very different from what her captors intended. As is usual with me, I wrote the beginning and the end of that story first — it bids fair to be novella/novelette length.

  13. Christopher Phoenix says:

    I gathered that much! Those Gan-Tem don’t ever seem to be without a weapon. *laughs* I just didn’t know whether it was a melee weapon or a ranged weapon. Plasma can be either, in SF- though “plasma rifles” wouldn’t work very well because plasma will not travel very far beyond the nozzle.

    A weaponized plasma cutting torch makes sense, especially since weapons have often evolved from tools in our history on this planet (rice threshers, anyone?).

    I’ll have to go through and reread all the Spider Silk stories, and be sure to tell me when the Stone Lyre is published! Your space opera reminds me of the best bits of Cherryh and Cordwainer Smith, but with a distinct flavor that is all your own.

    Is Spider Silk all told in shorter fiction, or do you have any plans to make a full novel in this universe? Both forms work well in space opera, but it would be nice to be able to stay and visit awhile at the Spider Silk’s hearth.

  14. Athena says:

    I’d consider plasma lances hybrid weapons, like their traditional equivalents. Because they’re customarily wielded within Gan-Tem towers, they need to be precision narrow-bore.

    Spider Silk is a novel and has four siblings (three prequels, one sequel) plus the novella of the Reckless launch. Some of these are completed but need global editing, others are partly written. There’s also a halo of linked stories, also at various stages of planning or completion, of which three (Dry Rivers, Planetfall, The Wind Harp) have been published.

    So what’s officially out is the tip of the iceberg! I’m delighted you like what you’ve seen and very flattered to be compared to Cherryh and Smith. And your words are definitely an incentive to continue this work.

  15. Christopher Phoenix says:

    So plasma lances are both ranged and melee… like historical spears. How far do you see one projecting the plasma stream? Real cutting torches only go a few inches to a foot, but I can imagine a more powerful, focused version projecting further. I guess it might look something like this.

    Your words fill me with anticipation- that’s a larger cycle than I ever hoped for! I’ve seen Planetfall and Wind harp but not Dry Rivers- is that also on the Crossed Genres website?

    I love unconventional space opera, so I’m quite excited by what I’ve seen of the Wind Harp. The last bit of excitement I had was stumbling upon Smith. In his work, as yours, I found space opera that focused on people- all different kinds of people, too. Even those who happened to have cat DNA.

    I’m glad I my words help you continue this work… and I look forward to the day when I can read the actual novel. Carry on, astrogator!

  16. Athena says:

    For the sake of the Gan-Tem towers’ structural integrity, I think the projection should not exceed a foot or so (though they’re engineering wizards, so it could easily be made adjustable).

    Indeed, Dry Rivers is on the CG site; here’s the link.

  17. Christopher Phoenix says:

    Yes- waving around a meter-long plasma stream would not be very safe! But I could imagine a Gan-Tem trying it if he or she had an adjustable plasma lance.

    Thanks for the link, I’ll read it! Is CG to be the publisher of the novel?

    BTW, I was wondering when I read Planetfall- around which star is Glorious Maiden? I assumed Alpha Centauri at first, but then it was mentioned that the system in or near a nebula.

  18. Athena says:

    CG is no longer publishing novels, so it will have to be another press.

    I was partial to Tau Ceti myself as the Glorious Maiden primary, because of my research on the tau gene (it’s a solitary G-type and is also supposed to have planets). But the nebula complicates matters. I’ll be happy to entertain alternatives!

  19. Christopher Phoenix says:

    The nebula does complicate matters. Most of the famous nebula are frustratingly far away- and since the Reckless is a long-generation arcship, it is seems unlikely that they traveled >1000lys. 10lys would be hard enough! I’ll have to investigate a list of nebula to find out which are the nearest.

    I always liked the orange star Epsilon Eridani since it is nearby and has suspected planets. A habitable planet there is at least a possibility. But I don’t think Glorious Maiden’s primary is a K-class star, and the nebula is lacking.

    I’ll see if I can’t think of a few more likely candidates once I’ve investigated nearby stars a little more thoroughly!

  20. Athena says:

    Please let me know if you come up with viable candidates! If you do, I’ll incorporate the most evocative one in the story. Also, the Reckless crew has another ace up its sleeve… (she says mysteriously)

  21. Christopher Phoenix says:

    Oh, really? It would be very exciting to contribute something to Spider Silk! I promise to tell you of any viable candidate stars I find.

    How could you drop that so nonchalantly? Now I’ll die of curiosity. *laughs* If you plan on keeping the secret, be sure to finish that novella sometime soon!

    It would be a help to know just how far the Reckless could have traveled in light-years, especially if the crew has some mystery that gives them an advantage. Are we limited to only nearby candidates or could stars further out factor in- <50 lys, <100 lys, or more?

  22. Athena says:

    Christopher — go for something beautiful and evocative, don’t worry about the distance (this should be a hint about the ace up their sleeve…)