On the Net

Where Are the CRISPR Cops?

by James Patrick Kelly
 

hardened

One of the pitfalls of writing SF set in the near future is that things never quite turn out the way we expect. So alas, there are no Moonbases, as my literary forebears predicted for the 2020s, much less a Mars colony. Neither is there a Soviet Union troubling the cultural and economic hegemony of the United States, as so many feared. And think of all the technology that never was. Flying cars www.theatlantic.com/ideas/archive/2019/01/will-we-ever-have-flying-cars/581473/? Nope. Humanoid domestic robots www.sciencedaily.com/terms/humanoid_robot.htm? Not anytime soon. Food pills www.popularmechanics.com/science/health/a8787/why-dont-we-have-food-replacement-pills-15248871? Nutritionists are dubious.

But such technological disappointments aren’t going to stop this SF writer (or any other, for that matter) from spinning new futures, probable or not. We readily acknowledge that our extrapolative conceits map onto a spectrum of possibility. For instance, consider the ubiquitous faster-than-light (FTL) starships http://sf-encyclopedia.com/entry/faster_than_light of space opera, which rely on rubber physics. Dear Reader, you do realize that FTL is impossible, given current understanding? Strictly speaking, the starship Enterprise is about as science fictional as a flying carpet. Other SF staples may be conceivable, like the Universal Translator http://sf-encyclopedia.com/entry/universal_translator, but just how they might be realized isn’t clear. But then there’s the videophone www.gizmodo.com/retro-video-phones-gallery-5705453, which has finally arrived, except it’s teensy and lives in our pockets. Videophones have passed from what might be called the squishy science fiction of FTL to hard science fiction www.bookriot.com/2018/01/02/hard-science-fiction that in certain quarters is considered our genre’s true quill. According to my New England pal and Asimov’s star Allen M. Steele www.allensteele.com: “Hard SF is the form of imaginative literature that uses either established or carefully extrapolated science as its backbone.” But one writer’s careful extrapolation is another’s wild conjecture.

However, it’s one of the pleasures of writing SF in this golden age of discovery that Tuesday’s squishy speculation becomes Wednesday’s science fact. Like so many of my colleagues, I have often written about post-humans who have been genetically modified either to survive in difficult environments or extend their mental or physical capabilities. At least a dozen such stories have appeared in these very pages. Mostly I just did a little hand waving about how this might have been accomplished to satisfy the plausibility scorekeepers. But believe me when I say I sat bolt upright in my desk chair in 2015 when I happened upon a TED Talk www.ted.com/talks/jennifer_doudna_we_can_now_edit_our_dna_but_let_s_do_it_wisely?language=en by the biochemist Jennifer Doudna http://en.wikipedia.org/wiki/Jennifer_Doudna. It was my first exposure to CRISPR, but I didn’t need Dr. Doudna’s lucid explanation to recognize that this was at once the most important and dangerous invention of the new century.

Or perhaps of all time.

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edits

Doudna began her talk with a simple declarative sentence that is revolutionary in its scope: “A couple of years ago, with my colleague, Emmanuelle Charpentier http://en.wikipedia.org/wiki/Emmanuelle_Charpentier, I invented a new technology for editing genomes.” Which changes everything, it says here. Understand that, until recently, techniques for modifying genomes were crude and very chancy. In gene therapy, for example, scientists used viruses as carriers to insert a gene into a cell’s genome, but the location of this insertion was unpredictable. Moreover, genes don’t work in isolation. They are embedded in DNA segments called regulatory DNA, which control how the gene’s instructions are expressed. A virus carrier might insert the gene near regulatory DNA that silences those instructions, or worse, garbles them with cancerous implications.

CRISPR, more properly known as CRISPR-Cas9, is a much more precise molecular tool that can edit specific sites on a DNA strand. For a more detailed and visual tour of the process, check out this animation https://youtu.be/2pp17E4E-O8. Meanwhile, here’s my oversimplified attempt at an explanation. (Warning: I’m an English major dabbling in advanced biochemistry)

The CRISPR tool is derived from the immune systems of single-celled organisms like bacteria. It uses simple guide RNA, created with just twenty letters of the genetic alphabet. Recall that this alphabet consists of the four nucleo­tides: Adenine (A), Guanine (G), Cytosine (C), and Thymine (T). In a CRISPR-Cas9 intervention, the RNA cruises along the double strand of DNA, looking for a very specific sequences of the “letters” AGCT—genetic “words,” if you will. When it finds the sequence it has been programmed to find, it pushes between the two entwined DNA strands, pulling them apart. This triggers a companion enzyme called Cas9, an acronym for CRISPR-associated protein 9, to munch on the separated strands, creating a complete break. The cell then defends itself by activating repair pathways. Broken strands of DNA are a big problem! Using multiple CRISPR tools, entire sequences—words—can be cut away before the cell rejoins the break. But a word can not only be deleted but replaced. Biochemists can create a different alphabet sequence, homologous to fit exactly to the ends of the strands cut by the Cas9, and the new word can take the place of the old.

But we must proceed cautiously with the word-processor metaphor. Although we have maps of the genomes of many organisms, much more research must occur before we understand exactly how genes interact to make cells do stuff. It is not so easy as swapping adjectives like happy with sad in a sentence, thus changing its meaning. While we may know what words to cut or replace, we need many more experiments before we can reliably predict what effects that editing will have. Given our current understanding, most edits will carry a risk of off-target mutations—that is, unintended and perhaps harmful changes. In the short term, CRISPR’s biggest contribution to science may be to make the experiments so vital to basic research not only faster but cheaper.

Or maybe not all that much cheaper. In 2012, Doudna and Charpentier published their landmark paper in Science http://science.sciencemag.org/content/337/6096/816 and shared information with other CRISPR researchers, most notably Feng Zhang www.broadinstitute.org/bios/feng-zhang of the Broad Institute www.broadinstitute.org, who was then able to demonstrate that the CRISPR tool could target and cut DNA in human cells. It wasn’t long before venture capitalists swooped in and competing patents were applied for and the future of CRISPR migrated from the laboratory to the financial markets and thence to the courts www.scientificamerican.com/article/all-you-need-to-know-for-round-2-of-the-crispr-patent-fight. After millions of dollars in lawyers’ fees chased the rights to what promises to be a new multi-billion—if not trillion—dollar industry, in September 2018, a U.S. appeals court upheld the patents www.statnews.com/2018/09/11/crispr-patent-decision-science held by M.I.T. and Harvard by way of Zhang and the Broad Institute. Researchers will be paying them substantial licensing fees far into the future.

While there has been no shortage of news reports about the latest CRISPR experiments, it has not, in my opinion, yet received the coverage it deserves. Consider the dubious experiments of Chinese scientist He Jiankui https://en.wikipedia.org/wiki/He_Jiankui, who evaded supervision and trashed research procedures in the race to be the first to create gene-edited babies www.technologyreview.com/s/613007/chinas-crispr-twins-a-timeline-of-news. In an attempt to build resistance to HIV, smallpox, and cholera, he altered the embryos of seven couples. At the time of his announcement, just one of the pregnancies had been successful. The mother gave birth to twin girls named Lulu and Nana. Later a third baby was born to another mother. Since then the experiment has been denounced and the reputations of scientists and corporations complicit in the project have been damaged. The government of China has ordered He Jiankui to suspend his research, and it appears that he is currently under house arrest. The scientific community has been scandalized, with many, including CRISPR patent winner Feng Zhang, calling for a global moratorium on gene-edited babies. But who will enforce this moratorium in a world of ambitious scientists and restless billionaires and reckless autocrats? The CRISPR cops? Consider that, as I write, there are reports of new research www.futurism.com/scientist-gene-hacked-babies-boosted-brains suggesting that the (posthuman?) twins’ ability to learn and retain memories may have been enhanced by He Jiankui’s intervention in their genomes.

You don’t have to be a science fiction writer to worry that the genetic genie is already out of the bottle.

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subgenres

If science fiction writers have a job description other than entertaining our starry-eyed readers, it is to muse about the impact of technology on our world. For the last few years, as we have come to recognize the existential threat of climate change, stories in a subgenre that has variously been called cli-fi www.bookriot.com/2018/05/03/climate-fiction (in its mainstream incarnation) and solarpunk https://solarpunks.net (here in genre) have been popping up regularly on tables of contents. Now that CRISPR has brought us to the cusp of a new and dangerous age of messing with our genome, perhaps it is time to revisit SF’s take on genetic engineering.

For example, Best Movies and TV Shows Featuring CRISPR and Genetic Engineering www.synthego.com/blog/crispr-movies-tv lists two dozen titles, ranging from the outright silly, like Rampage (2018) www.rampagethemovie.com/home to the thoughtful like Gattaca (1997) https://outtake.tribecashortlist.com/gattaca-the-dystopian-science-fiction-film-whose-time-has-come-9ede1bd35c5b and Okja (2017) https://www.gq.com/story/the-people-who-saw-okja-and-became-vegetarians. And yes, the classic Star Trek The Wrath of Khan (1982) www.denofgeek.com/us/movies/star-trek/243679/the-difficult-journey-of-star-trek-ii-the-wrath-of-khan makes the list.

­By the way, I was brought up short when I took a closer look at the website where this list appears. Synthego www.synthego.com is “a leading provider of genome engineering solutions.” They’re selling CRISPR tech! And while most scientists are cautious about public relations, the Synthego blog is exuberant with posts like Scientists Are Using CRISPR to Save Chocolate www.synthego.com/blog/fall-love-crispr-valentines-day and Real-Life X-Men: How CRISPR Could Give You Superpowers in the Future www.synthego.com/blog/could-crispr-make-x-men-a-realistic-possibility.

Sign me up!

For a literary and more profitable dive into the subgenre, refer to the ever-reliable Science Fiction Encyclopedia’s entry on Genetic Engineering http://sf-encyclopedia.com/entry/genetic_engineering. It will take you all the way back to the nineteenth century with H.G. Wells’s The Island of Doctor Moreau www.gutenberg.org/ebooks/159, through the mid-twentieth century with nods to James Blish’s Seedling Stars http://sfsite.com/08b/ss110.htm, a brilliant collection of pantropy stories about engineering humans to survive in alien environments, and Cordwainer Smith’s quirky tales of uplifted “underpeople” http://cordwainer-smith.com and then to the turn of the twenty-first century with Nancy Kress’s Sleepless series, beginning with the award-winning Beggars in Spain http://en.wikipedia.org/wiki/Beggars_in_Spain, right up to 2015 with the latest adventures of Michael Swanwick’s droll rascals Darger and Surplus http://sfsignal.com/archives/2016/04/interview-michael-swanwick-talks-about-his-darger-and-surplus-characters. You could spend the next decade catching up on what’s already been written.

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exit

But there will be many more stories and novels to come as the fallout from CRISPR changes our world. And this is one science fiction prediction I can make in all confidence, because I intend to write some of them myself!

Copyright © 2019 James Patrick Kelly

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